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Mechanisms related to the pathophysiology
and management of central hypothyroidism
Masanobu Yamada* and Masatomo Mori
S U M M ARY
Central hypothyroidism (CH) is defined as hypothyroidism due to
insufficient stimulation of the thyroid gland by TSH, for which secretion
or activity can be impaired at the hypothalamic or pituitary levels. Patients
with CH frequently present with multiple other pituitary hormone
deficiencies. In addition to classic CH induced by hypothalamic–pituitary
tumors or Sheehan syndrome, novel causes include traumatic brain injury
or subarachnoid hemorrhage, bexarotene (a retinoid X receptor agonist)
therapy, neonates being born to mothers with insufficiently controlled
Graves disease, and lymphocytic hypophysitis. Growth hormone therapy,
which may be used in children and adults, is now also recognized as a
possible cause of unmasking CH in susceptible individuals. In addition,
mutations in genes, such as TRHR, POU1F1, PROP1, HESX1, SOX3, LHX3,
LHX4 and TSHB, have been associated with CH. The difficulty in making
a clear diagnosis of CH is that the serum TSH levels can vary; values are
normal in most cases, but in some might be low or slightly elevated. Levels
of endogenous T4 in serum might also be subnormal. Appropriate doses
of levothyroxine for T4 replacement therapy have not been confirmed, but
might need to be higher than presently used empirically in patients with CH
and should be adjusted according to age and other hormone deficiencies, to
achieve free T4 concentrations in the upper end of the normal range.
Keywords bexarotene, GH therapy, subarachnoid hemorrhage,
traumatic brain injury, TSH-releasing hormone
Review criteria
We searched PubMed for publications with the following search terms: “central
hypothyroidism”, “hypothalamic hypothyroidism”, “pituitary hypothyroidism”
and “hypopituitarism” and combined these words with “pituitary adenomas”,
“Rathke’s cleft cyst”, “craniopharyngioma”, “empty sella” and “lymphocytic
hypophysitis”. All selected papers were English-language, full-text articles. Some
of the references were not included because of space restrictions.
M Yamada is Associate Professor, and M Mori is Professor and Chairman,
in the Department of Medicine and Molecular Science, Gunma University
Graduate School of Medicine, Gunma, Japan.
Correspondence
*Department of Medicine and Molecular Science, Gunma University Graduate School
of Medicine, 3–39–15 Showa-machi, Maebashi, Gunma 371–8511, Japan
myamada@med.gunma-u.ac.jp
Received 7 April 2008 Accepted 1 September 2008 Published online 21 October 2008
www.nature.com/clinicalpractice
doi:10.1038/ncpendmet0995
december 2008 vol 4 no 12  nature clinical practice ENDOCRINOLOGY & METABOLISM 683
INTRODUCTION
Hypothyroidism is a common disorder and
is most frequently caused by primary hypo­
thyroidism. Characteristic laboratory findings for
primary hypothyroidism are subnormal levels of
thyroid hormone and raised TSH levels (caused
by normal feedback regulation) in serum. Central
hypothyroidism (CH) results from disturbance
to the thyroid stimulation system. The precise
prevalence of CH is unknown, but it is thought
to be much lower than that of primary hypo­
thyroidism. However, CH arises from a number
of hypothalamic and pituitary disorders, the
most frequent of which is pituitary adenoma.1
Given that the prevalence of pituitary ade­nomas
in the general population is greater than 10%,
the true prevalence of CH might be much
higher than that reported.2 Approximately 15%
of 300 of our patients with pituitary adenomas
examined­ in the past year have had CH. Van Tijn
et al.3 reported the incidence of congenital CH
to be 1 per 16,404 neonates, with 13.5% among
these having permanent hypothyroidism.
Traumatic brain injury, subarachnoid hemor­
rhage, lymphocyte hypophysitis, or Sheehan
syndrome, any time up to several decades pre­
viously, might cause CH and lead to deficiency
in secretion of multiple pituitary hormones. A
full, detailed history should, therefore, be taken
and tests done for a variety of hormone deficien­
cies. The characteristic order and prevalence of
the disturbances of pituitary hormones differs
in different disorders and might help to identify
the origin of the CH.
In general practice, serum TSH is the best indi­
cator for detecting hypothyroidism and hyper­
thyroidism and for monitoring treatments of
thyroid disorders. This approach works, however,
only if the hypothalamic–pituitary–thyroid axis
is normal. Conversely, the strategy of first-line
TSH measurement can miss patients with CH.
In this Review, we focus on prevalence of CH
and thyroid hormone status, particularly serum
TSH level in each disorder, and discuss appropriate
management.
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TRH
TRH receptor
COA
T3
T3 T3
T3
T3
NcoR TR TSH
T3
T3
T3
Glycosylation Conjugation of T3
α and β chains
TSH
TSH
Secretion
TSH
TSH
Figure 1 The hypothalamic–pituitary–thyroid axis. TRH not only stimulates the
secretion of TSH from the pituitary but also regulates conjugation of the α and β
chain of the TSH molecule and affects glycosylation, which changes the biological
activity of TSH. Abbreviations: COA, coactivators; NcoR, nuclear receptor
corepressor; TR, thyroid hormone receptor; TRH, TSH-releasing hormone.
