Neuroscience and Biobehavioral Reviews 118 (2020) 669–680

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Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Associations between sex hormones, sleep problems and depression: A T

systematic review
M.W.L. Morssinkhofa,b,e, D.W. van Wylickb, S. Priester-Vinkc, Y.D. van der Werfd, M. den Heijere,
O.A. van den Heuvelb,d, B.F.P. Broekmana,b,f,*
a
OLVG Hospital, Department of Psychiatry and Medical Psychology, P.O. Box 95500, 1090 HM, Amsterdam, The Netherlands
b
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands
c
OLVG Hospital, Medical Library, Department of Research and Epidemiology, P.O. Box 95500, 1090 HM, Amsterdam, The Netherlands
d
Amsterdam UMC, Vrije Universiteit Amsterdam, Anatomy and Neurosciences, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands
e
Amsterdam UMC, Vrije Universiteit van Amsterdam, Department of Endocrinology, De Boelelaan 1117, Amsterdam, The Netherlands
f
Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A⁎STAR), Singapore

ARTICLE INFO ABSTRACT

Keywords: Sleep problems and depression are both common and have a high impact on quality of life. They are also strongly
Gonadal steroid hormones associated and commonly occur together. During the reproductive age, both sleep problems and depression are
Depression almost twice as common in women than men. Epidemiological studies show that women experience more sleep
Sleep problems and depressive symptoms around times when sex hormones change, such as puberty and menopause,
Insomnia
but it is unclear what effect sex hormones have on sleep problems and depression.
Estrogen
Progesterone
This systematic review aims to summarize and evaluate studies that investigated the relationship between sex
Testosterone hormones, sleep and depression.
Systematic review Systematic search resulted in 2895 articles, of which 13 met inclusion criteria.
Depressed patients showed worse sleep than controls, but no significant difference in endogenous hormone
levels was found. Additionally, higher endogenous estrogen was associated with better sleep in controls, but
associations between endogenous sex hormones and depressive symptoms were inconclusive. More research on
the effect of sex hormones on sleep and depression is necessary.

1. Introduction
1.1. Depression, sleeping problems and gender differences in prevalence
Depression and sleep problems are both significant issues in today’s
society; they have a high prevalence and impact daily functioning and
quality of life strongly. Depression and sleep problems are often inter­
twined: insomnia symptoms, such as difficulty falling asleep and
waking during the night, are common symptoms of depression
(American Psychiatric Association, 2013; Fava, 2004; Hayashino et al.,
2010) and poor sleep quality, insomnia and very long or short sleep
duration could be risk factors for depressive episodes (Lustberg and
Reynolds, 2000; Paunio et al., 2015; Baglioni et al., 2011; Neckelmann
et al., 2007; Zhai et al., 2015).
Differences in sleep physiology between depressed patients and
controls have been described using electroencephalogram (EEG) mea­
surements. Studies have found that depressed patients often have
longer sleep onset latencies (SOL) (Lovato and Gradisar, 2014), have
lower delta sleep ratios (meaning less deep sleep in the beginning of the
night) and spend less time in slow wave sleep (SWS), arrive at REM
(Rapid Eye Movement) sleep faster and experience more REM sleep
(Pillai et al., 2011). Interestingly, these altered sleep markers are also
seen in healthy controls who are at high risk for depression (Pillai et al.,
2011), which suggests that these sleep markers may predict future de­
pressive episodes (Palagini et al., 2013). After remission of depression,
the differences in REM sleep, slow wave sleep and delta sleep ratios
tend to reduce (Wichniak et al., 2013).
There is a widely known sex difference in the risk for sleep problems
and depression: it is found that women are 1.5 times more likely than
men to suffer from insomnia (Klink et al., 1992; Li et al., 2002; Zhang
and Wing, 2006) and two times more likely to suffer from depression
(Kessler et al., 1993; Kuehner, 2003), even after adjustment for race,
income and employment (Rai et al., 2013). In contrast, sleep EEG stu­
dies show that women on average have more SWS than men (Santhi

⁎
Corresponding author at: Amsterdam UMC, Department of Psychiatry, room ZH3A63, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
E-mail address: b.f.p.broekman@olvg.nl (B.F.P. Broekman).

