CLIMACTERIC 2015;18:3–5

Personal view: hormones and depression in

women
J. Studd

London PMS and Menopause Centre, London, UK

Key words: DEPRESSION, HORMONES, POSTNATAL DEPRESSION, PREMENSTRUAL SYNDROME, PMS

ABSTRACT
Depression is more common in women, occurring at times of hormonal fluctuations as premenstrual depres-
sion, postnatal depression and perimenopausal depression. These are all related to changes in hormone levels
Climacteric Downloaded from informahealthcare.com by McMaster University on 03/03/15

and constitute the diagnosis of reproductive depression. There is a risk that severe premenstrual depression
can be misdiagnosed as bipolar disorder and that women will be started on inappropriate antidepressants or
mood-stabilizing therapy. The most effective treatment for severe premenstrual syndrome is by suppression
of ovulation and suppression of the cyclical hormonal changes by transdermal estrogens or by GnRH analogs.
Postnatal depression is more common in women with a history of premenstrual depression and also responds
to transdermal estrogens. Transdermal testosterone gel can be also used in women who suffer loss of energy
and loss of libido which may be due to the inappropriate prescription of antidepressants. There is also a role
for the Mirena IUS and laparoscopic hysterectomy and oophorectomy in women who are progestogen-intol-
erant. The hormonal causation of certain common types of depression in women and the successful treatment
For personal use only.

by estrogens should be understood by psychiatrists and gynecologists.

It has been known for more than a century that depression
is more common in women than men1. Suicide attempts and
prescriptions for antidepressants are more common in women.
In fact, 70% of all antidepressants are prescribed for women.
The question is whether this is due to environmental, social
or hormonal factors. An endocrine cause is suggested by the
observation that this excess of depression occurs at times of
hormonal change such as in the days before a period as pre-
menstrual depression (premenstrual syndrome or premen-
strual dysphoric disorder) or in the weeks after pregnancy as
postnatal depression and the years approaching the meno-
pause as climacteric depression. This latter problem is at its
worst in the few years before the cessation of periods – the
transition phase2. This subgroup of depressive disorders is
called reproductive depression and is important because the
causation is endocrine rather than psychiatric and the most
effective and logical treatment will be by manipulation of
hormones rather than by antidepressants3.
Thus, it is helpful to recognize the association of depres-
sion with periods and pregnancy. Very often women with
reproductive depression will have a history of having severe
premenstrual syndrome as a teenager which becomes worse
with age. Almost invariably, this depression improves during
pregnancy but then frequently recurs as postnatal depression
some weeks or months after delivery, as the periods and cycles
return as premenstrual depression. This often becomes worse
with age3. It is often unsuccessfully treated with antidepres-
sants and the woman then develops a problem of recurrent
depression that continues not to respond to more antidepres-
sants. It is common for these women after years of unsuccess-
ful therapy to report that they last felt well without depression
during their last pregnancy many years ago4. This reproduc-
tive depression decreases in the postmenopausal years and
there is less evidence to suggest that estrogens are helpful in
this age group other than by removing vasomotor symptoms,
improving sleep and correcting painful vaginal atrophy.
The premenstrual and pregnancy link with depression is
supported by unpublished data from our clinic in that 68% of
perimenopausal depressed patients had premenstrual syndrome
as teenagers and 89% of women who had been pregnant had
no depression during pregnancy but 66% developed postnatal
depression; 58% who had been pregnant had suffered both
premenstrual depression and postnatal depression.
As the depression is cyclical, it can be and is frequently
misdiagnosed as bipolar disorder and hence patients can
be given treatment in the form of mood stabilizing drugs,

Correspondence: Professor J. Studd, London PMS and Menopause Centre, 46 Wimpole Street, London W1G 8SD, UK; E-mail: lister@studd.co.uk

COMMENTARY Received 03-01-2014

© 2015 International Menopause Society Revised 13-04-2014
DOI: 10.3109/13697137.2014.918595 Accepted 20-04-2014
 Hormones and depression in women
antidepressants, hospitalization or ECT5. Women with bipolar
disorder have a greater risk of developing postnatal depres-
sion6 and recent studies report that 67% of women with bipo-
lar disorder develop postnatal depression7. Jones and Crad-
dock confirmed this association and regarded it as conclusive
evidence that familial or genetic factors were implicated by
triggering puerperal episodes in women with bipolar disorder8.
An alternative view would be that many of these women had
severe premenstrual syndrome which improved when cycles
were absent in pregnancy and then developed postnatal depres-
sion as estrogen levels fell. Indeed, this may indeed be familial
or genetic but it involves the effect of hormones, both estra-
diol and progesterone, on the neurotransmitters serotonin and
GABA.
There is experimental evidence that women with a past
history of postnatal depression develop depression again after
a hormonal pseudo-pregnancy is suddenly withdrawn. Those
Climacteric Downloaded from informahealthcare.com by McMaster University on 03/03/15
without such a history did not develop depression9. As the
estradiol levels fall, 100-fold days after normal delivery this
change would produce mood problems in women susceptible
to changes in hormone levels.
The diagnosis of hormone-responsive depression is made by
the history and not from blood tests. Nor can measurement
of hormone levels exclude the diagnosis. These women are
premenopausal and will all have normal estradiol and FSH
levels. These two hormones have a wide normal range and
the levels may not be optimal for the individual, but it is a
For personal use only.
mistake to exclude an endocrine component to the depression
because the blood tests are normal and deny women effective
hormone therapy. Regrettably, this often happens in women
who believe, correctly, that their depression is ‘hormonal’.
Relevant clues in the history to indicate that there is a
hormonal basis for the depression are5:
(1) The monthly cyclicity of the depression;
(2) Premenstrual syndrome as a teenager;
(3) Pregnancy associated with a good mood with no depres-
sion;
(4) Postnatal depression;
(5) Depression becoming cyclical as periods return after
pregnancy;
(6) Runs of good days each month between episodes of
depression;
(7) Recurrent depression over the years without manic
attacks;
(8) Co-existent cyclical somatic premenstrual symptoms of
mastalgia, abdominal bloating and headache.
These clinical events have been tested in ten patients who have
been incorrectly diagnosed as suffering from bipolar disorder,
only to have their depression removed by transdermal
estrogens.
These perimenopausal women with long-standing depres-
sion have reproductive depression responsive to estrogens6.
Reproductive depression is an endocrine condition and not
a psychiatric problem. Antidepressants may be required at
some time in combination with estrogens10,11 but initially
4 Climacteric
Studd
the appropriate treatment is by estrogens. Oral estrogens are
probably effective particularly in perimenopausal women but
most of the scientific data concern transdermal hormones by
patches12 or implants13 for premenstrual syndrome, patches
for postnatal depression14 and patches15 or implants16 for cli-
macteric depression. The large study of postnatal depression14
demonstrated that transdermal estradiol is significantly better
than placebo, even in women who had failed to respond to
antidepressants. Not only is transdermal estradiol effective but
this route avoids the hepatic circulation and hence does not
stimulate the same coagulation factors that are induced by oral
estrogens. Thus, there is no increased risk of deep vein throm-
bosis or pulmonary embolus with transdermal estrogens.
The addition of testosterone is useful mainly for women who
also complain of loss of energy and loss of libido, although
it does have a mood-enhancing effect17. Testosterone is also
effective in treating the sexual dysfunction caused by antide-
pressants. It is an important addition to estrogens in women
who have lost their ovarian androgens following a total hys-
terectomy18 and develop symptoms of the female androgen
deficiency syndrome19, which typically are loss of energy,
libido and self-confidence as well as depression and head-
aches. Testosterone supplementation will usually remove these
problems and also, in combination with estrogen, improve
mood. Testosterone is not available by the oral route and tes-
tosterone patches have recently been discontinued; therefore,
it is usual to give testosterone by transdermal gel, although
unlicensed in women, or even by an implant, although the
availability of testosterone implants is currently intermittent.
Patients with a uterus who are having transdermal estro-
gens should have monthly progestogen to protect the endo-
metrium. Unfortunately, women with premenstrual syndrome
are usually progestogen-intolerant and even a low dose of
a low-potency progestogen for only 7 days instead of the
orthodox duration of 14 days may produce a recurrence of
premenstrual syndrome-type symptoms20. These patients may
respond to a change of progestogen or by taking the 7-day
course in alternate months or by using vaginal progesterone.
If not, many will opt for a Mirena intrauterine system. There
remains a small group of women who still have progestogen
intolerance and who decide not to try progestogen by any
route or any dose and instead opt for a laparoscopic hys-
terectomy and bilateral salpingo-oophorectomy with replace-
ment estradiol and testosterone. This intervention produces a
90%⫹ ‘cure’ of older women with reproductive depression
particularly severe premenstrual syndrome21,22.
The failure to recognize the hormonal component of
depression in women has serious consequences5,23,24. It is
commonplace for perimenopausal women to visit their
doctor complaining of depression with loss of energy, self-
confidence and libido, only to be prescribed antidepressants.
This is usually the worst treatment for symptoms which can
usually be quickly solved with estrogens. There has even been
an astonishing recent development of treating hot flushes and
sweats with antidepressants rather than the rapidly effective
estrogen. This is a legacy of the mostly discredited 2002 Wom-
en’s Health Initiative study .The current view is that hormone
 Hormones and depression in women
replacement therapy in this age group carries more benefits
than risks with fewer cardiac deaths from heart attack and
even fewer cases of breast cancer25,26. Transdermal estrogens
do not carry any increase in cases of deep vein thrombosis27.
A few psychiatrists are becoming aware that estrogen
therapy is a useful therapeutic option for a large subgroup
of women with depression11,14. The logic for such therapy
is strong but it is the lack of familiarity with gonadal hor-
mones that delays acceptance by psychiatrists. This should
be a straightforward challenge to encourage those special-
ists and general practitioners principally involved with
References
1. Dickens C. Household Words 1852;95:385–9
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2. Burger HG, Hale GE, Robertson DM, Dennerstein L. A review
of hormonal changes during the menopausal transition: focus on
findings from the Melbourne Women’s Midlife Health Project.
Hum Reprod Update 2007;13:559–65
3. Studd J, Nappi R. Reproductive depression. Gynecol Endocrinol
2012;28:42–5
4. Studd J. A guide to the treatment of depression in women by
estrogens. Climacteric 2011;14:637–42
5. Studd J. Severe premenstrual syndrome and bipolar disorder: a
frequent tragic confusion. Climacteric 2011;14:602
6. Freeman MP, Smith KW, Freeman SA, et al. The impact of repro-
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ductive events on the course of bipolar disorder in women. J Clin
Psychiatry 2002;63:284–7
7. Sharma V, Burt V, Ritchie H. Assessment and treatment of
bipolar II postpartum depression: a review. J Affect Disord 2010;
125:18–26
8. Jones I, Craddock N. Familiarity of the puerperal trigger in
bipolar disorder: results of a family study. Am J Psychiatry
2001;158:913–17
9. Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L,
Rubinow DR. Effects of gonadal steroids in women with a
history of postpartum depression. Am J Psychiatry 2000;157:
924–30
10. Graziottin A, Serafini A. Depression and the menopause: why
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76–81
11. Craig M. Should psychiatrists prescribe oestrogen therapy to
their female patients? Br J Psychiatry 2013;202:9–13
12. Watson NR, Studd JW, Savvas M, Garnett T, Baber RJ. Treat-
ment of severe premenstrual syndrome with oestradiol patches
and cyclical oral norethisterone. Lancet 1989;2:730–2
13. Magos AL, Brincat M, Studd JW. Treatment of the premenstrual
syndrome by subcutaneous estradiol implants and cyclical oral
norethisterone: placebo controlled study. Br Med J 1986;292:
1629–33
14. Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW.
Transdermal oestrogen for treatment of severe postnatal depres-
sion. Lancet 1996;347:930–3
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depression in women to understand and treat with the
appropriate hormones. It should not be necessary to refer
such patients to gynecologists as such therapy is effective
and safe. Only the occurrence of irregular bleeding needs a
specialist opinion.
Conflict of interest The author reports no confl ict of
interest. The author alone is responsible for the content and
writing of this paper.
Source of funding Nil.
15. Soares CN, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol
for the treatment of depressive disorders in perimenopausal
women: a double-blind, randomized, placebo-controlled trial.
Arch Gen Psychiatry 2001;58:529–34
16. Montgomery JC, Appleby L, Brincat M, et al. Effect of oestrogen
and testosterone implants on psychological disorders in the
climacteric. Lancet 1987;1(8528):297–9
17. Davis SR, McCloud P, Strauss BJG, Burger H. Testosterone
enhances estradiol’s effects on postmenopausal bone density and
sexuality. Maturitas 1995;21:227–36
18. Sherwin BB, Gelfand MM, Brender W. Androgen enhances sexual
motivation in females: a prospective crossover study of sex ster-
oid administration in the surgical menopause. Psychosom Med
1985;47:339–51
19. Sands R, Studd J. Exogenous androgens in postmenopausal
women. Am J Med 1995;98:76–9
20. Panay N, Studd J. Progestogen intolerance and compliance with
hormone replacement therapy in menopausal women. Hum
Reprod Update 1997;3:159–71
21. Casson P, Hahn PM, Van Vugt DA, Reid RL. Lasting response
to ovariectomy in severe intractable premenstrual syndrome. Am
J Obstet Gynecol 1990;162:99–105
22. Cronje WH, Vashisht A, Studd JW. Hysterectomy and bilateral
oophorectomy for severe premenstrual syndrome. Hum Reprod
2004;19:2152–5
23. Panay N, Studd JW. The psychotherapeutic effects of estrogens.
Gynecol Endocrinol 1998;12:353–65
24. Studd J, Panay N. Are oestrogens useful for the treatment of
depression in women? Best Pract Res Clin Obstet Gynaecol
2009;23:63–71
25. de Villiers TJ, Gass ML, Haines CJ, et al. Global consensus state-
ment on menopausal hormone therapy. Climacteric 2013;16:
203–4
26. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone
replacement therapy on cardiovascular events in recently postmen-
opausal women: randomised trial. BMJ 2012;345:2012:e6409
27. Renoux C, Dell’aniello S, Garbe E, Suissa S. Transdermal and
oral hormone replacement therapy and the risk of stroke: a nested
case-control study. BMJ 2010;340:c2519
5
 Open Journal of Depression, 2017, 6, 69-78
http://www.scirp.org/journal/ojd
ISSN Online: 2169-9674
ISSN Print: 2169-9658

Relation between Depression and Hormonal

Dysregulation

Neiane de Souza Duarte, Lucas Maciel de Almeida Corrêa, Larissa Rodrigues Assunção,
Arthur Aguiar de Menezes, Onássis Boeri de Castro, Leda Fabiélen Teixeira

Department of Medicine at Faculdades Integradas Aparício Carvalho—FIMCA, Porto Velho, Rondônia, Brazil

How to cite this paper: de Souza Duarte, Abstract

N., de Almeida Corrêa, L. M., Assunção, L.
R., de Menezes, A. A., de Castro, O. B., &
Teixeira, L. F. (2017). Relation between De-
pression and Hormonal Dysregulation. Open
Journal of Depression, 6, 69-78.
https://doi.org/10.4236/ojd.2017.63005
Received: May 25, 2017
Accepted: July 28, 2017
Published: July 31, 2017
Copyright © 2017 by authors and
Scientific Research Publishing Inc.
This work is licensed under the Creative
Commons Attribution International
License (CC BY 4.0).
http://creativecommons.org/licenses/by/4.0/
Open Access
Depression is a mental disorder, with different classifications which have as
main symptoms, persistent sadness, lack of interest, lack of pleasure, swings
between feelings of guilt and low self-esteem, sleep disorders and appetite. It is
known that hormonal changes can lead to significant emotional changes and
vice versa, due to changes in the central nervous system, action of hormones
on specific receptors or by metabolic changes, therefore, the endocrine dis-
orders become one of the possible causes of depression. This work is a study
of the major hormones associated with depression. It was drawn from a lite-
rature review, in which corticotrophin hormone, cortisol, estrogen, progeste-
rone and thyroid hormones were identified as the main hormones related to
depression. These hormones are essential for the correct functioning of the
metabolism, therefore, it is observed that hormonal changes may contribute to
the development of depression as well as aggravate it or even hamper the
treatment of patients who already have the disorder.

Keywords
Depression, Hormones, Endocrine Disorders

1. Introduction
World Health Organization (WHO) defines depression as a common mental
disorder, which, similar to the other depressive disturbances is characterized by
persistent sadness, lack of interest and pleasure, fluctuations between feelings of
guilt and low self-esteem, as well as sleep and/or appetite disorders that affect the
everyday operation. These manifestations occur in the different types of depres-
sion and are distinguished in terms of intensity, duration and mode of presenta-
tion (WHO, 2017). Major depression, from mild to moderate, is characterized by

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N. de Souza Duarte et al.

episodes of depressive symptoms and some functional disabilities. Severe de-

pression is accompanied by agitation and psychomotor retardation, as well as
marked somatic symptoms, frequently observed in chronic diseases (APA,
2014). In addition to these factors, depression is more prevalent in females. Ac-
cording to a study carried out in 23 European countries, the depressive disorder
is twice higher in women compared to men, reaching them mainly in the fertile
periods (Velde et al., 2010). This enhances the relation between hormonal varia-
tion and depression, since this is more common in females who undergo con-
stant hormonal influences due to the menstrual cycle. Evidence suggests that
hormonal changes may favor the onset of depression, since hormones may be
directly associated with the activation, inhibition, or modulation of central
nervous system mechanisms associated with depression.
It is known, for example, that around half of the depressed patients present an
increase in the reactivity of the hypothalamic-pituitary-adrenal (HPA) axis,
represented by the increase of CRH (corticotrophin releasing hormone)
(Varghese et al., 2001). This state of hormonal imbalance can lead to numerous
physiological changes, which would explain a common series of consequences to
the depressive syndrome, such as metabolic changes.
Seeman (1997) emphasize that estrogens, notably estradiol, play an active role
in the organization of brain development and play a crucial role in maintaining
brain activity. They also protect neurons from developmental dysfunctions
(Schizophrenia) and degenerative dysfunctions (Alzheimer’s disease). Cyclic
fluctuations in estrogen and progesterone increase stress responses, which make
them susceptible to depression and anxiety.
It is also observed that acutely depressed patients present an increase in free T4
in the cerebrospinal fluid (CSF), which reverts with the improvement in the condi-
tion (Kirkegaard et al., 1990), and low serum levels of T3 are associated with a
more rapid recurrence of depressive episodes (Jackson, 1998; Dayan et al., 2013).
Low levels of free thyroid hormones and elevated levels of thyroid stimulating
hormone (TSH), even within normal levels, are associated with delayed therapeu-
tic response in bipolar depression (Price et al., 2007). Disorders of thyroid function
are clearly related to the evolution and response to antidepressant treatment, and it
is often necessary to replace T4 in hypothyroidism, or potentiation with T3, in re-
sistance to antidepressant treatment (Teng et al., 2005).
Based on evidence found in studies linking hormonal dysregulation and de-
pression, a detailed description of the relation of major hormones associated
with depression will be given below.

2. Corticotrophin and Cortisol in Depression

Corticotropin-releasing hormone (CRH) is responsible for the regulation of
Adrenocorticotropic hormone (ACTH) release, which is related to the hypotha-
lamic-pituitary-adrenal (HPA) axis and associated with neurotransmission and
mediation in autonomic, immunological, neuroendocrine and cardiovascular
responses. Its release is induced by the production of corticotrophin-releasing

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 N. de Souza Duarte et al.

hormone (CRH), secreted by the neurons of the hypothalamic paraventricular

nucleus in the portal circulation of the pituitary gland. In the anterior pituitary,
CRH stimulates ACTH secreting cells to release ACTH into the bloodstream.
ACTH acts on the adrenal cortex promoting the release of Cortisol into the
bloodstream (Graeff, 2007).
CRH promotes the secretion of adrenocorticotrophic hormone (ACTH)
through the pituitary, leading to the release of cortisol (involved with stress and
adrenaline release), estrogen and mineralocorticoids. Some depressive and an-
xiety disorders are associated with increased corticoid production (cortisol),
while melancholic depression is in turn linked to increased CRH in the cere-
brospinal fluid (CSF) (Ayala, 2002).
CRH is the mainstay in the HPA axis and is essentially involved in the patho-
physiology of stress and consequently of depression, since many patients report
its onset after stressful events. In this sense, the pathophysiology of stress is sim-
ilar to the major depression, where in both cases there is decreased appetite,
sleep disturbances and hypervigilance. It is believed that reduced libido and
psychomotor changes in depression are associated with the release of this hor-
mone (Juruena et al., 2004). Major depression, in turn, is associated with the
abnormal release of CRH and deregulation of the HPA axis, consequently, in-
creased release of ACTH, in addition to excessive secretion of the corticosteroid
cortisol (hypercotisolemia). Depressed patients have altered amounts of CRH
mRNA and protein in the paraventricular nucleus (PVN) of the hypothalamus,
in addition to the increased amount of corticotrophin in the cerebrospinal fluid
(Graeff, 2007). A phenomenon linked to increased secretion of this hormone is
the alteration of REM sleep (Chellappa & Araújo, 2006), which becomes frag-
mented, where the decrease of “latency” to REM sleep is a persistent event in
depressive conditions. Other elements, such as the phenomena of maternal de-
privation and social isolation are triggers of depression, culminating in hyperac-
tivation of the HPA axis and the production of CRH.
In addition, during pregnancy, there is a large production of CRH, which is
cut shortly after delivery. It may help to develop postpartum depression asso-
ciated with the hormone concentration in the plasma (increased in the third
trimester of pregnancy). Ayala (Ayala, 2002) explains that “CRH circulates in
plasma in minimal amounts, except in the last trimester of pregnancy, when
there are considerable increases in serum levels.”
In an attempt to improve depressive symptoms, note whether CRH-selective
antagonist as a potential treatment option. Drugs that influence the production
and reception of corticosteroids are also being studied. Researchers have con-
cluded that there are antidepressants that have direct action on glucocorticoid
receptors, although their function is also linked to neurotransmitters and cyto-
kines (Juruena et al., 2004).

3. Depression and Female Sexual Hormones

It is believed that women have a greater tendency to develop depression due to

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N. de Souza Duarte et al.

drastic hormonal changes in puberty, in each menstrual cycle, in the postpartum

period, and in menopause. In the middle of uncertainties, evidence of depression
in women has pointed to sex hormones, because they affect mood, cognition,
and mental status (Li et al., 2005). Estrogen and progesterone are the ovarian
steroid hormones, responsible for the sexual development of the woman and the
menstrual cycle.
In recent years, more and more evidence has indicated that estrogen plays key
roles in the central nervous system. Recent research shows that not only affects
the hypothalamus, but also hippocampus and cerebellum, where most cognitive
functions, motor skills and mood are controlled (Justo et al., 2010).
Arpels (1996) state that “the brain in women, has been shown to be an estro-
gen target organ.” Its presence in the central nervous system is related to the
growth and differentiation of dendrites and axons in the developing brain, den-
drites arborization and synaptogenesis, in the production and release of neuro-
transmitters and as a protector against glutamatergic cytotoxicity (Li et al.,
2005).
At the beginning of puberty, the woman starts the production of gonadal
hormones, acquiring the so-called “periodicity”. This fact, coupled with the on-
set of abrupt hormonal changes, seems to contribute to the development of
mood disorders (Veras et al., 2005). These hormones influence the psychic state
of the adolescent by the modulation of the serotoninergic system (Amin et al.,
2005).
In addition to the typical hormonal changes of puberty, there are psychosocial
stresses that help increase the predisposition of the depressive disorder. Body
changes occur at about the same time that is seen the high rate of depression, in-
dicating a considerable probability of connection between the altered body im-
age, physical and hormonal changes and the onset of depression in puberty (Maj
et al., 2005).
A comparative study between institutionalized patients and controls from 7 to
17 years indicated that the serum level of 5-HT is reduced in patients with mood
disorder. In addition, the fact that there is a better response to treatment with
serotonergic medications, when compared to noradrenergic action, also corro-
borates the hypothesis. Therefore, the circulating hormones produced by the
gonads modulate brain neurotransmission and have a role in the regulation of
mood states (Scivoletto et al., 2009).
There is strong evidence that serotonin is mediating the effects of estrogens on
mood modulation and cognition. Studies in humans, particularly performed on
menopausal women who undergo estrogen therapy, have provided subsidies for
these assertions and identified situations in which mood and cognition changes
are accompanied by changes in serotonergic function and hormonal status
(Amin et al., 2005).
Estrogen has action in the central nervous system (CNS), even in regions that
have no action on the reproductive cycle. It has a trophic effect on cholinergic
neurons and significantly stimulates the expression of serotonergic type 2A re-

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 N. de Souza Duarte et al.

ceptors in areas that regulate both mood and cognition. The ability of estrogen
to act as a serotonergic agonist modulator is due not only to the increased ex-
pression of 5HT-2A receptors, but also through increased serotonin synthesis,
prolactin response to serotonergic agonists and monoamine oxidase (MAO) de-
gradation and reduction of the 5HT-1 binding sites and the serotonin transpor-
ter messenger ribonucleic acid (mRNA). All these actions have a similar antide-
pressant effect (Pecins-Thompson et al., 1998).
In contrast to estrogens, progesterone acts to increase MAO activity, resulting
in a decrease in serotonin levels and a depressive effect. In animal model studies
using labeled hormone, progesterone receptors were demonstrated in cells of the
medial hypothalamus and in the cells of the middle eminence region, cortex,
amygdala, hippocampus and coeruleous locus (Bloom, 1988). These are areas
associated with emotional reactions, behavior, learning and endocrine regula-
tion. In these areas, progesterone produces depressant effects on those functions.
It also presents anesthetic, tranquilizing, mood stabilizing properties, with re-
duced mental activities, and has anticonvulsive action. It would therefore have
opposite effects on estrogen on the CNS (Silva et al., 2006).

