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Acknowledgments                     congenital central hypothyroidism in i...
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  1. 1. review www.nature.com/clinicalpractice/endmet Mechanisms related to the pathophysiology and management of central hypothyroidism Masanobu Yamada* and Masatomo Mori S u M M a rY INTRODUCTION Central hypothyroidism (CH) is defined as hypothyroidism due to Hypothyroidism is a common disorder and insufficient stimulation of the thyroid gland by TSH, for which secretion is most frequently caused by primary hypo­ or activity can be impaired at the hypothalamic or pituitary levels. Patients thyroidism. Characteristic laboratory findings for with CH frequently present with multiple other pituitary hormone primary hypothyroidism are subnormal levels of deficiencies. In addition to classic CH induced by hypothalamic–pituitary thyroid hormone and raised TSH levels (caused tumors or Sheehan syndrome, novel causes include traumatic brain injury by normal feedback regulation) in serum. Central or subarachnoid hemorrhage, bexarotene (a retinoid X receptor agonist) hypothyroidism (CH) results from disturbance therapy, neonates being born to mothers with insufficiently controlled to the thyroid stimulation system. The precise Graves disease, and lymphocytic hypophysitis. Growth hormone therapy, prevalence of CH is unknown, but it is thought which may be used in children and adults, is now also recognized as a to be much lower than that of primary hypo­ possible cause of unmasking CH in susceptible individuals. In addition, thyroidism. However, CH arises from a number mutations in genes, such as TRHR, POU1F1, PROP1, HESX1, SOX3, LHX3, of hypothalamic and pituitary disorders, the LHX4 and TSHB, have been associated with CH. The difficulty in making most frequent of which is pituitary adenoma.1 a clear diagnosis of CH is that the serum TSH levels can vary; values are Given that the prevalence of pituitary adenomas normal in most cases, but in some might be low or slightly elevated. Levels in the general population is greater than 10%, of endogenous T4 in serum might also be subnormal. Appropriate doses the true prevalence of CH might be much of levothyroxine for T4 replacement therapy have not been confirmed, but higher than that reported.2 Approximately 15% might need to be higher than presently used empirically in patients with CH of 300 of our patients with pituitary adenomas and should be adjusted according to age and other hormone deficiencies, to examined in the past year have had CH. Van Tijn achieve free T4 concentrations in the upper end of the normal range. et al.3 reported the incidence of congenital CH Keywords bexarotene, GH therapy, subarachnoid hemorrhage, to be 1 per 16,404 neonates, with 13.5% among traumatic brain injury, TsH-releasing hormone these having permanent hypothyroidism. Traumatic brain injury, subarachnoid hemor­ RevIew CRITeRIA rhage, lymphocyte hypophysitis, or Sheehan We searched PubMed for publications with the following search terms: “central syndrome, any time up to several decades pre­ hypothyroidism”, “hypothalamic hypothyroidism”, “pituitary hypothyroidism” viously, might cause CH and lead to deficiency and “hypopituitarism” and combined these words with “pituitary adenomas”, “Rathke’s cleft cyst”, “craniopharyngioma”, “empty sella” and “lymphocytic in secretion of multiple pituitary hormones. A hypophysitis”. All selected papers were English­language, full­text articles. Some full, detailed history should, therefore, be taken of the references were not included because of space restrictions. 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 M Yamada is Associate Professor, and M Mori is Professor and Chairman, cator for detecting hypothyroidism and hyper­ in the Department of Medicine and Molecular Science, Gunma University thyroidism and for monitoring treatments of Graduate School of Medicine, Gunma, Japan. thyroid disorders. This approach works, however, only if the hypothalamic–pituitary–thyroid axis Correspondence *Department of Medicine and Molecular Science, Gunma University Graduate School is normal. Conversely, the strategy of first­line of Medicine, 3–39–15 Showa-machi, Maebashi, Gunma 371–8511, Japan TSH measurement can miss patients with CH. myamada@med.gunma-u.ac.jp In this Review, we focus on prevalence of CH and thyroid hormone status, particularly serum Received 7 April 2008 Accepted 1 September 2008 Published online 21 October 2008 www.nature.com/clinicalpractice TSH level in each disorder, and discuss appropriate doi:10.1038/ncpendmet0995 management. december 2008 vol 4 no 12 nature clinical practice endocrInoloGY & meTAbolISm 683
  2. 2. review www.nature.com/clinicalpractice/endmet or as homodimers. Many cofactors, such as TRH corepressors (nuclear receptor corepressor, silencing mediator of retinoid and thyroid hormone receptors, etc.) and coactivators TRH receptor (steroid receptor coactivator­1 and cyclic AMP response element binding­binding protein, etc.), are also involved in the regulation of tar­ COA T3 geted genes. Meanwhile, secreted thyroid T3 T3 T3 hormone reaches the hypothalamus and the T3 NcoR TR TSH pituitary, where it inhibits production and T3 T3 secretion of TRH and TSH, thereby establishing T3 the hypothalamic–pituitary–thyroid axis. If any Glycosylation Conjugation of T3 factor in this axis is disturbed, hypothyroidism α and β chains will occur. TSH TSH CAUSeS OF CLASSIC CeNTRAL Secretion HYPOTHYROIDISM TSH Adenoma TSH Pituitary adenomas are the most frequent causes of CH, accounting for more than half of all cases Figure 1 The hypothalamic–pituitary–thyroid axis. TRH not