https://doi.org/10.1016/j.neubiorev.2020.08.006
Received 13 March 2020; Received in revised form 30 July 2020; Accepted 11 August 2020
Available online 31 August 2020
0149-7634/ © 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/BY/4.0/).
M.W.L. Morssinkhof, et al.
et al., 2016) and higher power in theta and delta frequencies (Carrier
et al., 2001), indicating they actually experience deeper sleep than men.
1.2. Sex hormones in depression and sleep problems
An important biological difference between the sexes, especially
during the reproductive age, is the difference in the level of sex hor­
mones: testosterone, estrogen and progesterone. The sex differences in
prevalence of insomnia and depression appear from puberty onwards
(Salk et al., 2017) and seems to coincide with the timing of girls’ first
menstruation (Johnson et al., 2006). This suggests that female sex
hormones might partly account for the gender difference in prevalence
of depression and sleep problems.
Another indication that female sex hormones may affect mood is
found in women suffering from premenstrual syndrome (PMS). An es­
timated 48 % of women suffer from PMS symptoms (Direkvand-
Moghadam et al., 2014), reporting a depressed mood and fatigue in the
week before onset of menstruation (Baker and Driver, 2007; Halbreich
et al., 2003; Potter et al., 2009). In 13–18% of women, these symptoms
include severe anhedonia, lability and/or anxiety in such severity that it
fulfils the criteria of the DSM 5-classified “premenstrual dysphoric
disorder” or PMDD (APA, 2013; Halbreich et al., 2003; Hantsoo and
Epperson, 2015). Fatigue is a symptom of PMDD, which indicates that
sleep quality might also be affected in PMDD. Moreover, some studies
also reported associations between oral hormonal contraceptives (OC)
and depressive mood (Gingnell et al., 2013), antidepressant use
(Skovlund et al., 2016) and risk of suicide (Skovlund et al., 2018), al­
though these findings are not always replicated (Toffol et al., 2011;
Scheuringer et al., 2020; Hamstra et al., 2017). Hormonal contra­
ceptives suppress endogenous hormones by administering exogenous
hormones (Montoya and Bos, 2017), so whether these side effects are
caused by exogenous or endogenous hormone changes is not yet clear.
During the menopausal transition, when sex hormones strongly fluc­
tuate and eventually diminish, sleeping problems, reported as “trouble
sleeping” and “sleeping problems”, are a common complaint (Kravitz
et al., 2003; Schnatz et al., 2005) and depressed mood often occurs
(Cohen et al., 2006; Hay et al., 1994; Soares, 2010). Estrogen admin­
istration in some cases counteracts depressive symptoms and sleep
complaints in women during menopause (Miller, 2003; Sarti et al.,
2005). Altogether, we could say that relative changes in estrogen or
progesterone levels often seem to co-incide with an increase in de­
pressive symptoms and sleep problems.
In men, lowered testosterone levels have been associated with sleep
problems such as nocturnal awakenings and lower sleep efficiency and
symptoms of depression (Barrett-Connor et al., 2008; Westley et al.,
2015). For example, ageing men whose testosterone levels drop have an
increased risk for depressive symptoms (Seidman, 2003) and testos­
terone administration in depressed patients may lead to a reduction in
depressive symptoms (Zarrouf et al., 2009). Testosterone levels can,
conversely, also decline as a result of shortened or fragmented sleep,
possibly due to altered nocturnal testosterone secretion (Leproult and
Van Cauter, 2011; Schmid et al., 2012). Testosterone therapy is known
to possibly increase the risk of OSAS and sleep breathing disorders. Its
effect on sleep has only been tested once in older men, where testos­
terone was found to reduce sleep duration (Liu et al., 2003).
Preclinical studies in rodents offer insight into mechanistic effects of
sex hormones. Sudden estrogen withdrawal in rodents can increase
“depressive-like” behavior (Galea et al., 2001 Schiller et al., 2013) and
subsequent administration of estradiol can reduce these behaviors.
Administration of estradiol in sleep-deprived rats has shown varying
results on sleep, indicating it could either worsen (Schwartz and Mong,
2011) or facilitate recovery after sleep deprivation (Deurveilher et al.,
2009).
High doses of exogenous progesterone seem to have an anxiolytic
and sedative effect in humans (Söderpalm et al., 2004; van Broekhoven
et al., 2006). Progesterone administration seems to shorten non-REM
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Neuroscience and Biobehavioral Reviews 118 (2020) 669–680
sleep and prolong REM sleep duration in a similar fashion to agonistic
GABA-A receptor modulators (Lancel et al., 1996). This sedative effect
might be driven by metabolite products from progesterone, which can
affect GABA receptors (van Broekhoven et al., 2006). A progesterone
withdrawal paradigm in rats (Li et al., 2012) showed increased anhe­
donia and social withdrawal after a sudden reduction of progesterone in
rats, which was seen as a robust model for premenstrual dysphoric
disorder. Here, a possible underlying role of serotonin was explored,
but progesterone withdrawal did not seem to affect brain serotonin
levels and serotonin metabolite levels.
Testosterone administration has also shown to reduce depression-
like symptoms in young male mice (Buddenberg et al., 2009) as well as
ageing mice (Frye and Walf, 2009), and it also increased sleep duration
and NREM sleep in sleep-deprived mice. Importantly, testosterone can
also be metabolized into substances that act like agonistic GABA-A re­
ceptor modulators, as seen in progesterone metabolites (Edinger and
Frye, 2004), and it can be aromatized into estradiol, thus affecting es­
trogen receptors (Frye et al., 2008). Thus, there can be overlap between
effects of testosterone, progesterone and estrogen.
1.3. Aims of current systematic review
There is no recent overview on the relationship between sex hor­
mones, sleep and depressive symptoms. Manber and Armitage (1999)
published an insightful narrative review on the association between sex
hormones, sleep and depressive problems. Since then, new studies have
been conducted on this topic and new methods have been used, such as
the more reliable liquid chromatography–mass spectrometry (LC–MS)
for hormone measurements and advanced ambulant monitoring
methods for sleep. This systematic review of more recent studies, in­
cluding these methods, can provide new insights in the relation be­
tween sex hormones, sleep and depressive symptoms.
In this review, we aim to provide an overview of peer-reviewed
studies that investigated sex hormones, either via endogenous sex
hormone level measurements or interventions via exogenous hormones
(Intervention/Indicator and Control) in healthy reproductive-age adults
(Population and Control) and subjective and objective sleep and diag­
nosis of depression and/or depressive symptoms (Outcome), in retro­
spective, prospective and cross-sectional studies, with either an ob­
servational or interventional design (Study designs). These findings
could provide insight into whether sex hormones influence sleep pro­
blems and depressive symptoms.
2. Methods
A review protocol was developed based on the Preferred Reporting
Items for Systematic Reviews and Meta-Analysis (PRISMA) statement
(www.prisma-statement.org) (Moher et al., 2009) and was submitted to
Prospero under review number CRD42019125970.
2.1. Search protocol
Relevant studies were identified by searching PubMed, Embase/
Ovid, PsychINFO/Ovid, Cochrane Database of Systematic Reviews/
Wiley, Cochrane Central Register of Controlled Trials/Wiley, and Web
of Science/Clarivate Analytics from inception up to December 3rd 2019
(by MM and DW and SPV, information specialist). The following terms,
including synonyms and closely related words, were used as index
terms or free-text words: ‘sex hormones’, ‘sleep’ and ‘depression’. All
three search terms had to be present in title or abstract. Full search
strategies for all databases are available as Supplementary Information/
appendix. No language or other restrictions were applied to any of the
searches. Outside the defined search terms in aforementioned data­
bases, no other sources were searched.
Duplicate articles were excluded by the information specialist (SPV)
using EndNote (Thomson Reuters, 2017).
M.W.L. Morssinkhof, et al.
2.2. Eligibility criteria
Studies were included if they were empirical published studies after
1998. When a conference abstract was found, the full text study was
searched for inclusion. If no full text was available, studies were not
included. Additional criteria were:
- The study participants, or at least one group of participants in the
study, had to be of reproductive age (18–45 years old), non-meno­
pausal (regularly menstruating) and healthy (e.g. no chronic ill­
nesses, no endocrine disorders, no pregnancy (in women), no PCOS
(in women), no endometriosis (in women), no known infertility
problems, no reported psychiatric diagnoses except for depression or
PMDD).
- The study reported both sleep measurements, as well as symptoms
of depression or diagnoses of depression.
- The study either used interventions to exogenously influence sex
hormone levels, or measured endogenous sex hormone levels.
- Studies that assessed hormones were only included if they measured
estrogen, testosterone and/or progesterone.
o Intervention studies were only included if they provided pre- and
post-intervention measurements of both sleep and mood reports.
All included studies were carried out in accordance with the de­
claration of Helsinki; all participants provided informed consent.
2.3. Outcome measures
The most relevant outcomes were the effects of sex hormones on
sleep, effects of sex hormones on depression and the effect of sex hor­
mones on the interaction of sleep problems and depression. “Sex hor­
mones” either refers to measurement of endogenous sex hormone levels
or to exogenous sex hormone interventions. “Sleep” includes sleep
duration, sleep quality and/or sleep physiology, through either objec­
tive measurement (though actigraphy, EEG and/or polysomnography)