4. Depression and Thyroid Hormones

In a survey of 43 individuals diagnosed with depression (19 women and 24 men)
serum levels of thyroid hormones were tested (Berent et al., 2014). T3 was tested
in patients, where 13 patients were identified with low levels and 30 with normal
levels. Among the patients with low T3 levels, 4 had low levels of T4, and 24 had
normal levels of this hormone. Among patients with normal levels of T3, 3 pre-
sented low levels of T4. Considering all the values according to the gender of the
patient.
It has been observed that the reduction of thyroid hormones is directly linked
to the decrease in serotonin serum levels (Cleare et al., 1995). Bahls (1999) states
that serotonin is a neurotransmitter heavily involved with depression. When re-
searchers have investigated the relation between the serotoninergic system with
the thyroid hormone function, it was observed a decrease in the response of
prolactin and cortisol to 5-HT agonist d-fenfluramine in hypothyroid patients
not treated, which leads to believe 5-HT (5-hydroxytryptamine) decreases in
these cases. When sequenced in the investigation, they ratified what they had
observed, when they found that serum serotonin levels normalized with the re-
placement of thyroid hormones. They concluded that in hypothyroid cases, se-
rotonergic neurotransmission may decrease, and this condition may be reversed
with the replacement of hormones decline (Cleare et al., 1996).
As a justification for this considerable relationship between thyroid hormones
and serotonin, there is the effect of hormones on serotonergic autoreceptors.
The presynaptic 5-HT-1A receptors act detecting the presence of serotonin and
coupling to them by interrupting the flow of neuronal impulses and conse-
quently leading to a decrease in serotonin release. In depression there is an in-

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N. de Souza Duarte et al.

crease in the number of these receptors, so there is an increased uptake of sero-

tonin. The decrease in these autoreceptors results in the release of cortical and
hippocampal serotonin (Heal et al., 1998). A study with euthyroid rats (p =
0.011) (Gur et al., 1999) evidenced a significant loss of 5HT-1A autoinhibitory
sensitivity following T3 hormone administration. Studies (Bauer et al., 2002;
Whybrow et al., 1981) state that thyroid hormones reduce the sensitivity of
5-HT-1A autoreceptors. The results (Altshuler et al., 2001) indicate that the use
of T3 may then increase the cortical release of 5-HT.
The interaction of serotonin with thyroid hormone dysfunctions can also be
explained when related to the metabolizing enzymes of thyroid hormones
(Kirkegaard et al., 1998). Assuming that intracerebral T3 is a result of the dei-
odination of T4 by deiodinase II (D-II), it is observed the increased enzymatic
activity of D-II in hypothyroidism and decreased in hyperthyroidism.
If D-II increases T3 production, and therefore elevates local production of se-
rotonin (Kirkegaard et al., 1998), in contrast, type III deiodinase (D-III) is
shown to be increased in hyperthyroidism and decreased in hypothyroidism. It
is assumed that the D-III decreases production of T3 and indirectly serotonin
production. As we have seen, both hyperthyroidism and hypothyroidism have the
altered functioning of these enzymes, which metabolize thyroid hormones and thus
can modify brain levels of serotonin. The use of desipramine (Campos-Barros et
al., 1994) and fluoxetine (Baumgartner et al., 1994) in rats showed increased D-II
activity, and fluoxetine decreased the D-III. Thus, an increase of T3 and of cere-
bral serotonin occurring, is demonstrated the performance of these drugs as reg-
ulators of the neurotransmitter in cases of depression.
We can observe another perspective for the relation between thyroid hor-
mones and depression, from the point that serotonin seems to inhibit TRH
(thyrotropin releasing hormone) (Morley, 1981) and in cases of depressed pa-
tients, where serotonin is reduced, there is an increase in TRH as well as a sti-
mulus in TSH (thyroid stimulating hormone) secretion. This increase in TSH
leads to an increase in the production of T3 and T4, which by feedback tends to
reduce the serum TSH level, and thus there is a new plasma balance due to an
increased T4 concentration (Kirkegaard et al., 1990).
Another possible etiology for depression that is also related to thyroid hor-
mones is the lack of catecholamine, noradrenaline (NE) (Bahls, 1999). Rozanov
& Dratman (1996) found increased concentrations of T3 in the locus coerulus
and the lateral tegumentary nucleus of the rat brain, reinforcing studies (Mason
et al., 1993) that show higher concentrations of T3 in synaptosomes located in
the nuclei of noradrenergic neurotransmission (Dratman et al., 1987). Thus, it
has been suggested that T3 plays a special role in noradrenergic nuclei (Rozanov
et al., 1996): a role that regulates neurotransmission, which is important when
related to thyroid hormones, since noradrenaline is essential in the deiodination
of T4 into brain T3. In a 1969 study, they stated (Prange et al., 1969) that T3
caused an increase in the sensitivity of noradrenergic brain receptors. As shown
in studies (Rozanov et al., 1996) T3 is largely concentrated in regions of nora-

DOI: 10.4236/ojd.2017.63005 74 Open Journal of Depression

 N. de Souza Duarte et al.

drenergic neurotransmission, thus being shown to be a co-transmitter of cere-

bral noradrenaline.
T3 supposedly acts on beta-adrenergic post synaptic receptors (Whybrown et
al., 1981), a similar action with the antidepressant drugs, which explains why the
T3 is effective in antidepressant therapy in euthyroid individuals. It was there-
fore concluded that thyroid hormones help in recovery from depression by in-
creasing beta-adrenergic receptor function. Noradrenaline also participates in
the stimulation of the release of TRH and TSH (Morley, 1981). Therefore, a re-
duction in these hormones may result in a decrease in beta-adrenergic receptors,
and thus a decrease in noradrenergic neurotransmission. These adrenergic alte-
rations occur in thyroid diseases. In a study with lymphocytes from animals and
patients with changes in thyroid hormones, it was observed that beta-adrenergic
receptors were increased in cases of hyperthyroidism and decreased in cases of
hypothyroidism (Bilezikian et al., 1983; Fregly et al., 1975). For Linnoila et al.
(1983), a deficient concentration of brain T3 may lead to an inversion of the
amount of adrenergic receptors, where alpha-adrenergics will predominate over
beta-adrenergics. Although further evidence is needed on these findings, How-
land (1993) states that studies, even in animals, support the beta-adrenergic
neurotransmitter system in the pathogenesis of depression.

5. Conclusion
In summary, the main hormones associated with depression mentioned in this
article were: corticotrophin, cortisol, estrogen, progesterone and thyroid hor-
mones. The analyzed bibliographies demonstrated the relation of these hor-
mones in the regulation of the central nervous system, through the control of
specific receptors and metabolic intermediates. This makes it possible to asso-
ciate depression with hormonal dysregulation. High rates of cortisol, for exam-
ple, combined with depressive behaviors may be the first biological marker of
depression. In an antagonistic way, the estrogen has antidepressive action im-
proving the state of humor, while progesterone is linked to the decrease of sero-
tonin generating depressive effect. These hormones alter the production of se-
rotonin (5-HT) receptors, a neurotransmitter highly related to depression. In the
same way, thyroid hormones act. Thus, in addition to reduce the sensitivity of
serotonin, autoreceptors are also related to depression due to the alterations of
the metabolizing enzymes of these hormones, which can contribute to the de-
velopment of depression, as well as aggravate it or even make it difficult to treat
those who already have the disorder. Hormones, therefore, may be directly asso-
ciated with the activation, inhibition or modulation of central nervous system
mechanisms and consequent depression.

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Received: 13 May 2019    Revised: 6 April 2020    Accepted: 11 April 2020

DOI: 10.1002/jnr.24632

REVIEW

Pharmacological sex hormone manipulation as a

risk model for depression

Vibe G. Frokjaer1,2

1
Neurobiology Research Unit and Center
for Integrated Molecular Brain Imaging,
Copenhagen, Denmark
2
Psychiatric Center Copenhagen,
Copenhagen University Hospital,
Rigshospitalet, Copenhagen, Denmark
Correspondence
Vibe G. Frokjaer, Neurobiology Research
Unit 6931, Copenhagen University Hospital,
Rigshospitalet, Blegdamsvej 9, DK-2100
Copenhagen, Denmark.
Email: vibe.frokjaer@nru.dk
Abstract
Sex hormone transition may trigger severe depressive episodes in some women. In
order to map mechanisms related to such phenomena we developed a pharmaco-
logical preclinical human model using sex hormone manipulation with gonadotropin
releasing hormone agonist (GnRHa) in a placebo-controlled design. Here the find-
ings from this model is synthesized and discussed in the context of related literature
on hormonal contributions to reproductive mental health disorders. The GnRHa
model points to an estradiol-dependent depressive response in healthy women
undergoing short-term sex hormone manipulation with GnRHa, which is linked to
serotonin transporter changes (a key regulator of synaptic serotonin), a disengage-
ment of hippocampus, and an overengagement of brain networks recruited when
processing emotional salient information. Further, the GnRHa model suggest that
key brain regions in the reward circuit are less engaged in positive stimuli when un-
dergoing sex hormone manipulation, which may underlie anhedonia. Also, the work
supports that enhanced sensitivity to estrogen signaling at the level of gene expres-
sion may drive increased risk for depressive symptoms when exposed to sex ster-
oid hormone fluctuations. In conclusion, the GnRHa model work highlights brain
signatures of rapid and profound changes in sex steroid hormone milieu, which re-
flect plausible mechanisms by which risk for mood disorders works. This model
points to the role of estrogen dynamics and sensitivity, and offers a rationale for
personalized prevention in hormonal transition phases, for example pregnancy to
postpartum transition, perimenopause, and hormone treatments, which now can
move into clinical translation and ideally pave the way for protecting mental and
cognitive health.

KEYWORDS

brain imaging, estradiol, PET, MRI, reproductive mental health, steroid hormones

Edited by Cristina Ghiani. Reviewed by Lauren Osborne, Sophie Schweizer, and Julia Sacher.

The peer review history for this article is available at https://publo​ns.com/publo​n/10.1002/jnr.24632.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2020 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC

J Neurosci Res. 2020;98:1283–1292.  |

wileyonlinelibrary.com/journal/jnr    1283
 |
1284       FROKJAER
1 |  I NTRO D U C TI O N
Major depressive disorder (MDD) is expected to cause the highest
ranking disability and burden of disease by 2030 (WHO, 2008) and
strikingly affects twice as many women as men. Women are at a par-
ticularly heightened risk during hormonal transition phases such as
during puberty (Thapar, Collishaw, Pine, & Thapar, 2012), across late
pregnancy to postpartum (Munk-Olsen, Laursen, Pedersen, Mors, &
Mortensen, 2006) and perimenopause (Freeman, Sammel, Boorman,
& Zhang,  2014). Hormone-related risk mechanisms may even ex-
tend to exogenous hormone exposure (i.e., hormonal contraception)
(Skovlund, Morch, Kessing, & Lidegaard, 2016).
MDD is a heterogeneous and complex disorder and depressive
symptoms often occur transdiagnostically, for example in other
disorders such as bipolar disorder, schizophrenia, and neurodegen-
erative disorders. The etiological contributions to MDD are from a
multitude of environmental and genetic factors, and their interplay,
which indeed can be modified by steroid hormones. In line with
this, steroid hormone dynamics play a prominent role specifically in
MDD compared to other psychiatric disorders, that is schizophre-
nia, autism spectrum-, bipolar disorder, and alcoholism, as recently
emphasized by gene expression profiles in a large postmortem brain
study (Gandal et  al.,  2018). Yet, the underlying risk and resilience
mechanisms of MDD are far from clear and accordingly current pre-
ventive and treatment strategies are suboptimal. Identification and
stratification of high-risk individuals with distinct etiology and/or
responsiveness to certain triggers or treatments may help build a
rationale for much needed, personalized and precise treatment and
prevention of MDD (Schumann et al., 2014). We and others propose
that one such clinically important and distinct subgroup within MDD
is women who are sensitive to hormonal transitions.
In this review, I synthesize and discuss findings from a preclinical
human pharmacological sex hormone manipulation model we used in
healthy women to provide unique insights to how sex hormone fluctu-
ations may trigger depressive symptoms in some but not other women
(Fisher et  al.,  2017; Frokjaer et  al.,  2015; Henningsson et  al.,  2015;
Macoveanu et al., 2016; Mehta et al., 2019; Stenbaek, Budtz-Jorgensen,
Pinborg, Jensen, & Frokjaer, 2019; Stenbaek et al., 2016).
1.1 | Epidemiology of depressive episodes during
women's hormonal transitions
Strong epidemiological evidence suggests that women are at in-
creased risk for depressive episodes in hormonal transition phases,
such as across late pregnancy to postpartum or menopausal tran-
sition (Lokuge, Frey, Foster, Soares, & Steiner,  2011; Munk-Olsen
et al., 2006). This includes perinatal depression (PND), which accord-
ing to DSM-V criteria is defined as a depressive episode with onset
during pregnancy or up to 4 weeks postpartum. Even though the cur-
rent diagnostic classifications do not distinguish between antenatal
and postnatal onset of PND, there is considerable evidence pointing to
critical differences, for example in genetic risk factors, which are best
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Significance
This review synthesise and discuss findings from a preclini-
cal human pharmacological sex hormone manipulation model
of risk mechanisms for depressive episodes triggered by sex
hormone transitions in women. This model work highlights
brain signatures of rapid and profound changes in sex-steroid
hormone milieu, which reflect plausible mechanisms by which
risk for depression works. Specifically this model points to
the role of estrogen dynamics and sensitivity and offers a
rationale for personalized prevention in hormonal transition
phases, e.g. pregnancy to postpartum transition, perimeno-
pause and hormone treatments, which now can move into
clinical translation and ideally pave the way for protecting
mental and cognitive health.
characterized for postpartum onset (Elwood et al., 2019). Furthermore,
depressive episodes manifesting later than 4  weeks postpartum
may also have hormonal contributions in their pathophysiology and
the risk for depressive episodes are increased up to 5 months post-
partum (Munk-Olsen et  al.,  2006). PND affects 10%–20% of post-
partum mothers worldwide (Fellmeth, Fazel, & Plugge,  2017; Gavin
et al., 2005; Howard et al., 2014). Notably, PND may not only affect
new mothers but also can, especially if untreated, be adverse for their
offspring in terms of infant language and early cognitive develop-
ment (Evans et al., 2012) and future health (Pearson et al., 2013; Stein
et al., 2014). PND frequently has an onset in late pregnancy (Meltzer-
Brody, Boschloo, Jones, Sullivan, & Penninx, 2013) and may worsen
dramatically postpartum. Intriguingly, a large seminal Danish registry
study demonstrated that for new mothers, the risk for developing a
mental disorder, which necessitates admission to psychiatric hospi-
tal or outpatient clinic, peaks early postpartum at days 10 to 19, and
for unipolar depression is sustained until 5 months after birth (Munk-
Olsen et al., 2006). This timing coincides with the dramatic postpar-
tum decline in placenta-produced hormones that are built up during
pregnancy. However, PND frequently has an onset in late pregnancy.
Likewise, non-pathological manifestation of transient mental distress,
postpartum blues, temporally coincides with the drop in placenta-
produced steroid hormones and heightens the risk for postpartum
depressive episodes (O'Hara & Wisner,  2014). On the other hand,
while new fathers may also experience depressive symptoms, severe
adverse mental health responses to fatherhood, i.e. admission to psy-
chiatric hospital, are not increased 0–12 months postpartum (Munk-
Olsen et al., 2006). This emphasizes qualitative differences between
mothers and fathers in the nature of postpartum/parenthood transi-
tion and its consequences, and further support hormonal contribu-
tions to perinatal mental disorders.
Menopausal transition is another female life phase where
ovarian sex steroid hormone levels fluctuate dramatically. At this
time, women face about two- to fourfold increased risk for de-
pressive episodes (Bromberger et  al.,  2011; Freeman, Sammel, Liu,
et  al.,  2004). Interestingly, the strongest risk factor for developing

FROKJAER
Baseline Intervention Bleeding
CD 6.6 ± 2.2 CD 22 9 ± 3 days p.i.
Hamilton score GnRHa (n = 30) GnRHa: 10 ± 3 days p.i Subgroup of n = 38 Hamilton score
Brain imaging Placebo (n = 30) Placebo: 7 ± 3 days p.i Gene expression
Neuropsychology
Gene expression
Abbreviations: CD, cycle day; p.i, post intervention.
SE: Side effects score day 7, 12 and 30 p.i.
F I G U R E 1   GnRHa model study design and timings
depressive symptoms across menopausal transition is fluctuation of
estradiol around the women's own mean level (Freeman, Sammel, Lin,
& Nelson,  2006). Notably, at the time the postmenopausal state is
fully established and estradiol no longer fluctuates, that risk decreases
(Freeman et  al.,  2014). Also, in PND, sensitivity to estradiol fluctua-
tions seemingly is central to risk. This was demonstrated in a small
(N = 8*2) but seminal study by Bloch et al. (2000) showing that women
with a history of postpartum depression were differentially sensitive
to mood-destabilizing effects of ovarian steroids, that is estradiol and
progesterone particularly in the withdrawal phase but also present in
a hormone-stimulated phase (modelling pregnancy). Recent studies
have pointed to molecular mechanisms, in terms of gene expression
and epigenetic modifications, of such sensitivity to hormone changes,
in particular estrogen sensitivity (Guintivano, Arad, Gould, Payne, &
Kaminsky,  2014; Mehta et  al.,  2014). Finally, the ovarian hormone
sensitivity hypothesis is indirectly strengthened by observations in
women with premenstrual dysphoric disorder (PMDD) who indeed
develop depressive symptoms when exposed to ovarian steroid hor-
mone replacement after a period of hormonal suppression (Schmidt
et al., 2017), which again seem to involve epigenetic mechanisms re-
lated to estradiol (Marrocco et al., 2018).
With the pharmacological gonadotropin-releasing hormone ag-
onist (GnRHa) risk model we wanted to illuminate how hormone
transitions increase the risk for triggering depressive episodes, and
in particular we were interested in the role of estradiol dynamics. The
GnRHa model setup we applied introduces a biphasic estradiol fluc-
tuation (initially a stimulation and subsequently a suppression of the
hypothalamus–pituitary–gonadal [HPG] axis), which enabled us to
focus at the estradiol fluctuation-driven changes and their coupling
to early depressive-like symptoms in certain susceptible women,
a point of strength over previous study designs, which have more
focused at the late suppression phase in recovered patients (Bloch
et al., 2000).
2 | TH E G n R H a TR I A L S E T- U P
A detailed description of the trial and study population is available in
Frokjaer et al. (2015). The study is registered at ClinicalTrials.gov (ID:
NCT02661789). A brief overview is presented below.
|
10974547, 2020, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jnr.24632 by INASP/HINARI - PAKISTAN, Wiley Online Library on [12/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
      1285
Follow-up (1) Follow-up (2) Exit
Stimulation phase Supression phase
4 ± 2 days p.i. 16.2 ± 2.6 days p.i. 30 days p.i
SE
Imaging
Neuropsychology
Gene expression
2.1 | GnRHa is a pharmacological tool to manipulate
sex steroids
Pharmacologic intervention with continuous GnRHa, as can be ob-
tained by an implant, induces a biphasic ovarian hormone response
(Thomas, Jenkins, Lenton, & Cooke, 1986); after an initial stimulation
of the HPG axis, pituitary GnRHa receptors desensitize, and conse-
quently, ovarian sex steroid production is suppressed to menopausal
levels within about 10 to 14 days and is sustained for 28 days. The
GnRHa model thus mimics hormonal fluctuations and best matches
the menopausal transition stage (Harlow et  al.,  2012) and reflects
partly the physiological changes across the prepartum to postpar-
tum transition where placenta-produced hormones, including es-
tradiol, built up in pregnancy decline rapidly from the high levels
established during pregnancy.
2.2 | Study participants
Sixty-three healthy women (mean age 24.3  ±  4.9  years) were en-
rolled in this block randomized, placebo-controlled, and double-
blinded intervention study. Two women could not complete the
study program at follow-up due to anovulation and pregnancy,
respectively. Block randomization was performed to balance the
distribution of 5-HTTLPR genotype (LALA or not). All participants
(mean age 24.3 ± 4.9 years) had regular menstrual cycles (duration
23–35 days). Participants were screened by face-to-face interview,
gynecological ultrasound examinations, and blood tests to attest no
significant neurological, psychiatric, endocrinological, or gynecologi-
cal disorders.
2.3 | Intervention
Baseline assessments were performed in the midfollicular phase
(cycle day 6.6  ±  2.2) when ovarian hormone levels are most sta-
ble and time since the postovulatory estradiol drop is maximal.
Contingent upon ovulation in their natural cycle, participants re-
ceived a subcutaneous injection of a GnRHa implant (ZOLADEX,
a biodegradable copolymer impregnated with 3.6 mg of goserelin;
 |
1286       FROKJAER
AstraZeneca, London, United Kingdom) (n = 30) or saline (n = 30),
that is in the midluteal phase cycle day 22.6 ± 2.5, by a gynecologist
not involved in any subsequent interaction with the participants,
data collection, or analysis. This timing allowed a near-identical tim-
ing of menstrual bleeding (placebo group) and withdrawal bleeding
(GnRHa group), which enabled blinding. Follow-up was placed post-
bleeding at a time point late enough to allow the GnRHa group to
have entered their early ovarian suppression phase (16.2 ± 2.6 days
after intervention). An overview of the timing of baseline, interven-
tion, and follow-up relative to the menstrual cycle is provided in
Figure 1.
2.4 | Outcomes
Data from the following domains of interest were collected at base-
line and at follow-up: (a) clinical outcomes (Hamilton depression rat-
ing scale (HDRS) of 17 items and self-reported psychometrics), (b)
serotonin transporter (SERT) brain binding ([11C]DASB PET-scan),
(c) cognitive processing of emotions (fMRI faces task), (d) reward
processing (fMRI gambling task), (e) functional connectivity (resting-
state fMRI), (f) basic cognition (verbal affective memory and reaction
time), and (g) gene expression and DNA methylation changes across
intervention.
Also at baseline, self-reported NEO Personality Inventory-
Revised personality trait scores were filled online to derive the
neuroticism score. Neuroticism was considered relevant, since it is
a robust risk factor for developing major depression that might in-
teract with other risk factors in the interplay with markers of sero-
tonin signaling as shown previously (Frokjaer, Vinberg, et al., 2010).
Serial measurements of Profile of Mood States (POMS) were
available across the intervention period as specified in Stenbaek
et al. (2016).
For a subgroup of the latter 38 participants enrolled, an attempt
was made to characterize the magnitude of ovarian hormone in-
crease in the initial stimulatory phase of the GnRHa by adding hor-
mone measurements at the day of intervention (midluteal phase) and
3 to 5 days after intervention (stimulated phase, if GnRHa-group). At
these time points, material for gene expression was also collected
while DNA was only available from baseline and (late) follow-up
(Mehta et al., 2019).
3 |  C LI N I C A L O U TCO M E S A N D B R A I N
S I G N AT U R E S O F S E X - H O R M O N E
M A N I PU L ATI O N S W ITH G n R H a
The data presented below are published and discussed in detail
in the corresponding original articles (Fisher et  al.,  2017; Frokjaer
et  al.,  2015; Henningsson et  al.,  2015; Macoveanu et  al.,  2016;
Mehta et al., 2019; Stenbaek et al., 2016, 2019). Here we provide a
short synthesis and integrated discussion of the findings.
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3.1 | Summary of the GnRHa findings
As summarized in Table 1, GnRHa intervention induced depressive
symptoms that approached the level of a mild depressive state in
about 13% of the healthy women who participated in the study,
while the remaining participants experienced more subtle or no de-
pressive symptoms (Frokjaer et  al.,  2015). This number aligns well
with the known frequencies of PND of around 10%–20% (Fellmeth
et  al.,  2017; Gavin et  al.,  2005; Howard et  al.,  2014). Interestingly,
only by observer-dependent methods (semi-structured Hamilton
17-item interview) were the increased levels of depressive symp-
toms evident (Stenbaek et  al.,  2016). However, self-reported serial
day-to-day changes in total mood disturbances (by POMS) showed
labile mood in the GnRHa group only in women with elevated lev-
els of mood disturbances at baseline (Stenbaek et al., 2016). Further
analyses showed that mood disturbances were most pronounced
during day 0 to 5 corresponding to the early stimulation phase of
the intervention and was dependent on neuroticism levels such that
most extreme neuroticism scores (high or low) were most sensitive
to GnRHa intervention relative to placebo (Stenbaek et al., 2019).
Molecular brain imaging data showed that depressive responses
to GnRHa were coupled to increases in SERT binding in neocortex
suggesting a transiently reduced synaptic serotonin level and sup-
pressed serotonin signaling (Frokjaer et  al.,  2015). Functional MRI
with tasks probing emotional face processing pointed to a coupling
between depressive responses to GnRHa and an increased involve-
ment of anterior insula in processing emotions irrespective of emo-
tion valence (Henningsson et  al.,  2015). Furthermore, resting-state
fMRI suggested that GnRHa-induced depressive symptoms are
coupled to an overengagement of amygdala and a disengagement
of hippocampus in non-goal-oriented cognitive processes (Fisher
et  al.,  2017). Also, task-based fMRI using a gambling paradigm
showed that GnRHa reduces brain responses to reward (Macoveanu
et  al.,  2015). Specifically, the amygdala, which putatively helps en-
code the stimulus reward value in reward processing and plays a key
role in reward learning, was less engaged in processing positive stim-
uli pre- to post-GnRHa relative to placebo. Finally, in a very recent
study we showed that an a priori defined set of gene transcripts,
which were differentially expressed in third trimester in women who
later developed PND with postpartum onset (Mehta et al., 2014), was
also associated with depressive responses to GnRHa in a manner de-
pendent on estradiol changes and SERT changes (Mehta et al., 2019).
4 | D I S CU S S I O N
4.1 | Estradiol, serotonin brain signaling and brain
function
Our GnRHa data provide direct evidence for sex hormone manipula-
tion to trigger depressive symptoms in healthy women. The depres-
sive symptoms were subtle except in two to three participants who
 |

