Mechanisms related to the pathophysiology and management of ...

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Mechanisms related to the pathophysiology and management of central hypothyroidismMasanobu Yamada* and Masatomo Mori

INTRODUCTIONHypothyroidism is a common disorder and is most frequently caused by primary hypo­thyroidism. 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 hypo­thyroidism. 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 hemor­rhage, lymphocyte hypophysitis, or Sheehan syndrome, any time up to several decades pre­viously, 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 deficien­cies. 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 indi­cator for detecting hypothyroidism and hyper­thyroidism and for monitoring treatments of thyroid disorders. This approach works, however, only if the hypothalamic–pituitary–thyroid axis is normal. Conversely, the strategy of first­line 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.

SuMMarY 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

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 [email protected]

Received 7 April 2008 Accepted 1 September 2008 Published online 21 October 2008

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RevIew CRITeRIAWe 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 English­language, full­text articles. Some of the references were not included because of space restrictions.

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THe HYPOTHALAMIC–PITUITARY–THYROID AXISLevels of thyroid hormones in serum are tightly regulated by the hypothalamic–pituitary–thyroid axis (Figure 1). Hypothalamic TSH­releasing 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 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

or as homodimers. Many cofactors, such as corepressors (nuclear receptor corepressor, silencing mediator of retinoid and thyroid hormone receptors, etc.) and coactivators (steroid receptor coactivator­1 and cyclic AMP response element binding­binding protein, etc.), are also involved in the regulation of tar­geted 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 AdenomaPituitary 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 predomi­nant mechanism of hypopituitarism, including CH. The results of this pressure might be ische­mic 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 space­occupying 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 defi­ciencies were seen for luteinizing hormone/follicle­stimulating hormone (LH/FSH) in 85% of patients, growth hormone in 65%, adrenocortico­tropic 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%

T3

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T3T3

T3

T3T3

T3

T3

TSH

TRH

TSH

Conjugation ofα and β chains

COA

NcoR

TSH

Glycosylation

TRH receptor

SecretionTSH

TSH

TR

T3

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.

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of patients with CH showed normal TSH levels (unpublished data).

Tumors might secrete growth hormone, prolac­tin, 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 com­pared with those in healthy controls, suggest­ing CH. In a study of Cushing disease caused by ACTH­secreting 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 apoplexyPituitary tumor apoplexy often occurs in patients with untreated pituitary adenomas or after stimulation tests with hypothalamic hormones (such as TRH and corticotropin­releasing hormone) to assess pituitary hormone levels. Loss of hormone secretion, particu­larly of ACTH, and to a lesser extent TSH, can rapidly become life­threatening and requires urgent replacement therapy. Acute, severe hypo­pituitarism should be vigorously treated with glucocorticoids. If neuro­ophthalmological 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 hypogo­nadism, and hypocortisolism developed in 40%. Zayour et al.13 reported pituitary apoplexy in 13 patients with remarkably high intrasellar pres­sure, 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 nonprolactin­secreting macroadenomas indicate the presence of viable pituitary cells and a high likelihood of post­operative recovery of pituitary function. Patients with pituitary tumor apoplexy should undergo long­term monitoring for hypopituitarism,

including CH or recurrent pituitary adenoma, which should be treated if it occurs.

CraniopharyngiomaCraniopharyngioma 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, hypo­pituitarism arising after surgery or radiotherapy, including CH, is frequently observed (Table 1).

Rathke cleft cysts (also called craniopharyngeal cysts) are epithelial­cell­lined cystic lesions of the pituitary gland that are believed to derive from remnants of the Rathke pouch, a dorsal invagina­tion 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 fre­quently present with headaches, hypopituitarism to varying degrees, and visual disturbances, fol­lowed by diabetes inspidus. CH has been iden­tified in 7–35% of symptomatic patients,16–18

Table 1 Causes of central hypothyroidism.

Cause Congenital Acquired

Classic causes

Space-occupying lesions (brain or pituitary; pituitary adenoma, craniopharygioma, etc.)

Yes Yes

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, lymphocytic hypophysitis)

No Yes

Set point diseases (infant’s born to mothers with inadequately controlled Graves disease, etc.)