and/or subjective measurement (through sleep questionnaires).
Depression measurement either refers to self-reported measures of
symptoms of depression measured with questionnaires or a diagnosis of
depression by clinical interviews or by a physician.
2.4. Study selection
MM and DW independently screened the identified articles in a
blinded manner based on title and abstract using Rayyan QCRI software
(Ouzzani et al., 2016). MM and DW did not reach agreement on 7 ab­
stracts out of 2785 abstracts, which were conflict resolved by BB as a
third reviewer. This resulted in 38 papers to be reviewed in full text.
Full text screening was then performed independently by MM and DW
to see whether the articles fulfilled all inclusion and exclusion criteria.
Full text review resulted in 1 conflict, which was again resolved by the
third reviewer (BB). The final search result contained 13 included pa­
pers. The study selection is also displayed according to PRISMA
guidelines in Fig. 1 below.
2.5. Data extraction
Data extraction was performed by MM and DW with a custom-made
form to assess methods and outcomes of the studies. The custom-made
form contained the first author’s name, year of publication, journal,
study design, study objective, number of participants, age of partici­
pants, method of measuring or intervening in sex steroids, sleep mea­
surement instrument or method, mood or depression assessment in­
strument and key findings of every study. MM conducted the full data
extraction and DW verified the extraction. A compact version of the
data extraction table is displayed in Table 1.
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Neuroscience and Biobehavioral Reviews 118 (2020) 669–680
2.6. Quality assessment
Quality assessment of each article was performed in duplicate by
MM and DW by using National Institute of Health Quality Assessment
tools that matched the study setup (National Institutes of Health, 2014).
Each article was rated Good, Fair or Poor, according to the criteria from
the National Institute of Health Quality Assessment tool that was used.
Inter-rater agreement for quality assessment was 85 %. Conflicts were
resolved by BB as third reviewer. The specific tool used and full ratings
per item are reported in the results, the full rating per item and used
tool are supplied in Appendix A.
3. Results
3.1. Selection of included studies
Our search identified 4142 studies, of which 2895 remained after
duplicate removal. 2855 studies were then excluded based on abstract
and title. Full text screening of 40 studies, based on inclusion criteria,
resulted in 13 included studies. Fig. 1 also displays the full selection
procedure. Table 1 displays a summary of the methods and results of
each study. Two out of thirteen studies were sourced from the same
participant group (Hollander et al., 2001 & Freeman et al., 2004).
3.2. Designs and quality of the included studies
Ten studies were prospective, three studies were cross-sectional,
and no studies were retrospective. The quality of the included studies
was reasonably good; five studies were deemed of fair quality and eight
studies were deemed to be of good quality (National Institutes of
Health, 2014, full quality assessment form available in appendix 2).
Three out of the thirteen studies assessed effects of a sex hormone in­
tervention (Ben Dor et al., 2013; Gingnell et al., 2013; Toffol et al.,
2019) and ten out of thirteen studies assessed associations with en­
dogenous sex hormone levels (Antonijevic et al., 2003; Baker et al.,
2012; de Zambotti et al., 2015d; Freeman et al., 2004; Hollander et al.,
2001; Kische et al., 2016; Kravitz et al., 2005; Lee et al., 2000; Li et al.,
2015; Shechter et al., 2012). Three of the studies included a patient
group next to the control group, this group being either a group of
depressed patients or women suffering from premenstrual dysphoric
disorder (PMDD). The depressed patients from Antonijevic et al., 2003
were hospitalized for depression, the PMS/PMDD patients (from Baker
et al., 2012; Shechter et al., 2012) were diagnosed by prospectively
tracking two cycles of PMS/PMDD symptoms. The remaining ten stu­
dies only included non-depressed patients or had a mixed group of both
depressed and non-depressed participants. Study setups and sample
sizes are displayed in Fig. 2.
3.3. Hormone interventions and/or assessments
The study by Ben Dor et al. (2013) both intervened in and mon­
itored sex steroids. Five studies monitored the menstrual cycle and the
co-occurring changes in mood and sleep during the cycle (Baker et al.,
2012; Kravitz et al., 2005; Lee et al., 2000; Li et al., 2015; Shechter
et al., 2012); these studies generally divided the cycle in the follicular
phase (the first and second week of the cycle, which starts after onset of
menses and ends with an ovulation, with relatively low progesterone
and estrogen levels) and the luteal phase (the third and fourth week of
the cycle, in which progesterone levels peak). Two studies, based on the
same participant group, monitored absolute sex hormone levels over
longer periods of time (e.g. multiple months to years: Freeman et al.,
2004; Hollander et al., 2001). Three studies assessed hormone levels in
a cross-sectional designs (Antonijevic et al., 2003; de Zambotti et al.,
2015d; Kische et al., 2016). Sex hormone levels were measured in urine
(n = 3) or blood (n = 8), two studies conducted interventions without
hormone measurements (Fig. 3).
M.W.L. Morssinkhof, et al.
Fig. 1. Study selection process of the systematic review, according to PRISMA guidelines and using the PRISMA flow diagram format (Moher et al., 2009).
3.4. Measurement of depression and sleep
Two studies assessed depressive symptoms with MDD diagnoses
(Antonijevic et al., 2003; Freeman et al., 2004), while nine studies used
validated questionnaires for depressive symptoms (Baker et al., 2012;
Bartz et al., 2010; Ben Dor et al., 2013; de Zambotti et al., 2015d;
Freeman et al., 2004; Gingnell et al., 2013; Lee et al., 2000; Shechter
et al., 2012; Toffol et al., 2019) and six used non-validated question sets
or questionnaires for depression (Ben Dor et al., 2013; Gingnell et al.,
2013; Kische et al., 2016; Kravitz et al., 2005; Lee et al., 2000; Li et al.,
2015). A number of studies also combined both daily ratings of mood
and clinical depression questionnaires (Baker et al., 2012; Ben Dor
et al., 2013; Gingnell et al., 2013; Lee et al., 2000). Six studies assessed
sleep with EEG/PSG (Antonijevic et al., 2003; Baker et al., 2012; de
Zambotti et al., 2015d; Kische et al., 2016; Shechter et al., 2012), one
study used actigraphy (Lee et al., 2000), five studies used validated
sleep questionnaires (Baker et al., 2012; de Zambotti et al., 2015d;
Freeman et al., 2004; Hollander et al., 2001; Kische et al., 2016) and six
studies used sleep items from other questionnaires (Ben Dor et al.,
2013; Gingnell et al., 2013; Kravitz et al., 2005; Lee et al., 2000; Li
et al., 2015; Toffol et al., 2019). A number of studies combined different
methods of sleep assessment (Baker et al., 2012; de Zambotti et al.,
2015d; Kische et al., 2016; Lee et al., 2000). Because of the hetero­
geneity of assessment methods for sleep and depressive symptoms, it
was not possible to determine mean risk ratios or effect sizes of sex
hormones on depression or sleep across the studies.
3.5. Demographics of study participants
Only one study (Kische et al., 2016) included both male and female
participants. Studies varied in age range of participants; part of the
studies assessed participants at the end of the reproductive life phase
towards menopause (35–55 years old), others assessed only younger
women (18−27) or chose a broader age range. Kische et al. (2016) was
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Neuroscience and Biobehavioral Reviews 118 (2020) 669–680
included despite their age range, which exceeded our set age range
(18–45). This study was of additional value for our review as this was
the only study that included men, and the authors corrected for age in
all the reported results. The ages and sample sizes of all included studies
are also displayed in Fig. 2
3.6. Established link between sleep and depression
Most study outcomes on the association between sleep and de­
pression are consistent with previous research. They indicate an asso­
ciation between poor subjective sleep (daily diary, question item “Did
you have trouble sleeping”) and depressive mood (Kravitz et al., 2005).
Additionally, when subjective sleep quality worsens (measured using
St. Mary’s Sleep Questionnaire) depressive symptoms increase
(Hollander et al., 2001) and the risk of MDD diagnosis rises (Freeman
et al., 2004; Hollander et al., 2001). In studies using PSG measure­
ments, depressed participants were found to have a longer sleep onset
latency, spend more time in shallow sleep and show altered ratios of
delta sleep compared to controls (Antonijevic et al., 2003). Only Kische
et al. (2016) found no significant differences in sleep PSG or sleep
quality after grouping based on whether participants had experienced
depression in the past.
3.7. Link sex hormones and sleep
Kravitz et al. (2005) and Shechter et al. (2012) found that subjective
sleep quality is worse during the luteal phase (when progesterone levels
are highest) than during the follicular phase. Li et al. (2015) found that
higher urinary progesterone metabolites correlated with worse sleep
efficiency, and Baker et al. (2012) found that higher progesterone levels
correlated with more time being awake during the night. In contrast,
Lee et al. (2000) found that their low luteal progesterone group (non-
ovulating women) had more time spent awake during the night
(WASO), longer REM latency and more REM sleep in the luteal phase
 Table 1
Study design, measured variables and results of included studies, sorted alphabetically.
First author, Included participants (age Study design and Hormone measurement Study Depression Sleep assessment Results: sex hormones Results: sex hormones Results: association sleep-
year of range or mean) duration and/or intervention quality (symptom) subjective (S) and and sleep and depressive depressive symptoms
publication assessment objective (O) symptoms