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FROKJAER       1287

TA B L E 1   Main findings from the GnRHa clinical trial

Article N Main outcomes Main findings

Frokjaer et al. (2015) 30 GnRHa Changes from baseline in: GnRHa induced depressive symptoms (HDRS 17-
30 placebo • HDRS 17-item item) in about 13% relative to placebo
• Serotonin transporter binding (PET-scan) No main effects of GnRHa versus placebo on
• Estradiol serotonin transporter binding
The emergence of depressive symptoms was
associated with both increased serotonin
transporter binding in neocortex from baseline
and with the magnitude of estradiol decrease
Henningsson et al. 26 GnRHa Emotional faces fMRI No main effects of GnRHa versus placebo
(2015) 29 placebo • Amygdala (primary) Women who displayed larger GnRHa-induced
• medial prefrontal cortex increase in depressive symptoms had a larger
• anterior cingulate cortex increase in both negative and positive emotion-
• ventrolateral prefrontal cortex elicited activity in insula (anterior)
• insula
Macoveanu et al. 26 GnRHa Gambling fMRI: brain activation related to reward GnRHa reduced reward-related activation of
(2016) 29 placebo amygdala, relative to placebo

Stenbæk et al. (2016) 31 GnRHa • Affective verbal memory GnRHa was associated with slower reaction time
30 placebo • Reaction time and more labile mood relative to placebo
• Self-reported mental distress No effects of GnRHa were seen on affective
• Profile of mood states verbal memory
Fisher et al. (2017) 29 GnRHa rs-fMRI: functional connectivity (rs-FC) for seed No main effects of GnRHa versus placebo
29 placebo regions Women who displayed larger GnRHa-induced
• amygdala increase in depressive symptoms had an
• hippocampus increased amygdala–right temporal cortex rs-FC
• anterior cingulate and decreased hippocampus–cingulate rs-FC
• dorsal raphe, median raphe
• posterior cingulate cortex
Mehta et al. (2019) 30 GnRHa • A priori PND biomarker set of 116 gene Of the a priori defined PND predictive set of 116
30 placebo transcripts (from Mehta et al. 2014) genes, 19% were differentially expressed post-
GnRHa and 49% were differentially methylated
relative to placebo
Within the GnRHa group, a large proportion of
PND genes were significantly associated (gene
expression; DNA methylation) with changes in
depressive symptoms (28%; 66%), estradiol levels
(49%; 66%), and neocortex serotonin transporter
binding (8%; 45%) between baseline and later
follow-up
Stenbaek, Budtz- 28 GnRHa • Profile of mood states day 0 to 14 GnRHa with and without concomitant
Jorgensen, Pinborg, 27 placebo post-intervention. infertility-related stress heightened total mood
Jensen, and Frokjaer • Neuroticism personality scores at baseline disturbances most pronounced at the early
(2019) 37 IVF-GnRHa (NEO-PI-R) stimulatory phase day 0–5 post-GnRHa in a
manner dependent on neuroticism scores

met the clinical criteria of a mild depressive state. The emergence
of depressive symptoms was coupled to increases in SERT binding
(which lowers synaptic serotonin), and was dependent on the bi-
phasic estradiol fluctuation (Frokjaer et al., 2015). This implies tran-
siently compromised serotonin signaling in the mechanisms by which
sex steroid hormone fluctuations provoke depressive symptoms in
susceptible individuals. Serotonergic brain signaling is ostensibly dis-
turbed in individuals with MDD, also with postpartum onset, and tra-
ditionally constitutes a key target for pharmacological treatment (di
Scalea & Wisner, 2009); however, treatment success is disappointing
(Rush et al., 2006). Sex hormones target serotonergic neurons and
shape the adult female brain during hormonal transition periods
(Barth, Villringer, & Sacher,  2015). Thus it is likely that serotonin
signaling is affected during changes in sex steroid hormone milieu.
In particular, estradiol potently affects the key features of the sero-
tonin signaling system (Bethea, Lu, Gundlah, & Streicher, 2002), that
is synthesis, degradation, postsynaptic receptor distribution, includ-
ing induction of the main regulator of synaptic serotonin, SERT (Lu,
Eshleman, Janowsky, & Bethea, 2003; Suda, Segi-Nishida, Newton,
& Duman,  2008; Sumner et  al.,  2007). Also, importantly seminal
 |
1288       FROKJAER
studies have pointed to a role of increased enzymatic degradation of
monoamines in the brain (MAO-A activity) in postpartum depressive
symptoms (Sacher et al., 2010, 2015), which would further tend to
compromise not only serotonergic signaling but also other mono-
amines, that is dopamine and noradrenaline. Pharmacological treat-
ments of depressive episodes occurring in relation to peripartum
traditionally target SERT, i.e selective serotonin reuptake inhibitors
(SSRIs; Cooper, Willy, Pont, & Ray, 2007). Nevertheless, our GnRHa
results and that of others (Dowlati et al., 2017) support that the brain
architecture of hormonal transition includes key targetable features
beyond serotonin that ostensibly contributes to an increased risk for
depressive episodes most likely linked to the estradiol withdrawal
phase.
4.2 | Neuroprotective properties of estradiol and
estradiol sensitivity
We and others have shown that estradiol affects critical domains
and key brain regions (e.g., the hippocampus) known to be dysfunc-
tional in MDD (Barth et al., 2015, 2016; Comasco et al., 2014), which
putatively is linked to neuroprotective features of estradiol. Such
loss of neuroprotection may play a critical role particularly in es-
tradiol withdrawal phases, as for example postpartum. Specifically,
the GnRHa model highlights key regions in the reward circuit that
are less engaged in response to positive stimuli when undergoing
sex hormone manipulation as imaged in the ovarian hormone sup-
pression phase, which may drive anhedonia in depressive episodes
triggered by hormonal transitions. Also, in the same model, we have
shown a disengagement of hippocampus (Fisher et  al.,  2017), and
overengagement of brain networks recruited when processing emo-
tional salient information (Henningsson et al., 2015).
Sex steroid hormones support neuroprotection through pro-
cesses potentially driven by gene transcription and epigenetic
mechanisms and are likely moderated by serotonergic brain sig-
naling. Such steroid hormone-driven processes may explain why
pregnancy reorganizes brain structures in ways that, in healthy
conditions, may prepare the brain for motherhood (Hoekzema
et  al.,  2016). In particular, estrogen affects brain structure
and function, including synaptic remodeling and neurogene-
sis (Yankova, Hart, & Woolley,  2001) and hippocampal plasticity
(Barth et  al.,  2016). Estrogen replacement appears to have neu-
roprotective properties in animal models of early menopause
(Sohrabji,  2005) and affects the primary serotonin receptor sub-
type 2A in brain cortex (Frokjaer, Erritzoe, et  al.,  2010; Kugaya
et  al.,  2003; Moses-Kolko et  al.,  2003) and the SERT (Comasco,
Frokjaer, & Sundstrom-Poromaa,  2014; Lu et  al.,  2003), which is
a key regulatory protein in the system and marker of serotoner-
gic wiring. Further, human studies support a temporary neuro-
protective effect of hormonal replacement in early menopause as
reflected by increased hippocampal volumes (Lord, Buss, Lupien,
& Pruessner,  2008) and improved cognitive function (i.e., verbal
memory; Amin et al., 2006). Likewise, in healthy pregnancy, higher
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levels of estradiol are related to better verbal memory, which on
the contrary is not the case for pregnant women who develop
depressive symptoms (Hampson et  al.,  2015). Notably, a recent
clinical trial supports that estradiol replacement in perimenopause
protects against depressive episodes relative to placebo (Gordon
et al., 2018); however no tools are yet available to personalize or
to time such preventive strategies during life course.
In PND, recent data suggest that estradiol sensitivity predis-
poses women to PND, which can be demonstrated with proxy mark-
ers for estrogen sensitivity derived from blood of pregnant women
(i.e., DNA methylation Guintivano et al.,  2014 and gene expres-
sion Mehta et  al.,  2014), thus constituting a candidate biomarker.
Further strengthening the estradiol sensitivity hypothesis and
the candidate biomarker, RNA and DNA material from the GnRHa
study (Mehta et al., 2019) points to a link between these gene tran-
script PND markers (Mehta et al., 2014) and estradiol manipulation,
which intriguingly predicts depressive responses. Importantly, this
backtranslation from clinical PND biomarkers in pregnant cohorts
to the GnRHa sex hormone manipulation preclinical human model
further substantiates the estradiol sensitivity hypothesis of depres-
sive episodes triggered by hormonal transitions across reproductive
female life. Finally, the fact that we now can demonstrate an over-
lap between changes in gene expression and DNA methylation and
psychometrics between the GnRHa elicited patterns and the inde-
pendent clinical cohort of women with moderate to severe depres-
sive episodes postpartum further validates the psychopathological
importance of the phenomena triggered by the GnRHa manipula-
tion. It also supports GnRHa as a means of modelling mechanisms by
which hormonal transition can trigger depressive episodes in certain
sensitive women.
5 | C LI N I C A L PE R S PEC TI V E S A N D FU T U R E
D I R EC TI O N S
Additional studies are needed to translate findings from the GnRHa
model to clinically relevant groups of women. It is not yet known if
disturbed serotonin signaling (Frokjaer et  al.,  2015), brain network
recruitment (Henningsson et  al.,  2015; Macoveanu et  al.,  2016;
Stenbaek et  al.,  2016), and functional connectivity (Fisher
et al., 2017) translate to women who are sensitive to hormonal tran-
sitions, for example across the transition from natural pregnancy to
early postpartum in women with a history of PND. This will be a criti-
cally needed step towards informing a stratified setup for preven-
tion and clinical management of perinatal depression and to validate
potential biomarkers, that is of estradiol sensitivity, which may help
identify such subgroups of women.
To counterbalance risk contributions from postpartum with-
drawal from estradiol, transdermal estradiol has been suggested as
a promising treatment option for PND (Moses-Kolko, Berga, Kalro,
Sit, & Wisner, 2009) supported by a convergence of epidemiological,
preclinical, and clinical research, that is robust and rapid response to
estradiol in some pilot PPD trials, few side effects, and minimal breast

FROKJAER
milk passage to the infant (Pinheiro, Bogen, Hoxha, & Wisner, 2016).
However, a pilot clinical trial attempting to evaluate the effective-
ness was disappointing (Wisner et  al.,  2015). Intriguingly, estradiol
was administered at a late time point (up to 13  weeks postpartum)
where a depressive episode had already been established (Wisner
et  al.,  2015). It is not known if short-term estradiol applied in the
immediate postpartum, as a preventive strategy in a selected high-
risk group of women, may disrupt early risk mechanisms and protect
maternal brain health. Other promising new PND treatments include
allopregnanolone analogues, which have shown clinical efficacy;
however, notably, at the same time, a large placebo effect was ob-
served (Meltzer-Brody et  al.,  2018). Importantly, robust evidence
support heterogeneity of depressive episodes across the perinatal
period (Putnam et  al.,  2017), which needs to be embraced by re-
searchers and clinicians to fully exploit windows of opportunity for
personalized prevention and treatment for the disorder(s) (Galea &
Frokjaer, 2019). Notably, the GnRHa model suggests that both an in-
crease in estradiol, which is pronounced in late pregnancy, and a sub-
sequent withdrawal as seen postpartum, contribute critically to offset
brain biology and trigger depressive symptoms in susceptible women
(Fisher et  al.,  2017; Frokjaer et  al.,  2015; Henningsson et  al.,  2015;
Macoveanu et al., 2016; Stenbaek et al., 2016). Importantly, this may
explain why the risk for depressive symptoms peaks in the early post-
partum phase (Munk-Olsen et  al.,  2006) where carryover effects
from late pregnancy and effects of postpartum hormonal withdrawal
add up. Again this may be worsened by the effects of MAO-A ac-
tivity further depleting monoamines, including serotonin in the early
postpartum (Sacher et  al.,  2010, 2015). Intriguingly, this also raises
the hypothesis that perinatal depression with onset in late pregnancy
indeed have critical contributions from disturbed serotonin signaling
that, however, may not be fully compensated by SSRI treatment when
entering the postpartum withdrawal phase.
Risk mechanisms for developing depression identified by the
GnRHa model may identify key features of a clinical relevant “hor-
mone-sensitive subgroup” of the broader category of MDD. Recent
evidence from studies across menopausal transition supports the no-
tion that hormonal transitions may cause depressive symptoms in hor-
mone-sensitive individuals: Estradiol fluctuations around menopausal
transition are associated with first-time onset of MDD (Freeman
et al., 2006) and appears to be preventable by hormonal replacement
(Gordon et al., 2018). Another remarkable and recent register-based
finding, which again links exposure to hormonal transitions with de-
pression, has shown that starting on hormonal contraceptive is as-
sociated with an increased risk of developing a depressive episode
(Skovlund et  al.,  2016; Zettermark, Perez Vicente, & Merlo,  2018).
This finding has been replicated in an independent prospective cohort
study (de Wit et al., 2019). It remains unclear why the use of oral con-
traceptives increases the risk of a depressive episode in some women,
including to what extent suppression of endogenous estradiol may
play a role, and if these women can be identified by risk markers.
The GnRHa model does not align as well with sex hormone
dynamics putatively underlying premenstrual dysphoric mood dis-
order (PMDD) since the disorder seem to be linked to sensitivity to
|
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      1289
high premenstrual levels of the active metabolite of progesterone,
allopreganolone (Lanza di Scalea & Pearlstein,  2019), that most
likely does not vary substantially with short-term GnRHa manipu-
lation. However, allopregnanolone also may be linked to serotonin
brain signaling (Sundstrom Poromaa et  al.,  2018). Accordingly,
patients with PMDD appear to respond particularly well to cyclic
SSRI treatment administered prior to menses and similar to inhi-
bition of allopregnanolone (Bixo et  al.,  2017). Indeed, progester-
one and estradiol dynamics may interact in their effects on mental
health; for example as shown in women with borderline personal-
ity disorder high levels of progesterone may render a woman more
sensitive to estradiol deviations (lower than the women usual
mean) and elicit emotional and mood instability, impulsivity, irrita-
bility, and aggressive behaviors (Eisenlohr-Moul, DeWall, Girdler,
& Segerstrom,  2015), which also characterize PMDD. Those sex
steroid hormone interactions are not captured with the GnRHa
model, which also highlights why these complex phenomena need
to be studied in clinical cohorts.
Future studies evaluating preventive strategies in women at
high risk for depressive episodes triggered by hormonal transitions
and candidate biomarkers such as estrogen sensitivity, which may
help stratify risk, are warranted. Pharmacologically, such strategies
may target serotonergic signaling in late pregnancy and/or estradiol
replacement in the immediate postpartum. Other strategies may
include dietary supplies that can lower MAO-A activity (Dowlati
et al., 2017). In perimenopause, preventive strategies could include
a precision medicine approach to identifying women who may ben-
efit from hormonal replacement in combination with antidepressant
treatments. Also in a long-term perspective it needs to be deter-
mined if estrogen sensitivity markers based on gene transcription
profiles or epigenetics (Guintivano et al., 2014; Mehta et al., 2014,
2019) can work outside of the highly stimulated state of late preg-
nancy, for example via estrogen or steroid hormone-stimulated
assays and whether such markers also identify women at risk for
depressive episodes when exposed to other hormonal transitions;
however, this is so far unexplored.
Clearly, joint efforts to facilitate replications across data sets
and sites will be needed to validate potential risk stratification
and biomarker tools (Freeman, Sammel, Rinaudo, & Sheng,  2004;
Guintivano, Manuck, & Meltzer-Brody,  2018) and to optimize risk
and disease management to support mental health including affec-
tive cognitive functions, that is, across perimenopause and peripar-
tum. Ideally, advancing the understanding of hormonal contributions
to depressive episodes may also help fight stigma and be useful in
psychoeducation to support patient engagement in preventive ini-
tiatives and treatment compliance; however, this remains to be
tested in clinical trials.
6 | CO N C LU S I O N
The GnRHa model, given its placebo-controlled design and through
modeling the contributions from a biphasic estradiol fluctuation,
 |
1290       FROKJAER
allowed us to isolate the estradiol fluctuation-driven changes and
their coupling to early depressive-like symptoms in certain suscep-
tible women, a point of strength over previous study designs, which
have focused at the late suppression phase.
Taken together the GnRHa model provides an important source
of insights into the ways by which sex hormone fluctuations work
to trigger depressive episodes of great translational value. The
model supports that both an increase in estradiol and a subsequent
withdrawal contribute critically to brain architecture of risk for de-
pression in susceptible women who display estradiol sensitivity at
a molecular level. However, the relative contributions from estra-
diol increase phases and subsequent dramatic decreases are not
clarified and, accordingly, not yet exploited in current risk or disease
management.
Our data point to a distinct pathophysiology of depressive ep-
isodes related to hormonal transitions. If better understood, and
if bridging with observations in clinical cohorts, this may provide
a starting point for actual preventive and personalized treatment
strategies of relevant intensity to be tested in future studies.
C O N FL I C T O F I N T E R E S T
VGF declares that she has received honorarium as consultant for
SAGE therapeutics and as speaker for Lundbeck Pharma A/S.
ORCID
Vibe G. Frokjaer  https://orcid.org/0000-0002-9321-2365
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Hormones and Depression

DECEMBER 3, 2018

Depression Can Be A Symptom of

Hormone Imbalances
Imbalances in your hormones and depression are interrelated. Conventional medical

providers are quick to prescribe antidepressants when their patients present with
symptoms of depression, however hormones could actually be the cause.
Depression is a disease in and of itself, but it can also be a symptom of another

underlying disorder. If the underlying disorder isn’t addressed, then antidepressants

will only put a band-aid on the symptom and not treat the cause.

Antidepressants are the most commonly prescribed drug in the United States.

Chances are that if you walk into your primary care doctor’s office complaining of
feeling depressed, most are going to write you a prescription for an antidepressant

medication without ever considering that there may be something else going on.

Interestingly, the largest demographic taking antidepressants are women in their

forties and fifties. One out of every three women in this age group present with
symptoms of depression. This is quite telling because this is also the time that

women go through the phases of their lives called perimenopause and menopause.
Hormones undergo drastic changes and can produce many symptoms including
depression – another tell tale sign of the hormones and depression link.

Depressive symptoms associated with hormonal

imbalances can have other signs too, including:

Insomnia
Feeling overwhelmed
Fatigue
Weight gain or changes in appetite

Decreased pleasure in life

Decreased libido
Indecisiveness
Feelings of worthlessness or hopelessness

These are just a handful of things that may occur with hormonal imbalances, but
these can also be symptoms of depression so it’s important to explore causation.

It’s also important to note that imbalances in one hormone often occur alongside
imbalances in others. The endocrine system is the whole, and the glands/hormones
are the parts and they all need to be in balance to work in harmony together.
Types of Hormonal Imbalances Associated with
Depression

Progesterone

Both progesterone and estrogen hormones and depression can be linked.

Progesterone, one of the female sex hormones, is what helps prepare the uterus to

be an ideal place for a fertilized egg to grow. Estrogen is the hormone that prepares
the uterus by building up the lining. At around day 14 of a woman’s cycle,
progesterone levels rise which stops the uterine lining from building up. If there’s no

egg, then progesterone levels drop and the lining of the uterus is shed.

When a woman enters the perimenopause stage her life, the first hormone to wane is
progesterone. Reproductive years are starting to come to an end, so therefore, there’s

no reason for progesterone to keep preparing the uterus for pregnancy. During these
years, periods can become wildly erratic.

Fluctuations with progesterone levels can do the same thing to emotions by

changing the brain chemistry which can lead to depression. Estrogen becomes the
dominant hormone which can cause cortisol levels to rise and increase feelings of
anxiety.

Progesterone also stimulates GABA, the feel-good/stay-relaxed neurotransmitter

that’s also affected by the thyroid. When progesterone levels drop, GABA levels can
drop too leading to feelings of both anxiety and depression.

Progesterone is the hormone that regulates sleep cycles so it’s not uncommon for
women to begin to experience insomnia.

Estrogen

As progesterone levels decline in perimenopause, the delicate balance between

estrogen and progesterone is thrown off, which creates a condition called Estrogen
Dominance. This can occur at any age throughout a woman’s life, however it is
especially prominent in the perimenopause years. 
It’s important to note that it’s entirely possible for estrogen levels to be low, but to
still have Estrogen Dominance because it’s all about the ratio between the two
hormones. Estrogen Dominance can affect how the body assimilates thyroid
hormones, which can cause hypothyroidism, also causing depressive symptoms.

As a woman gets closer to menopause, estrogen levels begin to decline. This can
actually occur at any time during this phase as all hormones begin to fluctuate and
ebb.

Estrogen also helps to boost serotonin levels. Serotonin is a neurotransmitter, or

chemical compound, that helps to regulate mood. When serotonin levels decline, it
leads to feelings of depression and anxiety, thus if estrogen levels are low, serotonin

can also be low. Here you can easily see how changes in these hormones and
depression are easily related. In fact, many antidepressants belong to a group of
drugs called SSRIs, or Selective Serotonin Reuptake Inhibitors. These drugs aid in
increasing serotonin levels.

If deficient estrogen levels are the cause of depressed symptoms, treating the
deficiency will eliminate the symptom instead of masking it.

Women who have experienced depressive episodes during the reproductive years are
much more likely to experience depression around the menopausal years. Also,
women who have gone through surgical menopause (hysterectomy with removal of
the ovaries) are also more likely to experience depression than women who go
through natural menopause.

Testosterone

Testosterone has significant impact on mood and overall well-being. Decreased

testosterone has been linked to both depression and anxiety. Many women find that
once they get their testosterone deficiency addressed, that they feel like their old
selves again and have pep back in their step. Low T in women can also cause loss of
libido, fatigue, loss of muscle tone, and hair loss. Skin changes may also occur.

Thyroid
Hypothyroidism, or low functioning thyroid, can cause depressive symptoms. An
under-active thyroid causes a slow-down in the entire metabolism so it’s not

surprising that mood is low as well. The thyroid hormone, T3, is responsible for
creating energy in the mitochondria of the cells. Without enough T3, overall energy
levels fall. Besides depression, other common symptoms of hypothyroidism include
fatigue, weight gain or difficulty losing weight, joint pain, and hair loss.

Hypothyroidism can also cause a drop in the neurotransmitter GABA. A

neurotransmitter is a chemical that is produced by nerve cells and acts as a
messenger to transmit signals between neurons, etc. GABA is a chemical found
throughout the nervous system and in the cortex portion of the brain. It aids in
regulating mood, anxiety levels, emotional stability, pain response, reactions to
stress, and sleep, among other things. It’s thought of as the calming
neurotransmitter.

While hypothyroidism and depression are two separate diseases, they include some
of the same symptoms. If an underactive thyroid is the culprit, medication for the

thyroid can eliminate or lessen the depression symptoms.

Additionally, thyroid issues often crop up during times of hormonal flux such as
menopause in women or andropause in men.

For additional information about thyroid disease and treatment, click here. 

Adrenal Hormones and Depression

The adrenal glands produce the “stress hormones” such as adrenaline, cortisol, and
DHEA. It’s natural for adrenaline and cortisol to increase as a reaction to stress; they
are the “fight/flight” hormones. However, when they become over-activated by
chronic stress, the adrenal glands can become fatigued. Adrenal fatigue manifests in
different ways which include depression, anxiety, and difficulty dealing with stress.

During menopause women are more likely to experience fluctuations with cortisol.
When cortisol rises, it can contribute to weight gain and sleeplessness. However,
when levels decrease, it can create mood swings to include depression.