Yes No

Genetic mutations Yes No

Idiopathic Yes Yes

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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 syndromePrimary empty sella syndrome is a neuro­radiological 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 syn­drome 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 fre­quently associated with obesity, hypertension, headache, and nonspecific visual alterations. Hypopituitarism is present in 10–57% of patients, and hyperprolactinemia due to dis­tortion of the pituitary stalk is seen in 10–18%,19 but growth hormone deficiency is the most fre­quent 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 syndromeSheehan syndrome occurs as a result of ischemic pituitary necrosis due to severe postpartum hemorrhage, frequently causing panhypo­pituitarism (in 56–84% of cases) and selective hormone deficiency.20,21 As growth­hormone­secreting 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.

Radiation therapyExternal radiotherapy for tumors of the head and neck might affect the hypothalamus, pitu­itary, 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 signifi­cantly correlated with primary hypothyroidism. In patients with pituitary adenomas treated with fractionated radiotherapy and stereotactic radio­surgery, 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 hypo­thyroidism is high during the first 10 years after cranial irradiation.

NONCLASSIC CAUSeS OF CeNTRAL HYPOTHYROIDISMTraumatic brain injury and subarachnoid hemorrhageSeveral studies in the past few years have demon­strated a surprisingly high prevalence of hypo­pituitarism, 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 neuro­logical 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 trau­matic brain injury, LH/FSH and growth hormone deficiencies are more common than ACTH defi­ciency, which in turn is more common than TSH deficiency.26 By contrast, after subarachnoid hemorrhage, growth hormone and ACTH defi­ciency 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 hemor­rhage. 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 long­term moni­toring 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, hypo­pituitarism was diagnosed in 15 of 202 patients 5 or more years after the trauma; CH was diag­nosed in two of these patients 36 and 46 years after head trauma.27

Traumatic brain injury and aneurismal sub­arachnoid hemorrhage might cause lesions in the hypothalamic–pituitary region, including hemor­rhage, necrosis and fibrosis. Stalk lesion could induce infarction in the pituitary by damaging the portal blood supply.

Ligands selective for the retinoid X receptorBexarotene 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 T­cell lymphoma.29 In clinical trials of cutaneous T­cell 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

TSH suppression was greatest in patients treated with high­dose 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 individu­als 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 hetero­dimer with retinoid X receptor. Bexarotene, there­fore, probably directly inhibits the expression of the TSHB gene through its binding to the reti­noid X receptor. Sharma et al.29 and Sherman et al.32 reported that rexinoids directly suppressed TSH secretion, mRNA levels and promoter activ­ity 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 stimu­lated by bexarotene.33 This drug probably, there­fore, has at least two effects on thyroid function: suppression of TSH production and increased thyroid hormone metabolic clearance by mecha­nisms mediated by deiodinase and nondeiodinase enzymes. Although bexarotene­induced hypo­thyroidism 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 bexarotene­induced 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 concentra­tions, and a marked decrease in serum TSH levels, but no change is seen in reverse T3 concentra­tions. 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 replace­ment 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 concentra­tions are normal at presentation. The biological effects of this therapy remain controversial, however, since the serum T3 levels are also gener­ally 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 hypothyroid­ism 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 insulin­like 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 adeno­hypophysitis, 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, iso­lated hormone deficiency in 20%, and panhypo­pituitarism in 10%. Patients with lymphocytic hypophysitis often have ACTH deficiency (56%), in comparison with other hypothalamic–pituitary disorders, which are mostly associated with defi­ciencies 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 defi­ciency 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,

therefore, CH in lymphocytic hypophysitis is fre­quently associated with low serum TSH concen­trations. A case of isolated TSH deficiency has also been reported.40

Infants born to mothers with poorly controlled Graves diseaseThyrotoxic effects occur in about 1% of babies born to mothers with either active or previously treated Graves disease.41 High titers of thyroid­stimulating antibodies to TSH receptor in serum are generally present in these mothers, and thyro­toxicosis 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 tri­mester of pregnancy (Table 1).42 The incidence of this type of CH is at least 1 per 35,000 neo­nates, but the exact mechanism has not been fully elucidated. Higuchi et al.43 reported that the gesta­tional period earlier than 32 weeks is the critical time for CH to develop. Matsuura et al.44 reported that weak maternal thyroid­stimulating antibody activity and differences in the sensitivity of the thyroid grand to antibodies against TSH receptor might contribute.