Antonijevic 7 depressed women and 5 Cross-sectional case No intervention Fair MDD diagnosis S: None Associations between NR. Depression = ↓ time in
M.W.L. Morssinkhof, et al.

et al., 2003 controls (age range 20−44, control study Indwelling catheter O: Sleep EEG sleep and hormone levels stage 2 sleep * and ↑ SOL*.
mean age 28) measuring nocturnal in controls: NS. Ratio of SWS and delta-
secretion of estradiol, EEG activity between the
progesterone, LH and FSH first and second non-REM
period ↓ in depressed
patients vs. controls*.
Baker et al., 18 women with severe PMS Prospective case- No intervention Fair BDI-II and POMS S: PSQI PMS group (vs. controls): PMS group ↑ BDI scores ↑ P and ↑ E = ↓ % REM
2012 and 18 controls (age range control study (one Blood samples to measure O: Sleep PSG ↑ SWS*, ↓ stage 1 sleep*, in both phases*, sleep ↑ WASO
18−40, mean age 30) menstrual cycle, progesterone and estrogen ↑time in delta band* and deterioration of BDI P and E correlated with
measurement in delta wave amplitude*, ↑ scores in luteal phase in delta power in healthy
follicular and luteal awakenings*, ↓ feeling PMS group but not in group but not PMS
phase) refreshed after sleep*. control group*. group*.
Self-reported sleep onset Difference in P and E
= PSG sleep onset in levels in PMS vs.
both groups*. healthy group = NS
Ben Dor et al., 72 women (age range Prospective Administration of Good BDI every 2 weeks S: Daily Disturbed sleep ratings BDI depression scores Correlation of sadness,
2013 19−52, mean age 33) intervention study (2 leuprolide acetate (3.75 + Daily assessment of after leuprolide ↑*. after leuprolide ↑*. anxiety, or irritability with
months baseline, 2−3 mg im, administered in assessment of nighttime disturbed sleep symptoms:
months of leuprolide follicular phase) depressive mood disturbed sleep NS.
acetate) Assessment of estradiol O: None
serum level.
de Zambotti 11 women (age range 18-27, Cross-sectional Serum FSH, E2 and Fair BDI-II S: PSQI ↑ E = ↓ No. of arousals** NR. NR.