Studies on how Hormones and Depression are linked

There
have
been

numerous studies completed which show that your hormones and depression are
connected, particularly with women going through the menopausal years being at

much higher risk for developing depressive symptoms, even if they have no prior
history of depression.

Some studies have shown that the significant hormonal changes that occur can also
make a woman more vulnerable to physical and emotional challenges which can
significantly affect function and quality of life.

Interestingly, one of the studies of 476 women, aged 40 to 60, noted that
perimenopausal women experiencing depression were significantly more likely to
have vasomotor symptoms (hot flashes) than the women who were not suffering
from depressed symptoms.

For more detailed information regarding studies concerning hormones and

depression, click here. 

Our Approach at the Offices of Leigh Ann Scott, M.D. in Las

Colinas
Dr. Leigh Ann Scott and Nurse Practitioner Elise Lewis are both hormone experts.
Treatment begins with comprehensive lab testing to include hormones, as well as a
myriad of other health markers to give us a clear picture of any underlying issues
that may be the cause of your depression.

Additionally, we recognize that many factors can contribute to hormone imbalances

and symptoms. We discuss ways to improve diet and nutrition, stress management,
and ways to get better sleep. Read more about our Hormone Balancing here. 

Our philosophy is that everyone is unique and individual we realize that “normal”
varies from person to person. Our mission is to help you obtain optimal health and
feel great again.

Learn More About Hormone Balancing!

Restoring hormonal balance has many positive health benefits in addition to

providing relief from symptoms. Dr. Scott and her Nurse Practitioner,Elise Lewis offer
extensive laboratory testing to specifically identify which hormones might need
regulating as well as other factors that may be affecting your hormone balance. This
testing also looks at other health markers which provide a whole-body picture so that
optimal hormone balance can be achieved. They will prescribe only bioidentical
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pharmacies. These products are designed to mirror the hormones naturally produced
by the body.

Read More…

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Psychosomatics 2013:54:509–514 & 2013 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Review Article
The Effect of Testosterone Levels on Mood in Men:
A Review
Justin M. Johnson, M.D., Lisa B. Nachtigall, M.D., Theodore A. Stern, M.D.
Background: The effects of both high and low levels of
testosterone are wide ranging and can include changes in
mood, often overlapping with symptoms of mood
disorders. Objective: We sought to review the literature
on the correlation of high and low levels of testosterone
on mood disorders in men. Results: Based on limited
studies, high levels of testosterone are related to
increased rates of depression as well as hypomania,
OVERVIEW
Testosterone supplementation for the treatment of low
testosterone levels (“Low T”) in men has been the
subject of a major direct-to-consumer marketing cam-
paign. Because of this, many physicians are being asked
about symptoms of testosterone deficiency and are
being subjected to demands for testosterone supple-
mentation to treat a variety of symptoms consistent
with low testosterone levels. Moreover, many male
patients with psychiatric problems inquire about the
correlation between testosterone levels and low mood,
often because this is referenced in pharmaceutical
company-created television commercials. To address
increasingly common questions, physicians should
understand what is known and what is not known
about the relationship between testosterone and mood.
This paper attempts to summarize this relationship so
that practitioners may field and answer questions about
testosterone and mood. We summarize the physiology
of testosterone and discuss the effects of both elevated
and low levels of testosterone on mood. The effects of
testosterone on other neuropsychiatric conditions, such
as posttraumatic stress disorder, schizophrenia, and
cognitive disorders, are beyond the scope of this paper.
Psychosomatics 54:6, November/December 2013
whereas low levels of testosterone are related to
depressive disorders in certain subpopulations of
patients. There is insufficient evidence to conclude that
low testosterone level routinely leads to major depres-
sive disorder in men. Conclusions: Physicians should
consider screening for low testosterone levels in certain
subgroups of depressed men.
(Psychosomatics 2013; 54:509–514)
WHAT IS TESTOSTERONE?
Testosterone is a steroid hormone and the principle
androgen responsible for sexual development and the
maintenance of male secondary sexual characteristics.1
Testosterone, as a steroid hormone, crosses cellular
membranes and binds to testosterone receptors before
attaching to DNA and facilitating both RNA and
protein synthesis.1 Testosterone and its derivatives are
responsible for the growth of muscle mass and bones, for
the growth of the penis and the scrotum, and for the
development of male secondary sexual characteristics.2
It is primarily secreted from the testes in men. In women,
smaller amounts are secreted from the adrenals and
ovaries. Testosterone secretion is stimulated by the
pituitary leutenizing hormone (LH), which is cyclically
Received May 21, 2013; revised June 24, 2013; accepted June 25, 2013.
From Massachusetts General Hospital, Harvard Medical School. Send
correspondence and reprint requests to Justin M. Johnson, M.D., 15
Parkman Street, WACC 812, Boston, MA 02114. Massachusetts
General Hospital, Department of Psychiatry and Department of
Medicine, Endocrine Division; Harvard Medical School, Boston, MA.
& 2013 The Academy of Psychosomatic Medicine. Published by
Elsevier Inc. All rights reserved.
www.psychosomaticsjournal.org 509
The Effect of Testosterone Levels on Mood in Men
secreted in response to pulsatile gonadotropin-releasing
hormone by the hypothalamus.1
Although women secrete a small amount of testos-
terone, adult men have plasma concentrations of
testosterone that are 7 to 8 times that of women, and
because men also utilize more testosterone, their daily
production is actually about 20 times greater than that
of women.3,4 Average total testosterone levels in men
range between 300 and 1000 ng/dL.5 However, total
testosterone levels do not completely reflect physiologic
activity because most of the testosterone is bound by
various proteins; free testosterone is the only physio-
logically active form and it makes up about 1% to 2% of
the total serum testosterone.1 Despite this, most labo-
ratories measure only total serum testosterone levels and
except in cases of obesity or advanced age (480 years),
where protein-binding changes total testosterone levels,
this is presumed to be an appropriate measurement.6,7
Testosterone levels decrease gradually over the life-
span in healthy men.8,9 This pattern differs from the
sudden reduction in estrogen production following female
menopause.8 With normal aging in men, free, or bio-
available, testosterone levels can decrease by as much as
40% between the ages of 40 and 70 years.10 As many as
20% of men older than 60 years meet criteria for
hypogonadism as a result of a normal, age-related
testosterone decline, though a “normal” level of testoster-
one for men older than 60 years has yet to be established.11
The Endocrine Society's Clinical Guidelines Subcommit-
tee diagnoses hypogonadism in men with consistent
physical signs and symptoms and unequivocally low
testosterone levels.9 Studies based on these guidelines
have defined hypogonadism as 1 or more specific
symptoms (low libido, erectile dysfunction, or osteopo-
rosis) or 2 or more of the nonspecific symptoms (sleep
disturbance, depressed mood, lethargy, or low physical
performance) as well as total testosterone level less than
300 ng/dL or free-testosterone level less than 5 ng/dL.12
Low testosterone level has been linked with mild
anemia, reduced muscle bulk, increased body fat, and
decreased physical and work performance,9 as well as
fatigue, loss of vigor, irritability or depressed mood,
poor concentration, and disturbances of sleep.13 In
addition, androgen deficiency is associated with
delayed sexual development, reduced libido, a decrease
in spontaneous erections, gynecomastia, a loss of
axillary and pubic hair (and the reduced need for
shaving), testicular atrophy, infertility (with a low
sperm count), loss of height with low bone mass, and
510 www.psychosomaticsjournal.org
hot flushes.9 Replacement of testosterone has improved
cognition, motivation, mood, sleep, poor concentra-
tion, male libido, and has been shown to reduce anger
and irritability in hypogonadal men.14,15 Many of these
features overlap with symptoms of mood disorders.
WHAT IS THE EFFECT OF HIGH
TESTOSTERONE LEVELS ON MOOD?
Much of the information about the effects of elevated
testosterone on mood comes from case reports involv-
ing exogenous testosterone administration.5 There are
few reports that correlate elevated endogenous testos-
terone levels and mood disorders,16 though elevated
endogenous testosterone has more readily been asso-
ciated with increased aggressive and risk-taking behav-
ior.17 XYY males have been noted to have higher
average free-testosterone levels than XY males18;
however, no evidence exists for them having a higher
prevalence of mood disorders.18,19 A 2012 cross-
sectional study of 16 men and 51 women with bipolar
disorder found a correlation between testosterone
levels and the number of manic episodes and suicide
attempts, suggesting a correlation between mania—as
well as impulsive self-harm—and testosterone in those
already diagnosed with bipolar disorder.16 Although
studies looking at the effects of elevated endogenous
testosterone and mood disorders are lacking, studies
investigating the relationship between elevated exog-
enous testosterone levels and mood disorders do exist.5
One placebo-controlled study administered normal
men intramuscular (IM) injections of supraphysiologic
doses of testosterone (1000 mg) and found that self-
reported anger and hostility increased after 2 weeks when
compared with placebo.20 The authors did not specifically
comment on the presence of mood disorders.20 Many of
the cases involving the effects of exogenous testosterone
on mood disorders looked at abusers of anabolic steroids,
who took 10 to 100 times the physiologic doses of
testosterone, in cycles of 6 to 14 weeks.5 It is noteworthy
that anabolic steroids typically consist of multiple tes-
tosterone derivatives, not just testosterone. Several nat-
uralistic or anecdotal studies of anabolic steroid use
reported increased irritability, aggressivity, euphoria, and
maniclike symptoms, as well as multiple depressive
symptoms upon the withdrawal of the anabolic steroid.21
Pope and Katz compared 88 anabolic steroid-abusing
athletes with 68 nonsteroid-abusing athletes from the
Psychosomatics 54:6, November/December 2013

same gyms; they found that any mood disorder (depres-
sion, dysthymia, mania, or hypomania) was significantly
associated with steroid use when compared with nonusers
and to users when they were not using steroids.21 Others
reported similar findings, suggesting a correlation
between elevated exogenous testosterone and both hypo-
manic and depressive symptoms.5
WHAT ARE THE EFFECTS OF LOW
TESTOSTERONE ON MOOD?
When hypogonadal men visit with endocrinologists
they often complain of dysphoria, fatigue, irritability,
and loss of libido, symptoms that may correlate
with episodes of major depression.22 Reports of
severely hypogonadal men self-reporting more depres-
sive symptoms than eugonadal men also exist.23,24
Finally, the prevalence of major depressive episodes
increases with aging, just as testosterone is declining.
Because of these observations, many practitioners
assume that a connection exists between low testoster-
one levels and depressive syndromes.
Several studies have looked at this connection.
The Rancho Bernardo Study (a cross-sectional,
population-based study of male residents of a com-
munity in California) evaluated 856 men between the
ages of 50 and 89 years and measured free-testosterone
levels and assessed major depressive disorder (with the
Beck Depression Inventory).25 This study found that
after adjusting for age, exercise, and weight, there was
an inverse correlation between free-testosterone levels
and Beck Depression Inventory scores, that is, lower
testosterone levels correlated with more depressive
symptoms.25 The Veterans' Experience Study assessed
4393 Vietnam-era veterans, with a mean age of 38
years, and checked free-testosterone levels as well as
depressive symptoms with the Diagnostic Interview
Schedule.26 This study revealed that the correlation
between total testosterone level and depressive symp-
toms was nonlinear, i.e., there were higher levels of
depression at both the lowest extremes of total
testosterone levels and at the highest extremes of total
testosterone levels.26 Finally, the Massachusetts Male
Aging Study, another population-based survey of
1709 men between the ages of 40 and 70 years, assessed
free-testosterone levels and depressive symptoms on
the Centers for Epidemiologic Studies Depression
Scale (CES-D).27 This study showed no correlation
between free-testosterone levels and depressive
Psychosomatics 54:6, November/December 2013
Johnson et al.
symptoms.27 A comparable number of studies have
shown connections between low testosterone and
major depressive disorder, as those that have shown
no connection at all.22 The results of these 3 large
studies and the compilation of other small studies cited
earlier reveal that a correlation between lower testos-
terone level and major depressive disorder may not
exist at all and, at the very least, requires further study.
Despite this, there may be a connection between
low testosterone levels and other depressive subtypes.
Two studies showed that early morning testosterone
release is blunted in men with the melancholic depres-
sion, suggesting that this subtype of depression may be
more prevalent in those with low testosterone lev-
els.28,29 Men labeled as having treatment-resistant
depression, defined as not responding after an
adequate trial of antidepressant (one study used
4 weeks, another, 8 weeks), have also been shown to
possess low levels of testosterone.14 Men with major
depressive disorder and HIV infection show lower
average levels of testosterone.14 Lastly, a study of
older men in upstate New York, mean age of 70.8
years, compared men who met DSM-IV criteria for
dysthymia with those with major depressive disorder
and those who were nondepressed.30 This study
revealed that men with dysthymia had statistically
significant lower median testosterone levels than did
those with depression and those in the nondepressed
group; the latter 2 groups had equivalent median
testosterone levels.30 There has been at least 1 other
study that revealed similar findings.22
Although the overarching relationship between
low testosterone levels and major depression has yet to
be proven, the literature points toward a connection
within the aforementioned subtypes—men with
treatment-resistant depression, men with major
depression and HIV infection, men with dysthymia,
and elderly men (aged 460 years) with depression.
Despite this and because of multiple problems (such as
variable age ranges of participants, small sample sizes,
different androgen assays, measuring total vs free-
testosterone levels), further research is warranted.
IS TESTOSTERONE REPLACEMENT
BENEFICIAL TO THOSE WITH DEPRESSIVE
SYNDROMES?
Studies evaluating testosterone replacement and its
effect on abnormal mood have been numerous and
www.psychosomaticsjournal.org 511
The Effect of Testosterone Levels on Mood in Men
variable, but Zarrouf et al.14 performed a meta-analysis
in 2009 with the goal of assessing the specific effect of
testosterone replacement on major depressive disorder.
They looked at only randomized, double-blind,
placebo-controlled trials of patients diagnosed with
DSM-IV-defined major depressive disorder and moni-
tored them by changes in the Hamilton-D depression
rating scale. Seven trials met the criteria,14 composed of
355 patients with an age range of 18 to 70 years.14 Their
meta-analysis revealed a significant positive effect of
testosterone replacement on Hamilton-D depression
rating scale scores in depressed patients with hypogo-
nadism (with total testosterone levels less than 350
ng/dL), in depressed patients with HIV/AIDS, and in
depressed patients who used the gel, not the IM form of
testosterone.14 In the latter studies of IM testosterone,
though, supraphysiologic doses were used and there-
fore the difference between effects on Hamilton-D
depression rating scale scores between transdermal
and IM forms may be related to dose, not differences
in mode of administration. Two of these groups—men
with overt hypogonadism and men with both depres-
sion and HIV/AIDS—have more depressive symptoms
that correlate with lower levels of testosterone, and thus
may be more expected to respond to exogenous
testosterone administration. Despite these correlations,
this meta-analysis left out more than 1000 studies with
varying results, indicating that further study is war-
ranted. Studies assessing testosterone as an augmenta-
tion strategy for antidepressant treatment have also
been equivocal in their results.31 There are no further
analyses of differences between route of administration
or those using different types (such as free vs total) of
testosterone measurement.
WHAT IS AN APPROACH TO THE DIAGNOSIS
OF TESTOSTERONE DEFICIENCY IN MEN?
Psychiatrists evaluating any of the aforementioned
groups of male patients should consider checking
testosterone level. In addition, more specific physical
signs of low testosterone levels include delayed sexual
development, decreased libido, decreased spontane-
ous erections, gynecomastia, decreased pubic hair,
decreased need to shave, very small or shrinking testes,
low sperm count, height loss, nontraumatic fractures,
and hot flushes or sweats.9 Less specific signs include
mild anemia, reduced muscle bulk and strength,
increased body fat or body mass index, and diminished
512 www.psychosomaticsjournal.org
physical or work performance.9 If these physical signs
are present or if the patient falls into one of the groups
mentioned earlier (depressed men with HIV/AIDS,
men with dysthymia, or elderly men [age 4 60 years]
with depression), then it would be prudent to check a
morning serum total testosterone level (at 8 AM), after
obtaining a complete history and conducting a phys-
ical examination. One should also check routine
laboratory studies (such as complete metabolic panel,
complete blood count, thyroid-stimulating hormone,
hemoglobin A1c, fasting glucose, and a urine drug
screen) to rule out concomitant medical illness that
would also be on the differential. Other diagnoses that
may require treatment include hypothyroidism, ane-
mia, metabolic abnormalities, cancer, obstructive
sleep apnea, and substance abuse.
If the total testosterone level is normal (i.e.,
4350 ng/dL), then close monitoring is appropriate.
If total morning testosterone level is low (i.e., o350
ng/dL, or that is defined as “low” in one's laboratory),
then one should recheck the morning total testosterone
level, check LH and follicle-stimulating hormone
levels, and also consider checking free-testosterone
levels, if available in the hospital’s laboratory.9 If the
total testosterone level is assessed as normal on repeat
testing, then close follow-up is again appropriate.9 If
total or free-testosterone levels are low, if the LH and
follicle-stimulating hormone levels are elevated, and
the patient has consistent signs and symptoms of
hypogonadism, then it is appropriate to replete testos-
terone and obtain a karyotype for Klinefelter syn-
drome.9 Follicle-stimulating hormone and LH levels
are expected to be elevated with most forms of
hypogonadism.9 If the LH and follicle-stimulating
hormone levels are low, there may be a pituitary
abnormality; then, a prolactin level should be checked
and one should consider undergoing a brain magnetic
resonance imaging scan.9
The Endocrine Society recommends testosterone
therapy for symptomatic men with testosterone defi-
ciency, to induce and to maintain secondary sexual
characteristics and to improve sexual function, sense
of well-being, muscle mass, strength, and bone mineral
density. Exogenous testosterone administration typi-
cally produces few side effects, even at supraphysio-
logic doses, but side effects can include gynecomastia,
truncal acne, hair loss or growth, worsening of
obstructive sleep apnea, increased hematocrit, reduced
sperm production and testicular size, and problems
Psychosomatics 54:6, November/December 2013

related to mode of administration (such as skin
reactions with transdermal patches, skin irritation
from transdermal gel, pain at injection sites and
coughing episodes after IM injections).31 There is also
concern that testosterone administration can lead to
progression of prostate cancer or benign prostatic
hypertrophy and may be associated with adverse
cardiovascular events, although there is no direct
evidence for either of these concerns.31 Because of
these concerns, testosterone replacement is not rec-
ommended for patients with breast or prostate
cancer, with a palpable prostate nodule or induration,
or with a prostate-specific antigen level greater than
3 ng/mL, erythrocytosis, hyperviscosity, obstructive
sleep apnea, severe lower urinary tract symptoms, or
class III or IV heart failure.9 Treatment, like in most
of medicine, must weigh the benefits against the
potential risks and cases of borderline testosterone
levels may best be treated in consultation with an
endocrinologist.
CONCLUSIONS
Despite the pronouncements of the drug industry and
the common knowledge that testosterone levels affect
mood, our review indicates that the connection
between testosterone levels and mood disorders is
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1995; 81:3578–3583
25. Barrett-Connor E, Von Muhlen DG, Kritz-Silverstein D:
Bioavailable testosterone and depressed mood in older men:
The Rancho Bernardo Study. J Clin Endocrinol Metab
1999; 84:573–577
26. Booth A, Johnson DR, Granger DA: Testosterone and
men’s depression: the role of social behavior. J Health Soc
Behav 1999; 40:130–140
27. Araujo AB, Durante R, Feldman HA, et al: The relation-
ship between depressive symptoms and male erectile dys-
function: cross-sectional results from the Massachusetts
Male Aging Study. Psychosom Med 1998; 60:450–465
28. Rupprecht R, Rupprecht C, Rupprecht M, et al: Different
reactivity of the hypothalamo-pituitary-gonadal-axis in
depression and normal controls. Pharmacopsychiatry
1988; 21:438–439
29. Schweiger U, Deuschle M, Weber B, et al: Testosterone,
gonadotropin, and cortisol secretion in male patients with
major depression. Psychosom Med 1999; 61:292–296
30. Seidman SN, Araujo AB, Roose SP, et al: Low testosterone
levels in elderly men with dysthymic disorder. Am J
Psychiatry 2002:456–459159 2002:456–459
31. Seidman SN, Weiser M: Testosterone and mood in aging
men. Psychiatr Clin N Am 2013; 36:177–182
Psychosomatics 54:6, November/December 2013
Psychosomatics 2013:54:509–514 & 2013 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Review Article
The Effect of Testosterone Levels on Mood in Men:
A Review
Justin M. Johnson, M.D., Lisa B. Nachtigall, M.D., Theodore A. Stern, M.D.
Background: The effects of both high and low levels of
testosterone are wide ranging and can include changes in
mood, often overlapping with symptoms of mood
disorders. Objective: We sought to review the literature
on the correlation of high and low levels of testosterone
on mood disorders in men. Results: Based on limited
studies, high levels of testosterone are related to
increased rates of depression as well as hypomania,
OVERVIEW
Testosterone supplementation for the treatment of low
testosterone levels (“Low T”) in men has been the
subject of a major direct-to-consumer marketing cam-
paign. Because of this, many physicians are being asked
about symptoms of testosterone deficiency and are
being subjected to demands for testosterone supple-
mentation to treat a variety of symptoms consistent
with low testosterone levels. Moreover, many male
patients with psychiatric problems inquire about the
correlation between testosterone levels and low mood,
often because this is referenced in pharmaceutical
company-created television commercials. To address
increasingly common questions, physicians should
understand what is known and what is not known
about the relationship between testosterone and mood.
This paper attempts to summarize this relationship so
that practitioners may field and answer questions about
testosterone and mood. We summarize the physiology
of testosterone and discuss the effects of both elevated
and low levels of testosterone on mood. The effects of
testosterone on other neuropsychiatric conditions, such
as posttraumatic stress disorder, schizophrenia, and
cognitive disorders, are beyond the scope of this paper.
Psychosomatics 54:6, November/December 2013
whereas low levels of testosterone are related to
depressive disorders in certain subpopulations of
patients. There is insufficient evidence to conclude that
low testosterone level routinely leads to major depres-
sive disorder in men. Conclusions: Physicians should
consider screening for low testosterone levels in certain
subgroups of depressed men.
(Psychosomatics 2013; 54:509–514)
WHAT IS TESTOSTERONE?
Testosterone is a steroid hormone and the principle
androgen responsible for sexual development and the
maintenance of male secondary sexual characteristics.1
Testosterone, as a steroid hormone, crosses cellular
membranes and binds to testosterone receptors before
attaching to DNA and facilitating both RNA and
protein synthesis.1 Testosterone and its derivatives are
responsible for the growth of muscle mass and bones, for
the growth of the penis and the scrotum, and for the
development of male secondary sexual characteristics.2
It is primarily secreted from the testes in men. In women,
smaller amounts are secreted from the adrenals and
ovaries. Testosterone secretion is stimulated by the
pituitary leutenizing hormone (LH), which is cyclically
Received May 21, 2013; revised June 24, 2013; accepted June 25, 2013.
From Massachusetts General Hospital, Harvard Medical School. Send
correspondence and reprint requests to Justin M. Johnson, M.D., 15
Parkman Street, WACC 812, Boston, MA 02114. Massachusetts
General Hospital, Department of Psychiatry and Department of
Medicine, Endocrine Division; Harvard Medical School, Boston, MA.
& 2013 The Academy of Psychosomatic Medicine. Published by
Elsevier Inc. All rights reserved.
www.psychosomaticsjournal.org 509
The Effect of Testosterone Levels on Mood in Men
secreted in response to pulsatile gonadotropin-releasing
hormone by the hypothalamus.1
Although women secrete a small amount of testos-
terone, adult men have plasma concentrations of
testosterone that are 7 to 8 times that of women, and
because men also utilize more testosterone, their daily
production is actually about 20 times greater than that
of women.3,4 Average total testosterone levels in men
range between 300 and 1000 ng/dL.5 However, total
testosterone levels do not completely reflect physiologic
activity because most of the testosterone is bound by
various proteins; free testosterone is the only physio-
logically active form and it makes up about 1% to 2% of
the total serum testosterone.1 Despite this, most labo-
ratories measure only total serum testosterone levels and
except in cases of obesity or advanced age (480 years),
where protein-binding changes total testosterone levels,
this is presumed to be an appropriate measurement.6,7
Testosterone levels decrease gradually over the life-
span in healthy men.8,9 This pattern differs from the
sudden reduction in estrogen production following female
menopause.8 With normal aging in men, free, or bio-
available, testosterone levels can decrease by as much as
40% between the ages of 40 and 70 years.10 As many as
20% of men older than 60 years meet criteria for
hypogonadism as a result of a normal, age-related
testosterone decline, though a “normal” level of testoster-
one for men older than 60 years has yet to be established.11
The Endocrine Society's Clinical Guidelines Subcommit-
tee diagnoses hypogonadism in men with consistent
physical signs and symptoms and unequivocally low
testosterone levels.9 Studies based on these guidelines
have defined hypogonadism as 1 or more specific
symptoms (low libido, erectile dysfunction, or osteopo-
rosis) or 2 or more of the nonspecific symptoms (sleep
disturbance, depressed mood, lethargy, or low physical
performance) as well as total testosterone level less than
300 ng/dL or free-testosterone level less than 5 ng/dL.12
Low testosterone level has been linked with mild
anemia, reduced muscle bulk, increased body fat, and
decreased physical and work performance,9 as well as
fatigue, loss of vigor, irritability or depressed mood,
poor concentration, and disturbances of sleep.13 In
addition, androgen deficiency is associated with
delayed sexual development, reduced libido, a decrease
in spontaneous erections, gynecomastia, a loss of
axillary and pubic hair (and the reduced need for
shaving), testicular atrophy, infertility (with a low
sperm count), loss of height with low bone mass, and
510 www.psychosomaticsjournal.org
hot flushes.9 Replacement of testosterone has improved
cognition, motivation, mood, sleep, poor concentra-
tion, male libido, and has been shown to reduce anger
and irritability in hypogonadal men.14,15 Many of these
features overlap with symptoms of mood disorders.
WHAT IS THE EFFECT OF HIGH
TESTOSTERONE LEVELS ON MOOD?
Much of the information about the effects of elevated
testosterone on mood comes from case reports involv-
ing exogenous testosterone administration.5 There are
few reports that correlate elevated endogenous testos-
terone levels and mood disorders,16 though elevated
endogenous testosterone has more readily been asso-
ciated with increased aggressive and risk-taking behav-
ior.17 XYY males have been noted to have higher
average free-testosterone levels than XY males18;
however, no evidence exists for them having a higher
prevalence of mood disorders.18,19 A 2012 cross-
sectional study of 16 men and 51 women with bipolar
disorder found a correlation between testosterone
levels and the number of manic episodes and suicide
attempts, suggesting a correlation between mania—as
well as impulsive self-harm—and testosterone in those
already diagnosed with bipolar disorder.16 Although
studies looking at the effects of elevated endogenous
testosterone and mood disorders are lacking, studies
investigating the relationship between elevated exog-
enous testosterone levels and mood disorders do exist.5
One placebo-controlled study administered normal
men intramuscular (IM) injections of supraphysiologic
doses of testosterone (1000 mg) and found that self-
reported anger and hostility increased after 2 weeks when
compared with placebo.20 The authors did not specifically
comment on the presence of mood disorders.20 Many of
the cases involving the effects of exogenous testosterone
on mood disorders looked at abusers of anabolic steroids,
who took 10 to 100 times the physiologic doses of
testosterone, in cycles of 6 to 14 weeks.5 It is noteworthy
that anabolic steroids typically consist of multiple tes-
tosterone derivatives, not just testosterone. Several nat-
uralistic or anecdotal studies of anabolic steroid use
reported increased irritability, aggressivity, euphoria, and
maniclike symptoms, as well as multiple depressive
symptoms upon the withdrawal of the anabolic steroid.21
Pope and Katz compared 88 anabolic steroid-abusing
athletes with 68 nonsteroid-abusing athletes from the
Psychosomatics 54:6, November/December 2013