only stimulates the (Table 1). In a Spanish study, 45.5 cases of CH secretion of TSH from the pituitary but also regulates conjugation of the α and β were calculated to occur annually per 100,000 of chain of the TSH molecule and affects glycosylation, which changes the biological the general population, of which 61% were due to activity of TSH. Abbreviations: COA, coactivators; NcoR, nuclear receptor corepressor; TR, thyroid hormone receptor; TRH, TSH-releasing hormone. pituitary adenomas.4 Mechanical compression of portal vessels and the pituitary stalk, caused by the expanding adenoma, was postulated to be the predomi­ THe HYPOTHALAMIC–PITUITARY–THYROID nant mechanism of hypopituitarism, including AXIS CH. The results of this pressure might be ische­ Levels of thyroid hormones in serum are tightly mic necrosis of portions of the anterior lobe.1,5 regulated by the hypothalamic–pituitary–thyroid Increased intrasellar pressure can also lead to axis (Figure 1). Hypothalamic TSH­releasing compression of the portal vessels and impairs hormone (TRH) is secreted mainly from the the delivery of hypothalamic hormones to the paraventricular nucleus in the hypothalamus anterior pituitary.6 These mechanisms could be and reaches the median eminence through common to other space­occupying lesions in the axonal transport. TRH is then carried via the pituitary, as discussed later. hypothalamic portal vein to thyrotrophs, which In most cases, CH occurs concurrently with produce TSH, where it binds to TRH receptors other pituitary hormone deficiencies but isolated and stimulates the genes that express the TSH TSH deficiency has also been reported. In a study α and β subunits. Apart from these thyrotropic of 48 patients, 17%, 19%, 21%, 10% and 10% of effects, TRH also regulates the conjugation of patients had deficient levels of two, three, four, the TSH α and β chains and glycosylation of the five and six pituitary hormones, respectively, and TSH molecule to control its biological activity. one had isolated TSH deficiency. Hormone defi­ Mature TSH is secreted from the pituitary gland ciencies were seen for luteinizing hormone/ and reaches the thyroid gland, where it stimulates follicle­stimulating hormone (LH/FSH) in 85% of ncpendmet_2008_086f1.eps thyroid hormone production and release. patients, growth hormone in 65%, adrenocortico­ The main hormone secreted from the thyroid tropic hormone (ACTH) in 62%, TSH in 60%, gland is T4, which reaches the peripheral organs antidiuretic hormone in 23% and prolactin and is converted to T3 by deiodinase. T3 enters in 15%.6–8 Conversely, the prevalence of CH in the cell nuclei and binds to thyroid hormone patients with pituitary adenomas has not been receptor α and β isoforms on targeted genes, systematically assessed. Faglia et al.,9 in 1970, thereby regulating gene transcription. Thyroid identified CH in 15% of adenoma patients; we hormone receptors act on the targeted genes as have found a similar prevalence among 300 patients either heterodimers with the retinoid X receptor with pituitary adenomas, and approximately 75% 684 nature clinical practice endocrInoloGY & meTAbolISm YAmAdA And morI december 2008 vol 4 no 12
  3. 3. review www.nature.com/clinicalpractice/endmet of patients with CH showed normal TSH levels Table 1 Causes of central hypothyroidism. (unpublished data). Cause Congenital Acquired Tumors might secrete growth hormone, prolac­ Classic causes tin, gonadotropin or ACTH, leading to imbalance in the hypothalamic–pituitary–thyroid axis. Space-occupying lesions (brain or pituitary; Yes Yes pituitary adenoma, craniopharygioma, etc.) In patients with acromegaly due to adenomas that secrete growth hormone, Eskildsen et al.10 Radiation No Yes reported significantly reduced serum levels of Vascular disease (Sheehan syndrome, etc.) Yes Yes TSH and T4 in patients with adenomas com­ Nonclassic causes pared with those in healthy controls, suggest­ Traumatic brain injury or subarachnoid hemorrhage No Yes ing CH. In a study of Cushing disease caused by ACTH­secreting adenomas, 7 of 11 patients had Drug-induced (bexarotene, carbemazepine, etc.) No Yes low T4 levels, and in 4 patients thyroid hormone Growth hormone therapy No Yes levels normalized within 10 days of curative Infection (lymphocytic adenohypophysitis, No Yes surgery. Sibal et al.11 reported that in patients lymphocytic hypophysitis) with prolactinoma and macroadenoma treated Set point diseases (infant’s born to mothers with Yes No with dopamine agonists, reduced levels of LH/ inadequately controlled Graves disease, etc.) FSH were observed in 77% of patients, TSH in Genetic mutations Yes No 41% and ACTH in 23%. Idiopathic Yes Yes Pituitary tumor apoplexy Pituitary tumor apoplexy often occurs in patients with untreated pituitary adenomas including CH or recurrent pituitary adenoma, or after stimulation tests with hypothalamic which should be treated if it occurs. hormones (such as TRH and corticotropin­ releasing hormone) to assess pituitary hormone Craniopharyngioma levels. Loss of hormone secretion, particu­ Craniopharyngioma is a common parasellar larly of ACTH, and to a lesser extent TSH, can tumor that can arise from embryonic squamous rapidly become life­threatening and requires remnants of the Rathke pouch. These tumors are urgent replacement therapy. Acute, severe hypo­ often large, generally aggressive and frequently pituitarism should be vigorously treated with infiltrate surrounding brain structures. One glucocorticoids. If neuro­ophthalmological study reported deficiencies in growth hormone symptoms, such as visual impairment, sudden and LH/FSH in about 95% of patients and ACTH onset of severe headache and alteration of the