Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

51.Central Hypothyroidism

Enio Martino

Aldo Pinchera

Central hypothyroidism is defined as reduced thyroid hormone secretion resulting from deficient stimulation of an intrinsically normal thyroid gland by thyroid-stimulating hormone (thyrotropin, TSH). This condition can be the consequence of an anatomic or functional disorder of the pituitary gland, the hypothalamus, or both. Because the final result in both cases is deficient TSH secretion, the formerly used terms, “secondary hypothyroidism of pituitary origin, and tertiary hypothyroidism of hypothalamic origin,” resulting from absent or insufficient TSH stimulation by thyrotropin-releasing hormone (TRH), are no longer recommended. In addition, the pituitary and hypothalamic forms of central hypothyroidism cannot be distinguished easily on the basis of the serum TSH response to exogenous TRH administration, as suggested in the past. It had been thought that an increase in serum TSH after TRH administration indicated hypothalamic hypothyroidism, and the lack of a serum TSH response indicated pituitary hypothyroidism. It is now established that considerable overlap exists between the profile of serum TSH responses to TRH in the two conditions. Finally, TSH secretion can be impaired not only quantitatively but also qualitatively as a result of secretion of TSH that is biologically inactive (1,2). For these reasons, the term “central hypothyroidism” is now preferred because it includes both quantitative and qualitative abnormalities of TSH secretion, irrespective of the hypothalamic or pituitary origin of the disorder.

Central hypothyroidism is rarely an isolated defect, most often being part of a more complex deficit in pituitary hormone secretion, hypopituitarism, which can also affect gonadotropin, corticotropic hormone (ACTH), and growth hormone (GH) secretion. The hypothyroidism may be mild and overshadowed by the clinical features of other pituitary hormone defects, or it may be so severe as to dominate the clinical picture. Isolated TSH deficiency can occur as an autosomal-recessive trait resulting from a TSH-β subunit gene abnormality (3,4,5,6,7).

The prevalence of central hypothyroidism is unknown, but it is much rarer than primary hypothyroidism. The latter is found in about 1% to 2% of the general population. Based on the prevalence of pituitary tumors, central hypothyroidism has been estimated to occur in 0.0002% of the general population, but the true prevalence is probably higher considering that pituitary tumors are not the only cause of this disorder. In our experience, the frequency of central hypothyroidism in the general population is about 0.005%. Central hypothyroidism is distributed equally between the sexes, with an age peak in childhood for the idiopathic and genetic forms and a peak between 30 and 60 years of age for cases caused by lesions of the pituitary and hypothalamus.

Although central hypothyroidism is rare, from a clinical standpoint it is important to recognize it because it is often associated with defects of other pituitary hormones, and correction of hypothyroidism by thyroxine (T4) alone can precipitate acute adrenocortical insufficiency.

ETIOLOGY

Table 51.1 shows the different causes of central hypothyroidism, subdivided according to the main location of the lesion. Because several of these conditions can affect both the hypothalamus and the pituitary either simultaneously or sequentially, it is often impossible to locate the precise anatomic site of the deficiency. For example, in the presence of a large pituitary tumor, hypothyroidism may be caused by an intrinsic deficiency of the pituitary thyrotrophs or interruption of hypothalamic TRH input.

TABLE 51.1. CAUSES OF CENTRAL HYPOTHYROIDISM


Pituituary disorders

   Tumors

      Pituitary adenoma (functioning and nonfunctioning)

      Craniopharyngioma

      Meningioma

      Dysgerminoma

      Metastatic tumor

   Ischemic necrosis

      Postpartum (Sheehan's syndrome)

      Severe shock

      Diabetes millitus

   Trauma

   Aneurysm of internal carotid artery

   Iatrogenic

      Radiation therapy

      Surgery

   Infectious diseases

      Abscesses

      Tuberculosis

      Syphillis

      Toxoplamosis

      Trypanosomiasis

   Sarcoidosis

   Histiocytosis (Hand-Schuller-Christian disease)