THE HYPOTHALAMIC–PITUITARY–THYROID
AXIS
Levels of thyroid hormones in serum are tightly
regulated by the hypothalamic–pituitary–thyroid
axis (Figure 1). Hypothalamic TSH-releasing­
hormone (TRH) is secreted mainly from the
paraventricular nucleus in the hypothalamus
and reaches the median eminence through
axonal transport. TRH is then carried via the
hypo­thalamic portal vein to thyrotrophs, which
produce TSH, where it binds to TRH receptors
and stimulates the genes that express the TSH
α and β subunits. Apart from these thyrotropic
effects, TRH also regulates the conjugation of
the TSH α and β chains and glycosylation of the
TSH molecule to control its biological activity.
Mature TSH is secreted from the pituitary gland
and reaches the thyroid gland, where it stimulates
ncpendmet_2008_086f1.eps
thyroid hormone production and release.
The main hormone secreted from the thyroid
gland is T4, which reaches the peripheral organs
and is converted to T3 by deiodinase. T3 enters
the cell nuclei and binds to thyroid hormone
receptor α and β isoforms on targeted genes,
thereby regulating gene transcription. Thyroid
hormone receptors act on the targeted genes as
either heterodimers with the retinoid X receptor
684 nature clinical practice ENDOCRINOLOGY & METABOLISM
or as homodimers. Many cofactors, such as
co­repressors (nuclear receptor corepressor,
silencing mediator of retinoid and thyroid
hormone receptors, etc.) and coactivators
(steroid receptor coactivator-1 and cyclic AMP
response element binding-binding protein,
etc.), are also involved in the regulation of tar­
geted genes. Meanwhile, secreted thyroid
hormone reaches the hypo­thalamus and the
pituitary, where it inhibits production and
secretion of TRH and TSH, thereby establishing
the hypothalamic–pituitary–thyroid axis. If any
factor in this axis is disturbed, hypothyroidism
will occur.
CAUSES OF CLASSIC CENTRAL
HYPOTHYROIDISM
Adenoma
Pituitary adenomas are the most frequent causes
of CH, accounting for more than half of all cases
(Table 1). In a Spanish study, 45.5 cases of CH
were calculated to occur annually per 100,000 of
the general population, of which 61% were due to
pituitary adenomas.4
Mechanical compression of portal vessels
and the pituitary stalk, caused by the expanding
adenoma, was postulated to be the predomi­
nant mechanism of hypopituitarism, including
CH. The results of this pressure might be ische­
mic necrosis of portions of the anterior lobe.1,5
Increased intrasellar pressure can also lead to
compression of the portal vessels and impairs
the delivery of hypothalamic hormones to the
anterior pituitary.6 These mechanisms could be
common to other space-occupying lesions in the
pituitary, as discussed later.
In most cases, CH occurs concurrently with
other pituitary hormone deficiencies but isolated
TSH deficiency has also been reported. In a study
of 48 patients, 17%, 19%, 21%, 10% and 10% of
patients had deficient levels of two, three, four,
five and six pituitary hormones, respectively, and
one had isolated TSH deficiency. Hormone defi­
ciencies were seen for luteinizing hormone/
follicle­-stimulating­ hormone (LH/FSH) in 85% of
patients, growth hormone in 65%, adrenocortico­
tropic hormone (ACTH) in 62%, TSH in 60%,
antidiuretic hormone in 23% and prolactin
in 15%.6–8 Conversely, the prevalence of CH in
patients with pituitary adenomas has not been
systematic­ally assessed. Faglia et al.,9 in 1970,
identi­fied CH in 15% of adenoma patients; we
have found a similar prevalence among 300 patients
with pituitary adenomas, and ­approximately 75%
YAMADA AND MORI december 2008 vol 4 no 12

of patients with CH showed normal TSH levels
(unpublished data).
Tumors might secrete growth hormone, prolac­
tin, gonadotropin or ACTH, leading to im­balance
in the hypothalamic–pituitary–thyroid axis.
In patients with acromegaly due to adenomas
that secrete growth hormone, Eskildsen et al.10
reported significantly reduced serum levels of
TSH and T4 in patients with adenomas com­
pared with those in healthy controls, suggest­
ing CH. In a study of Cushing disease caused by
ACTH-secreting adenomas, 7 of 11 patients had
low T4 levels, and in 4 patients thyroid hormone
levels normalized within 10 days of curative
surgery. Sibal et al.11 reported that in patients
with prolactinoma and macroadenoma treated
with dopamine agonists, reduced levels of LH/
FSH were observed in 77% of patients, TSH in
41% and ACTH in 23%.
Pituitary tumor apoplexy
Pituitary tumor apoplexy often occurs in
patients with untreated pituitary adenomas
or after stimu­lation tests with hypothalamic
hormones (such as TRH and corticotropin-
releasing­ hormone) to assess pituitary hormone
levels. Loss of hormone secretion, particu­
larly of ACTH, and to a lesser extent TSH, can
rapidly become life-threatening­ and requires
urgent replacement therapy. Acute, severe hypo­
pituitarism should be vigorously treated with
glucocorticoids. If neuro-­ophthalmological
symptoms, such as visual impairment, sudden
onset of severe headache and alteration of the
level of consciousness, are present, emergency
surgery might be indicated.
Lubina et al.12 reported a series of 40 patients
with pituitary tumor apoplexy, in whom 63%
of adenomas were nonfunctional and 31% were
prolactinomas. CH was diagnosed in 54%, 79% of
patients developed hypogonadotrophic hypogo­
nadism, and hypocortisolism developed in 40%.