deficiency in more than 85%, with CH arising in level of consciousness, are present, emergency more than 90% and diabetes insipidus in 33%.14 surgery might be indicated. In another report, growth hormone deficiency Lubina et al.12 reported a series of 40 patients was noted in 73%, ACTH deficiency in 32% and with pituitary tumor apoplexy, in whom 63% hypogonadism in 77%, with CH being reported in of adenomas were nonfunctional and 31% were 25% and diabetes insipidus in 16%.15 Surgery on prolactinomas. CH was diagnosed in 54%, 79% of this type of tumor is difficult and, therefore, hypo­ patients developed hypogonadotrophic hypogo­ pituitarism arising after surgery or radiotherapy, nadism, and hypocortisolism developed in 40%. including CH, is frequently observed (Table 1). Zayour et al.13 reported pituitary apoplexy in 13 Rathke cleft cysts (also called craniopharyngeal patients with remarkably high intrasellar pres­ cysts) are epithelial­cell­lined cystic lesions of the sure, whereas serum concentrations of prolactin pituitary gland that are believed to derive from were generally low. These low serum prolactin remnants of the Rathke pouch, a dorsal invagina­ levels suggest the presence of ischemic necrosis of tion of the stomodeal ectoderm. Although these the anterior pituitary; normal or elevated serum cysts are found at autopsy in 13–22% of people, prolactin levels in patients with nonprolactin­ they generally remain asymptomatic throughout secreting macroadenomas indicate the presence of life. If patients become symptomatic, they most fre­ viable pituitary cells and a high likelihood of post­ quently present with headaches, hypopituitarism operative recovery of pituitary function. Patients to varying degrees, and visual disturbances, fol­ with pituitary tumor apoplexy should undergo lowed by diabetes inspidus. CH has been iden­ long­term monitoring for hypopituitarism, tified in 7–35% of symptomatic patients,16–18 december 2008 vol 4 no 12 YAmAdA And morI nature clinical practice endocrInoloGY & meTAbolISm 685
  4. 4. review www.nature.com/clinicalpractice/endmet while deficiencies of growth hormone, LH/FSH Radiation therapy and ACTH, and panhypopituitarism, respectively, External radiotherapy for tumors of the head have been observed in 13–66%, 15–43%, 6–23% and neck might affect the hypothalamus, pitu­ and 13–19% of patients. itary, and/or the thyroid gland.24 CH has been observed in 20–50% of patients irradiated for empty sella syndrome nasopharyngeal or paranasal sinus tumors, and Primary empty sella syndrome is a neuro­ in 6–65% of patients irradiated for brain tumors radiological entity characterized by a sella filled (Table 1). The risk of developing CH is related with cerebrospinal fluid and a flattened pituitary to the total radiation dose. Bhandare et al.24 gland due to raised pressure in the sella turcica. examined 312 patients between 1964 and 2000, This syndrome has been reported in 6–20% of who were treated with radiation therapy for unselected autopsies. Secondary empty sella syn­ extracranial head and neck tumors. Clinical CH drome is induced by surgery or radiation therapy was observed in 17 (5%) patients, with a median for pituitary adenomas, traumatic injury, infection, clinical latency of 4.8 years, while clinical primary and Sheehan syndrome. hypothyroidism was observed in 40 (20%) Primary empty sella syndrome is more patients, in whom the median clinical latency common in women than men and is fre­ was 3.1 years. Multivariate analysis revealed that quently associated with obesity, hypertension, fractionation, adjuvant chemotherapy, and total headache, and nonspecific visual alterations. dose to the pituitary did not significantly correlate Hypopituitarism is present in 10–57% of with CH, but total dose to the thyroid was signifi­ patients, and hyperprolactinemia due to dis­ cantly correlated with primary hypothyroidism. tortion of the pituitary stalk is seen in 10–18%,19 In patients with pituitary adenomas treated with but growth hormone deficiency is the most fre­ fractionated radiotherapy and stereotactic radio­ quent pituitary hormone deficiency. CH has surgery, hypopituitarism developed as a delayed also been identified in some cases (Table 1). complication in 12% of patients at a median of Cannavò et al.20 examined 43 patients with 84 months.25 Similarly, in cancer survivors the primary empty sella syndrome and found CH cumulative incidence of central and mixed hypo­ in two; growth hormone deficiency was present thyroidism is high during the first 10 years after in 15, hypothalamic hypogonadism in 11, and cranial irradiation. adrenal insufficiency in 5. In the two CH cases, serum TSH levels were at the lowest limit of the NONCLASSIC CAUSeS OF CeNTRAL normal range. HYPOTHYROIDISM Traumatic brain injury and subarachnoid Sheehan syndrome hemorrhage Sheehan syndrome occurs as a result of ischemic Several studies in the past few years have demon­ pituitary necrosis due to severe postpartum strated a surprisingly high prevalence of hypo­ hemorrhage, frequently causing panhypo­ pituitarism, including CH, induced by traumatic pituitarism (in 56–84% of cases) and selective brain injury or subarachnoid hemorrhage hormone deficiency.20,21 As growth­hormone­ (Table 1).1,26 The prevalence of hypopituitarism in secreting cells are located in the lower and lateral the chronic phase after traumatic brain injury and regions of the pituitary gland, deficiency of this aneurismal subarachnoid hemorrhage is 28% and hormone is observed in most patients with 47%, respectively. The estimated overall incidence Sheehan syndrome. of traumatic brain injury in Europe is 235 cases per Sheehan syndrome can cause lactation failure 