Download Central Hypothyroidism - e

CME Review Article #16
0021-972X/2002/1203-0218
The Endocrinologist
Copyright © 2002 by Lippincott Williams & Wilkins
CHIEF EDITOR’S NOTE: This article is the 16th of 36 that will be published in 2002 for which a total of up to 36 Category 1 CME
credits can be earned. Instructions for how credits can be earned appear after the Table of Contents.
Central Hypothyroidism
A. Gudmundsdottir, M.D.* and J. A. Schlechte, M.D.†
missed if a TSH is the only screening test used for
detection of thyroid disease, and we recommend
measurement of both free thyroxine and TSH for
screening purposes. The treatment is the same as
in primary hypothyroidism except that TSH cannot be used to monitor therapy. It is important to
assess the pituitary adrenal axis before starting
levothyroxine to avoid precipitation of adrenal
crisis in patients with adrenal insufficiency. ■
Most patients with hypothyroidism have thyroid
failure or primary hypothyroidism. Central hypothyroidism (CH) is caused by impaired stimulation of a normal thyroid gland by hypothalamic
or pituitary hormones. Most cases of CH are
caused by pituitary tumors, but genetic defects
causing abnormalities in the thyroid-stimulating
hormone (TSH) subunit also lead to CH. The
symptoms are similar to those of primary hypothyroidism, and most patients with CH will
also have signs and symptoms of other anterior pituitary dysfunction. The diagnosis of CH can be
The Endocrinologist 2002; 12: 218–223
roid failure that occurs as a result of TSH or TRH deficiency.
Some authors prefer the terms secondary (TSH deficiency)
and tertiary (TRH deficiency) hypothyroidism based on the
response of TSH after administration of TRH. However,
there is frequent overlap between secondary and tertiary
forms, and CH is a more appropriate term [1].
Learning Objectives
• Identify the causes and pathogenetic mechanisms
underlying acquired, congenital, and transient central hypothyroidism (CH).
• Describe the clinical and endocrinological characteristics of CH.
• Recall the most effective treatment of CH, the best
marker of treatment response, and the perils of undertreatment and overtreatment.
Pathogenesis
Thyrotropin-releasing hormone is a 26-kd protein that
occurs in the hypothalamus, pituitary, gastrointestinal
tract, pancreatic islets, and reproductive tract. It has a halflife of 3 minutes and stimulates the secretion, synthesis,
and glycosylation of TSH. In healthy subjects, the administration of TRH causes a dose-dependent increase in TSH,
prolactin, and growth hormone (GH).
Thyroid-stimulating hormone is synthesized and secreted by the thyrotrophs of the anterior pituitary. It is a 28kd glycoprotein composed of and subunits and contains
approximately 15% carbohydrate. The subunit is unique
and determines the biologic specificity. The unit is identical to the subunit of luteinizing hormone, folliclestimulating hormone, and chorionic gonadotropin. Thyroidstimulating hormone secretion is pulsatile, peaking in the
late evening. Variation in the carbohydrate chains has a major impact on the biological properties of TSH. Highly sialylated TSH has impaired intrinsic bioactivity and a long
Introduction
P
❦
ituitary secretion of thyroid-stimulating hormone (TSH) occurs in response to release of the
hypothalamic-releasing hormone, thyrotropinreleasing hormone (TRH). Central hypothyroidism (CH) is the term used to describe thy-
*Fellow in Endocrinology and Metabolism and †Professor of Medicine,
University of Iowa Hospitals and Clinics, Iowa City, Iowa, U.S.A.
Address correspondence to: J. A. Schlechte, M.D., Department of Internal
Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive,
Iowa City, IA 52242. Telephone: 319-384-8305; Fax: 319-384-8325;
E-mail: [email protected]’
The authors have disclosed that they have no significant relationships with or
financial interests in any commercial company pertaining to this educational
activity.
218
Central Hypothyroidism
half-life. In normal circumstances, isoforms of TSH secreted
at night have a higher degree of sialylation than isoforms secreted during the day, accounting for a lower bioactivity ratio [2]. In adults with primary hypothyroidism, TSH isoforms
are also highly sialylated with impaired bioactivity [2]. On
the contrary, a normal fetus has extremely bioactive asialoTSH isoforms circulating during the third trimester. Hypothalamic TRH exerts its effects by regulating TSH posttranslational oligosaccharide processing and release of TSH
[2]. This results in multiple molecular forms of circulating
TSH in variable physiological and pathological states. Subjects with primary or CH have abnormalities in pulsatile
TSH secretion, including a blunted or absent nocturnal
surge. Thyroid-stimulating hormone is secreted into the systemic circulation and stimulates growth of the thyroid gland,
along with synthesis and release of thyroid hormones. Thyroid hormones then exert negative feedback at the hypothalamus and pituitary to regulate TRH and TSH levels [3].