Although frequently transient, thyroid dys­function 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 maternal­to­fetal 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 anti­bodies, 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 MUTATIONSSeveral 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 single­base

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substitution (Gly85Arg at the 29th codon [G29R] in the CAGYC region of the TSHβ subunit) was identified.46 Inheritance was autosomal reces­sive. Three­dimensional imaging analysis has demonstrated that this CAGYC region is impor­tant 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 hetero­zygotes 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 identi­fied. 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 con­centrations 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 muta­tions 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 com­pound 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 administra­tion. CH in this patient was mild with normal serum TSH level and the only manifestation was short stature.

The pituitary­specific transcription factor Pit­1, a member of the POU homeodomain family, regu­lates the expression of TSHβ, growth hormone and prolactin genes. Mutation of the POU1F1 gene causes combined pituitary hormone deficiencies, including complete growth hormone and pro­lactin 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

The PROP1 gene encodes a 226 amino acid transcription factor that is involved in the early development of several lineages of anterior pitu­itary 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 hypo­gonadotropic hypogonadism, but the hormonal phenotype can vary in severity and in age of onset. In some patients, CH develops during ado­lescence.51 Some patients undergo spontaneous puberty before developing central hypogonadism and only a subset of patients show adrenal insuf­ficiency. 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 hor­mone 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 septo­optic dysplasia, and LHX3 mutations are sometimes associated with rigid cervical spines. In patients with LHX4 muta­tions, 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 X­linked hypopituitarism and mental retardation, and has been associated with variable combina­tions of CH, delayed pubertal development, and growth hormone deficiency.52

LeSSONS FROM ANIMAL MODeLSSeveral 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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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 depres­sion, 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 con­verted 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

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 HYPOTHYROIDISMUsual screening for hypothyroidism, including assessment for cretinism, with measurements of serum TSH levels might not detect CH, but a T4­based screening might be useful. The most effective way to diagnose CH might be measure­ment 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 differ­ences in TSH levels have been suggested: hypoadrenalism raising serum TSH levels; decreased secretion of somatostatin from the hypothalamus resulting in increased TSH secre­tion; and reduced biological and receptor binding activity of TSH. In humans, oral administration of TRH could improve abnormal TSH glycosyl­ation 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 intra­venous 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 pat­terns. 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 TRH­stimulated 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,

ncpendmet_2008_086f2.eps

Subnormal T4 levels withinappropriately low TSH levels

Check other hormone deficiencies

Pituitary adenoma,craniopharyngioma,

other SOL

Post-TBI or SAH,Sheehan syndrome,

post-GH therapy,drug-related, LAH

Mutations in TSHB,PROP1, POU1F1,

etc.

MRI of the pituitary

Take history of symptomsand medications

Gene test

Infant and child Adult

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.

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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 HYPOTHYROIDISMAlthough TRH and TSH administration are theo­retically 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 con­sumption 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 fre­quently 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 hypo­thyroidism, 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 recom­mended 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 indi­viduals 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

the fact that the levothyroxine dose is inadequate. Raising levels of free T4 might, therefore, be neces­sary in patients with GH deficiency.35 Similarly, higher doses may be required for postmenopausal women receiving estrogen­based therapies.68 Patients with CH treated with bexarotene com­monly 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 characteris­tics 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 levothy­roxine 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 con­centrations of free T3 in serum.66 In addition, a meta­analysis 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

YesNo

Start low-dose levothyroxine(~1.6 μg/kg body weight andadjusted for age and other

hormone deficiencies)

Free T4 levels in upperlevel of normal range

Investigate tumor

Operation

Re-evaluation

Transient subtype?

Stop levothyroxine

Hypoadrenalism?

Replace glucocoticoid1–2 weeks before

starting levothyroxineNo

No

Yes

Yes

Figure 3 Proposed algorithm for the treatment of central hypothyroidism.

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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 interleukin­2 receptor, sex­hormone­binding globulin, angiotensin­converting enzyme, cross­linked carboxyterminal telopeptide of type I collagen and osteocalcin can be used as clinical and biochemical peripheral parameters.

Furthermore, in some cases CH might be rever­sible 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 hyper­thyroid mothers generally consists of short­term supplementation with levothyroxine.

CONCLUSIONSThe 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

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AcknowledgmentsWe thank K Horiguchi and R Umezawa for their help collating and analyzing articles.

Competing interestsThe authors declared no competing interests.

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