100,000 people in the general population yearly. and amenorrhea, adrenal insufficiency and In a review by Benvenga et al.27, hypopituitarism CH, which has been reported in about 90% of after traumatic brain injury was reported to occur patients (Table 1). Serum TSH levels in most in a male to female ratio of 5:1, with about 60% patients are within normal limits in the acute and of the patients being in the age range 11–29 years; late phases, although severe hypothyroidism can road accidents accounted for half of the cases. arise.22 Serum TSH levels are often paradoxically Since the signs and symptoms of hypopituitarism elevated due to the reduced biological activity, as might be subtle and could overlap with the neuro­ discussed below.23 Furthermore, the time from logical and psychiatric sequelae of traumatic brain birth to the onset of hormone deficiency can injury and subarachnoid hemorrhage, this type vary from several days to a few decades. of hypopituitarism remains undiagnosed in many 686 nature clinical practice endocrInoloGY & meTAbolISm YAmAdA And morI december 2008 vol 4 no 12
  5. 5. review www.nature.com/clinicalpractice/endmet cases. Patients’ quality of life is impaired and they TSH suppression was greatest in patients treated have an adverse metabolic profile, which might with high­dose therapy (>300 mg/m2 bexarotene contribute to morbidity and poor recovery after daily) and in those with a history of treatment these events. with interferon α. Golden et al.31 reported that In patients with hypopituitarism after trau­ a single dose of a rexinoid in healthy individu­ matic brain injury, LH/FSH and growth hormone als could rapidly and specifically reduce levels of deficiencies are more common than ACTH defi­ TSH and thyroid hormones in serum; no changes ciency, which in turn is more common than TSH were seen to prolactin, cortisol, and triglyceride deficiency.26 By contrast, after subarachnoid concentrations. hemorrhage, growth hormone and ACTH defi­ In the hypothalamic–pituitary–thyroid axis the ciency is more common than LH/FSH and TSH thyroid hormone receptor has two isoforms—α deficiency. CH is observed in 1–10% of patients and β—and works on the target DNA as a hetero­ after traumatic brain injury and 3–9% of patients dimer with retinoid X receptor. Bexarotene, there­ in the chronic phase of subarachnoid hemor­ fore, probably directly inhibits the expression of rhage. In CH induced by traumatic brain injury, the TSHB gene through its binding to the reti­ approximately 40% of patients show normal noid X receptor. Sharma et al.29 and Sherman et serum TSH levels but 40% show low TSH and al.32 reported that rexinoids directly suppressed 10% have high TSH levels that are associated TSH secretion, mRNA levels and promoter activ­ with subnormal T4 levels. ity of TSHB gene, and levels of deiodinase type 2 The onset of hypopituitarism is not related to mRNA, but had no direct effect on hypothalamic the severity of trauma,28 but long­term moni­ TRH levels. In addition, they found that rexinoids toring is recommended. If hypopituitarism does stimulate type 1 iodothyronine deiodinase activity occur, it generally does so within 1 year in most in the liver and pituitary. cases but, importantly, it might arise several Peripheral metabolism other than that of years after the index event. In one study, hypo­ deiodinase has also been reported to be stimu­ pituitarism was diagnosed in 15 of 202 patients lated by bexarotene.33 This drug probably, there­ 5 or more years after the trauma; CH was diag­ fore, has at least two effects on thyroid function: nosed in two of these patients 36 and 46 years suppression of TSH production and increased after head trauma.27 thyroid hormone metabolic clearance by mecha­ Traumatic brain injury and aneurismal sub­ nisms mediated by deiodinase and nondeiodinase arachnoid hemorrhage might cause lesions in the enzymes. Although bexarotene­induced hypo­ hypothalamic–pituitary region, including hemor­ thyroidism was observed in mice without rhage, necrosis and fibrosis. Stalk lesion could thyroid receptor β, which suggests that this effect induce infarction in the pituitary by damaging is independent of the action of this receptor, the the portal blood supply. involvement of the thyroid receptor α isoform cannot be excluded.34 A history of interferon α Ligands selective for the retinoid X receptor therapy should be noted and any correlation with Bexarotene is a synthetic retinoid analog that bexarotene­induced CH should be monitored by has specific affinity for the retinoid X receptor measuring serum TSH and free T4 levels. and belongs to a group of compounds called rexinoids, which are approved for treatment of Growth hormone therapy cutaneous T­cell lymphoma.29 In clinical trials In normal individuals, administration of growth of cutaneous T­cell lymphoma, oral bexarotene hormone can cause a slight reduction of serum T4 therapy was associated with severe but reversible concentrations, an increase in serum T3 concentra­ hypertriglyceridemia in 79% of patients and CH tions, and a marked decrease in serum TSH levels, in 40% (Table 1), the latter of which was related to but no change is seen in reverse T3 concentra­ marked reductions in serum TSH and T4 levels.30 tions. Conversely, growth hormone deficiency During bexarotene therapy, serum TSH levels masks CH, and this disorder might become have been reported to decline from a mean of evident only after administration of replacement 2.2 mIU/l to 0.05 mIU/l and those of free T4 from therapy (Table 1).35 A notable reduction in serum 12.9 pmol/l to 5.8 pmol/l. In one report, 19 of 27 T4 levels without a substantial increase in serum patients receiving bexarotene had symptoms or TSH was reported in 36% of euthyroid adults signs of hypothyroidism, particularly fatigue and with growth hormone deficiency, and T4 replace­ intolerance of cold temperatures. The degree of ment therapy was required.36 Furthermore, 16% december 2008 vol 4 no 12 YAmAdA And morI nature clinical practice endocrInoloGY & meTAbolISm 687