673
et al., 2015d mean age 29) observational study Progesterone O: Sleep PSG ↓ Arousal index **
(cross-sectional with
assessment in follicular
phase)
Freeman et al., 436 women (age range Prospective No intervention Good CES-D and DSM S: St. Mary’s sleep NR. ↑E levels = ↑ CES-D Poor sleep → MDD
2004 35−47, mean age 41) observational cohort Serum estradiol, FSH, LH MDD diagnosis questionnaire levels *. diagnosis, also after
study (4 years, 6 and testosterone at every O: None correction for
assessments each 8 assessment. antidepressants*.
months apart)
Gingnell et al., 34 women with previous Prospective, double Placebo vs. oral Good STAI-S and S: disrupted sleep Post treatment pill group Pill group ↑ daily N.R.
2013 mood symptoms when on blind randomized contraceptive MADR-S, daily symptom ↑ fatigue* and disordered depression symptoms in
oral contraceptives, controlled trial on (monophasic) for one symptom ratings O: None sleep* than pre-treatment final treatment week*
randomized to placebo (n = monophasic oral month/treatment cycle and than placebo post- than own baseline and
17) and oral contraceptive contraceptives (one No hormone treatment final treatment of
(OC) (n = 17) (age range month) measurements N.B. Women assigned to placebo group
18−45, mean age 25) placebo had higher rates MADR-S scores ↑ in pill
or disordered sleep at group
baseline**
Hollander et al., 436 women (age range Prospective Serum E2, FSH, LH, Good CES-D S: St. Mary’s ↓ E2 level over time → ↑ Association depressive ↑ depressive symptoms =
2001 35−47, mean age 41) observational cohort DHEAS and testosterone. Hospital Sleep poor sleep over time symptoms and E2: NS. ↑ poor sleep*, also after
study (4 follicular questionnaire (only in women aged adjustment for E2 levels.
phase assessments O: None 45+).
over 2 years)
Kische et al., 213 women and 204 men Cross-sectional Serum testosterone (T), Fair Questions about S: ISI, ESS In men: NR Grouping based on
2016 (age range 22−81, mean age observational study androstenedione (ASD), E1 previous O: Sleep PSG ↑ ASD = ↓ total sleep depressive symptoms →
52) and E2. depressive time* ↓ ESS score*. ↑ E2/ sleep differences NS.
symptoms TT ratio* and ↑ SHBG* =
↓ WASO
In women:
(continued on next page)
Neuroscience and Biobehavioral Reviews 118 (2020) 669–680
 Table 1 (continued)

First author, Included participants (age Study design and Hormone measurement Study Depression Sleep assessment Results: sex hormones Results: sex hormones Results: association sleep-
year of range or mean) duration and/or intervention quality (symptom) subjective (S) and and sleep and depressive depressive symptoms
publication assessment objective (O) symptoms

↑ E2 = ↑ ESS and ↑PSQI.

↑ E2/TT ratio = ↑ESS and
M.W.L. Morssinkhof, et al.

Kravitz et al., 196 women (age range
2005 42–52, mean age 47)
Lee et al., 2000 34 women, 22 of whom
ovulated (high luteal
progesterone levels) and 12
of whom did not (low luteal
progesterone levels) (age
range 25−39, mean age 32)
Li et al., 2015. 19 women, (age range
18−43, mean age 34)
↓ PSQI.
Prospective All not menopausal; Good Daily negative S: Daily report of Reported sleep quality: NR ↑ Negative mood = ↑
observational cohort menopause status checked mood symptoms trouble sleeping best mid-cycle (when E trouble sleeping*.
study (one menstrual through ovulation tests. O: None peaks) and worst in luteal
cycle) Urinary PdG, E1c, FSH and phase (when P levels are
LH highest).
Prospective case- No intervention Good CES-D and POMS S: POMS fatigue Luteal phase P levels and ↑ P in luteal phase = ↑ POMS and sleep in
control study (one Blood samples to measure scale sleep: NS. POMS mood during follicular phase: NS.
menstrual cycle, progesterone and estrogen O: Sleep PSG Menstrual cycle and total luteal phase*. ↑ increase in REM latency
measurement in sleep time, SOL, SE or Correlation with CES-D from follicular to luteal
follicular and luteal WASO in whole group: or the specific POMS phase = worse mood in
phase) NS. depression score: NS. luteal phase*.
Low luteal progesterone Low luteal P group (vs. ↓ POMS mood = ↓ sleep
group = ↑ WASO, longer high luteal P group): ↓ time duration.
REM latency and ↑ % positive mood state
REM sleep high luteal POMS score from
progesterone group. follicular to luteal
phase: ↓*.
Prospective No intervention Good Mood items from S: Previous ↑ E1G = ↑ SE*. NR ↑ Previous night’s sleep
observational cohort Assessment of urinary E1G the DLQ Nights’ Sleep, ↑ PdG = ↓ SE*. positively = ↑ positive
study (42 days) and PdG Daytime mood** ↓ negative
Sleepiness from mood**

674
Shechter et al., 7 women with PMDD and
2012 sleep complaints and 5
controls (mean age 31 years
old)
Toffol et al., 182 women attending
2019 gynecology clinic either
starting (n = 68), continuing
(n = 62) or switching (n =
52) their current hormonal
contraceptive (HC) (aged 18
or older)
the DLQ
O: Actigraphy (n
= 13)
Prospective case- No intervention Good Prospectively S: None REM sleep ↓ in early P levels in PMDD vs. PMDD group ↑SWS * * and
control study (one full Measured urinary monitored PMDD O: Sleep PSG luteal phase vs. early control is N.S. ↓ melatonin * than
menstrual cycle, progesterone symptoms follicular phase (both controls.
measurements every groups)*.
3rd night)
Prospective Intervention: hormonal Fair BDI-13 S: Insomnia Insomnia symptoms more Starting group had n = N.R.
observational cohort contraceptives (including symptoms, early likely in HC starters, 6 (9%) who reported
study both short-term awakening significant after self-harm at follow up,
contraceptives (e.g. oral) O: None controlling for kind of significantly higher
and long-acting (e.g. IUD, contraceptive (long vs. than other groups.
implant) short-acting)* All self-harming
No hormone Early awakening participants reported
measurements significantly more some psychological
persistent in continuers symptoms at baseline, 2
had psychiatric
diagnosis.