Etiology
Acquired Central Hypothyroidism
In most cases, CH develops in patients with pituitary
and/or hypothalamic diseases. This may be caused by a reduced mass of functioning thyrotrophs, defects in TRH stimulation, or a reduced bioactivity of circulating TSH [4]. Table
1 lists a variety of causes of CH. Pituitary adenomas are the
most common cause of CH [3]. A tumor may produce other
pituitary hormones or lead to decreased TSH production
from compression of the gland. Meningiomas and craniopharyngiomas can cause CH, but metastatic tumors to the
hypothalamus and pituitary are a rare cause. In patients with
postpartum pituitary necrosis (Sheehan syndrome) and panhypopituitarism, TSH can be unexpectedly normal or increased. Circulating TSH in these patients has a higher
degree of sialylation and decreased biological activity compared with that of normal subjects [5]. External radiation
therapy caused CH in 65% of patients treated for brain tumors [6]. In pediatric cancer survivors who received head irradiation, subtle CH developed in 30%. Five of 62 patients
had abnormal basal serum TSH or free thyroxine (FT4) levels. The other 57 had normal TSH and FT4 but had a blunted
nocturnal TSH surge or delayed TSH response to TRH [7].
Hypopituitarism can also appear after excision of a pituitary
adenoma. Webb et al. [8] identified TSH deficiency in 10.5%
of patients with normal preoperative pituitary function.
Genetic Defects
Congenital CH has been described in several families
as being caused by mutations in the TSH– subunit gene.
The Endocrinologist
Table 1
Causes of Central Hypothyroidism
Tumors
Benign: pituitary adenomas, cysts, craniopharyngiomas
Malignant: metastatic from lung, breast, etc.
Ischemic necrosis
Sheehan syndrome
Shock
Iatrogenic
Surgery
Radiation
Infectious
Tuberculosis
Infiltrative lesions
Sarcoidosis
Hemochromatosis
Fungal infections
Toxoplasmosis
Syphilis
Histiocytosis
Autoimmune lymphocytic hypophysitis
Genetic abnormalities in TSH
Aneurysm of ICA
Trauma
Idiopathic
ICA, internal carotid artery; TSH, thyroid-stimulating hormone.
These mutations introduce truncated proteins that cannot
dimerize with the -subunit or, alternatively, produce a
mutated TSH that is biologically inactive [9,10].
Five Japanese families with familial inherited TSH deficiency have been reported [11]. Three have a single base
substitution in the same area, suggesting that they originated from the same single founder. The resulting amino
acid substitution affects the molecular conformation of the
-subunit, making it unable to bind with the -subunit.
The mutation generated a new MaeI cleavage site that can
be used for DNA diagnosis. The other two families, studied
by the same investigators, are expected to have a different
mutation. Other families have since been described in Brazil
[12], Greece [13], and other countries [10,14–16]. The inheritance pattern is usually autosomal recessive and the
families are frequently highly inbred. The patients have hypothyroidism at birth. A goiter is not present and thyroid radioiodine uptake is low. In three affected children from the
Greek families, there was no significant TSH response after
TRH stimulation. Their mutation was found to be different
from that described by Hayashizaki et al. [11] in the Japanese families. The TSH– subunit is generally undetectable
in patients with mutations that prevent the assembly of the
heterodimer. However, there are other mutations in which
the heterodimerization is not completely prevented and the
affected patients have variable serum TSH concentrations,
219
Central Hypothyroidism
depending on the measurement method used [12,14–16].
This mutant heterodimer has preserved immunoreactivity
but not bioactivity, which results in a reduced ratio between
biologic and immunoreactive TSH. The subunit has been
found to be significantly increased in these patients [10,12].
The TSH deficiency is most often isolated, with other pituitary hormones being normal.
Central hypothyroidism has also been reported with a
nonsense mutation in the pituitary-specific transcription
activator, POU1F1 (formerly known as Pit-1) [17]. This
defect is associated with other pituitary hormone deficiencies. This clinical picture may also result from gene mutations of other transcription factors such as Prop-1 [18],
Hesx1 [19,20], and Lhx3 [21]. Levels of GH, prolactin, and
TSH in patients with Prop-1 mutations are, on average,
slightly higher than those in patients with Pit-1 mutations;
however, all levels are in the subnormal range [22].