   Hemosiderosis

   Chronic lymphocytic hypophysitis

   Pituitary aplasia or hypoplasia

   Idiopathic

Hypothalamic disorders

   Tumors

   Suprasellar extension of pituitary adenoma

   Craniopharyngioma

   Meningioma

   Glioma and other brain tumors

   Metastatic tumors

Trauma

Ischemic necrosis

Iatrogenic

   Radiation therapy

   Surgery

Infections

   Abscresses

   Tuberculosis

   Syphilis

   Toxoplasmosis

Sarcoidosis

Histiocytosis

Congenital malformations

   Basal encephalocele

   Septo-optic dysplasia

Idopathic


Pituitary adenoma is the most frequent cause of central hypothyroidism, accounting for more than half the cases (8). The tumor may be nonfunctioning or it may secrete GH, prolactin (PRL), or both, or, less frequently, ACTH or gonadotropins. Varying degrees of hypopituitarism may result from compression of the nontumorous portion of the pituitary. The pituitary stalk and the hypothalamus also may be involved by suprasellar extension of the tumor. Interference with the adenohypophyseal blood flow is an additional factor. Rarely, hypopituitarism may result from hemorrhage within a pituitary adenoma (pituitary apoplexy) (8).

Primary extrasellar brain tumors can cause central hypothyroidism (8,9,10). Metastases to the hypothalamic–pituitary region arising from carcinomas of the breast, lung, and occasionally other sites are infrequent and usually reflect the presence of advanced disease. Hypopituitarism is rare because of the limited survival of these patients and, when present, usually is preceded or accompanied by diabetes insipidus. Craniopharyngioma is a relatively frequent cause of central hypothyroidism, especially in younger patients. Meningiomas, gliomas, and nontumorous mass lesions are rare causes of central hypothyroidism.

Postpartum pituitary necrosis (Sheehan's syndrome) is now rare in developed countries as a result of improved health care, but it remains a relatively common cause of adult panhypopituitarism (8,11,12). Pituitary insufficiency does not occur unless most of the anterior pituitary is affected. In Sheehan's syndrome, increased serum TSH levels in the afternoon and a loss of the nocturnal TSH surge have been described (13).

Although less frequent, pituitary necrosis also may occur in patients with severe shock resulting from nonobstetric conditions, such as diabetes mellitus, traumatic head injury, and in association with cerebrovascular accidents, increased intracranial pressure, or epidemic hemorrhagic fever (8), and in patients who are being maintained on mechanical respirators (14). Other rare disorders that lead to central hypothyroidism include vasculitis, aneurysms of the internal carotid artery, and rupture of an aneurysm of the circle of Willis. Hypothalamic rather than pituitary lesions can also be the cause of central hypothyroidism in patients who have had severe head injury. Indeed, the first case of documented hypothalamic hypothyroidism was ascribed to a lesion in the hypothalamus resulting from head trauma (15). In addition, central hypothyroidism, often associated with various defects of pituitary function, may be due to closed head injury (16).

External radiotherapy for tumors of the head and neck can affect the hypothalamus, the pituitary, and the thyroid, and hypothyroidism often results from damage of one or more of these structures. Hypothyroidism resulting from pituitary or hypothalamic dysfunction was observed in 20% to 53% of patients irradiated for nasopharyngeal or paranasal sinus tumors (17) and in 65% of patients, both children and adults, irradiated for brain tumors (18). On the contrary, other researchers (19,20) reported a 6% incidence of central hypothyroidism in two series of patients irradiated for childhood brain tumor, after a mean follow-up of 12 years. TSH deficiency also can result from direct irradiation of the pituitary, either by conventional external radiotherapy or by computed tomography (CT)–particle radiotherapy for GH-secreting adenomas or other pituitary tumors (8). Overall, the risk of the development of central hypothyroidism is related to the total radiation dose, being higher for intracranial solid tumors, which are treated with higher radiation doses (21,22,23).

If not present initially, central hypothyroidism may result from surgical therapy of pituitary tumors. Radical excision of large pituitary tumors induces hypothyroidism in about 10% of patients, but selective removal of microadenomas rarely is followed by impaired TSH secretion.