∼ indicates predictor-outcome association, = indicates correlation, * indicates p < 0.05, ** indicates p < 0.01, *** indicates p < 0.0001, NR = not reported, NS = not significant. PSG = polysomnography, SWS = Slow
Wave Sleep, ArI = Arousal Index, ISI = Insomnia Severity Index, ESS = Epworth Sleepiness Scale, PSQI = Pittsburgh Sleep Quality Index, MDD = Major Depressive Disorder, PMDD = Premenstrual Dysphoria Disorder,
PMS = Premenstrual Syndrome, CES-D = Center for Epidemiological Studies Depression Scale, BDI = Beck Depression Inventory, BDI-13 = 13-item Beck Depression Inventory, MADR-S = Montgomery–Åsberg
Depression Rating Scale, STAI-S = State-Trait Anxiety Inventory, DLQ = Daily Life Questionnaire, POMS = profile of mood scale.
P = progesterone, E = estradiol, T = testosterone, PdG = pregnanediol (main urinary metabolite for progesterone), E1 = estrone, E2 = estradiol, OC = oral contraceptives, ISI = insomnia severity index, PdG =
pregnanediol, ASD = androsterone, SHDG = Sex hormone-binding globulin.
Neuroscience and Biobehavioral Reviews 118 (2020) 669–680
M.W.L. Morssinkhof, et al.
compared to the high luteal progesterone group (ovulating women).
Kravitz et al. (2005) also found that participants reported the best
sleep during the mid-menstrual cycle phase, when estrogen levels are
highest. Li et al. (2015) found that estrogen metabolite level was po­
sitively associated with sleep efficiency, also indicating better sleep
when estrogen levels were higher.
de Zambotti et al. (2015) found higher estrogen levels to be asso­
ciated with fewer arousals during sleep. Lowered estrogen levels were
associated with poorer sleep over time in Hollander et al. (2001), but
this was only significant in the older (45+) age group. Kische et al.
(2016) found that higher estrogen levels were associated with more
daytime sleepiness and more sleeping problems. A higher ratio of es­
tradiol to testosterone (E2/TT ratio) was associated with more daytime
sleepiness and fewer sleeping problems.
Baker et al. (2012) found that both higher progesterone and es­
trogen levels were correlated with lower percentage REM sleep, an
increase in WASO, and an increase in delta power, but only in control
participants and not in women with PMS.
In summary, both higher and lower endogenous progesterone levels
(through absence of ovulation, or after suppression progesterone levels)
seem to worsen sleep quality. Higher endogenous estrogen levels might
have a positive effect on sleep quality, although the results vary
strongly.
3.8. Link sex hormones and depression
No significant sex hormone differences were found in the depressed
group compared to healthy controls in the study of Antonijevic et al.
(2003). Baker et al. (2012) and Shechter et al. (2012) found no sig­
nificant differences in sex hormone levels (estrogen and progesterone)
between women with PMDD and controls. Lee et al. (2000) showed that
women with lower luteal progesterone (because of anovulation) had
worse mood scores in the luteal phase compared to their own follicular
phase, as well as compared to the high progesterone/ovulatory group.
Freeman et al. (2004) found that higher estrogen levels were associated
with more depressive symptoms, although their method included long-
term changes in estrogen instead of short term changes as reported by
Baker et al. (2012) and Shechter et al. (2012).
Thus, depressed participants do not seem to have different absolute
sex hormone levels than control participants. There are indications,
however, that changes in sex hormones, specifically progesterone and
estrogen, over time could be accompanied by increasing depressive
symptoms.
3.9. Hormone intervention results
Ben Dor et al. (2013) suppressed both estrogen and progesterone
levels which was subsequently associated with an increase in reported
sleep difficulties. In the study of Ben Dor et al. (2013) suppression of
both progesterone and estrogen was related to a small increase in de­
pressive symptoms of the participants.
Gingnell et al. (2013) only included women who previously ex­
perienced side effects from the oral contraceptive pill (88% of partici­
pants reported depressive mood and 20% reported disturbed sleep as
previous side effects). They used a double-blind placebo-controlled
setup and showed that the contraceptive pill, but not placebo, had
significant negative effects on sleep and depression in the treatment
group. Toffol et al. (2019) showed that symptoms of insomnia are more
likely after starting hormonal contraceptives (after controlling for
whether the contraceptive method was short term, like the pill, or long
term, like an IUD or implant). They also found an increase in odds for
self-harm, with 6 out of 68 women (9%) reporting self-harm behavior
after starting hormonal contraception, while none of the women in the
other groups reported self-harm. All self-harm reporting participants
reported some psychological symptoms at baseline, with 2 out of 6
having a previous psychiatric diagnosis. Thus, both suppression of
675
Neuroscience and Biobehavioral Reviews 118 (2020) 669–680
endogenous sex hormones as well as OC use has been associated with an
increase in reported sleep problems and sometimes to increased de­
pressive symptoms. Whether these effects are caused by the exogenous
hormones in the contraceptives, or the changes in endogenous hormone
levels (altered by the contraceptives) is not yet clear.
3.10. The relation between sex hormones, sleep and mood
Women with PMDD had more slow wave sleep (Baker et al., 2012;
Shechter et al., 2012) and had longer and more prominent delta band
activity (Baker et al., 2012) than women without PMDD, although
absolute endogenous progesterone and estrogen levels between the
groups were similar.
Only one study of all included studies reported the three-way in­
teraction between sleep, depressive disorder and sex hormones: Lee
et al. (2000) included 34 women (age range 25−39) and showed that a
stronger increase in REM latency from the follicular to luteal phase was
associated with an increase in negative mood. Thus, for understanding
the interaction between sleep, sex hormones and mood, the studies that
investigated differences between women with PMDD and healthy con­
trols, and the women with low or high endogenous progesterone were
useful. Women with more depressive symptoms through PMDD showed
altered sleep despite similar endogenous hormone levels, and women
with lower progesterone levels had a stronger increase in negative
mood if their REM sleep timing changed more throughout their cycle.
4. Discussion
4.1. Summary
This systematic review summarizes and compares studies that ex­
amine sex hormones, sleep problems and depressive symptoms or a
diagnosis of depression. It shows that previous studies mainly in­
vestigated the influence of endogenous female gonadal sex hormones,
with most studies exploring effects of endogenous short-term fluctua­
tions (in the form of menstrual cycle monitoring) (n = 5), and only a
few studies exploring effects of long-term hormone changes (e.g. pro­
spective female ageing studies over a number of years) (n = 3). Studies
in males are lacking (n = 1), and no studies assessed the effect of ad­
ministered testosterone. Moreover, controlled pre-post studies assessing
the influence of sex hormone interventions are sparse (n = 2).
Synthesis of the results of this systematic review firstly replicates