  6. 6. review www.nature.com/clinicalpractice/endmet of patients with growth hormone deficiency who therefore, CH in lymphocytic hypophysitis is fre­ had previously received T4 replacement therapy quently associated with low serum TSH concen­ required repeat therapy at a higher dose. Raising trations. A case of isolated TSH deficiency has also low free T4 levels to the middle or upper levels of been reported.40 the reference range is widely recommended, as is the raising of free T4 levels to the upper limits Infants born to mothers with poorly of normal in patients whose free T4 concentra­ controlled Graves disease tions are normal at presentation. The biological Thyrotoxic effects occur in about 1% of babies effects of this therapy remain controversial, born to mothers with either active or previously however, since the serum T3 levels are also gener­ treated Graves disease.41 High titers of thyroid­ ally increased by the therapy.37 Martins et al.38 stimulating antibodies to TSH receptor in serum reported, therefore, that growth hormone are generally present in these mothers, and thyro­ replacement increased the biological effect of toxicosis is transient. By contrast, congenital CH serum T4, suggesting that serum T4 levels should is also observed in neonates born to mothers with be raised to the high end of the normal range only inadequately controlled Graves disease and high in patients with growth hormone deficiency who serum thyroid hormone levels during the last tri­ are not receiving replacement therapy. mester of pregnancy (Table 1).42 The incidence Although the mechanism of hypothyroid­ of this type of CH is at least 1 per 35,000 neo­ ism after growth hormone replacement therapy nates, but the exact mechanism has not been fully remains unclear, this therapy has been reported elucidated. Higuchi et al.43 reported that the gesta­ to increase peripheral deiodination of T4 to T3 tional period earlier than 32 weeks is the critical and secretion of somatostatin, thereby blocking time for CH to develop. Matsuura et al.44 reported TSH secretion from the pituitary. Whether this that weak maternal thyroid­stimulating antibody effect is mediated by insulin­like growth factor I activity and differences in the sensitivity of the or is controlled directly by growth hormone is thyroid grand to antibodies against TSH receptor not unknown. might contribute. Although frequently transient, thyroid dys­ Lymphocytic hypophysitis function related to congenital CH was shown Lymphocytic hypophysitis is an autoimmune by Kempers et al.45 to be permanent in some inflammatory disease of the pituitary gland patients, with possible need for thyroid hormone that has several clinical forms, such as adeno­ replacement therapy. Ultrasound imaging of hypophysitis, infundibuloneurohypophysitis or the thyroid gland showed decreased size and panhypophysitis.39 Women are affected slightly echogenicity, and heterogeneous echotexture. more frequently than men, with the difference Insufficient TSH secretion due to excessive being greatest during pregnancy or shortly after maternal­to­fetal thyroid hormone transfer delivery. Associated partial hypopituitarism is could inhibit fetal growth and development of seen in approximately half of all patients, iso­ the thyroid gland. The occurrence, type and lated hormone deficiency in 20%, and panhypo­ severity of thyroid dysfunction in offspring is pituitarism in 10%. Patients with lymphocytic dependent on maternal thyroid status and use hypophysitis often have ACTH deficiency (56%), of antithyroid drugs, and the presence of anti­ in comparison with other hypothalamic–pituitary bodies, such as those against the TSH receptor. disorders, which are mostly associated with defi­ Most babies with thyroid dysfunction related ciencies in growth hormone or LH/FSH.39 CH is to congenital CH showed low thyroid hormone present in 44% of lymphocytic hypophysitis cases levels and normal serum TSH levels. (Table 1), LH/FSH deficiency in 42%, growth hormone deficiency in 26%, and prolactin defi­ GeNeTIC MUTATIONS ciency in 25%. In lymphocytic panhypophysitis Several genetic mutations causing CH have been the prevalence of growth hormone deficiency reported, including mutations of the TSHB, increases to 51%. TRHR, POU1F1, PROP1, HESX1, SOX3, LHX3, We reviewed 63 case reports of lymphocytic LHX4 genes and the leptin receptor genes LEPR hypophysitis, and found that CH was identified and LEP (Table 1). Mutations of the TSHB gene in 37 (59%). Serum TSH levels were normal in 19 are being reported with increasing frequency. (51%) cases, low in 16 (43%), and slightly elevated Familial isolated TSH deficiency was described in 2 (5%). Compared with pituitary adenomas, by Miyai et al. in 1971, and later a single­base 688 nature clinical practice endocrInoloGY & meTAbolISm YAmAdA And morI december 2008 vol 4 no 12