An inactivating mutation in the TRH receptor gene
has been described as a cause of CH in one patient [23].
This 9-year-old boy was referred for evaluation of short
stature and had markedly delayed bone maturation as the
only presenting symptom. Although his total thyroxine
(T4) was low, at neonatal screening he had a normal TSH.
He was found to have been a compound heterozygote,
having inherited a different mutated allele from each of
the parents. Both mutations resulted in a receptor with reduced or absent biological activity.
In addition, there is some evidence that a group of CH
patients have TRH deficiency [24]. This is difficult to document because various serum components interfere with
the TRH assay. As noted, TRH has a short half-life and its
origin in peripheral blood is uncertain. These patients may
benefit from repetitive exogenous TRH administration.
Transient Central Hypothyroidism
Central hypothyroidism can be temporary in patients
with severe nonthyroidal illness. This includes major surgery,
trauma, chronic renal failure, depression, anorexia, and fasting. It can also be found in the elderly. Thyroid-stimulating
hormone can remain low for up to 1 month after treatment
of hyperthyroidism, regardless of treatment method. A similar phenomenon is observed after withdrawal of T4 therapy
in patients with multinodular goiter. Other medications that
inhibit TSH secretion include dopamine, glucocorticoids,
and somatostatin. A careful history and evaluation of the circumstances surrounding abnormal thyroid function tests are
crucial to avoid unnecessary diagnostic tests.
Cases of reversible CH have been described in patients with cutaneous T-cell lymphoma treated with highdose bexarotene [25]. This retinoid X–receptor-selective
220
ligand suppressed TSH secretion in 26 of 27 patients during therapy. Serum concentrations of free thyroxine decreased, also. Nineteen patients had symptoms or signs of
hypothyroidism that were not present at baseline. Among
10 patients that were studied after discontinuation of the
treatment, serum TSH returned to normal in nine.
Congenital Hypothyroidism
The prevalence of congenital hypothyroidism is approximately 1 in 4,000 births, and newborn screening is routine in the United States and other countries [26]. Because
of screening, congenital hypothyroidism is no longer a significant cause of mental retardation in industrialized societies.
Samples of T4 or TSH are obtained 24 to 48 hours after birth.
The cause of congenital hypothyroidism includes thyroid
dysgenesis (aplasia, hypoplasia, ectopy), thyroid dyshormonogenesis, transient hypothyroidism (usually caused by
iodine, drugs, or maternal antibodies), and hypothalamic–
pituitary hormone deficiency (also known as CH). Central
hypothyroidism accounts for only approximately 5% of
cases. The most common cause is thyroid malformations. Infants with abnormal test results should be recalled quickly to
confirm the diagnosis and start treatment.
Most infants with low FT4 (20–25 mU/L) and low
TSH (20–25 U/mL) levels are premature, manifesting
transient hypothyroxinemia of prematurity. If TSH deficiency is suspected, measurements of GH and cortisol may
indicate panhypopituitarism. The presence of hypoglycemia
in a term neonate should suggest GH and/or adrenocorticotrophic deficiency. Further evaluation should include a
TRH test and imaging of the brain to identify hypothalamic–pituitary anomalies. In addition, DNA tests permit
rapid identification of point mutations in the TSH– gene
as discussed.
Therapy in infants with CH is similar to therapy for
other congenital hypothyroid states. It is extremely important to rapidly normalize the serum T4 concentration. The
serum T4 should then be maintained at more than 103
nmol/L (8 g/dL) throughout the first year of treatment.
Alternatively, FT4 measurements can be used and
should be maintained in the upper half of the normal range
for the method [26]. The recommended initial dose of T4 is
10 to 15 g/kg per day or 50 g daily for the average term
infant weighing 3 to 4.5 kg. Therapy should be monitored
at 4- to 6-week intervals during the first 6 months, at 2- to
3-month intervals between ages 6 and 24 months, and at 3to 6-month intervals thereafter. If the initial diagnosis cannot be established definitively, levothyroxine can be withdrawn for 30 days at age 2 to 3 years without compromising
brain maturation to allow reassessment [26].