the assumed bidirectional relationship between sleep and depression,
showing that depressed patients have prolonged sleep latency and more
subjective sleep problems. Additionally, an increase in sleep problems
can result in - or accompany an increase of - depressive symptoms or a
diagnosis of depression.
Secondly, the evidence for a direct relationship between en­
dogenous sex hormone levels and sleep seems to be stronger than the
evidence for a relationship between endogenous sex hormone levels
and depressive symptoms. Higher estrogen levels may be protective
against reported sleep problems, a relationship between endogenous
hormone levels and depression was inconclusive. In the studies that
used a hormone intervention, all three interventions did show an effect
on sleep and mood. Both suppression of endogenous sex hormones with
leuprolide as well as administration of exogenous hormones through
hormonal contraceptives showed negative effects on sleep quality and
an increase in depressive symptoms, although the effect sizes varied
strongly (Cohen’s d in Toffol et al.: 0.12; in Ben Dor et al.: 58.3) or were
calculated from a specific sample that is not easily generalized to the
general population (Gingnell et al. tested only women who experienced
side effects from OC before; Cohen’s d: 0.66).
Two out of the three administration studies showed indications that
not all women, but a subgroup of women may be vulnerable to these
effects. Toffol et al. (2019) found that women who showed self-harm
behavior after starting hormonal contraceptives all reported negative
M.W.L. Morssinkhof, et al.
psychological symptoms before starting the hormonal contraceptives.
Gingnell et al. (2013) only included women who had previously ex­
perienced depressive symptoms while using hormonal contraceptives,
and found that, even in a placebo-controlled setup, women who were
provided hormonal contraceptives experienced significant depressive
mood and disturbed sleep. This suggests that women with a history of
psychological problems and women with previous depressive symptoms
during hormonal contraceptives use may have an increased risk for
developing psychological problems when starting hormonal contra­
ceptives.
Interestingly, the studies comparing sleep controls with women who
suffer from PMDD, a hormone-related mood disorder seem to show the
opposite of the sleep changes that have been found in persons with
major depressive disorder. Women with PMDD show more SWS
Fig. 3. Visualization and summary of the found possible interactions between sleep, depression and sex hormones. Green arrows represent the known connection
between sleep and depressive symptoms, orange arrows and text boxes represent the hypothetical effects based on the current literature described in this review.
676
Neuroscience and Biobehavioral Reviews 118 (2020) 669–680
Fig. 2. Visualization of study setups and samples. – Mean
sample sizes (A) and age ranges (B) of included studies, sorted
alphabetically by name of first author. (A): red circle displays
an observational study, blue triangle represents an interven­
tion study. (B): Black squares display lowest and upper age,
diamond shape displays mean age; dashed lines display studies
that only included women, solid line represents studies that
included both men and women. Shechter et al. (2012) did not
report an age range, Toffol et al. (2019) did not report mean
age or age ranges, De Zambotti et al. (2015) reported a mean
age that was higher than the age range.
whereas depressed people have less SWS in comparison to healthy
controls; women with PMDD have longer and more prominent delta
band activity (indicating more deep sleep) whereas depressed people
show a decrease in delta activity; in women with PMDD, as well as the
women in Lee et al. (2000), a longer REM latency predicts worse mood,
whereas in depression a shorter REM latency is seen. These findings
suggest that PMDD is not a periodic ‘worsening’ of depression, but may
be a truly different disorder with respect to sleep architecture.
4.2. Limitations
The studies included in this systematic review have several meth­
odological limitations.
The prospective long-term studies had multiple measurements over
M.W.L. Morssinkhof, et al.
time, with multiple momentary cross-sectional assessments of sex hor­
mones, sleep and/or mood. Although the analyses of these studies did
assess correlations between sex hormones, sleep problems and mood at
each measurement session, their analyses could determine whether sex
hormone changes over time make individuals more vulnerable for sleep
problems or depression. Thus, lack of longitudinal data analyses limited
the scope of these studies.
Lee et al. (2000) was the only study that assessed the association
between sleep, mood and sex hormones. They found that participant’s
negative mood did not correlate with sleep variables in the follicular
phase, but in the luteal phase participants with a higher increase in
REM sleep latency (which is also seen in depressed patients) reported
worse mood scores. The finding that the association between negative
mood and REM sleep latency was only seen in the luteal phase might
suggest that women are more vulnerable to depression or depressive
moods during the luteal phase, even if they do not necessarily suffer
from PMDD. This study also found that participants with high proges­
terone levels showed a bettermood, in contradiction to other studies
that found that higher progesterone levels had a negative effect on
mood. However, this could be related to a bias in the study design.
Their participants were all women who wanted to conceive, but 12 out
of 34 did not experience an ovulation in the month of testing. Ovulation
was determined by the researchers through luteal progesterone levels
(with high levels of progesterone indicating ovulation), but it is not
described in the study whether participants themselves knew whether
they had ovulated. It is possible that the lack of ovulation may have
affected the anovulatory women’s mood negatively, since the differ­
ences in mood scores may also be affected by their disappointment in
lack of ovulation that cycle.
Only one study (Kische et al., 2016) included male participants in
their setup. In men, the effect of endogenous changes in sex hormones
are harder to study, since they have no defined moments where their
sex hormones endogenously fluctuate (e.g. menstrual cycles). Although
the association between testosterone and sleep has been investigated
(Leproult and Van Cauter, 2011; Schmid et al., 2012; Wittert, 2014),
studies on the relationship between testosterone, sleep and depression
are scarce. An important note in the findings of Kische et al. is that their
participants’ age range was partially outside of the set age range in this
review. Although they corrected for age in their analyses, in the in­
terpretation of their results it should be noted that the results also
contain postmenopausal women and older men, who both have lower
endogenous hormone levels than their younger counterparts (Freeman
et al., 2004; Muller et al., 2003).
Studies with both pre-and post-measurements in healthy women
starting hormonal interventions (such as oral contraceptives) are very
underrepresented in this field. Our initial full search did find three
studies on sleep and depression in users and non-users of oral contra­