  7. 7. review www.nature.com/clinicalpractice/endmet substitution (Gly85Arg at the 29th codon [G29R] The PROP1 gene encodes a 226 amino acid in the CAGYC region of the TSHβ subunit) was transcription factor that is involved in the early identified.46 Inheritance was autosomal reces­ development of several lineages of anterior pitu­ sive. Three­dimensional imaging analysis has itary cells. Mutations cause combined pituitary demonstrated that this CAGYC region is impor­ hormone deficiency that is autosomal recessive tant for heterodimerization of the α chain with and associated with deficiency of LH/FSH, growth the β chain subunit to form a complete TSH hormone, TSH, prolactin and, less frequently, molecule. Other mutations, such as 313delT ACTH. Hormone deficiency is less severe than (C105Vfs114X) and Q49X, have been reported, that with the POU1F1 mutation. Patients often and all cases were either compound hetero­ present with growth retardation, CH, and hypo­ zygotes or homozygotes. Some mutations have gonadotropic hypogonadism, but the hormonal been confirmed as founder mutations. phenotype can vary in severity and in age of In severe cases of CH, such as patients with onset. In some patients, CH develops during ado­ G29R mutations, typical signs and symptoms lescence.51 Some patients undergo spontaneous of cretinism without goiter have been identi­ puberty before developing central hypogonadism fied. Radioiodine uptake in the thyroid glands is and only a subset of patients show adrenal insuf­ poor, and increases after administration of TSH. ficiency. The mechanism underlying the variable In patients with TSHB mutations, serum TSH expression of combined hormone deficiency is, is undetectable in some, and in patients with however, unknown. Pituitary size can also vary G29R mutations, endogenous T4 and T3 con­ among patients; it is not uncommon to find centrations are low or undetectable. In patients pituitary masses in affected children than can be with the Q49X mutation, however, circulating potentially mistaken for craniopharyngiomas or TSH is detectable by immunoassay but has no pituitary adenomas. biological activity. Furthermore, serum TSH Mutations causing combined pituitary hor­ level has been reported as moderately increased mone deficiency have been also described in in homozygotes with 313delT (C105Vfs114X) the HESX1, SOX3, LHX3, and LHX4 genes. In in an assay system.47 Values measured by other addition to manifestations of the deficiency assay systems were, however, normal. Therefore, of pituitary hormones, HESX1 mutations are the reported TSH levels in patients with muta­ associated with septo­optic dysplasia, and LHX3 tions of the TSHB gene seem to depend on the mutations are sometimes associated with rigid assay system used. cervical spines. In patients with LHX4 muta­ The first TRH receptor mutation was reported tions, cerebellar defects, and abnormalities of by Collu et al.48 in 1997, and the patient had com­ the sella turcica at the central skull base have pound heterozygosity for deletions of three amino been reported. The duplication containing the acid residues (Ser115, Ile116, and Thr117) and one SOX3 gene has been reported in families with replacement (Ala118Thr). The patient showed no X­linked hypopituitarism and mental retardation, TSH or prolactin response to TRH administra­ and has been associated with variable combina­ tion. CH in this patient was mild with normal tions of CH, delayed pubertal development, and serum TSH level and the only manifestation was growth hormone deficiency.52 short stature. The pituitary­specific transcription factor Pit­1, LeSSONS FROM ANIMAL MODeLS a member of the POU homeodomain family, regu­ Several animal models have been studied to lates the expression of TSHβ, growth hormone gain insight into CH. In TRH knockout mice and prolactin genes. Mutation of the POU1F1 gene we showed typical tertiary hypothyroidism with causes combined pituitary hormone deficiencies, low serum thyroid hormone levels and slightly including complete growth hormone and pro­ elevated serum TSH levels.53 As seen in humans, lactin deficiency as well as CH. Typically, patients TRH testing revealed exaggerated response of have severe growth retardation and, several years serum TSH; however, the increase of serum T3 later, develop CH. Levels of T4 and T3 in serum in response to elevated TSH was significantly are low, whereas those of TSH remain in the lower impaired, indicating reduced biological activity end of the normal range. Most reported cases of serum TSH. Furthermore, the TRH knockout show autosomal recessive inheritance, but the mice showed mild hyperglycemia with minor Arg271Trp mutation in POU1F1 shows dominant impairment of insulin secretion from pancreatic β negative and autosomal dominant patterns.49,50 cells. Since TRH has been reported to be localized december 2008 vol 4 no 12 YAmAdA And morI nature clinical practice endocrInoloGY & meTAbolISm 689
  8. 8. review www.nature.com/clinicalpractice/endmet Subnormal T4 levels with Adult deiodinase knockout mice was impaired at all Infant and child inappropriately low TSH levels levels, including the hypothalamus, pituitary, and thyroid gland, suggesting that disturbance of D3 might cause a novel type of CH in humans. Check other hormone deficiencies DIAGNOSIS OF CeNTRAL HYPOTHYROIDISM Usual screening for hypothyroidism, including assessment for cretinism, with measurements Take history of symptoms of serum TSH levels might not detect CH, but a Gene test and medications T4­based 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 MRI of the pituitary low serum TSH probably indicate CH (Figure 2), although some patients with CH have slightly high TSH levels as discussed before. Mutations in TSHB, Pituitary adenoma, Post-TBI or SAH, Several mechanisms leading to the differ­ PROP1, POU1F1, craniopharyngioma, Sheehan syndrome, ences in TSH levels have been suggested: etc. other SOL post-GH therapy, drug-related, LAH hypoadrenalism raising serum TSH levels; decreased secretion of somatostatin from the Figure 2 Proposed algorithm for the diagnosis and confirmation of central hypothalamus resulting in increased TSH