Volume 12, Number 3
Central Hypothyroidism
Clinical Features
The clinical features of CH are similar to those of primary hypothyroidism but generally milder. The skin may
not be as coarse and dry as in primary hypothyroidism,
periorbital and peripheral edema are uncommon, and
hoarseness is not prominent in patients with CH [1]. Common symptoms include cold intolerance, constipation, fatigue, lethargy, muscle cramps, and weight gain. Physical
findings include bradycardia, hypothermia, slow speech, and
a prolonged relaxation phase of the deep tendon reflexes.
Children may present with stunted growth and delay in
bone development. Dwarfism and cretinism may occur in
the rare familial forms. In patients with hypopituitarism, deficiency of GH and gonadotropin may precede TSH insufficiency. Delayed skeletal maturation in children may be the
sign of GH deficiency. Gonadotropin insufficiency causes
impotence, loss of libido, diminished beard growth, and testicular atrophy in men. Women may present with amenorrhea, infertility, and breast atrophy. Hypoglycemia may be
the result of hypocortisolism, and adrenal insufficiency may
result in anorexia and weight loss. Diabetes insipidus is frequently seen with craniopharyngiomas and with infiltrative
diseases of the hypothalamus.
Diagnosis
The diagnosis of CH is based on the demonstration of
low-serum thyroid hormone along with inappropriately reduced, normal, or slightly increased TSH. If serum TSH is
used as the initial screening test for thyroid disease, the diagnosis of CH can easily be missed. For this reason, we agree
with those who recommend measurement of both FT4 and
TSH for screening. Alternatively, serum FT4 can be assessed
if the patient has symptoms suggestive of hypothyroidism or
hypopituitarism in the presence of a normal serum TSH. It
is important to remember that most patients with CH will
also have deficiencies in other pituitary hormones. Therefore, the clinical picture will vary widely.
The reason for normal or high TSH levels in some patients with CH is that the TSH is bioinactive but remains
immunoactive and thus measurable by immunometric assay. This finding may be partly explained by degree of sialylation of the TSH molecules in CH, which is controlled by
TRH. A recent study showed that patients with hypothalamic–pituitary disease had TSH with reduced bioactivity,
along with a decreased number of functioning thyrotrope
cells [27]. In normal circumstances, TSH is secreted in a diurnal rhythm with a surge that begins in the late evening
and reaches a peak at the onset of sleep. This nocturnal
surge is absent in many patients with CH. To assess the
The Endocrinologist
nocturnal surge, TSH samples should be obtained every 30
minutes from 11:00 PM to 2:00 AM.
A TRH stimulation test involves administration of 200
to 500 g or 5 g/kg of TRH, then measurement of TSH at
20- and 60-minute intervals after injection. A delayed response is defined as a peak serum TSH concentration that
occurs 60 or more minutes after TRH administration,
whereas a normal response peaks at 20 to 30 minutes [1].
Classically, this test was used to identify the cause of CH.
The serum TSH response to TRH should be impaired in pituitary hypothyroidism but preserved in hypothalamic hypothyroidism. It has been shown, however, that serum TSH
responses to TRH differ little in patients with hypothalamic
or pituitary disorders [1]. A delayed TSH response to TRH
is a characteristic but not specific finding in hypothalamic
disease, and some patients with unequivocal hypothalamic
disorder have a low or normal serum TSH response to TRH.
Yamakita [28] studied six patients with an idiopathic
isolated deficit of TSH secretion and found blunted responses to TRH stimulation in all patients without a TSH
surge. They suggested that both of these tests should be performed when CH is suspected, because routine biochemical
data and clinical symptoms cannot easily detect this disease.
Magnetic resonance imaging of the hypothalamic
area and pituitary gland is indicated in patients with biochemical evidence of CH. Computed tomography with
coronal views through the pituitary is an alternative if
magnetic resonance imaging is unavailable.
Therapy
The goal of therapy in CH is to restore and maintain
euthyroidism. This is best performed with levothyroxine.
Unlike primary hypothyroidism, serum TSH cannot be used
for monitoring treatment in CH. Ferreti et al. [4] examined
a variety of clinical and biochemical parameters as indices
of thyroid hormone action in 37 patients with CH, with and
without administration of levothyroxine therapy. The
biochemical markers included thyroid hormone, TSH, cholesterol, sex hormone-binding protein, angiotensin-converting enzyme, carboxyl-terminal telopeptide of type I
collagen, bone glucose-lowering agent protein and serum
soluble IL-2 receptors. The clinical parameters (heart rate,
blood pressure, body mass index, skin findings, and edema)
lacked specificity for the diagnosis or follow-up of CH patients, probably because of associated hormonal deficiencies
that usually do not occur in primary hypothyroidism. The
most reliable marker was serum FT4. Free triiodothyronine
(FT3) remained normal in 25% of patients with low FT4.