ceptives. However, these studies were cross-sectional, and included
long-time oral contraceptive users, whose oral contraceptives did not
represent a hormonal intervention. Thus, we decided not to include
these studies for this review.
An important consideration in some of the studies, especially the
hormone suppression study by Ben Dor et al., is that hormones can also
affect physical state. A well-known factor around menopause is that
women can experience hot flashes, presumably due to drops in en­
dogenous estrogen and progesterone, which at night can also affect
sleep quality and nocturnal awakenings (Joffe et al., 2013). Indeed, Ben
Dor et al. reported an increase in hot flashes in their participants after
suppression of sex hormones. OC might have also side effects such as
lower libido and weight gain, both of which can affect users’ quality of
life. Additionally, both lower libido and weight gain can be symptoms
of depression in validated depression questionnaires, and as a con­
sequence oral contraceptive side effects might also cause depression
scale scores to increase. Altogether, the physical effects of sex hormone
changes can also affect sleep and depression indirectly.
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Neuroscience and Biobehavioral Reviews 118 (2020) 669–680
4.3. Implications
Estrogen has been associated with sleep, which may be relevant for
clinical purposes. Sex hormone levels were not clearly associated with
depressive symptoms nor a diagnosis of depression. It is possible that
not the absolute sex hormone levels, but relative changes in sex hor­
mone levels are related to mood changes (Bloch et al., 2003). For ex­
ample, a relative reduction in testosterone levels in men is associated
with an increase in depressive symptoms, although in the same parti­
cipants absolute testosterone levels do not seem to correlate with re­
ported depressive symptoms (Kische et al., 2018).
Another explanation is that there may be individual differences in
the sensitivity for sex hormone changes causing some individuals to be
more susceptible to hormonal mood complaints. Mechanisms involving
differences in neurosteroids (Rapkin, 1999; Sundström Poromaa et al.,
2003), MAO-receptors (Sacher et al., 2010) and GABA-A receptors
(Bäckström et al., 2011; Klatzkin et al., 2006) have been proposed to
explain individual vulnerability for the effects of sex hormones.
The hypothesis that hormone-related depressive symptoms have a
different etiology than MDD has also been suggested in previous studies
in menopausal women and women with PMDD (Klatzkin et al., 2010;
Kornstein et al., 2010). These studies suggest that hormonal depressive
complaints may have a different underlying mechanism. One finding
supporting this hypothesis is that these “hormonal depression phases”
respond to different treatments which seem to target sex hormones and
their metabolites.. For example, intermittent use of the antidepressant
fluoxetine (Prozac) relieves PMDD symptoms in a matter of days,
whereas the effect is usually noticeable after 6–8 weeks in MDD
(Steinberg et al., 2012; Steiner et al., 2003), which may be related to
the much faster effect of fluoxetine on progesterone metabolites (Devall
et al., 2015; Steiner et al., 2003). Additionally, depressive symptoms
during menopause can be relieved through sex hormone replacement
therapy (Gordon and Girdler, 2014).
4.4. Conclusion
This systematic review shows that studies on endogenous sex hor­
mone levels, sleep and depression have mainly been conducted in
women, and that studies on exogenous sex hormone administration are
rare. Based on the current literature there seems to be more evidence
for an association between absolute sex hormone levels and sleep
problems, than a relation between absolute sex hormone levels and
depressive symptoms or a diagnosis of depression.
Our findings underscore large gaps in the field of neuroendocri­
nology and psychiatry: prospective, controlled administration studies
on sex hormones and the effect of short-term hormonal changes on
sleep and mood are lacking. This is remarkable given that millions of
people use hormonal medications worldwide, such as hormonal con­
traceptives, sex hormone replacement and hormone suppressors.
Furthermore, men are underrepresented in this area of research.
4.5. Future recommendations
Since sleep problems and depression are common and impact on
quality of life, it is useful to understand if and how sex hormones
contribute to these problems. Therefore more studies on endogenous
sex hormones and exogenous sex hormone changes over time are
needed.
The studies that were currently included used a wide range of ob­
servations and interventions, as a consequence these data were deemed
unfit for a meta-analysis. If the body of research in this field grows, this
will make it possible to do meta-analyses to assess effects of specific
interventions or endogenous hormones on sleep and depression (e.g.
hormone suppression, oral contraceptives or endogenous hormone
changes).
Further studies in this area are warranted to understand which
M.W.L. Morssinkhof, et al.
groups may possibly benefit from sex hormone use, and which groups
may be more vulnerable for negative effects of changes in sex hormone
levels, contributing to the field of “precision psychiatry”. These studies
should also take into account that depressive episodes in times of
changes in sex hormone levels (such as during pregnancy and post­
partum, PMDD or menopause) may have a different entity, which may
require different therapeutic approaches.
Some sex-specific and sex-sensitive therapeutic approaches for de­
pression and sleeping problems have already been described. It was
shown that a single dose of the antipsychotic olanzapine increases SWS
and deep sleep in women, whereas it decreases SWS and deep sleep in
men (Giménez et al., 2011). The American Food and Drug Adminis­
tration (FDA) renewed its guideline for the benzodiazepine Zolpidem to
a 50 % lower dose in women because it metabolizes more slowly in
women, the first ever sex-specific guideline for benzodiazepines
(Cubała et al., 2010; US Food and Drug Administration, 2018). As
mentioned, the antidepressant fluoxetine is intermittently prescribed
against depressive symptoms in PMDD. In 2019 a specific anti­
depressant for postpartum depression, brexanolone (Zulresso), an ana­
logue of a progesterone metabolite, was fast-track approved by the FDA
(Canady, 2019; US Food and Drug Administration, 2019). These de­
velopments already indicate a growth in research on sex-specific
knowledge and treatment options in sleep problems and depression,
and future research should further clarify the effects of sex hormones as
well.
Funding
This study was supported by a Veni grant (grant number 91619085,
2018), from the NWO, Netherlands, received by BB. The sponsor did
not have any role in study design, the collection, analysis and inter­
pretation of data; in the writing of the manuscript; and in the decision
to submit the article for publication. Systematic review number PROSP­
ERO 2019 CRD42019125970.
Declaration of Competing Interest
Prof. van den Heuvel reports previous support by Benecke, other
authors report no other conflicts of interest.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at https://doi.org/10.1016/j.neubiorev.2020.08.006.
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