Purulent hypophysitis may occur in patients with septicemia or by direct extension of infection from neighboring areas (24). Abscesses also may develop in pituitary tumors or craniopharyngiomas (8). Granulomatous lesions of diverse etiology, including tuberculosis, syphilis, and giant cell granuloma, are rare causes of pituitary insufficiency (8). Pituitary sarcoidosis often is associated with granulomatous lesions in the neurohypophysis and the hypothalamus (25). Histiocytosis (Hand-Sch□ller-Christian disease) may involve the pituitary and result in varying degrees of hypopituitarism (8). The neurohypophysis also is affected in most patients, leading to diabetes insipidus. In hemochromatosis, iron pigment accumulates in the cytoplasm of anterior pituitary cells and can lead to fibrosis of the anterior pituitary and hypopituitarism. Central hypothyroidism may occur in thalassemia patients treated with frequent blood transfusions (26,27) and in patients with African trypanosomiasis (28). Chronic lymphocytic hypophysitis has been described with or without pituitary insufficiency in association with autoimmune thyroiditis or adrenalitis (8).

Pituitary aplasia or hypoplasia is a rare congenital defect, usually associated with other severe malformations (8,29). These infants usually die shortly after birth, and evidence of multiple endocrine failure is found at autopsy.

Rare cases of hereditary panhypopituitarism have been reported in association with a small but normally shaped sella turcica (30).

Idiopathic hypopituitarism indicates a deficiency of one or more of the anterior pituitary hormones in the absence of any demonstrable pathology. Idiopathic TSH deficiency usually occurs in association with GH deficiency (31), but secretion of other pituitary hormones also may be deficient. An autosomal-recessive deficiency of pituitary hormones (except ACTH) was reported in a consanguineous Brazilian kindred (32). The finding of a normal, exaggerated, or delayed serum TSH response to TRH in most of these patients suggests the presence of a hypothalamic lesion (33). Birth trauma has been implicated as the etiologic factor secondary to the use of vacuum extraction or breech delivery in the histories of many of these patients.

Isolated TSH deficiency has been reported in patients with a pituitary tumor, empty sella (34), or diabetes mellitus (35), but in most instances no apparent cause has been identified, and the anatomic site of the lesion was not identified (36). A few of these patients had an increased serum TSH response to TRH, but most had no change in serum TSH, suggesting that the defect was at the level of the pituitary (8). The defect may be partial rather than complete, and therapy with thyroid hormone may facilitate the release of small amounts of TSH after TRH administration (36). Although more common in adults, isolated TSH deficiency also occurs in children and may result in a secondary impairment of GH secretion, simulating primary deficiency of TSH and GH (8). In these patients, GH secretion is restored after initiation of T4 therapy.

Inherited isolated TSH deficiency resulting in congenital central hypothyroidism has been described in a few families (3,4,5). It is due to single-base substitutions, nonsense mutations, or deletions in the TSH-β subunit (3,4,5). These abnormalies are inherited or autosomal-recessive traits (37). Mutations in the TSH-β gene have been reported with increasing frequency, suggesting that they might be more common than previously thought (6,7,38,39). Recently, defects in pituitary-specific transcription factors (Pit-1 and PROP-1) have been described (40,41,42,43,44,45,46,47). Pit-1 is a pituitary-specific transcription factor belonging to the POU family, which regulates mammalian development. It binds to the promoter region of the GH and PRL genes and plays an important role in regulation of the expression of the TSH-β gene. PROP-1 leads to ontogenesis of pituitary cells, and inactivating mutations result in several degree of hypopituitarism. A rare cause of isolated central hypothyroidism recently is an inactivating mutation of the TRH receptor gene (48). Otherwise genetic causes of central hypothyroidism include mutations of the LHX3 gene (associated with rigid cervical spine) (49), of the HESX1 gene (associated with septoptic dysplasia) (50,51) and of the leptin receptor gene (associated with obesity) (52). A summary of the reported genetic abnormalities are shown in Table 51.2 (see Chapter 2).