Zayour et al.13 reported pituitary apoplexy in 13
patients with remarkably high intrasellar pres­
sure, whereas serum concentrations of prolactin
were generally low. These low serum prolactin
levels suggest the presence of ische­mic necrosis of
the anterior pituitary; normal or elevated serum
prolactin levels in patients with nonprolactin-
secreting macroadenomas indicate the presence of
viable pituitary cells and a high likelihood of post­
operative recovery of pituitary function. Patients
with pituitary tumor apoplexy should undergo
long-term monitoring for hypopituitarism,
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Table 1 Causes of central hypothyroidism.
Cause Congenital Acquired
Classic causes
Space-occupying lesions (brain or pituitary; Yes Yes
pituitary adenoma, craniopharygioma, etc.)
Radiation No Yes
Vascular disease (Sheehan syndrome, etc.) Yes Yes
Nonclassic causes
Traumatic brain injury or subarachnoid hemorrhage No Yes
Drug-induced (bexarotene, carbemazepine, etc.) No Yes
Growth hormone therapy No Yes
Infection (lymphocytic adenohypophysitis, No Yes
lymphocytic hypophysitis)
Set point diseases (infant’s born to mothers with Yes No
inadequately controlled Graves disease, etc.)
Genetic mutations Yes No
Idiopathic Yes Yes
including CH or recurrent pituitary adenoma,
which should be treated if it occurs.
Craniopharyngioma
Craniopharyngioma is a common parasellar
tumor that can arise from embryonic squamous
remnants of the Rathke pouch. These tumors are
often large, generally aggressive and frequently
infiltrate surrounding brain structures. One
study reported deficiencies in growth hormone
and LH/FSH in about 95% of patients and ACTH
deficiency in more than 85%, with CH arising in
more than 90% and diabetes insipidus in 33%.14
In another report, growth hormone deficiency
was noted in 73%, ACTH deficiency in 32% and
hypogonadism in 77%, with CH being reported in
25% and diabetes insipidus in 16%.15 Surgery on
this type of tumor is difficult and, therefore, hypo­
pituitarism arising after surgery or radiotherapy,
including CH, is frequently observed (Table 1).
Rathke cleft cysts (also called craniopharyngeal­
cysts) are epithelial-cell-lined cystic lesions of the
pituitary gland that are believed to derive from
remnants of the Rathke pouch, a dorsal invagina­
tion of the stomodeal ectoderm. Although these
cysts are found at autopsy in 13–22% of people,
they generally remain asympto­matic throughout
life. If patients become symptomatic, they most fre­
quently present with headaches, ­hypo­pituitarism
to varying degrees, and visual disturbances, fol­
lowed by diabetes inspidus. CH has been iden­
tified in 7–35% of sympto­matic patients,16–18
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while deficiencies of growth hormone, LH/FSH
and ACTH, and panhypopituitarism, respectively,
have been observed in 13–66%, 15–43%, 6–23%
and 13–19% of patients.
Empty sella syndrome
Primary empty sella syndrome is a neuro­
radiological entity characterized by a sella filled
with cerebrospinal fluid and a flattened pituitary
gland due to raised pressure in the sella turcica.
This syndrome has been reported in 6–20% of
unselected autopsies. Secondary empty sella syn­
drome is induced by surgery or radiation therapy
for pituitary adenomas, traumatic injury, infection,
and Sheehan syndrome.
Primary empty sella syndrome is more
common in women than men and is fre­
quently associated with obesity, hypertension,
headache, and nonspecific visual alterations.
Hypopituitarism is present in 10–57% of
patients, and hyperprolactinemia due to dis­
tortion of the pituitary stalk is seen in 10–18%,19
but growth hormone deficiency is the most fre­
quent pituitary hormone deficiency. CH has
also been identified in some cases (Table 1).
Cannavò et al.20 examined 43 patients with
primary empty sella syndrome and found CH
in two; growth hormone deficiency was present
in 15, hypothalamic hypogonadism in 11, and
adrenal insufficiency in 5. In the two CH cases,
serum TSH levels were at the lowest limit of the
normal range.
Sheehan syndrome
Sheehan syndrome occurs as a result of ische­mic
pituitary necrosis due to severe postpartum
hemor­rhage, frequently causing pan­hypo­
pituitarism (in 56–84% of cases) and selective
hormone deficiency.20,21 As growth-hormone-
secreting cells are located in the lower and lateral
regions of the pituitary gland, deficiency of this
hormone is observed in most patients with
Sheehan syndrome.
Sheehan syndrome can cause lactation failure
and amenorrhea, adrenal insufficiency and
CH, which has been reported in about 90% of
patients (Table 1). Serum TSH levels in most
patients are within normal limits in the acute and
late phases, although severe hypothyroidism can
arise.22 Serum TSH levels are often ­paradoxically
elevated due to the reduced biological activity, as
discussed below.23 Furthermore, the time from
birth to the onset of hormone deficiency can
vary from several days to a few decades.