same gyms; they found that any mood disorder (depres-
sion, dysthymia, mania, or hypomania) was significantly
associated with steroid use when compared with nonusers
and to users when they were not using steroids.21 Others
reported similar findings, suggesting a correlation
between elevated exogenous testosterone and both hypo-
manic and depressive symptoms.5
WHAT ARE THE EFFECTS OF LOW
TESTOSTERONE ON MOOD?
When hypogonadal men visit with endocrinologists
they often complain of dysphoria, fatigue, irritability,
and loss of libido, symptoms that may correlate
with episodes of major depression.22 Reports of
severely hypogonadal men self-reporting more depres-
sive symptoms than eugonadal men also exist.23,24
Finally, the prevalence of major depressive episodes
increases with aging, just as testosterone is declining.
Because of these observations, many practitioners
assume that a connection exists between low testoster-
one levels and depressive syndromes.
Several studies have looked at this connection.
The Rancho Bernardo Study (a cross-sectional,
population-based study of male residents of a com-
munity in California) evaluated 856 men between the
ages of 50 and 89 years and measured free-testosterone
levels and assessed major depressive disorder (with the
Beck Depression Inventory).25 This study found that
after adjusting for age, exercise, and weight, there was
an inverse correlation between free-testosterone levels
and Beck Depression Inventory scores, that is, lower
testosterone levels correlated with more depressive
symptoms.25 The Veterans' Experience Study assessed
4393 Vietnam-era veterans, with a mean age of 38
years, and checked free-testosterone levels as well as
depressive symptoms with the Diagnostic Interview
Schedule.26 This study revealed that the correlation
between total testosterone level and depressive symp-
toms was nonlinear, i.e., there were higher levels of
depression at both the lowest extremes of total
testosterone levels and at the highest extremes of total
testosterone levels.26 Finally, the Massachusetts Male
Aging Study, another population-based survey of
1709 men between the ages of 40 and 70 years, assessed
free-testosterone levels and depressive symptoms on
the Centers for Epidemiologic Studies Depression
Scale (CES-D).27 This study showed no correlation
between free-testosterone levels and depressive
Psychosomatics 54:6, November/December 2013
Johnson et al.
symptoms.27 A comparable number of studies have
shown connections between low testosterone and
major depressive disorder, as those that have shown
no connection at all.22 The results of these 3 large
studies and the compilation of other small studies cited
earlier reveal that a correlation between lower testos-
terone level and major depressive disorder may not
exist at all and, at the very least, requires further study.
Despite this, there may be a connection between
low testosterone levels and other depressive subtypes.
Two studies showed that early morning testosterone
release is blunted in men with the melancholic depres-
sion, suggesting that this subtype of depression may be
more prevalent in those with low testosterone lev-
els.28,29 Men labeled as having treatment-resistant
depression, defined as not responding after an
adequate trial of antidepressant (one study used
4 weeks, another, 8 weeks), have also been shown to
possess low levels of testosterone.14 Men with major
depressive disorder and HIV infection show lower
average levels of testosterone.14 Lastly, a study of
older men in upstate New York, mean age of 70.8
years, compared men who met DSM-IV criteria for
dysthymia with those with major depressive disorder
and those who were nondepressed.30 This study
revealed that men with dysthymia had statistically
significant lower median testosterone levels than did
those with depression and those in the nondepressed
group; the latter 2 groups had equivalent median
testosterone levels.30 There has been at least 1 other
study that revealed similar findings.22
Although the overarching relationship between
low testosterone levels and major depression has yet to
be proven, the literature points toward a connection
within the aforementioned subtypes—men with
treatment-resistant depression, men with major
depression and HIV infection, men with dysthymia,
and elderly men (aged 460 years) with depression.
Despite this and because of multiple problems (such as
variable age ranges of participants, small sample sizes,
different androgen assays, measuring total vs free-
testosterone levels), further research is warranted.
IS TESTOSTERONE REPLACEMENT
BENEFICIAL TO THOSE WITH DEPRESSIVE
SYNDROMES?
Studies evaluating testosterone replacement and its
effect on abnormal mood have been numerous and
www.psychosomaticsjournal.org 511
The Effect of Testosterone Levels on Mood in Men
variable, but Zarrouf et al.14 performed a meta-analysis
in 2009 with the goal of assessing the specific effect of
testosterone replacement on major depressive disorder.
They looked at only randomized, double-blind,
placebo-controlled trials of patients diagnosed with
DSM-IV-defined major depressive disorder and moni-
tored them by changes in the Hamilton-D depression
rating scale. Seven trials met the criteria,14 composed of
355 patients with an age range of 18 to 70 years.14 Their
meta-analysis revealed a significant positive effect of
testosterone replacement on Hamilton-D depression
rating scale scores in depressed patients with hypogo-
nadism (with total testosterone levels less than 350
ng/dL), in depressed patients with HIV/AIDS, and in
depressed patients who used the gel, not the IM form of
testosterone.14 In the latter studies of IM testosterone,
though, supraphysiologic doses were used and there-
fore the difference between effects on Hamilton-D
depression rating scale scores between transdermal
and IM forms may be related to dose, not differences
in mode of administration. Two of these groups—men
with overt hypogonadism and men with both depres-
sion and HIV/AIDS—have more depressive symptoms
that correlate with lower levels of testosterone, and thus
may be more expected to respond to exogenous
testosterone administration. Despite these correlations,
this meta-analysis left out more than 1000 studies with
varying results, indicating that further study is war-
ranted. Studies assessing testosterone as an augmenta-
tion strategy for antidepressant treatment have also
been equivocal in their results.31 There are no further
analyses of differences between route of administration
or those using different types (such as free vs total) of
testosterone measurement.
WHAT IS AN APPROACH TO THE DIAGNOSIS
OF TESTOSTERONE DEFICIENCY IN MEN?
Psychiatrists evaluating any of the aforementioned
groups of male patients should consider checking
testosterone level. In addition, more specific physical
signs of low testosterone levels include delayed sexual
development, decreased libido, decreased spontane-
ous erections, gynecomastia, decreased pubic hair,
decreased need to shave, very small or shrinking testes,
low sperm count, height loss, nontraumatic fractures,
and hot flushes or sweats.9 Less specific signs include
mild anemia, reduced muscle bulk and strength,
increased body fat or body mass index, and diminished
512 www.psychosomaticsjournal.org
physical or work performance.9 If these physical signs
are present or if the patient falls into one of the groups
mentioned earlier (depressed men with HIV/AIDS,
men with dysthymia, or elderly men [age 4 60 years]
with depression), then it would be prudent to check a
morning serum total testosterone level (at 8 AM), after
obtaining a complete history and conducting a phys-
ical examination. One should also check routine
laboratory studies (such as complete metabolic panel,
complete blood count, thyroid-stimulating hormone,
hemoglobin A1c, fasting glucose, and a urine drug
screen) to rule out concomitant medical illness that
would also be on the differential. Other diagnoses that
may require treatment include hypothyroidism, ane-
mia, metabolic abnormalities, cancer, obstructive
sleep apnea, and substance abuse.
If the total testosterone level is normal (i.e.,
4350 ng/dL), then close monitoring is appropriate.
If total morning testosterone level is low (i.e., o350
ng/dL, or that is defined as “low” in one's laboratory),
then one should recheck the morning total testosterone
level, check LH and follicle-stimulating hormone
levels, and also consider checking free-testosterone
levels, if available in the hospital’s laboratory.9 If the
total testosterone level is assessed as normal on repeat
testing, then close follow-up is again appropriate.9 If
total or free-testosterone levels are low, if the LH and
follicle-stimulating hormone levels are elevated, and
the patient has consistent signs and symptoms of
hypogonadism, then it is appropriate to replete testos-
terone and obtain a karyotype for Klinefelter syn-
drome.9 Follicle-stimulating hormone and LH levels
are expected to be elevated with most forms of
hypogonadism.9 If the LH and follicle-stimulating
hormone levels are low, there may be a pituitary
abnormality; then, a prolactin level should be checked
and one should consider undergoing a brain magnetic
resonance imaging scan.9
The Endocrine Society recommends testosterone
therapy for symptomatic men with testosterone defi-
ciency, to induce and to maintain secondary sexual
characteristics and to improve sexual function, sense
of well-being, muscle mass, strength, and bone mineral
density. Exogenous testosterone administration typi-
cally produces few side effects, even at supraphysio-
logic doses, but side effects can include gynecomastia,
truncal acne, hair loss or growth, worsening of
obstructive sleep apnea, increased hematocrit, reduced
sperm production and testicular size, and problems
Psychosomatics 54:6, November/December 2013

related to mode of administration (such as skin
reactions with transdermal patches, skin irritation
from transdermal gel, pain at injection sites and
coughing episodes after IM injections).31 There is also
concern that testosterone administration can lead to
progression of prostate cancer or benign prostatic
hypertrophy and may be associated with adverse
cardiovascular events, although there is no direct
evidence for either of these concerns.31 Because of
these concerns, testosterone replacement is not rec-
ommended for patients with breast or prostate
cancer, with a palpable prostate nodule or induration,
or with a prostate-specific antigen level greater than
3 ng/mL, erythrocytosis, hyperviscosity, obstructive
sleep apnea, severe lower urinary tract symptoms, or
class III or IV heart failure.9 Treatment, like in most
of medicine, must weigh the benefits against the
potential risks and cases of borderline testosterone
levels may best be treated in consultation with an
endocrinologist.
CONCLUSIONS
Despite the pronouncements of the drug industry and
the common knowledge that testosterone levels affect
mood, our review indicates that the connection
between testosterone levels and mood disorders is
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Psychosomatics 54:6, November/December 2013
 Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 63–71

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

Are oestrogens useful for the treatment of depression

in women?
John Studd, DSc, MD, FRCOG, Professor of Gynaecology a, *,
Nick Panay, BSc, MRCOG, MFFP, Consultant Obstetrician &
Gynaecologist, Specialist in Reproductive Medicine & Surgery b
a
Chelsea & Westminster Hospital, London, UK
b
Queen Charlotte’s & Chelsea Hospital, London, UK

Keywords: The relationship between mood changes and the menstrual cycle
depression has been recognized for many years. Initial treatments involved
menopause removal of the ovaries to prevent fluctuation of oestradiol, but this
HRT was also associated with the long-term effects of hypo-oestro-
hormone-related depression genism such as osteoporosis or heart disease. More recently, the
use of high-dose oestrogen has been explored with some success.
A diagnosis of hormone-related depression is made on the history,
where the problem is worse at a time of hormone fluctuation such
as occurs in the premenstrual phase, in the postnatal period and in
the years leading up to the menopause. Many women may only
feel well for a minority of days in the month and the problem can
become chronic. Antidepressant medication is not usually
successful, although this is often the preferred treatment for
general practitioners and psychiatrists, possibly because of the
potential side-effects of high-dose oestrogen administration. This
chapter covers the diagnosis and treatment of premenstrual
depression, postnatal depression and depression occurring in the
climacteric period to emphasize the chronic nature of the problem
and the best ways of diagnosing and relieving this distressing
condition.
Ó 2008 Published by Elsevier Ltd.

* Corresponding author.
E-mail address: harley@studd.co.uk (J. Studd).

1521-6934/$ – see front matter Ó 2008 Published by Elsevier Ltd.

doi:10.1016/j.bpobgyn.2008.11.001
64 J. Studd, N. Panay / Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 63–71

On 26 December 1851, Charles Dickens attended the patients’ Christmas dance at St Luke’s Hospital
for the Insane. On describing his visit in an article for ‘Household Words’, he commented that the
experience of the asylum proved that insanity was more prevalent amongst women than men. Of the
18,759 inmates over the century, 11,162 had been women. He added: ‘it is well known that female
servants are more frequently affected by lunacy than any other class of persons.’ This passage is one of
the very few references in Victorian literature that alludes to a relationship between gender and
depression. To the authors’ knowledge, there are no references relating reproductive function to
depression, although Jane Eyre’s red room and Berthe Mason’s monthly madness may be coded
examples of this from Charlotte Bronte’s pen.
Reference to hospital admissions, population studies, suicide attempts or the prescription of
antidepressants confirms that depression is more common among women than men.1 The challenge
remains to determine whether this increase in depression is environmental, reflecting women’s
perceived role in contemporary society, or due to hormonal changes.
It is clear that this excess of depression in women starts at puberty and is no longer present in
the sixth and seventh decades of life. The peaks of depression occur at times of hormonal fluctuation
in the premenstrual phase, the postnatal phase and the climacteric perimenopausal phase, particularly
in the 1–2 years before periods cease. This triad of hormone-responsive mood disorders often occurs in
the same vulnerable woman. These patients can often be treated effectively by oestrogens. Trans-
dermal oestrogen patches of 200 mg have been used in published placebo controlled studies, but
a 100-mg dose is often effective.
Depressed perimenopausal women in the fifth decade of life who are still menstruating may also
give a history of worsening premenstrual depression, as well as physical manifestations of hormonal
fluctuations such as menstrual migraine. These women will usually have enjoyed a very good mood
during the latter half of pregnancy when hormonal levels were stable, but then followed by postnatal
depression for several months. When the periods return, the depression classically becomes cyclical,
and with the approach of the menopause, the depression can become constant.
Reproductive events also affect the course of bipolar disorder in women; 67% of such women have
a history of postnatal depression. Of these, all will have had episodes of depression after subsequent
pregnancies. In addition, women who do not use hormone replacement therapy (HRT) are significantly
more likely than women who were using HRT to report worsening of depressive symptoms during the
perimenopause.
Psychiatrists rarely prescribe hormones, preferring antidepressants. Their diagnosis is often
a chronic relapsing depressive illness resulting from a ‘premorbid history of depression’, in spite of the
depression being postnatal or premenstrual in timing. This key information often needs to be identified
by direct, detailed enquiry to avoid suboptimal therapy.
The clue to the use of oestrogens came with the important and somewhat eccentric paper by Klaiber
et al2 who performed a placebo controlled study of very-high-dose oestrogens in patients with chronic
relapsing depression. The women had various diagnoses and were both premenopausal and post-
menopausal. They were given conjugated equine oestrogen (CEO) 5 mg daily with an increase in dose
of 5 mg each week until a maximum of 30 mg/day was reached. There was a huge improvement in
depression on these high doses, but this work has not been repeated because of anxiety over high-dose
oestrogens.

Biological plausibility

It is generally accepted that endogenous oestrogenic steroids have a pivotal influence on the
development of the female central nervous system (CNS) through genomic organizational effects in
fetal life. Recent work has shown that both a and ß oestrogen receptors are located in the hypothal-
amus and other parts of the CNS.3 It is therefore not surprising that exogenous oestrogens may have
benefits in controlling mood, cognition and neuronal health.
It has long been recognized that non-genomic effects can also be produced by activation of the
CNS neuroreceptors to alter the concentration of neurotransmitter amines such as serotonin and
noradrenaline.4
 J. Studd, N. Panay / Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 63–71 65

Oestrogen can increase the level of serotonin in a number of ways: it can enhance the degradation of
monoamine oxidase (which catabolizes serotonin); it displaces tryptophan from its albumin-binding
sites, making more available for serotonin synthesis; and it also enhances the transport of serotonin.5
This explains how oestrogen can improve mood, when used in ovarian cycle stabilizing doses, as
depression is largely due to falling levels of serotonin.

Premenstrual syndrome

This condition was mentioned in the 4th Century BC by Hippocrates but became a medical epidemic
in the 19th Century. Victorian physicians were aware of menstrual madness, hysteria, chlorosis and
ovarian mania, as well as the more commonplace neurasthenia. In the 1870s, Maudsley6, the most
distinguished psychiatrist of the time, wrote ‘.The monthly activity of the ovaries which marks the
advent of puberty in women has a notable effect upon the mind and body; wherefore it may become an
important cause of mental and physical derangement.’ This and other female maladies were
recognized, rightly or wrongly, to be due to the ovaries. As a consequence, bilateral oophorectomy
(Battey’s operation7) became fashionable, being performed in approximately 150 000 women in North
America and Northern Europe between 1870 and 1900. Longo8, in his brilliant historical essay on the
decline of Battey’s operation, posed the question of whether or not it worked. Of course, they had no
knowledge of osteoporosis and the devastation of long-term oestrogen deficiency, but it did appear to
cure the ‘menstrual/ovarian madness’ [the Victorian way of labelling severe premenstrual syndrome
(PMS)]. The essential logic of this operation was to remove cyclical ovarian function, but happily this
can now be achieved effectively by simpler means.
Only in 1931 was the phrase ‘premenstrual tension’ introduced by Frank9, who described 15 women
with the typical symptoms of PMS as known today. Greene and Dalton extended the definition to ‘PMS’
in 195310, recognizing the wider range of symptoms.
Severe PMS is a poorly understood collection of cyclical symptoms which cause considerable
psychological and physical distress. The psychological symptoms of depression, loss of energy, irrita-
bility, loss of libido and abnormal behaviour, as well as the physical symptoms of headaches, breast
discomfort and abdominal bloating may occur for up to 14 days each month. There may also be
associated menstrual problems, pelvic pain and menstrual headaches, and the woman may only enjoy
as few as 7 good days per month. These symptoms can have a significant impact on the day-to-day
functioning of women. It is estimated that up to 95% of women have some form of PMS, and
approximately 5% of women of reproductive age will be severely affected, with disruption of their daily
activities. Considering these figures, it is disturbing that many of the women who finally reach
specialist PMS clinics have been told repeatedly that there are no treatments available and that they
should simply ‘live with it’. In addition, many commonly used treatments of PMS, particularly
progesterone or progestogens, have been shown by placebo controlled trials not to be ineffective and
may even make the symptoms worse for some women.
The exact cause of PMS is uncertain, but it is likely to be related to hormonal fluctuations during the
menstrual cycle and the resulting complex interaction between ovarian steroid hormones (e.g.
progesterone or allopregnenalone) and CNS neurotransmitters (e.g. GABA and serotonin). These
cyclical neuroendocrine changes produce the varied premenstrual symptoms in women who are
sensitive to the changes in their normal reproductive hormone levels.

Oestrogens

PMS does not occur if there is no ovarian function11 and it does not occur before puberty, after the
menopause or after oophorectomy. It also does not occur during pregnancy. It is therefore not
surprising that hysterectomy with conservation of the ovaries does not always cure PMS12, as patients
are left with the usual cyclical symptoms and cyclical headaches in spite of the absence of menstru-
ation. This condition, best-called ‘the ovarian cycle syndrome’13, may not be recognized as hormonal in
aetiology since there is no reference point of menstruation. The failure to make this diagnosis is
regrettable because these monthly symptoms of depression, irritability, mood change, bloating and
66 J. Studd, N. Panay / Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 63–71

headaches which may affect women for most days in the month can easily be treated by suppression of
ovarian function with oestrogen, often given by the transdermal route.
A ‘medical Battey’s operation’ can be achieved using gonadotrophin-releasing hormone (GnRH)
analogues. Leather et al14 demonstrated that 3 months of goserelin therapy cures all of the symptom
groups of PMS. The long-term risk of goserelin therapy is bone demineralization, but the same group
showed that addback therapy with a product containing 2 mg oestradiol valerate and cyclical
levonorgestrel maintains bone density at both the spine and the hip as well as alleviating vasomotor
side-effects.15 Although symptom improvement is sustained with addback therapy, bloating, tension
and irritability can recur due to the cyclical progestogen. The tissue-selective agent tibolone and
low-dose continuous combined HRT are therefore better addback preparations as these do not
regenerate the hormonal fluctuations of the ovarian cycle.16
In a Scandinavian study, Sundstrom et al used low-dose GnRH analogues (buserelin 100 mg) with
good results on the symptoms of PMS, but the treatment still caused anovulation in as many as 56% of
patients.17 Danazol is another method to treat PMS by inhibiting pituitary gonadotrophins, but it has
side-effects including androgenic and virilizing effects. When used in the luteal phase alone18, danazol
relieved mastalgia but not the general symptoms of PMS although side-effects were minimal.
Greenblatt et al showed the effects of oestrogen implants that were initially investigated as contra-
ceptives.19 The first study of their use in PMS was by Magos et al20 using 100-mg oestradiol implants,
which have been shown to inhibit ovulation using ultrasound and Day 21 progesterone measurements.
Although 84% of subjects improved with placebo implants, each symptom cluster improved to a greater
extent in the active oestradiol group. In addition, the placebo effect waned after a few months
compared with a continued response to oestradiol. These patients were also given 12 days of oral
progestogen per month to prevent endometrial hyperplasia and irregular bleeding21, and it was clear
that the addition of progestogen attenuated the beneficial effect of oestrogen. Subsequently, a placebo
controlled trial of cyclical norethisterone in well-oestrogenized hysterectomized women reproduced
the typical symptoms of PMS.20 This study of cyclical oral progestogen in oestrogen-primed women
was described as the model for PMS. It is also significant that progestogen intolerance is a common
reason why older, postmenopausal women stop taking HRT22, particularly if they have a past history of
PMS or progesterone intolerance. Progestogens may cause PMS-like symptoms in these women in the
same way that endogenous cyclical progesterone secretion is the probable fundamental cause of PMS.
One hundred milligram implants of oestradiol are rarely used due to concerns regarding tachy-
phylaxis; pellets of oestradiol 50 mg or 75 mg with testosterone 100 mg are now inserted instead.
These women require endometrial protection using either oral progestogen or a levonorgestrel-
releasing intra-uterine system (LNG-IUS).23 As women with PMS respond well to oestrogens but are
often intolerant to progestogens, it is commonplace to reduce the orthodox 13-day course of proges-
togen to 10 or 7 days starting, for convenience, on the first day of every calendar month. Thus, the
menstrual cycle is reset.
The LNG-IUS also plays an important role in preventing PMS-like symptoms as it protects the
endometrium without significant systemic absorption. A recent study has shown a 50% decrease in
hysterectomies since the introduction of the LNG-IUS in 1995.21 With its profound effect on heavy
menstrual bleeding and the possibility of less progestogenic side-effects, the LNG-IUS could be a very
promising component of PMS treatment in the future.
Hormone implants are not licensed in all countries and are unsuitable for women who may wish to
discontinue treatment easily in order to become pregnant. Oestradiol patches are an alternative and
the authors’ original double-blind crossover study used a 200-mg oestradiol patch twice weekly.24 This
produced plasma oestradiol levels of 800 pmol/L and suppressed luteal-phase progesterone and
ovulation. Once again, this treatment was better than placebo in every symptom cluster of PMS. This is
now the authors’ treatment of choice in severe PMS.
Subsequently, a randomized but uncontrolled observational study from the authors’ PMS clinic
indicated that PMS sufferers could have the same beneficial response to 100-mg patches as they do with
the 200-mg dose. They also have fewer symptoms of breast discomfort and bloating, and there is less
anxiety from the patient or general practitioner about high-dose oestrogen therapy.25 Day 21
progesterone assays in patients receiving 100 mg showed low anovulatory levels, prompting the
intriguing question that even this moderate dose may suppress ovulation reliably and be contraceptive.
 J. Studd, N. Panay / Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 63–71 67

These patches would be particularly appropriate for those requiring contraception, but further studies
are needed.
Although the efficacy of oestradiol in the treatment of PMS has been demonstrated in placebo
controlled trials, its value has not been exploited by psychiatrists anywhere in the world. The benefit of
this therapy in severe PMS is probably due to the inhibition of ovulation, but there is also likely to be
a central mental tonic effect. This was shown by Klaiber et al2, in their study of high-dose CEO, and in
other psycho-endocrine studies of climacteric depression26 and postnatal depression27 that demon-
strated the benefit of high-dose transdermal oestrogens for these conditions.
Hysterectomy is an appropriate treatment for some women and also carries advantages in terms of
relief of menstrual problems.28 It is important that women who have a hysterectomy and bilateral
salpingo-oophorectomy have effective replacement therapy, and they may also require replacement of
the ovarian androgens. Implants of oestradiol 50 mg and testosterone 100 mg are an ideal route and
combination of hormones for this long-term therapy following hysterectomy, with a continuation rate
of 90% at 10 years.21 The authors have unpublished data of 47 such patients who have had a hyster-
ectomy, bilateral salpingo-oophorectomy and implants of oestradiol and testosterone for severe PMS
who have gone through many years of treatment with transdermal oestrogens and cycle progestogens.
The symptoms are now absent in all patients, and all but one are ‘very satisfied’ with the outcome.