TABLE 51.2. GENETIC ABNORMALITIES IN THYROTROPIN SYNTHESIS


Mutations in the thyrotropin-releasing hormone receptor

Mutations in the PROP-1 gene

Mutations in the Pit-1 gene

Mutations in the TSH-β gene

Mutations in the HESX1 gene

Mutations in the LHX3 gene

Mutations in the leptin receptor


PATHOGENESIS

Hyposecretion of TSH in pituitary hypothyroidism may be ascribed to a reduced mass of functioning thyrotrophs as a consequence of various lesions, including mechanical compression by tumor, destruction by vascular, inflammatory, or physical injuries, aplasia, or hypoplasia. In these patients, low serum TSH levels and no response to TRH are the expected findings.

Several explanations are possible for idiopathic isolated TSH deficiency. Provided that the thyrotrophs are present and morphologically intact, the abnormality could reside in the TRH receptor or at some subsequent step in the transmission of the hypothalamic message, in the process of TSH synthesis, or in the mechanism of TSH release. Isolated

TSH deficiency in children has been found in association with pseudohypoparathyroidism (53); other patients with this disorder have had primary hypothyroidism (54).

In inherited TSH deficiency resulting from an abnormal TSH-β subunit, a few families had a single-base mutation in nucleotide 145 of exon 2 of the gene, with substitution of glycine for arginine in the 29th amino acid. This substitution causes a conformational change in TSH-β that hampers its dimerization with the α subunit to form a complete TSH molecule. In two families, the molecular abnormality was a nonsense mutation in nucleotide 94 of exon 2, leading to premature termination of TSH-β synthesis at amino acid 11 (4,5,55). With the increasing reports of TSH-β mutations, it appears that many of the mutations are clustered in a “hot spot” involving codon 105 in exon 3. This results in a truncated TSH-β subunit that is unable to dimerize with the α subunit. Central hypothyroidism has been related to a mutation in the pituitary specific transcription factor POU1F1, in the context of multiple pituitary hormone deficiencies (40,41,42,43). This clinical picture also may result from mutations of the PROP1 gene (45,46,47), which encodes a homeodomain protein expressed briefly in the embryonic pituitary and necessary for POU1F1 expression (56). The hormonal phenotype consists of gonadotropin, PRL, GH, and TSH deficiency. The pituitary usually is normal in size, albeit a family with PROP-1 gene mutations and an enlarged anterior pituitary has been reported (57). Recently, Riepe et al. (58) reported variations in pituitary size in two brothers with inactivating PROP-1 deletions, the gland being enlarged at an early age and hypoplastic after 12 years. Vallette-Kasic et al. (59) reported that nine patients from eight unrelated families who had homozygous PROP-1 gene defects located in exon 2. The clinical manifestations of GH and TSH deficiency are variable, as is hypogonadism. Late-onset hypocortisolism has been reported as a part of combined pituitary hormone deficiency in two patients with a homozygous deletion of the PROP-1 gene (60).

Hypothalamic hypothyroidism is commonly attributed to TRH deficiency, whether from acquired or congenital abnormalities of the hypothalamus. These patients have low or normal serum TSH levels that increase after the administration of TRH. No evidence directly supports the concept of TRH deficiency as the cause of hypothalamic hypothyroidism, because of the interference of various serum components in the available TRH radioimmunoassays, the rapid degradation of TRH by serum, and the uncertain origin of TRH in the peripheral blood. Indeed, most TRH is derived from extrahypothalamic sources (61). Indirect evidence favoring TRH deficiency as the cause of hypothyroidism in these patients has come from the demonstration that their hypothyroidism can be corrected by the repetitive administration of TRH (62,63). The causes of TRH deficiency are unknown but might be related to reduced TRH synthesis resulting from some destructive lesions of the hypophysiotropic areas of the hypothalamus. In addition, a single patient with TRH receptor gene mutation has been reported (48). The patient was a 9-year-old boy with a compound heterozygous inactivating mutation of the TRH receptor gene.