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Radiation therapy
External radiotherapy for tumors of the head
and neck might affect the hypothalamus, pitu­
itary, and/or the thyroid gland.24 CH has been
observed in 20–50% of patients irradiated for
nasopharyngeal or paranasal sinus tumors, and
in 6–65% of patients irradiated for brain tumors
(Table 1). The risk of developing CH is related
to the total radiation dose. Bhandare et al.24
examined­ 312 patients between 1964 and 2000,
who were treated with radiation therapy for
extracranial head and neck tumors. Clinical CH
was observed in 17 (5%) patients, with a median
clinical latency of 4.8 years, while clinical primary
hypothyroidism was observed in 40 (20%)
patients, in whom the median clinical latency
was 3.1 years. Multivariate analysis revealed that
fractiona­tion, adjuvant chemotherapy, and total
dose to the pituitary did not significantly correlate
with CH, but total dose to the thyroid was signifi­
cantly correlated with primary hypothyroidism.
In patients with pituitary adenomas treated with
fractionated radiotherapy and stereotactic radio­
surgery, hypopituitarism developed as a delayed
complication in 12% of patients at a median of
84 months.25 Similarly, in cancer survivors the
cumulative incidence of central and mixed hypo­
thyroidism is high during the first 10 years after
cranial irradiation.
NONCLASSIC CAUSES OF CENTRAL
HYPOTHYROIDISM
Traumatic brain injury and subarachnoid
hemorrhage
Several studies in the past few years have demon­
strated a surprisingly high prevalence of hypo­
pituitarism, including CH, induced by trau­matic
brain injury or subarachnoid hemor­rhage
(Table 1).1,26 The prevalence of hypo­pituitarism in
the chronic phase after traumatic brain injury and
aneurismal subarachnoid hemorrhage is 28% and
47%, respectively. The estimated overall incidence
of traumatic brain injury in Europe is 235 cases per
100,000 people in the general popu­lation yearly.
In a review by Benvenga et al.27, hypo­pituitarism
after traumatic brain injury was reported to occur
in a male to female ratio of 5:1, with about 60%
of the patients being in the age range 11–29 years;
road accidents accounted for half of the cases.
Since the signs and symptoms­ of hypopituitarism
might be subtle and could overlap with the neuro­
logical and psychiatric sequelae of traumatic brain
injury and sub­arachnoid hemor­rhage, this type
of hypopituitarism remains undiag­nosed in many
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cases. Patients’ quality of life is impaired and they
have an adverse metabolic profile, which might
contribute to morbidity and poor recovery after
these events.
In patients with hypopituitarism after trau­
matic brain injury, LH/FSH and growth hormone
deficiencies are more common than ACTH defi­
ciency, which in turn is more common than TSH
deficiency.26 By contrast, after subarachnoid
hemorrhage, growth hormone and ACTH defi­
ciency is more common than LH/FSH and TSH
deficiency. CH is observed in 1–10% of patients
after traumatic brain injury and 3–9% of patients
in the chronic phase of subarachnoid hemor­
rhage. In CH induced by traumatic brain injury,
approximately 40% of patients show normal
serum TSH levels but 40% show low TSH and
10% have high TSH levels that are associated
with subnormal T4 levels.
The onset of hypopituitarism is not related to
the severity of trauma,28 but long-term moni­
toring is recommended. If hypopituitarism does
occur, it generally does so within 1 year in most
cases but, importantly, it might arise several
years after the index event. In one study, hypo­
pituitarism was diagnosed in 15 of 202 patients
5 or more years after the trauma; CH was diag­
nosed in two of these patients 36 and 46 years
after head trauma.27
Traumatic brain injury and aneurismal sub­
arachnoid hemorrhage might cause lesions in the
hypothalamic–pituitary region, including hemor­
rhage, necrosis and fibrosis. Stalk lesion could
induce infarction in the pituitary by ­damaging
the portal blood supply.
Ligands selective for the retinoid X receptor
Bexarotene is a synthetic retinoid analog that
has specific affinity for the retinoid X receptor
and belongs to a group of compounds called
rexinoids, which are approved for treatment of
cutaneous T-cell lymphoma.29 In clinical trials
of cutaneous T-cell lymphoma, oral bexarotene
therapy was associated with severe but reversible
hypertriglyceridemia in 79% of patients and CH
in 40% (Table 1), the latter of which was related to
marked reductions in serum TSH and T4 levels.30
During bexarotene therapy, serum TSH levels
have been reported to decline from a mean of
2.2 mIU/l to 0.05 mIU/l and those of free T4 from
12.9 pmol/l to 5.8 pmol/l. In one report, 19 of 27
patients receiving bexarotene had symptoms or
signs of hypo­thyroidism, particularly fatigue and
intoler­ance of cold temperatures. The degree of
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TSH suppression was greatest in patients treated
with high-dose therapy (>300 mg/m2 bexarotene
daily) and in those with a history of treatment
with interferon α. Golden et al.31 reported that
a single dose of a rexinoid in healthy individu­
als could rapidly and specifically reduce levels of
TSH and thyroid hormones in serum; no changes
were seen to prolactin, cortisol, and triglyceride
concentrations.
In the hypothalamic–pituitary–thyroid axis the
thyroid hormone receptor has two isoforms­—α
and β—and works on the target DNA as a hetero­
dimer with retinoid X receptor. Bexarotene, there­
fore, probably directly inhibits the expression of
the TSHB gene through its binding to the reti­
noid X receptor. Sharma et al.29 and Sherman et
al.32 reported that rexinoids directly suppressed
TSH secretion, mRNA levels and promoter activ­
ity of TSHB gene, and levels of deiodinase type 2
mRNA, but had no direct effect on hypothalamic
TRH levels. In addition, they found that rexinoids
stimu­late type 1 iodothyronine deiodinase activity
in the liver and pituitary.