Postnatal depression

Postnatal depression is another example of depression caused by fluctuations of sex hormones,

which has the potential to be treated effectively by hormones. It is a common condition that affects
10–15% of women following childbirth and may persist for over 1 year in 40% of those affected. There
does seem to be a lack of any overall influence of psychosocial background factors in determining
vulnerability to this postnatal disorder, although it can be recurrent.
Although common, the disease is often not reported to healthcare professionals, particularly general
practitioners or visiting midwives, as the exhaustion and depression are regarded as normal. Indeed,
the symptoms of postnatal depression may be confused with the normal sequelae of childbirth. The
symptoms can consist of depressed mood with lack of pleasure with the baby or any interest in the
surroundings. There may be sleep disturbance, either insomnia or hypersomnia. There may be loss of
weight, loss of energy and certainly loss of libido together with agitation, retardation and feelings of
worthlessness or guilt. Thoughts of death and suicide are common.
Postnatal depression is not more common after a long or difficult labour, caesarean section or
separation from the baby after birth, nor is it determined by education or socio-economic group. The
only environmental factor that seems to be important is the perceived amount of support given by the
partner. There is no doubt that the first 6 or more months after delivery can be an exhausting time, full
of anxiety and insecurity in mothers with the new responsibility of the baby. Even allowing for that,
there does seem to be a clear hormonal aspect to this condition.
Postnatal depression is severe and more prolonged in women who are lactating, and lower
oestradiol levels are found in depressed women following delivery compared with controls. It is
probable that the low oestradiol levels associated with breast feeding and the higher incidence of
depression are related in a causative way.
The authors studied the effect of high-dose transdermal oestrogens in this condition in an attempt
to close the circle of studies treating the triad of hormone-responsive mood disorders: premenstrual
depression, climacteric depression and postnatal depression. This was a double-blind placebo
controlled trial of 60 women with major depression which began within 3 months of childbirth and
persisted for up to 18 months postnatally.27 All of the women had been resistant to antidepressants,
and the diagnosis of postnatal depression was made by two psychiatrists who were experts in the field.
Breastfeeding women were excluded from the study. Participants were given either placebo patches or
transdermal 200- mg oestradiol patches daily for 3 months without any added progestogen. After 3
months, cyclical medroxyprogesterone acetate 10 mg daily was added for 12 days each month. The
women were assessed monthly by a self-rating of depressive symptoms on the Edinburgh Postnatal
Depression Score (EPDS) and by clinical psychiatric interview. Both groups were severely depressed
with a mean EPDS score of 21.8 before treatment. During the first month of therapy, the women who
68 J. Studd, N. Panay / Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 63–71

received oestrogen improved rapidly and to a greater extent than the controls. None of the other factors
(age; psychiatric, obstetric or gynaecological history; severity and duration of current episode of
depression; and concurrent antidepressant medication) influenced the response to treatment.
The study showed that the mean EPDS score was less for women in the active group at 1 month and
then maintained for 8 months, and that the percentage with EPDS scores >14 (diagnostic of postnatal
depression) was reduced by 50% at 1 month and 90% at 5 months. This was much better than the
placebo response.
Not only did this study show that transdermal oestrogens were effective for the treatment of
postnatal depression, but a subsequent study by Lawrie et al29 showed that depot progestogen was less
effective than placebo with deterioration in the severity of postnatal depression. This provides a further
example of the mood-elevating effect of oestrogens and the depressing effect of progestogen.
An uncontrolled study showed similar improvements using sublingual oestradiol in 23 women with
major postnatal depression.30 These women had plasma levels of 79.0 pmol/L before treatment,
342 pmol/L at 1 week and 480 pmol/L at 8 weeks following treatment. There was improvement in 12 of
the 23 patients at 1 week and 19 of the 23 patients after 2 weeks. The mean Montgomery Asberg
Depression Rating Scale (MADRS) was 40.7 before treatment, 11 at 1 week and 2 at 8 weeks after
treatment. At the end of the second week of treatment, the MADRS scores were compatible with
clinical recovery in 19 of the 23 patients. This study demonstrated a rapid response to oestradiol in this
group of profoundly hypo-oestrogenic women. Further placebo controlled studies are required,
together with information about bleeding patterns, to support or refute the authors’ original paper.27
Postnatal depression can be mimicked by hormonal manipulation as shown in the study of Bloch
et al.31 Sixteen women, eight with a history of postnatal depression, had hypogonadism induced with
leuprolide acetate. Pregnancy was simulated using addback supraphysiological doses of oestradiol and
progesterone for 8 weeks and then both steroids were withdrawn. Five of the eight women, 62.5% with
a history of postnatal depression and none of the women without a prior history, developed significant
mood symptoms during the withdrawal period.
This study supported the view that the reproductive hormones, oestradiol and progesterone, are
involved in the development of postnatal depression in a specific group of women. Furthermore, the
study showed that women with a history of postnatal depression are differentially sensitive to the
mood-destabilizing effects of gonadal steroids.

Climacteric depression

Like many aspects of depression in women, the diagnosis of climacteric depression and its treat-
ment remain controversial. This may be because there is no real evidence of an excess of depression
occurring after the menopause, nor any evidence that oestrogens help postmenopausal depression or
what used to be called ‘involutional melancholia’. This is quite true and indeed many women with
longstanding depression improve considerably when their periods stop. This is because the depression
created by PMS, heavy painful periods, menstrual headaches and the exhaustion that attend excess
blood loss disappears. Therefore, the longitudinal studies of depression carried out by many
psychologists, particularly those as notable as Hunter32, have shown no peak of depression in a large
population of menopausal women. Randomized studies have also shown no significant improvement
in depressed postmenopausal women.33
The depression that occurs in women around the time of the menopause is at its worst in the 2 or 3
years before periods stop. This, of course, is perimenopausal depression and is no doubt related to
premenstrual depression as it becomes worse with age and with falling oestrogen levels.
The earliest placebo controlled study which defined the precise menopausal syndrome showed that
oestrogens helped hot flushes, night sweats and vaginal dryness. They also had a mood-elevating
effect.34 This work was further supported by the work of Campbell and Whitehead35 who used
conjugated equine oestrogens, and by the study of Montgomery et al22 using higher-dose oestradiol
implants. This study of 90 peri- and postmenopausal women with depression showed considerable
improvement in the treatment group compared with placebo, but only in the perimenopausal women.
There was no improvement in depression in the postmenopausal women with this treatment
 J. Studd, N. Panay / Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 63–71 69

compared with placebo. This effect is not transient and the improvement in depression was maintained
at 23 months. The dropout rate among those in the placebo group was very high.
The therapeutic potential of oestrogens in the treatment of depressed perimenopausal women is
now being recognized by psychiatrists in the USA. Soares et al36 studied 50 such women: 26 with major
depressive disorder, 11 with dysthymic depression and 30 with minor depressive illness. They treated
them with 100-mg oestradiol patches in a 12-week placebo controlled study. There was a remission of
depression in 17 of 25 treatment patients (68%) and five of 25 placebo patients (20%). This improve-
ment occurred regardless of the DSM-IV diagnosis.
Rasgon et al37 studied 16 perimenopausal women with unipolar major depressive disorder for an
8-week period in an open protocol trial comparing CEO 0.3 mg with fluoxetine daily. There was
a greater response with oestrogen alone. All but two of the patients responded but the response was
greater in those receiving oestrogen therapy, and it was significant that the reduction in depression
scores began rapidly after the first week of treatment.
More recently, Harlow et al38 studied 976 perimenopausal women with and without a history of
major depression. The patients with a history of depression had higher levels of follicle-stimulating
hormone and lower levels of oestradiol at enrolment to the study, and those women with a history of
antidepressant medication had three times the rate of early menopause. A similar excess rate was
found in perimenopausal women with a history of severe depression.
It is reassuring for ‘menopausologists’ to read the recent views of some psychiatrists that ‘periods of
intense hormonal fluctuations have been associated with the heightened prevalence and exacerbation
of underlying psychiatric illness, particularly the occurrence of premenstrual dysphoria, puerperal
depression and depressive treatment during the perimenopause’. ‘It is speculated that sex steroids
such as oestrogens, progestogens, (sic), testosterone and DHEA exert a significant modulation of brain
functioning. There are preliminary, although promising, data on the use of oestradiol (particularly
transdermal oestradiol to alleviate depression during the menopause.’38 Neuropsychiatrists have also
conceded that ‘there is a clear need to examine the necessary duration of HRT for neuroprotection to
decrease a woman’s risk for depression, cognitive dysfunction and development of Alzheimer’s
disease’.39

Progestogen intolerance

Women having oestrogen therapy must have cyclical progestogen if they still have a uterus in order
to prevent irregular bleeding and endometrial hyperplasia. The problem is that women with hormone-
responsive depression enjoy a mood-elevating effect with oestrogens that can be attenuated by the
progestogen40, which can produce depression, tiredness, loss of libido, irritability and breast
discomfort (i.e. all of the symptoms of PMS), particularly in women with a history or previous history of
PMS. This has been demonstrated clearly in a randomized trial of norethisterone vs placebo in
oestrogenized hysterectomized women.20
If women become depressed with 10–12 days of progestogen, some gynaecologists may
consider halving the dose, decreasing the duration or changing the progestogen used, although
little is known regarding their adequacy in protecting the endometrium.23 It is the policy in the
authors’ unit to shorten the duration of progestogen in women with hormone-responsive
depression when there are adverse side-effects with the gestogen. Therefore, the authors would
use transdermal oestrogens, either 100-mg or 200-mg oestradiol patches or 50-mg oestradiol
implants, and then reset menstrual bleeding by prescribing norethisterone 5 mg for the first 7 days
of each calendar month. Although this duration of progestogen administration is unlicensed for
endometrial protection, it will produce a regular bleed on approximately Day 10 or 11 of each
calendar month.
Should heavy withdrawal bleeds occur, the duration of progestogen can be extended to the more
orthodox 12 days, or an LNG-IUS can be inserted to avoid the need for oral progestagen. An alternative
to the LNG-IUS is vaginal progesterone pessaries or gel to minimize systemic progestogenic side-
effects. It is not unusual for women at this stage, who are aware of the benefits of oestrogens and the
problems of their menstrual cycles, to request hysterectomy and bilateral salpingo-oophorectomy with
the use of unopposed oestradiol and often testosterone.41
70 J. Studd, N. Panay / Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 63–71

Conclusions

Oestrogen therapy has been shown to be effective for the treatment of postnatal depression,
premenstrual depression and perimenopausal depression; the triad of hormone-responsive mood
disorders. Transdermal oestradiol 100 mg or 200 mg produces plasma levels of 300 pmol/L and
600 pmol/L, respectively, and represent the optimum therapy. These patients often require plasma
levels of more than 600 pmol/L for efficacy as there does appear to be a dose–response effect. In non-
hysterectomized women, cyclical progestogen should be added for endometrial protection. The most
effective long-term medical therapy is oestradiol patches or oestradiol implants with the LNG-IUS,
which minimizes systemic PMS-like side-effects thus maximizing efficacy. Consideration should also
be given to the addition of testosterone since it may improve wellbeing, depression, libido and energy,
particularly where patients have only partially responded to oestrogen therapy alone. Ultimately,
a hysterectomy plus bilateral salpingo-oophorectomy and implants with oestradiol and testosterone
may be requested.
The effect of oestrogen on the CNS, particularly mood and depression, remains a controversial area.
However, there are now convincing data for the psychotherapeutic benefits of oestrogens in the triad of
hormone-responsive depressive disorders. It is reassuring that an increasing number of psychiatrists
now accept that there is a place for gynaecological intervention in the management of these depressive
disorders, although they remain strangely reluctant to commence hormone therapy, no doubt because
they are unfamiliar with the side-effects of mastalgia, vaginal bleeding or PMS symptoms.42 Research
should continue in this area to ensure that, in the future, clinicians consider using oestrogen, not just
antidepressants, when women present with a hormone-responsive psychiatric illness. Women with
depression may also be at greater risk of coronary artery disease, hypertension, stroke and osteoporosis
as well as non-suicidal death.43 Panic attacks in menopausal women may also increase risk, as
demonstrated in the Women’s Health Initiative study.44

Practice points

 oestrogen is more likely to be successful in treating hormone-related depression than anti-

depressant medications. A high circulating concentration is often required to achieve relief
 the diagnosis is made on the history of longstanding problems with depression related to
fluctuating hormone levels such as premenstrually, postnatally or in the years prior to the
menopause

Research agenda

 the impact of hormone-related depression on long-term health should be determined with

longitudinal cohort studies
 the mechanism of the effect of oestradiol needs further evaluation, along with whether
inhibition of hormone fluctuation is more significant than the actual level itself

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European Journal of Endocrinology (1998) 138 1–9

REVIEW

The role of thyroid hormones in depression

Carsten Kirkegaard and Jens Faber
Department of Internal Medicine F, Hillerød Sygehus, and Department of Endocrinology E, Frederiksberg Hospital, Denmark
(Correspondence should be addressed to C Kirkegaard, Department of Internal Medicine F, Hillerød Sygehus, DK-3400 Hillerød, Denmark)

Introduction groups of depressed patients (reviewed in 1, 2),

During the last 30 years a huge number of scientific
articles have appeared on the subject of relationships
between psychiatric disease and thyroid hormones.
These studies have demonstrated the presence of
numerous changes in the hypothalamo–pituitary–
thyroid (HPT) axis, mainly in patients with depression,
but also in patients with other psychiatric diseases.
Simultaneously, many studies have been published on
the possible therapeutic effects in depression of the
hormones involved in the HPT axis.
Despite great efforts to standardize the classification
of depression, this is still a less well-defined disease,
possibly including several subtypes with different
pathogenesis and biochemical abnormalities. Further-
more the classification has changed over time, making it
difficult to interpret previously published data. The most
accepted classifications are the DSM-IV and ICD-10.
These cover a spectrum from minor depression (neuro-
tic depression) through major depression to melancholic
(endogenous and psychotic) depression. Furthermore
major and melancholic depressions are divided into uni-
and bipolar depressions, the latter also demonstrating
episodes of mania. Rapid cycling bipolar psychosis is a
subgroup of the bipolar depression, demonstrating four
or more episodes in any year of observation.
The present review focuses on the concentrations of
hormones of the HPT-axis seen in uni- and bipolar
depression, their relation to relapse after antidepres-
sive treatment, and a survey of therapeutic trials with
thyrotropin-releasing hormone (TRH), thyroid-stimu-
lating hormone (TSH) and thyroid hormones, as well as
the effect of the various drugs used in depression on the
HPT-axis. The hypothesis is put forward that the
changes seen in the HPT-axis during depression might
be explained by cerebral serotonin deficiency, and that
tri-iodothyronine (T3) treatment, to some degree, can
revert this deficiency.
Iodothyronines in depression
An overall picture of thyroid-related disturbances seen
in depression is given in Table 1.
Thyroxine (T4)
Serum T4 levels, both total and non-protein-bound
(free), are consistently found as normal to increased in
approximately 25% of the patients having levels above
the reference range. The different findings might be
explained by the different severity of depression among
the patients studied, since some studies have found a
correlation between the severity of depression and
serum T4 levels (2). An additional explanation might
be that the depressed patient is often in a state of semi-
starvation, and thus may present changes in the HPT-
axis similar to those seen in patients with nonthyroidal
somatic illness, elevated serum T4 and 3,30 ,50 -tri-
iodothyronine (rT3), and reduced serum T3.
Turnover studies using radiolabeled T4 in a small
group of depressed patients have demonstrated that also
the daily production rate (PR) of T4 is significantly
increased, by 30% (3). This finding contrasts with the
unaltered T4 PR found in groups of patients with
different nonthyroidal illnesses (4). These studies used a
noncompartmental kinetic approach for the evaluation
of PRs. This method correctly estimates the PR of T4.
Increased PR of T4 in depressed patients thus suggests
that the thyroid gland is stimulated abnormally in the
depressed patient.
The concentration of free T4 in cerebrospinal fluid
(CSF) seems relatively increased during depression,
since recovery is followed by a reduction (5). The ratio
between CSF and serum free T4 levels has been found to
be 0·6, both before and after recovery of depression due
to electro-convulsive treatment (ECT) (5). This suggests
that CSF T4 concentrations follow systemic levels, and
that transport of T4 into CSF is restricted. An alternative
explanation is that T4 is taken up directly into brain
tissues, and partly undergoes deiodination, thus yield-
ing less T4 into the CSF.
T3
Serum T3 levels in depressed patients are often found
normal, but several studies have found reduced levels,
typically in more severely depressed patients (1, 2).
Serum T3 levels are influenced by numerous factors
which all may be present in the depressed patient:
starvation, concomitant somatic illness and medication,
and changes (increase) in cortisol levels. When present
these factors all tend to decrease serum T3 levels (4, 6).
This makes interpretation of serum T3 concentrations
difficult. Serum free T3 levels have been found both