secre­ hypothyroidism. Abbreviations: GH, growth hormone; LAH, lymphocytic tion; and reduced biological and receptor binding adenohypophysitis; SAH, subarachnoid hemorrhage; SOL, space-occupying activity of TSH. In humans, oral administration lesions; TBI, traumatic brain injury. of TRH could improve abnormal TSH glycosyl­ ation due to high levels of mannose, biantennary oligosaccharide moieties, and a reduced degree in insulin vesicles in the β cells, it might regulate of sialylation.58,59 insulin secretion. The diagnostic value of TRH stimulation Rodents have two subtypes of TRH receptors has been evaluated in several studies.60–62 (1 and 2) but the corresponding complementary Administration of TRH to normal individuals DNA for rodent TRH receptor 2 has not been produces a consistent rise in serum TSH levels. identified in humans. Rabeler et al.54 developed Peak values are seen at 15–30 min, with notable a mouse model with TRH receptor 1 knocked decrease starting at 60 min. During TRH testing, out and showed similar mild hypothyroidism plasma TSH is measured before and 15 (optional), to TRH knockout mice, but the serum TSH 30, 60, 120, and 180 (optional) min after intra­ level remained normal. Zeng et al.55 established venous administration of TRH (10 µg/kg body another line of TRH receptor 1 knockout mice weight, 200 µg or 500 µg). Generally, normal and reported increased anxiety, mild depres­ responses of TSH are defined as ∆TSH greater sion, and hyperglycemia similar to that seen in than 4.0–5.0 mIU/l, absent or blunted responses TRH knockout mice. From these observations, as ∆TSH less than 4.0–5.0 mIU/l or a twofold isolated TRH deficiency clearly does not reduce peak increase of TSH at 15 min or 30 min, and the serum TSH level. excessive or delayed responses as ∆TSH >20.0– Most peripherally active endogenous T3 is con­ 25.0 mIU/l or a peak response after 60 min. Many verted from T4 by peripheral type 2 deiodinase. CH patients show either blunted or delayed pat­ Type 3 deiodinase degrades T3 and T4 to the terns. Evaluation of results of TRH tests have, inactive forms, T2 and reverse T3, respectively. however, varied across studies. Mice with type 3 deiodinase knocked out showed To evaluate the biological activity of circulating perinatal thyrotoxicosis with elevated serum T3 TSH, the increment of serum T3 or free T3 in levels, due to the impaired clearance of T3.56,57 response to increased TSH might be used.63 From postnatal day 15, however, these mice Free T3 responses to TRH­stimulated TSH have exhibited CH with low T4 and T3 and normal been observed in normal individuals, yielding or modestly increased TSH levels in serum. increases of 29–37% (mean increase 32%) at A subsequent study demonstrated that the 120 min after the stimulation, while free T4 levels hypothalamic–pituitary–thyroid axis in type 3 increase by 14% (unpublished data). In CH, ncpendmet_2008_086f2.eps 690 nature clinical practice endocrInoloGY & meTAbolISm YAmAdA And morI december 2008 vol 4 no 12
  9. 9. review www.nature.com/clinicalpractice/endmet this response might be blunted. Distinguishing Hypoadrenalism? between hypothalamic CH and pituitary CH No Yes by TRH test can be difficult. Conversely, normal TRH tests also do not exclude abnormalities in the hypothalamic–pituitary–thyroid axis. Replace glucocoticoid Although loss of the nocturnal surge of serum Investigate tumor 1–2 weeks before TSH level has been used to assess CH, this Yes No starting levothyroxine approach is still controversial.64,65 MRI could be required for most suspected cases of CH to detect origin of hypothalamic or pituitary disorders. Operation Start low-dose levothyroxine (~1.6 μg/kg body weight and adjusted for age and other MANAGeMeNT OF CeNTRAL hormone deficiencies) HYPOTHYROIDISM Although TRH and TSH administration are theo­ Re-evaluation retically ideal for treatment of CH, they have Free T4 levels in upper been abandoned because of high monetary costs, No level of normal range limited applicability and instability of TRH after Transient subtype? oral administration. Most patients with CH are, therefore, treated with levothyroxine (Figure 3). Yes Deficiencies of hormones other than TSH should be considered before starting treatment. When Stop levothyroxine ACTH deficiency is also present, glucocorticoid therapy should be started at least 1 week before Figure 3 Proposed algorithm for the treatment of central hypothyroidism. 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 the fact that the levothyroxine dose is inadequate. with pituitary tumor apoplexy, should receive Raising levels of free T4 might, therefore, be neces­ corticosteroids during the acute stage. Patients sary in patients with GH deficiency.35 Similarly, with lymphocytic adenohypophysitis also fre­ higher doses may be required for postmenopausal quently have ACTH deficiency. Although the women receiving estrogen­based therapies.68 efficacy of restoring pituitary function remains Patients with CH treated with bexarotene com­ unclear, glucocorticoid therapy has been used to monly require high doses of thyroid hormone reduce the size of the pituitary.39 for replacement therapy, often twice the typical Use of an average dose of levothyroxine dose used to treat primary hypothyroidism. This 1.6 µg/kg body weight daily can generally restore difference might be due to certain characteris­ a euthyroid state in adults with primary hypo­ tics of CH and to increased clearance of thyroid thyroidism, but the optimum dose or dose hormone. Hypertriglyceridemia should also range for CH is unclear.66 In a sizeable subset of be monitored and treated in patients with CH patients with CH, serum free T4 levels remain at