Peripheral metabolism other than that of
de­iodinase has also been reported to be stimu­
lated by bexarotene.33 This drug probably, there­
fore, has at least two effects on thyroid function:
suppression of TSH production and increased
thyroid hormone metabolic clearance by mecha­
nisms mediated by deiodinase and non­deiodinase
enzymes. Although bexarotene-induced hypo­
thyroidism was observed in mice without
thyroid receptor β, which suggests that this effect
is independent of the action of this receptor, the
involvement of the thyroid receptor α isoform
cannot be excluded.34 A history of interferon α
therapy should be noted and any correlation with
bexarotene­-induced CH should be monitored by
measuring serum TSH and free T4 levels.
Growth hormone therapy
In normal individuals, administration of growth
hormone can cause a slight reduction of serum T4
concentrations, an increase in serum T3 concentra­
tions, and a marked decrease in serum TSH levels,
but no change is seen in reverse T3 concentra­
tions. Conversely, growth hormone deficiency
masks CH, and this disorder might become
evident only after administration of replacement
therapy (Table 1).35 A notable reduction in serum
T4 levels without a substantial increase in serum
TSH was reported in 36% of euthyroid adults
with growth hormone deficiency, and T4 replace­
ment therapy was required.36 Furthermore, 16%
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of patients with growth hormone deficiency who
had previously received T4 replacement therapy
required repeat therapy at a higher dose. Raising
low free T4 levels to the middle or upper levels of
the reference range is widely recommended, as
is the raising of free T4 levels to the upper limits
of normal in patients whose free T4 concentra­
tions are normal at presentation. The bio­logical
effects of this therapy remain controversial,
however, since the serum T3 levels are also gener­
ally increased by the therapy.37 Martins et al.38
reported, therefore, that growth hormone
replacement increased the biological effect of
serum T4, suggesting that serum T4 levels should
be raised to the high end of the normal range only
in patients with growth hormone deficiency who
are not receiving­ replacement therapy.
Although the mechanism of hypothyroid­
ism after growth hormone replacement therapy
remains unclear, this therapy has been reported
to increase peripheral deiodination of T4 to T3
and secretion of somatostatin, thereby blocking
TSH secretion from the pituitary. Whether this
effect is mediated by insulin-like growth factor I
or is controlled directly by growth hormone is
not unknown.
Lymphocytic hypophysitis
Lymphocytic hypophysitis is an autoimmune
inflammatory disease of the pituitary gland
that has several clinical forms, such as adeno­
hypophysitis, infundibuloneurohypophysitis­ or
panhypophysitis.39 Women are affected slightly
more frequently than men, with the difference
being greatest during pregnancy or shortly after
delivery. Associated partial hypopituitarism is
seen in approximately half of all patients, iso­
lated hormone deficiency in 20%, and panhypo­
pituitarism in 10%. Patients with lymphocytic
hypophysitis often have ACTH deficiency (56%),
in comparison with other hypothalamic–­pituitary
disorders, which are mostly associated with defi­
ciencies in growth hormone or LH/FSH.39 CH is
present in 44% of lymphocytic hypophysitis cases
(Table 1), LH/FSH deficiency in 42%, growth
hormone deficiency in 26%, and pro­lactin defi­
ciency in 25%. In lymphocytic panhypo­physitis
the prevalence of growth hormone deficiency
increases to 51%.
We reviewed 63 case reports of lymphocytic
hypophysitis, and found that CH was identified
in 37 (59%). Serum TSH levels were normal in 19
(51%) cases, low in 16 (43%), and slightly elevated
in 2 (5%). Compared with ­pituitary adenomas,
688 nature clinical practice ENDOCRINOLOGY & METABOLISM
therefore, CH in lymphocytic hypo­physitis is fre­
quently associated with low serum TSH concen­
trations. A case of isolated TSH ­deficiency has also
been reported.40
Infants born to mothers with poorly
controlled Graves disease
Thyrotoxic effects occur in about 1% of babies
born to mothers with either active or previously
treated Graves disease.41 High titers of thyroid-
stimulating antibodies to TSH receptor in serum
are generally present in these mothers, and thyro­
toxicosis is transient. By contrast, congenital CH
is also observed in neonates born to mothers with
inadequately controlled Graves disease and high
serum thyroid hormone levels during the last tri­
mester of pregnancy (Table 1).42 The incidence
of this type of CH is at least 1 per 35,000 neo­
nates, but the exact mechanism has not been fully
eluci­dated. Higuchi et al.43 reported that the gesta­
tional period earlier than 32 weeks is the critical
time for CH to develop. Matsuura et al.44 reported
that weak maternal thyroid-stimulating antibody
activity and differences in the sensitivity of the
thyroid grand to antibodies against TSH receptor
might contribute.
Although frequently transient, thyroid dys­
function related to congenital CH was shown
by Kempers et al.45 to be permanent in some
patients, with possible need for thyroid hormone
replacement therapy. Ultrasound imaging of
the thyroid gland showed decreased size and
echogenicity, and heterogeneous echotexture.