q 1998 Society of the European Journal of Endocrinology

2 C Kirkegaard and J Faber
Table 1 Changes in total and free serum concentrations, CSF concentrations, and production rates of various hormones in patients with
depression. Relevant references are given in parentheses.
Total serum
T4 Increased (1, 2)
T3 Unaltered (1, 2)
Decreased (1, 2)
rT3 Increased (2, 11)
Unaltered (5, 9)
TSH Decreased, but elevated in
comparison to T4 production
(1, 3, 13–17). In TCA-
resistance and RCBP, increased
TSH possible (27–30)
Dmax TSH Decreased (1, 2, 13)
Increased (27–30)
TRH — —
Somatostatin — —
TCA ¼ tricyclic antidepressants; RCBP ¼ rapid cycling of bipolar psychosis.
normal and reduced (2). However, methods for the
measurement of free T3 in serum often give spurious,
mainly reduced levels, in diseased patients (7). Ultra-
filtration seems the method of choice (7, 8), and using
this technique we have found unaltered free T3 levels in
depression (9). The daily PR of T3 in unmedicated,
moderately depressed patients has been studied using
tracer turnover techniques, and T3 PR was found
normal (3). This was quite different from patients with
various nonthyroidal illnesses, in whom a 40% reduc-
tion in T3 PR has been demonstrated (4). The com-
bination of an increased T4 PR and an unaltered T3 PR
in depression suggests a reduced deiodination of T4 into
T3, as also seen in nonthyroidal illness, but with more
substrate (T4) availability than in somatic nonthyroidal
illnesses. However, correct interpretation of noncom-
partmental tracer studies is based on the assumption
that the tracer injected is distributed freely into all tissue
compartments (4). If anything, some degree of under-
estimation of T3 PR might take place when performing
T3 kinetics in humans (4), but conflicting results are
available on this issue (10).
The reduced conversion of T4 into T3 seen during
depression (3) might be due to reduced deiodination
enzyme activity. However, in which compartment of the
human body this takes place is at present unknown.
This could in theory be the brain, but unfortunately we
are not aware of any data on intracerebral T3 content or
CSF levels of T3 in depression.
rT3
Changes in serum total as well as free rT3 levels in
depression seem to follow those seen for serum total and
free T4, respectively (2, 5, 11).
CSF levels of rT3 have been studied in different types
of depression, and have been found highest in the
endogenous type (12). Similar to changes in serum, CSF
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 138
Free serum CSF Production rate
Increased (1, 2) Increased (5) Increased (3)
Unaltered (2, 9) — Unaltered (3)
Decreased (2)
Unaltered (2) Increased (5, 12) —
Increased (5, 11)
— — —
— — —
Increased (20, 21) —
Unaltered (22)
Decreased (24–26) —
free rT3 concentrations seem to follow CSF free T4 levels
(5), but the ratio of CSF to serum free rT3 has been
found to be approximately 26, which is quite different
from that of T4 (0.6) (5). This ratio for rT3 did not
change after recovery from the depression, and this
suggests that intracerebral concentration of rT3 is
high in humans, and that rT3 in brain is mainly
derived from local production from T4. This enzym-
atic production seems not changed in depression, and
this argues against rT3 as a pathogenic factor in
depression.
TSH in depression
Previously, changes in circulating levels of TSH in
depressed patients were evaluated using the TSH
response to intravenous TRH, due to lack of sufficiently
sensitive TSH assays. The response in TSH has usually
been evaluated as the peak value minus basal TSH
(DTSH). Normal DTSH to 200 mg TRH i.v. is typically 2–
16 mU/l. Patients with depression, as a group, have
reduced DTSH, and approximately 25% have DTSH
below 2 mU/l in endogenous (melancholic) depression
(1). Using newer, and more sensitive TSH methods,
basal TSH values correlate closely to peak TSH as well as
DTSH (13–15). According to this, depressed patients
seem to have some degree of reduced basal serum TSH,
but within the normal range (13, 15). Basal as well as
DTSH using a sensitive TSH assay have been studied in
various types of depression, and those patients with
endogenous depression had the lowest levels of both
basal TSH and DTSH (13), DTSH being a mean of
3.6 mU/l.
The diurnal variation of serum TSH is, in healthy
man, associated with a surge in TSH around midnight.
In untreated depression this diurnal variation seems
attenuated (16). After complete recovery from depression
the diurnal TSH variation seemed to be re-established, but
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 138
no or incomplete recovery still harbored an attenuated
diurnal variation (17).
In one study the interrelation between serum TSH
concentrations and the daily production of T4 and T3 in
endogenous depression was evaluated (3). Six depressed
patients were compared with seven subjects with L-T4-
treated hypothyroidism. These two groups had quite
similar T4 and T3 PRs, both having an equal T4 PR/T3
PR ratio. Serum TSH level using a sensitive assay was a
median 0.11 mU/l among L-T4-treated hypothyroid
subjects, but 0.90 mU/l in depressed patients, signifi-
cantly higher than in the L-T4-treated hypothyroid
group (3). This suggests an inappropriate secretion of
TSH (in relation to the elevated thyroidal production of
T4) in patients with endogenous depression, compatible
with some degree of central over-stimulation of the
thyroid in the untreated depressed state.
The apparent paradox that serum TSH levels are
found slightly decreased among depressed patients, and
our statement of inappropriately elevated serum TSH
levels in comparison to daily production of T4 and T3
(3), can be compared with the situation of chronic TRH
stimulation (by oral administration) in man. In this
experimental setting, TRH induced an initial increase in
serum TSH, whereas later, at the time when serum T4
and T3 began to increase, serum TSH levels were nor-
malized and were unable to respond to repeated TRH
stimulation (18, 19). Thus chronic stimulation with
TRH in man can provoke a pattern in serum levels of
TSH, T4 and T3 similar to those seen in the depressed
patient.
Chronic stimulation of the thyrothrophs in the
pituitary during depression might be caused by TRH,
since TRH levels have been found elevated in CSF in two
studies (in total 31 patients) (20, 21), although normal
levels were found in a third study including 17 patients
(22). Serum TSH levels are also influenced by soma-
tostatin, which inhibits the TSH release from the
pituitary (23). Three studies have found that the CSF
concentration of somatostatin is reduced during depres-
sion (24–26). This might contribute to an increase in
serum TSH levels.
Two subgroups of the depression syndrome seem to
present with a different pattern in the HPT-axis. One
group consists of patients with bipolar depression
(27, 28), and another group of patients is characterized
by a depression resistant to treatment with tricyclic
antidepressants (TCA) (29, 30). Both groups have a
tendency towards slightly elevated basal serum TSH
levels (approximately 20% have levels above the upper
normal reference range), or exaggerated TSH response
to TRH stimulation. These changes seem independent of
previous or ongoing lithium treatment, and probably
reflect some degree of thyroid insufficiency. Immuno-
logical mechanisms seem to play a role, since patients
with bipolar depression have increased frequency of sera
positive for antithyroid peroxidase (anti-TPO) antibodies
(28). Whether this is an epiphenomenon to bipolar
Thyroid hormones in depression 3
depression, or might be considered as one of several
pathogenic factors, is at present unknown. Interestingly,
postpartum changes in mood seem to be associated
with the presence of anti-TPO antibodies and thyroid
dysfunction (31). Thyroid hormone substitution might
therefore be of potential benefit in alleviating depressive
symptoms in the puerperal period. A preliminary study,
in which L-T4 was administered immediately after
delivery, in fact resulted in reduced depression score
among the L-T4-treated women compared with placebo
treatment (32).
Predictive value of changes of DTSH
Another interesting aspect of the TSH response to TRH
is the possible predictive value of the changes before and
after antidepressive treatment. It is a typical clinical
finding that depressed patients, after recovery following
ECT, demonstrate a high frequency of early relapse,
typically within 6 months, if not treated prophylacti-
cally with antidepressive medication. We have repeat-
edly demonstrated that those patients with early relapse
of endogenous depression have not normalized their
reduced TSH response to TRH, despite clinical recovery.
This has been demonstrated after treatment with ECT as
well as sleep deprivation (i.e. nonpharmacological treat-
ment modalities) (1, 33, 34). More than 80% of those
patients with early relapse did not change their maxi-
mal TSH response to TRH (Dmax TSH). An unchanged
Dmax TSH was defined as post-treatment Dmax TSH
minus pre-treatment Dmax TSH (DDmax TSH) less than
2 mU/l. By contrast more than 80% of those patients
who remained clinically cured for more than 6 months
had a DDmax TSH exceeding 2 mU/l (1). Serum T4 as
well as free T4 levels remained elevated in those patients
with early relapse and continued reduced Dmax TSH
(9). Thus a continued disturbance of the HPT-axis
despite clinical improvement of endogenous depression
suggests that the patient is not clinically cured. How-
ever, other studies in patients treated with antidepres-
sive medication, rather than nonpharmacological
treatment, have been unable to confirm these results (2).
In a small group of patients treated with amitriptyline
we confirmed this lack of predictive value of the TRH test
(33). Thus it is possible that the use of antidepressive
medication might interfere with the HPT-axis on
multiple sites, thus blurring the finding seen in the
unmedicated, clinically cured patient. Alternatively, in
the studies using TCA, the TRH tests have been
performed with intervals too long to maintain a stable
DTSH in patients not cured of depression.
Relationships between depression and
thyroid hormones – a hypothesis
The pathogenesis of endogenous depression is not
known, and is most probably multifactorial. The
4 C Kirkegaard and J Faber
Figure 1 Decreased brain serotonin levels (serotonin (¹)) activate (indicated by (þ)) the HPT-axis, and increased T3 (by endogenous as
well as exogenous sources) increases brain serotonin levels (feed-back) – a hypothesis. D-II and D-III refer to iodothyronine deiodinases
type II and III, respectively. 3,30 -T2: 3,30 -diiodothyronine.
currently favored hypothesis is that a lack of serotonin
in the brain has a central role (35). This hypothesis has
generated the development of effective antidepressive
drugs belonging to the group of serotonin re-uptake
inhibitors. TRH seems under a constant inhibition by
serotonin, and reduced intracerebral serotonin concen-
tration will lead to increased TRH concentrations in
brain tissue (reviewed in 23) (Fig. 1). As a consequence,
TSH secretion will be stimulated. In addition CSF levels
of somatostatin are reduced in depression. Since TSH
secretion is under a constant inhibition of somatostatin
(23), the consequence might be a further stimulated
TSH secretion. Increased TSH levels result in enhanced
thyroidal production of T4 and T3. Due to the thyroid–
pituitary feedback, increased T4 and T3 levels tend to
reduce serum TSH levels, reaching a new steady state
usually within the normal range. The new TSH levels
are, however, inappropriately elevated in relation to the
increased T4 production (3).
Acute as well as chronic T3 treatment has been
shown to increase the serotonin levels in the cerebral
cortex of rats (36). In man, plasma serotonin levels
correlate positively with T3 concentrations (37, 38),
and treatment of hyperthyroidism results in a reduction
in serum serotonin levels (37). Brain serotonin levels in
rats seem similarly affected, i.e. synthesis is reduced in
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 138
hypothyroidism (39) and increased in hyperthyroidism
(40, 41).
Thus the findings that reduced intracerebral seroto-
nin concentrations lead to increased TRH and thereby
to increased thyroid hormone levels, and that increased
T3 levels lead to an increase in brain serotonin, seem to
constitute a classical feedback mechanism relevant to
alleviation of depression.
Intracerebral T3 seems mainly a result of local
production by deiodination of T4. In general, at least
three deiodinating enzymes seem capable of affecting
the turnover of T4 and T3 (reviewed in 42). The type-I
deiodinase (D-I) results in both inner (5-) and outer (50 -)
ring deiodination, mainly of T4, which thereby provides
a circulating source of T3 to the peripheral tissues. The
type-II deiodinase (D-II) results in outer (50 -) ring
deiodination, mainly of T4. This enzyme functions to
regulate intracellular T3 levels in those tissues where T3
is most critical, such as brain and pituitary. In line with
this, the enzyme activity is increased in hypothyroidism
and reduced in hyperthyroidism. The type-III (D-III)
enzyme results in inner (5-) ring deiodination, of both
T4 into rT3, and T3 into 3,30 -T2, and, in contrast to the
D-II, but similar to D-I, its activity is increased in
hyperthyroidism and decreased in hypothyroidism.
Whereas all three enzymes are present in rat brain
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 138
(42), human brain tissues seem to contain only D-II and
D-III enzymes (43). The properties of the D-II and D-III
enzymes in rat and human tissues seem quite similar
(43). Thus D-II activity increases T3 production in brain
and pituitary, and consequently also the local produc-
tion of serotonin. In addition, D-III activity might be
expected to decrease the local concentration of T3 and
indirectly of serotonin in brain tissues.
Studies of the influence of several known antidepres-
sive drugs on rat D-II and D-III enzyme activities have
revealed a similar pattern: lithium (44), des-imipramine
(45), carbamazepine (46), and fluoxetine (47) have been
shown to enhance the activity of the D-II enzyme resulting
in increased local T3 concentrations in brain tissues. Also
sleep deprivation of rats, which is a known treatment
modality for depression, has been shown to increase the
D-II activity (48). In contrast, lithium, carbamazepine,
and fluoxetine have been shown to decrease the activity
of the D-III enzyme (44, 46, 47), also resulting in
increased local T3 concentration (for overview, see
Fig. 1). Although this is an attractive pattern, a contra-
dictory study has demonstrated that lithium decreases
the activity of D-II in mouse neural and pituitary tissues
(49). One must also be aware that the above mentioned
changes are not necessarily found in the same regions of
the brain, and furthermore it is not known whether
these regions have any relevance to depression.
The consequence of the effect of the antidepressive
drugs on the D-II and D-III enzyme activities is an
increased local T3 concentration in brain tissues and, as
discussed above, this might increase local serotonin
concentration, and thus might form an additional
biological basis for the positive effect of these drugs in
alleviating the depressive state.
Thus the hypothesis that a major pathogenic factor
for depression is serotonin deficiency is sufficient to
explain the changes seen in the HPT-axis. However,
another hypothesis, put forward many years ago, has
been that the depressed patient suffers a state of local
hypothyroidism in the brain. This hypothesis, originally
based on the similarities of symptoms seen in hypo-
thyroidism and depression, seems supported by the
finding that T3 treatment alleviated the depressive
symptoms (50). Reduced T3 content in brain tissues
leads to serotonin deficiency in brain tissues, and thus is
sufficient to explain the findings in the HPT-axis seen in
depression (Fig. 1).
Both hypotheses can explain that (i) patients with
thyroid insufficiency are especially sensitive to develop
depression (51, 52), (ii) T3 treatment is beneficial also in
euthyroid, depressed patients, (iii) pharmacological
stimulation of the D-II and inhibition of the D-III brain
enzyme could be expected to have a beneficial effect on
the depression, and (iv) T3 treatment might be at least
as effective as T4 treatment. Only the serotonin
deficiency hypothesis might explain the low normal
serum TSH and low Dmax TSH seen during depression,
and that patients with continued low Dmax TSH after
Thyroid hormones in depression 5
apparent recovery from depression are subject to early
relapse. This parameter can thus be regarded as a
marker of continued active disease.
Another fruitful hypothesis developed for the biologi-
cal explanation of depression suggested that depression
was due to a state of relative brain deficiency of cate-
cholamines, especially norepinephrine (53). This has
formed the basis of the development of another group of
useful antidepressive drugs, norepinephrine re-uptake
inhibitors. In 1981 Whybrow & Prange Jr (54)
hypothesized that thyroid hormones, by enhancing
beta-adrenergic receptor function, promote transmis-
sion in central noradrenergic pathways and accelerate
recovery. Later, the same group (55) demonstrated that
T3 levels in rat brain synaptosomes are much higher
than whole brain levels, and that T3 but not T4 can be
released from depolarized synaptosomes. Recently
Rozanov & Dratman (56) found increased T3 concen-
trations in nuclei and projection sites of rat central
noradrenergic systems. These studies suggest that T3
may play a neuromodulatory or neurotransmitter role
in the noradrenergic central nervous system. Norepine-
phrine stimulates the release of both TRH and TSH (23),
and therefore norepinephrine deficiency cannot explain
the changes in the HPT-axis seen in depression,
especially the increased CSF TRH levels. However the
hypothesis is fully compatible with the beneficial effect
of T3 treatment in depression.
Treatment of depression with hormones
of the HPT-axis
The similarities between symptoms seen in depression
and untreated hypothyroidism have lead to several
clinical trials in which thyroid hormones have been
given to depressed patients, either alone or in combina-
tion with other antidepressive treatment modalities.
Treatment without other treatment modalities
TRH In the 1970s a number of studies demonstrated a
mild but transient improvement in mood in depressed
patients treated with TRH for a few days or at most 3
weeks. Later other studies including controlled double-
blind designs, failed to demonstrate any beneficial effect
of TRH (reviewed in 57).
T3 T3 given as the only drug to depressed patients has
been evaluated in only two studies. Feldmesser-Reiss
(50) treated 24 patients with depression or melancholia
with 10–15 mg T3 daily, and observed considerable
improvement in 10 patients. Wilson et al. (58) gave
25 mg, increasing to 62.5 mg, of T3 daily for 9 days to
nine patients, which apparently was as effective on
depression as imipramine, as evaluated by the Hamilton
rating scale. Imipramine plus T3 had no additional
effect. Unfortunately this otherwise randomized,
double-blind study had no placebo group. Thus in
6 C Kirkegaard and J Faber
these two studies T3 given alone seems to have an
antidepressive effect, but placebo-controlled studies are
lacking.
TSH and T4 We are not aware of any studies using TSH
or T4 as the only treatment of depressed patients.
Treatment in combination with other
treatment modalities
Several studies have evaluated the effect of the hor-
mones of the HPT-axis. These studies can be separated
into two typical designs: (i) either combination therapy
with thyroid hormone and some kind of antidepressive
treatment from the beginning, or (ii) adjunction of
thyroid hormones to patients refractory to conventional
antidepressive medication (nonresponders).
Initial combination therapy with T3 or TSH in
depression Concerning the initial combination therapy,
only the effect of T3 has been evaluated. Repeatedly in
randomized, double-blind placebo-controlled studies,
20 to 50 mg T3 per day in combination with TCA has
been shown to shorten the period of depression as
compared with TCA alone (59–62), but the final
number of recovered patients was not influenced (59,
60, 62). However, in two other well-conducted trials,
but with fewer patients, no additional effect of T3 with
TCA could be demonstrated (63, 64). The studies
demonstrating a beneficial effect of addition of T3 to
TCA included in total 112 patients, whereas the two
negative studies included only 29 patients. Furthermore
the majority of patients studied were females.
The effect of T3 does not seem to be due to changed
metabolism of TCA, and might thus be regarded as an
independent factor (65).
Unfortunately no studies are available concerning
the effect of the addition of T3 to the modern serotonin
re-uptake inhibitory drugs.
In one study T3 or placebo was given to patients
receiving ECT (66). Patients treated with T3 needed
significantly fewer number of ECTs, and demonstrated
less damage to memory functions, in comparison to the
placebo group.
One study demonstrated a beneficial effect of TSH
over placebo (in a randomized, double-blind fashion)
when given to nine patients as intramuscular injections
(10 units of TSH on day 1 and day 8) in adjunction to
TCA (67). This study has unfortunately not been
repeated, but it seems likely that the effect of TSH is
due to an increased thyroidal secretion of T4 and T3.
T3 and T4 in refractory depression (nonresponders)
T3 treatment of the depressed patient resistant to TCA
was first reported beneficial in an open study without a
placebo group (68). Since then the positive effect of 25–
50 mg T3 daily as an adjunctive therapy has been
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 138
confirmed in many studies, including a recent meta-
analysis (69), which included four randomized double-
blind trials (in total 69 patients) and three unblinded
studies using historical controls (in total 185 patients).
This analysis also discussed in detail those studies which
did not find any beneficial effect of T3. Overall the
addition of T3 to TCA increased the response rate
significantly from 24 to 57%.
In another randomized double-blind study Joffe et al.
(70) compared the ability of T3 and lithium to convert
nonresponders to TCA into responders, i.e. reduce the
depressive symptoms on a Hamilton Rating Scale. T3
was equally effective as lithium, and both drugs were
superior to placebo.
No formal studies (only case reports) concerning the
effect of the addition of T3 in depressed patients resistant
to therapy with monoamine oxidase inhibitors or
serotonin re-uptake inhibitors exist.
One study has compared the effect of physiological
doses of T4 (150 mg daily) and T3 (37.5 mg daily) as
adjunctive therapy to nonresponders after 4 weeks on
TCA. They found that T3 was more effective than T4
(71). Although randomized and double-blind, no
placebo group was included, thus it is uncertain
whether T4 is superior to placebo.
Interestingly, an open, uncontrolled trial on nine
L-T4-substituted hypothyroid patients (median 150 mg
daily) with depression and no response to TCA
treatment, reported that seven of these patients
recovered from depression after the addition of T3
(72), suggesting a decreased deiodination of T4 to T3 in
brain.
In another open trial on six nonresponding patients
(to TCA) with nonrapid cycling bipolar affective
disorders, Baumgartner (73) gave supraphysiological
doses of T4 (250–500 mg daily) resulting in a reduced
number of relapses. The results of this preliminary study
are also compatible with a reduced deiodination of T4
to T3.
In the rapid cycling form of bipolar affective disorders,
T4 adjunctive therapy has, in an open design without
placebo controls (in total eight patients), been found to
reduce both manic and depressive symptoms as well as
number of relapses when given in supraphysiological
doses (up to 500 mg daily) (74, 75).
These studies are all compatible with an inhibition of
the D-II deiodinase or a stimulation of the D-III
deiodinase in brain tissues (resulting in a reduced
local T3 concentration) in affective disorders.
Antidepressive drugs – effect on thyroid
hormones
Changes in thyroid hormone and TSH levels during
treatment of depressed patients with TCA and serotonin
re-uptake inhibitors seem a result of the underlying
psychiatric disorder, or its epiphenomena, i.e. increased
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 138
serum cortisol and starvation, and not due to a direct
effect of the drug on hormone secretion, plasma protein-
binding and turnover (1, 17, 76).
In contrast lithium inhibits the secretion of thyroid
hormones from the thyroid gland, resulting in an
increase in serum TSH (77, 78) and thyroid auto-
antibodies (79), which in susceptible patients might
lead to overt hypothyroidism (79). This effect of lithium
might result in a decreased supply of thyroid hormones
to the brain, which according to the presented
hypothesis is inconvenient. However the antidepressive
effect of lithium has been demonstrated to be positively
correlated to serum levels of T3 (80, 81) and negatively
to serum TSH levels (82). The effects of lithium on the
deiodinases D-II and D-III with the result of local
increase of T3 (see above) might counteract the
inappropriate effect of lithium on the thyroid hormone
secretion.
Carbamazepine, an anti-epileptic drug, which also
has some antidepressive effect, influences the HPT-axis
in a complex manner. In addition to the earlier
mentioned effect on the brain deiodinases (Fig. 1),
carbamazepine seems to enhance the hepatic (D-I)
deiodination of both T4 and T3 (83). Thus these patients
often present with low to normal serum levels of T4 and
T3, but normal TSH levels (83), suggestive of some
inhibitory effect on the thyrotrophs as well.
Conclusions
It is hypothesized that the changes seen in the HPT-axis
in untreated depression might be explained partly by a
cerebral serotonin deficiency. These changes tend to
increase serum levels of T3, which subsequently might
increase serotonin content in the brain. Although this
hypothesis is attractive, it is based on few and small
studies, which clearly need confirmation.
Subjects with thyroid insufficiency seem especially
susceptible to the development of depression.
Well established antidepressive treatment modalities
influence the brain deiodinases D-II and D-III, which are
responsible for the local T3 production in brain tissues,
in a manner leading to increased T3 concentrations.
Defects of the brain deiodinases might be a pathogenic
factor in depression.
While the effect of the addition of physiological doses
of T3 to TCA is well documented in depression,
confirmatory studies are needed concerning the effect
of T3 given alone, and T3 given in addition to ECT.
In refractory depressions, the addition of T3 to TCA
has been shown to be equal to the addition of lithium,
and superior to the addition of placebo or T4, to TCA in
alleviating depressive symptoms. The superiority of T3
compared with T4 as adjunctive therapy must be further
evaluated.
No studies exist on the effect of T3 as adjunctive
therapy to the serotonin re-uptake inhibitors, nor on the
effect of T3 in rapid cycling depression.
Thyroid hormones in depression 7
The effects of thyroid hormones, TSH and TRH, on
the depressive syndrome have been extensively studied
during the past three decades. Despite the fact that
many of these studies are more than 20 years old, many
fulfill modern criteria of good clinical science, in terms of
using the randomized, double-blind placebo-controlled
design. Throughout this review, we have made efforts to
describe the design of the studies cited. However, the
potential weakness of these studies is the relatively small
number of patients enrolled in the different treatment
modalities. This is especially relevant, since the depres-
sive syndrome is a heterogenous group of disorders
affecting a large number of subjects; and furthermore
the diagnostic criteria have changed over the years.
Therefore previous findings should be re-evaluated,
using modern scientific principles, and including a large
number of patients. Furthermore, the effect of especially
T3 in combination with various antidepressive treat-
ment modalities (TCA, serotonin re-uptake inhibitors,
ECT, sleep deprivation) should be studied.
The depressive syndrome is most likely a pathogeni-
cally heterogenous group. Patients are characterized
phenomenologically, not by biological markers. Even
phenomenologically identical groups might harbor
different pathogenic subgroups of depression. Therefore
future studies should also focus on identification of
biological abnormalities in those patients who benefit
from T3 treatment, in order to identify in which
subgroups T3 treatment should be used.
In the light of the substantial amounts of data on the
beneficial effect of T3 in depression, the restricted usage
of T3 in this setting is surprising. T3 given in physio-
logical doses is cheap and the monitoring is easy due to
the new sensitive TSH assays. However, precautions
should be taken in patients with concurrent heart
disease, since T3 may sensitize the heart to the
arrythmogenic effects of TCA. Suicidal patients espe-
cially seem to be exposed if they take overdoses of T3 and
TCA in combination.
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Received 27 February 1997
Accepted 14 July 1997
European Journal of Endocrinology (1998) 138 1–9

REVIEW

The role of thyroid hormones in depression

Carsten Kirkegaard and Jens Faber
Department of Internal Medicine F, Hillerød Sygehus, and Department of Endocrinology E, Frederiksberg Hospital, Denmark
(Correspondence should be addressed to C Kirkegaard, Department of Internal Medicine F, Hillerød Sygehus, DK-3400 Hillerød, Denmark)

Introduction groups of depressed patients (reviewed in 1, 2),

During the last 30 years a huge number of scientific
articles have appeared on the subject of relationships
between psychiatric disease and thyroid hormones.
These studies have demonstrated the presence of
numerous changes in the hypothalamo–pituitary–
thyroid (HPT) axis, mainly in patients with depression,
but also in patients with other psychiatric diseases.
Simultaneously, many studies have been published on
the possible therapeutic effects in depression of the
hormones involved in the HPT axis.
Despite great efforts to standardize the classification
of depression, this is still a less well-defined disease,
possibly including several subtypes with different
pathogenesis and biochemical abnormalities. Further-
more the classification has changed over time, making it
difficult to interpret previously published data. The most
accepted classifications are the DSM-IV and ICD-10.
These cover a spectrum from minor depression (neuro-
tic depression) through major depression to melancholic
(endogenous and psychotic) depression. Furthermore
major and melancholic depressions are divided into uni-
and bipolar depressions, the latter also demonstrating
episodes of mania. Rapid cycling bipolar psychosis is a
subgroup of the bipolar depression, demonstrating four
or more episodes in any year of observation.
The present review focuses on the concentrations of
hormones of the HPT-axis seen in uni- and bipolar
depression, their relation to relapse after antidepres-
sive treatment, and a survey of therapeutic trials with
thyrotropin-releasing hormone (TRH), thyroid-stimu-
lating hormone (TSH) and thyroid hormones, as well as
the effect of the various drugs used in depression on the
HPT-axis. The hypothesis is put forward that the
changes seen in the HPT-axis during depression might
be explained by cerebral serotonin deficiency, and that
tri-iodothyronine (T3) treatment, to some degree, can
revert this deficiency.
Iodothyronines in depression
An overall picture of thyroid-related disturbances seen
in depression is given in Table 1.
Thyroxine (T4)
Serum T4 levels, both total and non-protein-bound
(free), are consistently found as normal to increased in
approximately 25% of the patients having levels above
the reference range. The different findings might be
explained by the different severity of depression among
the patients studied, since some studies have found a
correlation between the severity of depression and
serum T4 levels (2). An additional explanation might
be that the depressed patient is often in a state of semi-
starvation, and thus may present changes in the HPT-
axis similar to those seen in patients with nonthyroidal
somatic illness, elevated serum T4 and 3,30 ,50 -tri-
iodothyronine (rT3), and reduced serum T3.
Turnover studies using radiolabeled T4 in a small
group of depressed patients have demonstrated that also
the daily production rate (PR) of T4 is significantly
increased, by 30% (3). This finding contrasts with the
unaltered T4 PR found in groups of patients with
different nonthyroidal illnesses (4). These studies used a
noncompartmental kinetic approach for the evaluation
of PRs. This method correctly estimates the PR of T4.
Increased PR of T4 in depressed patients thus suggests
that the thyroid gland is stimulated abnormally in the
depressed patient.
The concentration of free T4 in cerebrospinal fluid
(CSF) seems relatively increased during depression,
since recovery is followed by a reduction (5). The ratio
between CSF and serum free T4 levels has been found to
be 0·6, both before and after recovery of depression due
to electro-convulsive treatment (ECT) (5). This suggests
that CSF T4 concentrations follow systemic levels, and
that transport of T4 into CSF is restricted. An alternative
explanation is that T4 is taken up directly into brain
tissues, and partly undergoes deiodination, thus yield-
ing less T4 into the CSF.
T3
Serum T3 levels in depressed patients are often found
normal, but several studies have found reduced levels,
typically in more severely depressed patients (1, 2).
Serum T3 levels are influenced by numerous factors
which all may be present in the depressed patient:
starvation, concomitant somatic illness and medication,
and changes (increase) in cortisol levels. When present
these factors all tend to decrease serum T3 levels (4, 6).
This makes interpretation of serum T3 concentrations
difficult. Serum free T3 levels have been found both