Total T3 and T4 were less reliable. Optimization of therapy
is extremely important because overtreatment can con221
Central Hypothyroidism
tribute to increased fracture risk, which may already be present because of concomitant gonadotroph and GH deficiency. Undertreatment with levothyroxine may increase
the cardiovascular risk. FT3 appeared to be more sensitive
than FT4 for detecting overtreatment. FT4 was more useful
in identifying undertreated CH patients. Serum levels of
creatine kinase along with FT4 and FT3 may be useful in detecting undertreatment. Soluble IL-2 receptor is a sensitive
marker of biological effects of thyroid hormone on lymphocytes in various thyroid diseases [29]. Unlike sex hormonebinding protein or markers of bone resorption, soluble IL-2
receptor levels are independent of gonadal status, glucocorticoid replacement, and free thyroid hormone level. It is
therefore the most useful additional biochemical index of
thyroid status in CH patients. The mean daily levothyroxine replacement dose at the end of the study was 1.6 g/kg
in patients younger than age 60 years and 1.3 g/kg in patients older than age 60 years. This is similar to findings in
subjects with primary hypothyroidism [30]. No difference
was found according to sex or origin of the disease (pituitary
vs. hypothalamic). Before initiating levothyroxine therapy,
the need for glucocorticoid therapy should be assessed and
replacement should be initiated if necessary.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Conclusions
Central hypothyroidism is most often caused by diseases of the pituitary or hypothalamus. When the diagnosis
is suspected by the finding of low FT4 and inappropriately
low, normal, or slightly increased TSH, other pituitary hormone deficiencies need to be considered. The lack of a nocturnal TSH surge and a delayed TSH response to TRH
support the diagnosis of CH and imaging of the pituitary is
indicated. Congenital isolated CH with undetectable or low
TSH is suggestive of TSH– subunit mutations, particularly
when levels of glycoprotein hormone subunit are high
[10]. In these patients, the hypothyroid state is not detected
at neonatal screening because most centers only use TSH
evaluation on a dry blood spot. This can result in a delay in
diagnosis and severe hypothyroidism. A delay in treatment
can result in mild to severe mental and growth retardation.
Symptoms of hypothyroidism in the neonatal period
necessitate an immediate comprehensive workup including
molecular genetic studies, regardless of the screening results.
12.
13.
14.
15.
16.
17.
18.
19.
20.
References
1. Martino E, Bartalena L, Pinchera A: Central hypothyroidism. In
Werner and Ingbar’s the Thyroid edited by Braverman LE, p. 762.
Philadelphia, Lippincott Williams & Wilkins 2000.
2. Persani L, Borgato S, Romoli R, et al.: Changes in the degree of sia222
21.
22.
lylation of carbohydrate chains modify the biological properties of
circulating thyrotropin isoforms in various physiological and pathological states. J Clin Endocrinol Metab 1998; 83: 2486–92.
Samuels MH, Ridgway EC: Central hypothyroidism. Endocrinol
Metab Clin North Am 1992; 21: 903–19.
Ferreti E, Persani L, Jaffrain-Rea M, et al.: Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 1999; 84: 924–9.
Oliveira JHA, Persani L, Beck-Peccoz P, et al.: Investigating the
paradox of hypothyroidism and increased serum thyrotropin (TSH)
levels in Sheehan’s syndrome: characterization of TSH carbohydrate content and bioactivity. J Clin Endocrinol Metab 2001; 86:
1694–9.
Constine LS, Woolf PD, Cann D, et al.: Hypothalamic-pituitary
dysfunction after radiation for brain tumors N Engl J Med 1993;
328: 87.
Rose SR, Lustig RH, Pitukcheewanont P, et al.: Diagnosis of hidden
central hypothyroidism in survivors of childhood cancer. J Clin Endocrinol Metab 1999; 84: 4472–9.
Webb SM, Rigla M, Wagner A, et al.: Recovery of hypopituitarism
after neurosurgical treatment of pituitary adenomas. J Clin Endocrinol Metab 1999; 84: 3696–700.