Insufficient TSH secretion due to excessive
maternal-to-fetal thyroid hormone transfer
could inhibit fetal growth and development of
the thyroid gland. The occurrence, type and
severity of thyroid dysfunction in offspring is
dependent on maternal thyroid status and use
of anti­thyroid drugs, and the presence of anti­
bodies, such as those against the TSH receptor.
Most babies with thyroid dysfunction related
to congenital CH showed low thyroid hormone
levels and normal serum TSH levels.
GENETIC MUTATIONS
Several genetic mutations causing CH have been
reported, including mutations of the TSHB,
TRHR, POU1F1, PROP1, HESX1, SOX3, LHX3,
LHX4 genes and the leptin receptor genes LEPR
and LEP (Table 1). Mutations of the TSHB gene
are being reported with increasing frequency.
Familial isolated TSH deficiency was described
by Miyai et al. in 1971, and later a single-base
YAMADA AND MORI december 2008 vol 4 no 12

substitution (Gly85Arg at the 29th codon [G29R]
in the CAGYC region of the TSHβ subunit) was
identified.46 Inheritance was autosomal reces­
sive. Three-dimensional imaging analysis has
demonstrated that this CAGYC region is impor­
tant for heterodimerization of the α chain with
the β chain subunit to form a complete TSH
molecule. Other mutations, such as 313delT
(C105Vfs114X) and Q49X, have been reported,
and all cases were either compound hetero­
zygotes or homozygotes. Some mutations have
been confirmed as founder mutations.
In severe cases of CH, such as patients with
G29R mutations, typical signs and symptoms
of cretinism without goiter have been identi­
fied. Radioiodine uptake in the thyroid glands is
poor, and increases after administration of TSH.
In patients with TSHB mutations, serum TSH
is undetectable in some, and in patients with
G29R mutations, endogenous T4 and T3 con­
centrations are low or undetectable. In patients
with the Q49X mutation, however, circulating
TSH is detectable by immunoassay but has no
biological activity. Furthermore, serum TSH
level has been reported as moderately increased
in homozygotes with 313delT (C105Vfs114X)
in an assay system.47 Values measured by other
assay systems were, however, normal. Therefore,
the reported TSH levels in patients with muta­
tions of the TSHB gene seem to depend on the
assay system used.
The first TRH receptor mutation was reported
by Collu et al.48 in 1997, and the patient had com­
pound heterozygosity for deletions of three amino
acid residues (Ser115, Ile116, and Thr117) and one
replacement (Ala118Thr). The patient showed no
TSH or prolactin response to TRH administra­
tion. CH in this patient was mild with normal
serum TSH level and the only manifestation was
short stature.
The pituitary-specific transcription factor Pit-1,
a member of the POU homeodomain family, regu­
lates the expression of TSHβ, growth hormone
and prolactin genes. Mutation of the POU1F1 gene
causes combined pituitary hormone deficiencies,
including complete growth hormone and pro­
lactin deficiency as well as CH. Typically, patients
have severe growth retardation and, several years
later, develop CH. Levels of T4 and T3 in serum
are low, whereas those of TSH remain in the lower
end of the normal range. Most reported cases
show autosomal recessive inheritance, but the
Arg271Trp mutation in POU1F1 shows dominant
negative and ­autosomal ­dominant patterns.49,50
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The PROP1 gene encodes a 226 amino acid
transcription factor that is involved in the early
development of several lineages of an­terior pitu­
itary cells. Mutations cause combined pituitary
hormone deficiency that is autosomal recessive
and associated with deficiency of LH/FSH, growth
hormone, TSH, prolactin and, less frequently,
ACTH. Hormone deficiency is less severe than
that with the POU1F1 mutation. Patients often
present with growth retardation, CH, and hypo­
gonadotropic hypogonadism, but the hormonal
phenotype can vary in severity and in age of
onset. In some patients, CH develops during ado­
lescence.51 Some patients undergo spontaneous
puberty before developing central hypogonadism
and only a subset of patients show adrenal insuf­
ficiency. The mechanism underlying the variable
expression of combined hormone deficiency is,
however, unknown. Pituitary size can also vary
among patients; it is not uncommon to find
pituitary masses in affected children than can be
potentially mistaken for cranio­pharyngiomas or
­pituitary adenomas.
Mutations causing combined pituitary hor­
mone deficiency have been also described in
the HESX1, SOX3, LHX3, and LHX4 genes. In
addition to manifestations of the deficiency
of pituitary hormones, HESX1 mutations are
associ­ated with septo-optic dysplasia, and LHX3
mutations are sometimes associated with rigid
cervical spines. In patients with LHX4 muta­
tions, cerebellar defects, and abnormalities of
the sella turcica at the central skull base have
been reported. The duplication containing the
SOX3 gene has been reported in families with
X-linked hypopituitarism and mental retardation,
and has been associated with variable combina­
tions of CH, delayed pubertal development, and
growth hormone deficiency.52
LESSONS FROM ANIMAL MODELS
Several animal models have been studied to
gain insight into CH. In TRH knockout mice
we showed typical tertiary hypothyroidism with
low serum thyroid hormone levels and slightly
elevated serum TSH levels.53 As seen in humans,
TRH testing revealed exaggerated response of
serum TSH; however, the increase of serum T3
in response to elevated TSH was significantly
impaired, indicating reduced biological activity
of serum TSH. Furthermore, the TRH knockout
mice showed mild hyperglycemia with minor
impairment of insulin secretion from pan­creatic β
cells. Since TRH has been reported to be localized
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Subnormal T4 levels with Adult
Infant and child
inappropriately low TSH levels
Check other hormone deficiencies
Take history of symptoms
Gene test
and medications
MRI of the pituitary
Mutations in TSHB, Pituitary adenoma, Post-TBI or SAH,
PROP1, POU1F1, craniopharyngioma, Sheehan syndrome,
etc. other SOL post-GH therapy,
drug-related, LAH
Figure 2 Proposed algorithm for the diagnosis and confirmation of central
hypothyroidism. Abbreviations: GH, growth hormone; LAH, lymphocytic
adenohypophysitis; SAH, subarachnoid hemorrhage; SOL, space-occupying
lesions; TBI, traumatic brain injury.
in insulin vesicles in the β cells, it might regulate
insulin secretion.