receiving bexarotene. the low end of the normal range with empirical Combination therapy comprising levothy­ levothyroxine therapy. A dose similar to that used roxine and liothyronine has been tried with the for primary hypothyroidism has been recom­ aim of normalizing the tissue concentration of T4 mended for patients with CH, with the aim of and T3. Administration of liothyronine 0.16 µg/kg achieving serum concentrations of free T4 in body weight might provide additional beneficial the upper end of the normal range rather than effects on ankle reflex time and working memory, within the middle or lower values.66,67 but could also result in supraphysiological con­ CH therapy might need to be tailored to the centrations of free T3 in serum.66 In addition, a individual. Children might require high doses meta­analysis showed no benefit of combination (around 4.0 µg/kg daily), whereas elderly indi­ therapy over levothyroxine monotherapy.69 viduals might require low doses (around 1.0 µg/kg In many cases of CH, measurement of serum daily). Furthermore, GH deficiency, which is TSH levels cannot be used to monitor therapy common in patients with CH, could impair response, since negative feedback regulation of conversion of T4 into active T3, thereby masking TSH by thyroid hormones can remain intact. ncpendmet_2008_086f3.eps december 2008 vol 4 no 12 YAmAdA And morI nature clinical practice endocrInoloGY & meTAbolISm 691
  10. 10. review www.nature.com/clinicalpractice/endmet When the basal level of serum TSH is normal in References 1 Schneider HJ et al. (2007) Hypopituitarism. Lancet patients with CH, concentrations may decrease 369: 1461–1470 to very low values after treatment.70 Serum levels 2 Martino E et al. (2005) Central hypothyroidism. In of cholesterol, creatinine phosphokinase, soluble Werner and Ingabar’s The Thyroid: A Fundamental and Clinical Text, 754–768, edn 9 (Eds Braverman LE interleukin­2 receptor, sex­hormone­binding and Utiger RD) Philadelphia, PA: Lippincott Williams & globulin, angiotensin­converting enzyme, cross­ Wilkins linked carboxyterminal telopeptide of type I 3 van Tijn DA et al. (2005) Neonatal detection of congenital hypothyroidism of central origin. J Clin collagen and osteocalcin can be used as clinical Endocrinol Metab 90: 3350–3359 and biochemical peripheral parameters. 4 Regal M et al. 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JAMA 298: 1429–1438 46 Miyai K (2007) Congenital thyrotropin deficiency—from 27 Benvenga S et al. (2000) Clinical review 113: discovery to molecular biology, postgenome and hypopituitarism secondary to head trauma. J Clin preventive medicine. Endocr J 54: 191–203 Endocrinol Metab 85: 1353–1361 47 Partsch CJ et al. (2006) Initially elevated TSH 28 Aimaretti G and Ghigo E (2007) Should every and congenital central hypothyroidism due to a patient with traumatic brain injury be referred to an homozygous mutation of the TSH beta subunit gene: endocrinologist? Nat Clin Pract Endocrinol Metab 3: case report and review of the literature. Exp Clin 318–319 Endocrinol Diabetes 114: 227–234 29 Sharma V et al. (2006) Effects of rexinoids on 48 Collu R et al. (1997) A novel mechanism for isolated thyrotrope function and the hypothalamic-pituitary- central hypothyroidism: inactivating mutations in the thyroid axis. Endocrinology 147: 1438–1451 thyrotropin-releasing hormone receptor gene. 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  12. 12. review www.nature.com/clinicalpractice/endmet Acknowledgments congenital central hypothyroidism in infants. J Clin combination of T4 and triiodothyronine. J Clin Endocrinol We thank K Horiguchi and Endocrinol Metab 93: 410–419 Metab 92: 4115–4122 R Umezawa for their help 62 Mehta A et al. (2003) Is the thyrotropin-releasing 67 Alexopoulou O et al. (2004) Clinical and hormonal collating and analyzing hormone test necessary in the diagnosis of central characteristics of central hypothyroidism at diagnosis articles. hypothyroidism in children. J Clin Endocrinol Metab 88: and during follow-up in adult patients. Eur J Endocrinol 5696–5703 150: 1–8 63 Horimoto M et al. (1995) Bioactivity of thyrotropin (TSH) 68 Arafah BM (2001) Increased need for thyroxine in Competing interests in patients with central hypothyroidism: comparison women with hypothyroidism during estrogen therapy. The authors declared no between in vivo 3,5,3'-triiodothyronine response to TSH N Engl J Med 344: 1743–1749 competing interests. and in vitro bioactivity of TSH. J Clin Endocrinol Metab 69 Grozinsky-Glasberg S et al. (2006) Thyroxine- 80: 1124–1128 triiodothyronine combination therapy versus thyroxine 64 Mönig H et al. (1999) Blunted nocturnal TSH surge does monotherapy for clinical hypothyroidism: meta-analysis not indicate central hypothyroidism in patients after of randomized controlled trials. J Clin Endocrinol Metab pituitary surgery. Exp Clin Endocrinol Diabetes 107: 91: 2592–2599 89–92 70 Ferretti E et al. (1999) Evaluation of the adequacy of 65 Darzy KH and Shalet SM (2005) Circadian and stimulated levothyroxine replacement therapy in patients with thyrotropin secretion in cranially irradiated adult cancer central hypothyroidism. J Clin Endocrinol Metab 84: survivors. J Clin Endocrinol Metab 90: 6490–6497 924–929 66 Slawik M et al. (2007) Thyroid hormone replacement 71 Webb SM et al. (1999) Recovery of hypopituitarism after for central hypothyroidism: a randomized controlled neurosurgical treatment of pituitary adenomas. trial comparing two doses of thyroxine (T4) with a J Clin Endocrinol Metab 84: 3696–3700 694 nature clinical practice endocrInoloGY & meTAbolISm YAmAdA And morI december 2008 vol 4 no 12

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