Medeiros-Neto G, Lacerda L, Wondisford FE: Familial congenital
hypothyroidism caused by abnormal and bioinactive TSH due to
mutations in the beta-subunit gene. Trends Endocrinol Metab 1997.
Bonomi M, Proverbio MC, Weber G, et al.: Hyperplastic pituitary
gland, high serum glycoprotein hormone alpha-subunit, and variable circulating thyrotropin (TSH) levels as hallmark of central hypothyroidism due to mutations of the TSH beta gene. J Clin
Endocrinol Metab 2001; 86: 1600–4.
Hayashizaki Y, Hiraoka Y, Tatsumi K, et al.: Deoxyribonucleic Acid
Analyses of Five Families with Familial Inherited Thyroid Stimulating Hormone Deficiency. J Clin Endocrinol Metab 1990; 71: 792–6.
Medeiros-Neto G, Herodotuou DT, Rajan S, et al.: A circulating,
biologically inactive thyrotropin caused by a mutation in the beta
subunit gene. J Clin Invest 1996; 97: 1250–5.
Dacou-Voutetakis C, Feltquate DM, Drakopoulou M, et al.: Familial hypothyroidism caused by a nonsense mutation in the thyroidstimulating hormone beta-subunit gene. Am J Hum Genet 1990;
46: 988–93.
Doeker BM, Pfaffle RW, Pohlenz J, et al.: Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin
beta-subunit gene follows an autosomal recessive inheritance. J
Clin Endocrinol Metab 1998; 83: 1762–5.
Biebermann H, Liesenkotter KP, Emeis M, et al.: Severe congenital
hypothyroidism due to a homozygous mutation of the betaTSH
gene. Pediatr Res 1999; 46: 170–3.
Heinrichs C, Parma J, Scherberg HN, et al.: Congenital central isolated hypothyroidism caused by a homozygous mutation in the
TSH-beta subunit gene. Thyroid 2000; 10: 387–91.
Pfaffle RW, DiMattia GE, Parks JS, et al.: Mutation of the POUspecific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 1992; 257: 1118–21.
Wu W, Cogan JD, Pfaffle RW, et al.: Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet 1998; 18:
147–9.
Dattani MT, Martinez-Barbera JP, Thomas PQ, et al.: Mutations in
the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 1998; 19: 125–33.
Thomas PQ, Dattani MT, Brickman JM, et al.: Heterozygous HESX1
mutations associated with isolated congenital pituitary hypoplasia
and septo-optic dysplasia. Hum Mol Genet 2001; 10(1): 39–45.
Netchine I, Sobrier ML, Krude H, et al.: Mutations in LHX3 result
in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet 2000; 25: 182–6.
Pfaffle RW, Blankenstein O, Wuller S, et al.: Combined pituitary
Volume 12, Number 3
Central Hypothyroidism
23.
24.
25.
26.
hormone deficiency: role of Pit-1 and Prop-1. Acta Paediatr 1999;
88(S433): 33–41.
Collu R, Tang J, Castagne J, et al.: A novel mechanism for isolated
central hypothyroidism: inactivating mutations in the thyrotropinreleasing hormone receptor gene. J Clin Endocrinol Metab 1997;
82: 1561–5.
Gharib H, Abboud CF: Primary idiopathic hypothalamic hypothyroidism. Am J Med 1987; 83: 171–4.
Sherman SI, Jayashree G, Haugen BR, et al.: Central hypothyroidism associated with retinoid X receptor-selective ligands. N
Engl J Med 1999; 340: 1075–9.
Fisher DA: Management of congenital hypothyroidism. J Clin Endocrinol Metab 1991; 72: 523–9.
The Endocrinologist
27. Persani L, Feretti E, Borgato S, et al.: Circulating thyrotropin bioactivity in sporadic central hypothyroidism. J Clin Endocrinol Metab
2000; 85: 3631–5.
28. Yamakita N, Komaki T, Takao T, et al.: Usefulness of thyrotropin
(TSH)-releasing hormone test and nocturnal surge of TSH for diagnosis of isolated deficit of TSH secretion. J Clin Endocrinol
Metab 2001; 86: 1054–60.
29. Koukkou E, Panayiotidis P, Thalassinos N: Serum soluble interleukin-2 receptors as an index of the biological activity of thyroid
hormones in hyperthyroidism. J Endocrinol Invest 1995; 18:
253–7.
30. Sawin CT, Herman T, Molitch ME, et al.: Aging and the thyroid.
Am J Med 1983; 75: 206–9
223