Rodents have two subtypes of TRH receptors
(1 and 2) but the corresponding complementary
DNA for rodent TRH receptor 2 has not been
identified in humans. Rabeler et al.54 developed
a mouse model with TRH receptor 1 knocked
out and showed similar mild hypothyroidism
to TRH knockout mice, but the serum TSH
level remained normal. Zeng et al.55 established
another line of TRH receptor 1 knockout mice
and reported increased anxiety, mild depres­
sion, and hyperglycemia similar to that seen in
TRH knockout mice. From these observations,
isolated TRH deficiency clearly does not reduce
the serum TSH level.
Most peripherally active endogenous T3 is con­
verted from T4 by peripheral type 2 dei­odinase.
Type 3 deiodinase degrades T3 and T4 to the
inactive forms, T2 and reverse T3, respectively.
Mice with type 3 deiodinase knocked out showed
perinatal thyrotoxicosis with elevated serum T3
levels, due to the impaired clearance of T3.56,57
From postnatal day 15, however, these mice
exhibited CH with low T4 and T3 and normal
or modestly increased TSH levels in serum.
A subsequent study demonstrated that the
hypothalamic­–pituitary–thyroid axis in type 3
ncpendmet_2008_086f2.eps
690 nature clinical practice ENDOCRINOLOGY & METABOLISM
deiodinase knockout mice was impaired at all
levels, including the hypothalamus, pituitary, and
thyroid gland, suggesting that disturbance of D3
might cause a novel type of CH in humans.
DIAGNOSIS OF CENTRAL HYPOTHYROiDISM
Usual screening for hypothyroidism, including
assessment for cretinism, with measurements
of serum TSH levels might not detect CH, but a
T4-based screening might be useful. The most
effective way to diagnose CH might be measure­
ment of serum levels of free T4 and TSH.
Subnormal levels of free T4 and inappropriately
low serum TSH probably indicate CH (Figure 2),
although some patients with CH have slightly
high TSH levels as discussed before.
Several mechanisms leading to the differ­
ences in TSH levels have been suggested:
hypoadrenalism­ raising serum TSH levels;
decreased secretion of somatostatin from the
hypo­thalamus resulting in increased TSH secre­
tion; and reduced biological and receptor binding
activity of TSH. In humans, oral admini­stration
of TRH could improve abnormal TSH glycosyl­
ation due to high levels of mannose, biantennary
oligosaccharide moieties, and a reduced degree
of sialylation.58,59
The diagnostic value of TRH stimulation
has been evaluated in several studies.60–62
Administration of TRH to normal individuals
produces a consistent rise in serum TSH levels.
Peak values are seen at 15–30 min, with notable
decrease starting at 60 min. During TRH testing,
plasma TSH is measured before and 15 (optional),
30, 60, 120, and 180 (optional) min after intra­
venous administration of TRH (10 µg/kg body
weight, 200 µg or 500 µg). Generally, normal
responses of TSH are defined as ∆TSH greater
than 4.0–5.0 mIU/l, absent or blunted responses
as ∆TSH less than 4.0–5.0 mIU/l or a twofold
peak increase of TSH at 15 min or 30 min, and
excessive or delayed responses as ∆TSH >20.0–
25.0 mIU/l or a peak response after 60 min. Many
CH patients show either blunted or delayed pat­
terns. Evaluation of results of TRH tests have,
however, varied across studies.
To evaluate the biological activity of circulating­
TSH, the increment of serum T3 or free T3 in
response to increased TSH might be used.63
Free T3 responses to TRH-stimulated TSH have
been observed in normal individuals, yielding
increases of 29–37% (mean increase 32%) at
120 min after the stimulation, while free T4 levels
increase by 14% (unpublished data). In CH,
YAMADA AND MORI december 2008 vol 4 no 12

this response might be blunted. Distinguishing
between hypo­thalamic CH and pituitary CH
by TRH test can be difficult. Conversely, normal
TRH tests also do not exclude abnormalities in
the hypothalamic­–pituitary–thyroid axis.
Although loss of the nocturnal surge of serum
TSH level has been used to assess CH, this
approach is still controversial.64,65 MRI could be
required for most suspected cases of CH to detect
origin of hypothalamic or pituitary disorders.
MANAGEMENT OF CENTRAL
HYPOTHYROIDISM
Although TRH and TSH administration are theo­
retically ideal for treatment of CH, they have
been abandoned because of high monetary costs,
limited applicability and instability of TRH after
oral administration. Most patients with CH are,
therefore, treated with levothyroxine­ (Figure 3).