q 1998 Society of the European Journal of Endocrinology

2 C Kirkegaard and J Faber
Table 1 Changes in total and free serum concentrations, CSF concentrations, and production rates of various hormones in patients with
depression. Relevant references are given in parentheses.
Total serum
T4 Increased (1, 2)
T3 Unaltered (1, 2)
Decreased (1, 2)
rT3 Increased (2, 11)
Unaltered (5, 9)
TSH Decreased, but elevated in
comparison to T4 production
(1, 3, 13–17). In TCA-
resistance and RCBP, increased
TSH possible (27–30)
Dmax TSH Decreased (1, 2, 13)
Increased (27–30)
TRH — —
Somatostatin — —
TCA ¼ tricyclic antidepressants; RCBP ¼ rapid cycling of bipolar psychosis.
normal and reduced (2). However, methods for the
measurement of free T3 in serum often give spurious,
mainly reduced levels, in diseased patients (7). Ultra-
filtration seems the method of choice (7, 8), and using
this technique we have found unaltered free T3 levels in
depression (9). The daily PR of T3 in unmedicated,
moderately depressed patients has been studied using
tracer turnover techniques, and T3 PR was found
normal (3). This was quite different from patients with
various nonthyroidal illnesses, in whom a 40% reduc-
tion in T3 PR has been demonstrated (4). The com-
bination of an increased T4 PR and an unaltered T3 PR
in depression suggests a reduced deiodination of T4 into
T3, as also seen in nonthyroidal illness, but with more
substrate (T4) availability than in somatic nonthyroidal
illnesses. However, correct interpretation of noncom-
partmental tracer studies is based on the assumption
that the tracer injected is distributed freely into all tissue
compartments (4). If anything, some degree of under-
estimation of T3 PR might take place when performing
T3 kinetics in humans (4), but conflicting results are
available on this issue (10).
The reduced conversion of T4 into T3 seen during
depression (3) might be due to reduced deiodination
enzyme activity. However, in which compartment of the
human body this takes place is at present unknown.
This could in theory be the brain, but unfortunately we
are not aware of any data on intracerebral T3 content or
CSF levels of T3 in depression.
rT3
Changes in serum total as well as free rT3 levels in
depression seem to follow those seen for serum total and
free T4, respectively (2, 5, 11).
CSF levels of rT3 have been studied in different types
of depression, and have been found highest in the
endogenous type (12). Similar to changes in serum, CSF
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 138
Free serum CSF Production rate
Increased (1, 2) Increased (5) Increased (3)
Unaltered (2, 9) — Unaltered (3)
Decreased (2)
Unaltered (2) Increased (5, 12) —
Increased (5, 11)
— — —
— — —
Increased (20, 21) —
Unaltered (22)
Decreased (24–26) —
free rT3 concentrations seem to follow CSF free T4 levels
(5), but the ratio of CSF to serum free rT3 has been
found to be approximately 26, which is quite different
from that of T4 (0.6) (5). This ratio for rT3 did not
change after recovery from the depression, and this
suggests that intracerebral concentration of rT3 is
high in humans, and that rT3 in brain is mainly
derived from local production from T4. This enzym-
atic production seems not changed in depression, and
this argues against rT3 as a pathogenic factor in
depression.
TSH in depression
Previously, changes in circulating levels of TSH in
depressed patients were evaluated using the TSH
response to intravenous TRH, due to lack of sufficiently
sensitive TSH assays. The response in TSH has usually
been evaluated as the peak value minus basal TSH
(DTSH). Normal DTSH to 200 mg TRH i.v. is typically 2–
16 mU/l. Patients with depression, as a group, have
reduced DTSH, and approximately 25% have DTSH
below 2 mU/l in endogenous (melancholic) depression
(1). Using newer, and more sensitive TSH methods,
basal TSH values correlate closely to peak TSH as well as
DTSH (13–15). According to this, depressed patients
seem to have some degree of reduced basal serum TSH,
but within the normal range (13, 15). Basal as well as
DTSH using a sensitive TSH assay have been studied in
various types of depression, and those patients with
endogenous depression had the lowest levels of both
basal TSH and DTSH (13), DTSH being a mean of
3.6 mU/l.
The diurnal variation of serum TSH is, in healthy
man, associated with a surge in TSH around midnight.
In untreated depression this diurnal variation seems
attenuated (16). After complete recovery from depression
the diurnal TSH variation seemed to be re-established, but
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 138
no or incomplete recovery still harbored an attenuated
diurnal variation (17).
In one study the interrelation between serum TSH
concentrations and the daily production of T4 and T3 in
endogenous depression was evaluated (3). Six depressed
patients were compared with seven subjects with L-T4-
treated hypothyroidism. These two groups had quite
similar T4 and T3 PRs, both having an equal T4 PR/T3
PR ratio. Serum TSH level using a sensitive assay was a
median 0.11 mU/l among L-T4-treated hypothyroid
subjects, but 0.90 mU/l in depressed patients, signifi-
cantly higher than in the L-T4-treated hypothyroid
group (3). This suggests an inappropriate secretion of
TSH (in relation to the elevated thyroidal production of
T4) in patients with endogenous depression, compatible
with some degree of central over-stimulation of the
thyroid in the untreated depressed state.
The apparent paradox that serum TSH levels are
found slightly decreased among depressed patients, and
our statement of inappropriately elevated serum TSH
levels in comparison to daily production of T4 and T3
(3), can be compared with the situation of chronic TRH
stimulation (by oral administration) in man. In this
experimental setting, TRH induced an initial increase in
serum TSH, whereas later, at the time when serum T4
and T3 began to increase, serum TSH levels were nor-
malized and were unable to respond to repeated TRH
stimulation (18, 19). Thus chronic stimulation with
TRH in man can provoke a pattern in serum levels of
TSH, T4 and T3 similar to those seen in the depressed
patient.
Chronic stimulation of the thyrothrophs in the
pituitary during depression might be caused by TRH,
since TRH levels have been found elevated in CSF in two
studies (in total 31 patients) (20, 21), although normal
levels were found in a third study including 17 patients
(22). Serum TSH levels are also influenced by soma-
tostatin, which inhibits the TSH release from the
pituitary (23). Three studies have found that the CSF
concentration of somatostatin is reduced during depres-
sion (24–26). This might contribute to an increase in
serum TSH levels.
Two subgroups of the depression syndrome seem to
present with a different pattern in the HPT-axis. One
group consists of patients with bipolar depression
(27, 28), and another group of patients is characterized
by a depression resistant to treatment with tricyclic
antidepressants (TCA) (29, 30). Both groups have a
tendency towards slightly elevated basal serum TSH
levels (approximately 20% have levels above the upper
normal reference range), or exaggerated TSH response
to TRH stimulation. These changes seem independent of
previous or ongoing lithium treatment, and probably
reflect some degree of thyroid insufficiency. Immuno-
logical mechanisms seem to play a role, since patients
with bipolar depression have increased frequency of sera
positive for antithyroid peroxidase (anti-TPO) antibodies
(28). Whether this is an epiphenomenon to bipolar
Thyroid hormones in depression 3
depression, or might be considered as one of several
pathogenic factors, is at present unknown. Interestingly,
postpartum changes in mood seem to be associated
with the presence of anti-TPO antibodies and thyroid
dysfunction (31). Thyroid hormone substitution might
therefore be of potential benefit in alleviating depressive
symptoms in the puerperal period. A preliminary study,
in which L-T4 was administered immediately after
delivery, in fact resulted in reduced depression score
among the L-T4-treated women compared with placebo
treatment (32).
Predictive value of changes of DTSH
Another interesting aspect of the TSH response to TRH
is the possible predictive value of the changes before and
after antidepressive treatment. It is a typical clinical
finding that depressed patients, after recovery following
ECT, demonstrate a high frequency of early relapse,
typically within 6 months, if not treated prophylacti-
cally with antidepressive medication. We have repeat-
edly demonstrated that those patients with early relapse
of endogenous depression have not normalized their
reduced TSH response to TRH, despite clinical recovery.
This has been demonstrated after treatment with ECT as
well as sleep deprivation (i.e. nonpharmacological treat-
ment modalities) (1, 33, 34). More than 80% of those
patients with early relapse did not change their maxi-
mal TSH response to TRH (Dmax TSH). An unchanged
Dmax TSH was defined as post-treatment Dmax TSH
minus pre-treatment Dmax TSH (DDmax TSH) less than
2 mU/l. By contrast more than 80% of those patients
who remained clinically cured for more than 6 months
had a DDmax TSH exceeding 2 mU/l (1). Serum T4 as
well as free T4 levels remained elevated in those patients
with early relapse and continued reduced Dmax TSH
(9). Thus a continued disturbance of the HPT-axis
despite clinical improvement of endogenous depression
suggests that the patient is not clinically cured. How-
ever, other studies in patients treated with antidepres-
sive medication, rather than nonpharmacological
treatment, have been unable to confirm these results (2).
In a small group of patients treated with amitriptyline
we confirmed this lack of predictive value of the TRH test
(33). Thus it is possible that the use of antidepressive
medication might interfere with the HPT-axis on
multiple sites, thus blurring the finding seen in the
unmedicated, clinically cured patient. Alternatively, in
the studies using TCA, the TRH tests have been
performed with intervals too long to maintain a stable
DTSH in patients not cured of depression.
Relationships between depression and
thyroid hormones – a hypothesis
The pathogenesis of endogenous depression is not
known, and is most probably multifactorial. The
4 C Kirkegaard and J Faber
Figure 1 Decreased brain serotonin levels (serotonin (¹)) activate (indicated by (þ)) the HPT-axis, and increased T3 (by endogenous as
well as exogenous sources) increases brain serotonin levels (feed-back) – a hypothesis. D-II and D-III refer to iodothyronine deiodinases
type II and III, respectively. 3,30 -T2: 3,30 -diiodothyronine.
currently favored hypothesis is that a lack of serotonin
in the brain has a central role (35). This hypothesis has
generated the development of effective antidepressive
drugs belonging to the group of serotonin re-uptake
inhibitors. TRH seems under a constant inhibition by
serotonin, and reduced intracerebral serotonin concen-
tration will lead to increased TRH concentrations in
brain tissue (reviewed in 23) (Fig. 1). As a consequence,
TSH secretion will be stimulated. In addition CSF levels
of somatostatin are reduced in depression. Since TSH
secretion is under a constant inhibition of somatostatin
(23), the consequence might be a further stimulated
TSH secretion. Increased TSH levels result in enhanced
thyroidal production of T4 and T3. Due to the thyroid–
pituitary feedback, increased T4 and T3 levels tend to
reduce serum TSH levels, reaching a new steady state
usually within the normal range. The new TSH levels
are, however, inappropriately elevated in relation to the
increased T4 production (3).
Acute as well as chronic T3 treatment has been
shown to increase the serotonin levels in the cerebral
cortex of rats (36). In man, plasma serotonin levels
correlate positively with T3 concentrations (37, 38),
and treatment of hyperthyroidism results in a reduction
in serum serotonin levels (37). Brain serotonin levels in
rats seem similarly affected, i.e. synthesis is reduced in
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 138
hypothyroidism (39) and increased in hyperthyroidism
(40, 41).
Thus the findings that reduced intracerebral seroto-
nin concentrations lead to increased TRH and thereby
to increased thyroid hormone levels, and that increased
T3 levels lead to an increase in brain serotonin, seem to
constitute a classical feedback mechanism relevant to
alleviation of depression.
Intracerebral T3 seems mainly a result of local
production by deiodination of T4. In general, at least
three deiodinating enzymes seem capable of affecting
the turnover of T4 and T3 (reviewed in 42). The type-I
deiodinase (D-I) results in both inner (5-) and outer (50 -)
ring deiodination, mainly of T4, which thereby provides
a circulating source of T3 to the peripheral tissues. The
type-II deiodinase (D-II) results in outer (50 -) ring
deiodination, mainly of T4. This enzyme functions to
regulate intracellular T3 levels in those tissues where T3
is most critical, such as brain and pituitary. In line with
this, the enzyme activity is increased in hypothyroidism
and reduced in hyperthyroidism. The type-III (D-III)
enzyme results in inner (5-) ring deiodination, of both
T4 into rT3, and T3 into 3,30 -T2, and, in contrast to the
D-II, but similar to D-I, its activity is increased in
hyperthyroidism and decreased in hypothyroidism.
Whereas all three enzymes are present in rat brain
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 138
(42), human brain tissues seem to contain only D-II and
D-III enzymes (43). The properties of the D-II and D-III
enzymes in rat and human tissues seem quite similar
(43). Thus D-II activity increases T3 production in brain
and pituitary, and consequently also the local produc-
tion of serotonin. In addition, D-III activity might be
expected to decrease the local concentration of T3 and
indirectly of serotonin in brain tissues.
Studies of the influence of several known antidepres-
sive drugs on rat D-II and D-III enzyme activities have
revealed a similar pattern: lithium (44), des-imipramine
(45), carbamazepine (46), and fluoxetine (47) have been
shown to enhance the activity of the D-II enzyme resulting
in increased local T3 concentrations in brain tissues. Also
sleep deprivation of rats, which is a known treatment
modality for depression, has been shown to increase the
D-II activity (48). In contrast, lithium, carbamazepine,
and fluoxetine have been shown to decrease the activity
of the D-III enzyme (44, 46, 47), also resulting in
increased local T3 concentration (for overview, see
Fig. 1). Although this is an attractive pattern, a contra-
dictory study has demonstrated that lithium decreases
the activity of D-II in mouse neural and pituitary tissues
(49). One must also be aware that the above mentioned
changes are not necessarily found in the same regions of
the brain, and furthermore it is not known whether
these regions have any relevance to depression.
The consequence of the effect of the antidepressive
drugs on the D-II and D-III enzyme activities is an
increased local T3 concentration in brain tissues and, as
discussed above, this might increase local serotonin
concentration, and thus might form an additional
biological basis for the positive effect of these drugs in
alleviating the depressive state.
Thus the hypothesis that a major pathogenic factor
for depression is serotonin deficiency is sufficient to
explain the changes seen in the HPT-axis. However,
another hypothesis, put forward many years ago, has
been that the depressed patient suffers a state of local
hypothyroidism in the brain. This hypothesis, originally
based on the similarities of symptoms seen in hypo-
thyroidism and depression, seems supported by the
finding that T3 treatment alleviated the depressive
symptoms (50). Reduced T3 content in brain tissues
leads to serotonin deficiency in brain tissues, and thus is
sufficient to explain the findings in the HPT-axis seen in
depression (Fig. 1).
Both hypotheses can explain that (i) patients with
thyroid insufficiency are especially sensitive to develop
depression (51, 52), (ii) T3 treatment is beneficial also in
euthyroid, depressed patients, (iii) pharmacological
stimulation of the D-II and inhibition of the D-III brain
enzyme could be expected to have a beneficial effect on
the depression, and (iv) T3 treatment might be at least
as effective as T4 treatment. Only the serotonin
deficiency hypothesis might explain the low normal
serum TSH and low Dmax TSH seen during depression,
and that patients with continued low Dmax TSH after
Thyroid hormones in depression 5
apparent recovery from depression are subject to early
relapse. This parameter can thus be regarded as a
marker of continued active disease.
Another fruitful hypothesis developed for the biologi-
cal explanation of depression suggested that depression
was due to a state of relative brain deficiency of cate-
cholamines, especially norepinephrine (53). This has
formed the basis of the development of another group of
useful antidepressive drugs, norepinephrine re-uptake
inhibitors. In 1981 Whybrow & Prange Jr (54)
hypothesized that thyroid hormones, by enhancing
beta-adrenergic receptor function, promote transmis-
sion in central noradrenergic pathways and accelerate
recovery. Later, the same group (55) demonstrated that
T3 levels in rat brain synaptosomes are much higher
than whole brain levels, and that T3 but not T4 can be
released from depolarized synaptosomes. Recently
Rozanov & Dratman (56) found increased T3 concen-
trations in nuclei and projection sites of rat central
noradrenergic systems. These studies suggest that T3
may play a neuromodulatory or neurotransmitter role
in the noradrenergic central nervous system. Norepine-
phrine stimulates the release of both TRH and TSH (23),
and therefore norepinephrine deficiency cannot explain
the changes in the HPT-axis seen in depression,
especially the increased CSF TRH levels. However the
hypothesis is fully compatible with the beneficial effect
of T3 treatment in depression.
Treatment of depression with hormones
of the HPT-axis
The similarities between symptoms seen in depression
and untreated hypothyroidism have lead to several
clinical trials in which thyroid hormones have been
given to depressed patients, either alone or in combina-
tion with other antidepressive treatment modalities.
Treatment without other treatment modalities
TRH In the 1970s a number of studies demonstrated a
mild but transient improvement in mood in depressed
patients treated with TRH for a few days or at most 3
weeks. Later other studies including controlled double-
blind designs, failed to demonstrate any beneficial effect
of TRH (reviewed in 57).
T3 T3 given as the only drug to depressed patients has
been evaluated in only two studies. Feldmesser-Reiss
(50) treated 24 patients with depression or melancholia
with 10–15 mg T3 daily, and observed considerable
improvement in 10 patients. Wilson et al. (58) gave
25 mg, increasing to 62.5 mg, of T3 daily for 9 days to
nine patients, which apparently was as effective on
depression as imipramine, as evaluated by the Hamilton
rating scale. Imipramine plus T3 had no additional
effect. Unfortunately this otherwise randomized,
double-blind study had no placebo group. Thus in
6 C Kirkegaard and J Faber
these two studies T3 given alone seems to have an
antidepressive effect, but placebo-controlled studies are
lacking.
TSH and T4 We are not aware of any studies using TSH
or T4 as the only treatment of depressed patients.
Treatment in combination with other
treatment modalities
Several studies have evaluated the effect of the hor-
mones of the HPT-axis. These studies can be separated
into two typical designs: (i) either combination therapy
with thyroid hormone and some kind of antidepressive
treatment from the beginning, or (ii) adjunction of
thyroid hormones to patients refractory to conventional
antidepressive medication (nonresponders).
Initial combination therapy with T3 or TSH in
depression Concerning the initial combination therapy,
only the effect of T3 has been evaluated. Repeatedly in
randomized, double-blind placebo-controlled studies,
20 to 50 mg T3 per day in combination with TCA has
been shown to shorten the period of depression as
compared with TCA alone (59–62), but the final
number of recovered patients was not influenced (59,
60, 62). However, in two other well-conducted trials,
but with fewer patients, no additional effect of T3 with
TCA could be demonstrated (63, 64). The studies
demonstrating a beneficial effect of addition of T3 to
TCA included in total 112 patients, whereas the two
negative studies included only 29 patients. Furthermore
the majority of patients studied were females.
The effect of T3 does not seem to be due to changed
metabolism of TCA, and might thus be regarded as an
independent factor (65).
Unfortunately no studies are available concerning
the effect of the addition of T3 to the modern serotonin
re-uptake inhibitory drugs.
In one study T3 or placebo was given to patients
receiving ECT (66). Patients treated with T3 needed
significantly fewer number of ECTs, and demonstrated
less damage to memory functions, in comparison to the
placebo group.
One study demonstrated a beneficial effect of TSH
over placebo (in a randomized, double-blind fashion)
when given to nine patients as intramuscular injections
(10 units of TSH on day 1 and day 8) in adjunction to
TCA (67). This study has unfortunately not been
repeated, but it seems likely that the effect of TSH is
due to an increased thyroidal secretion of T4 and T3.
T3 and T4 in refractory depression (nonresponders)
T3 treatment of the depressed patient resistant to TCA
was first reported beneficial in an open study without a
placebo group (68). Since then the positive effect of 25–
50 mg T3 daily as an adjunctive therapy has been
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 138
confirmed in many studies, including a recent meta-
analysis (69), which included four randomized double-
blind trials (in total 69 patients) and three unblinded
studies using historical controls (in total 185 patients).
This analysis also discussed in detail those studies which
did not find any beneficial effect of T3. Overall the
addition of T3 to TCA increased the response rate
significantly from 24 to 57%.
In another randomized double-blind study Joffe et al.
(70) compared the ability of T3 and lithium to convert
nonresponders to TCA into responders, i.e. reduce the
depressive symptoms on a Hamilton Rating Scale. T3
was equally effective as lithium, and both drugs were
superior to placebo.
No formal studies (only case reports) concerning the
effect of the addition of T3 in depressed patients resistant
to therapy with monoamine oxidase inhibitors or
serotonin re-uptake inhibitors exist.
One study has compared the effect of physiological
doses of T4 (150 mg daily) and T3 (37.5 mg daily) as
adjunctive therapy to nonresponders after 4 weeks on
TCA. They found that T3 was more effective than T4
(71). Although randomized and double-blind, no
placebo group was included, thus it is uncertain
whether T4 is superior to placebo.
Interestingly, an open, uncontrolled trial on nine
L-T4-substituted hypothyroid patients (median 150 mg
daily) with depression and no response to TCA
treatment, reported that seven of these patients
recovered from depression after the addition of T3
(72), suggesting a decreased deiodination of T4 to T3 in
brain.
In another open trial on six nonresponding patients
(to TCA) with nonrapid cycling bipolar affective
disorders, Baumgartner (73) gave supraphysiological
doses of T4 (250–500 mg daily) resulting in a reduced
number of relapses. The results of this preliminary study
are also compatible with a reduced deiodination of T4
to T3.
In the rapid cycling form of bipolar affective disorders,
T4 adjunctive therapy has, in an open design without
placebo controls (in total eight patients), been found to
reduce both manic and depressive symptoms as well as
number of relapses when given in supraphysiological
doses (up to 500 mg daily) (74, 75).
These studies are all compatible with an inhibition of
the D-II deiodinase or a stimulation of the D-III
deiodinase in brain tissues (resulting in a reduced
local T3 concentration) in affective disorders.
Antidepressive drugs – effect on thyroid
hormones
Changes in thyroid hormone and TSH levels during
treatment of depressed patients with TCA and serotonin
re-uptake inhibitors seem a result of the underlying
psychiatric disorder, or its epiphenomena, i.e. increased
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 138
serum cortisol and starvation, and not due to a direct
effect of the drug on hormone secretion, plasma protein-
binding and turnover (1, 17, 76).
In contrast lithium inhibits the secretion of thyroid
hormones from the thyroid gland, resulting in an
increase in serum TSH (77, 78) and thyroid auto-
antibodies (79), which in susceptible patients might
lead to overt hypothyroidism (79). This effect of lithium
might result in a decreased supply of thyroid hormones
to the brain, which according to the presented
hypothesis is inconvenient. However the antidepressive
effect of lithium has been demonstrated to be positively
correlated to serum levels of T3 (80, 81) and negatively
to serum TSH levels (82). The effects of lithium on the
deiodinases D-II and D-III with the result of local
increase of T3 (see above) might counteract the
inappropriate effect of lithium on the thyroid hormone
secretion.
Carbamazepine, an anti-epileptic drug, which also
has some antidepressive effect, influences the HPT-axis
in a complex manner. In addition to the earlier
mentioned effect on the brain deiodinases (Fig. 1),
carbamazepine seems to enhance the hepatic (D-I)
deiodination of both T4 and T3 (83). Thus these patients
often present with low to normal serum levels of T4 and
T3, but normal TSH levels (83), suggestive of some
inhibitory effect on the thyrotrophs as well.
Conclusions
It is hypothesized that the changes seen in the HPT-axis
in untreated depression might be explained partly by a
cerebral serotonin deficiency. These changes tend to
increase serum levels of T3, which subsequently might
increase serotonin content in the brain. Although this
hypothesis is attractive, it is based on few and small
studies, which clearly need confirmation.
Subjects with thyroid insufficiency seem especially
susceptible to the development of depression.
Well established antidepressive treatment modalities
influence the brain deiodinases D-II and D-III, which are
responsible for the local T3 production in brain tissues,
in a manner leading to increased T3 concentrations.
Defects of the brain deiodinases might be a pathogenic
factor in depression.
While the effect of the addition of physiological doses
of T3 to TCA is well documented in depression,
confirmatory studies are needed concerning the effect
of T3 given alone, and T3 given in addition to ECT.
In refractory depressions, the addition of T3 to TCA
has been shown to be equal to the addition of lithium,
and superior to the addition of placebo or T4, to TCA in
alleviating depressive symptoms. The superiority of T3
compared with T4 as adjunctive therapy must be further
evaluated.
No studies exist on the effect of T3 as adjunctive
therapy to the serotonin re-uptake inhibitors, nor on the
effect of T3 in rapid cycling depression.
Thyroid hormones in depression 7
The effects of thyroid hormones, TSH and TRH, on
the depressive syndrome have been extensively studied
during the past three decades. Despite the fact that
many of these studies are more than 20 years old, many
fulfill modern criteria of good clinical science, in terms of
using the randomized, double-blind placebo-controlled
design. Throughout this review, we have made efforts to
describe the design of the studies cited. However, the
potential weakness of these studies is the relatively small
number of patients enrolled in the different treatment
modalities. This is especially relevant, since the depres-
sive syndrome is a heterogenous group of disorders
affecting a large number of subjects; and furthermore
the diagnostic criteria have changed over the years.
Therefore previous findings should be re-evaluated,
using modern scientific principles, and including a large
number of patients. Furthermore, the effect of especially
T3 in combination with various antidepressive treat-
ment modalities (TCA, serotonin re-uptake inhibitors,
ECT, sleep deprivation) should be studied.
The depressive syndrome is most likely a pathogeni-
cally heterogenous group. Patients are characterized
phenomenologically, not by biological markers. Even
phenomenologically identical groups might harbor
different pathogenic subgroups of depression. Therefore
future studies should also focus on identification of
biological abnormalities in those patients who benefit
from T3 treatment, in order to identify in which
subgroups T3 treatment should be used.
In the light of the substantial amounts of data on the
beneficial effect of T3 in depression, the restricted usage
of T3 in this setting is surprising. T3 given in physio-
logical doses is cheap and the monitoring is easy due to
the new sensitive TSH assays. However, precautions
should be taken in patients with concurrent heart
disease, since T3 may sensitize the heart to the
arrythmogenic effects of TCA. Suicidal patients espe-
cially seem to be exposed if they take overdoses of T3 and
TCA in combination.
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Received 27 February 1997
Accepted 14 July 1997