Deficiencies of hormones other than TSH should
be considered before starting treatment. When
ACTH deficiency is also present, glucocorticoid
therapy should be started at least 1 week before
initiation of levothyroxine to avoid increased con­
sumption of cortisol and worsening of the ACTH
deficiency, which can induce crisis. Patients with
hypopituitarism at presentation, particularly those
with pituitary tumor apoplexy, should receive
cortico­steroids during the acute stage. Patients
with lymphocytic adeno­hypophysitis also fre­
quently have ACTH deficiency. Although the
efficacy of restoring pituitary function remains
unclear, gluco­corticoid therapy has been used to
reduce the size of the pituitary.39
Use of an average dose of levothyroxine
1.6 µg/kg body weight daily can generally restore
a euthyroid state in adults with primary hypo­
thyroidism, but the optimum dose or dose
range for CH is unclear.66 In a sizeable subset of
patients with CH, serum free T4 levels remain at
the low end of the normal range with empirical
levo­thyroxine therapy. A dose similar to that used
for primary hypothyroidism has been recom­
mended for patients with CH, with the aim of
achieving serum concentrations of free T4 in
the upper end of the normal range rather than
within the middle or lower values.66,67
CH therapy might need to be tailored to the
individual. Children might require high doses
(around 4.0 µg/kg daily), whereas elderly indi­
viduals might require low doses (around 1.0 µg/kg
daily). Furthermore, GH deficiency, which is
common in patients with CH, could impair
conversion of T4 into active T3, thereby masking
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Hypoadrenalism?
No Yes
Replace glucocoticoid
Investigate tumor
1–2 weeks before
Yes No starting levothyroxine
Operation Start low-dose levothyroxine
(~1.6 μg/kg body weight and
adjusted for age and other
hormone deficiencies)
Re-evaluation
Free T4 levels in upper
No level of normal range
Transient subtype?
Yes
Stop levothyroxine
Figure 3 Proposed algorithm for the treatment of central hypothyroidism.
the fact that the levothyroxine dose is inadequate.
Raising levels of free T4 might, therefore, be neces­
sary in patients with GH deficiency.35 Similarly,
higher doses may be required for postmenopausal
women receiving estrogen-based therapies.68
Patients with CH treated with bexaro­tene com­
monly require high doses of thyroid hormone
for replacement therapy, often twice the typical
dose used to treat primary hypo­thyroidism. This
difference might be due to certain characteris­
tics of CH and to increased clearance of thyroid
hormone. Hypertriglyceridemia should also
be monitored and treated in patients with CH
receiving ­bexarotene.
Combination therapy comprising levo­­thy­
roxine and liothyronine has been tried with the
aim of normalizing the tissue concentration of T4
and T3. Administration of liothyronine 0.16 µg/kg
body weight might provide additional beneficial
effects on ankle reflex time and working memory,
but could also result in supraphysiological con­
centrations of free T3 in serum.66 In addition, a
meta-analysis showed no benefit of combination
therapy over levothy­roxine monotherapy.69
In many cases of CH, measurement of serum
TSH levels cannot be used to monitor therapy
response, since negative feedback regulation of
TSH by thyroid hormones can remain intact.
ncpendmet_2008_086f3.eps
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When the basal level of serum TSH is normal in
patients with CH, concentrations may decrease
to very low values after treatment.70 Serum levels
of cholesterol, creatinine phosphokinase, soluble
interleukin-2 receptor, sex-hormone-binding
globulin, angiotensin-converting enzyme, cross-
linked carboxyterminal telopeptide of type I
collagen and osteocalcin can be used as clinical
and biochemical peripheral parameters.
Furthermore, in some cases CH might be rever­
sible and monitoring of pituitary function could
eliminate the need for lifelong substitution therapy.
Surgery is reported to lead to an improvement in
anterior pituitary function in approximately 35%
of patients with pituitary adenoma and CH.71
Treatment of CH in neonates born to hyper­
thyroid mothers generally consists of short-term
supplementation with levothyroxine.
CONCLUSIONS
The real prevalence of CH is probably higher than
that reported. When inappropriately low serum
TSH levels are associated with subnormal free
T4 levels, hypothyroidism from a central origin
should be investigated. New causes of CH, such
as that following traumatic brain injury or GH
treatment, are becoming apparent and require
large prospective studies to assess prevalence and
appropriate management.
KEY POINTS
■ In many cases of central hypothyroidism
(CH) serum TSH level remains normal, but
CH should always be investigated if serum
TSH levels are inappropriately low along with
subnormal T4 levels
■ Most cases of central hypothyroidism are
accompanied by other hormone deficiencies,
which should be examined, particularly those of
the adrenocorticotropic hormone–adrenal axis
■ Important causes are pituitary adenoma (for
which hypothalamic–pituitary–thyroid axis and
adrenal axis function should be assessed),
post-traumatic brain injury and subarachnoid
hemorrhage
■ To evaluate the biological activity of circulating
TSH, the increment of serum free T3 in the
TSH-releasing hormone test might be used,
but a normal result does not exclude CH
■ Appropriate doses of levothyroxine for central
hypothyroidism might be higher than empirical
doses currently used to achieve serum free T4
levels in the normal range
692 nature clinical practice ENDOCRINOLOGY & METABOLISM
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Acknowledgments
We thank K Horiguchi and
R Umezawa for their help
collating and analyzing
articles.
Competing interests
The authors declared no
competing interests.
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