Reduced stimulation of the pituitary by TRH also may result from suprasellar lesions preventing TRH from reaching the anterior pituitary, as in tumorous or vascular lesions involving the pituitary stalk. The delayed serum TSH response to TRH in these patients could be explained by the fact that TRH reaches the pituitary through the systemic circulation and not through the hypothalamic–pituitary portal system.

A possible explanation for idiopathic hypothalamic hypothyroidism is the excessive production of substances, such as dopamine or somatostatin, that inhibit TSH secretion (64,65). Some indirect support for this concept was provided by the demonstration that naloxone pretreatment resulted in the normalization of a subnormal serum TSH response to TRH in a patient with hypothyroidism (66). The effect of naloxone might be related to the experimental evidence indicating that opiates inhibit TSH secretion by increasing production of a hypothalamic TSH inhibitory factor, such as dopamine (67).

In central hypothyroidism, irrespective of the underlying lesion, the nocturnal surge of serum TSH that occurs in normal subjects (68,69) is reduced or abolished (69,70,71,72), although this finding may be equivocal in some patients (72). This loss is due to diminished TSH pulse amplitude with relatively preserved pulse frequency. The loss of the nocturnal surge in TSH secretion may contribute to thyroid hypofunction because it appears that the thyroid is most stimulated at night after the nocturnal surge. Evaluation of the nocturnal serum TSH surge appears to be a sensitive diagnostic test in children with central hypothyroidism (73).

Administration of GH to children with idiopathic GH deficiency may result in central hypothyroidism (74). It has been postulated that GH administration leads to increased secretion of somatostatin, thereby blocking TSH release (74). Other studies documented a subnormal nocturnal TSH surge in GH-deficient children prior to GH therapy, with no further changes in the pituitary–thyroid axis function after GH administration (75). GH therapy also increases peripheral conversion of T4 to triiodothyronine (T3), which may result in biochemical changes that mimic central hypothyroidism, such as low serum T4 concentrations and impaired TSH secretion (76,77). GH therapy of GH-deficient children does not require thyroid hormone therapy (78). Recently, Porretti et al (79) reported the effects of recombinant human GH replacement therapy on thyroid function in a series of 66 adult GH-deficient patients, 49 of whom had central hypothyroidism adequately treated with T4. Forty-seven percent of euthyroid subjects and 18% of patients with central hypothyroidism had reduced serum free T4 levels at the end of the study, suggesting that GH deficiency might mask central hypothyroidism.

BIOLOGICALLY INACTIVE TSH

Secretion of biologically inactive TSH accounts for some cases of central hypothyroidism. The association of low serum thyroid hormone levels with normal or slightly high serum TSH concentrations has often been observed in patients with pituitary or hypothalamic disorders (64,80,81). This finding could not be explained by the coexistence of primary thyroid failure because the patients had an adequate thyroidal response to exogenous TSH (80,81) and no evidence of thyroid autoimmune disease (80). Nevertheless, the thyroid appeared to be unresponsive to endogenous TSH, because administration of TRH resulted in a normal or even an exaggerated serum TSH response that was followed by an inadequate thyroidal release of T3. This finding suggested that the immunoreactive TSH secreted in these patients might have reduced or absent biologic activity. This possibility was documented by evaluating the biologic activity of circulating TSH by a cytochemical assay (80) or by an adenylyl cyclase stimulation assay in thyroid plasma membranes, rat thyroid FRTL-5 cells (82,83), and in Chinese hamster ovary cells transfected with the recombinant human TSH receptor (CHO-R cells) (84). These studies showed that the biologic activity of serum TSH and the ratio between biologic and immunoreactive TSH (B/I) are reduced in some patients with central hypothyroidism.

Although the acute intravenous administration of TRH did not substantially modify the biologic activity of TSH, chronic oral TRH treatment (40 mg daily for 4 weeks) was associated with an increase in both the biologic and receptor-binding activities of TSH (1,84). These observations suggest that TRH is required to produce TSH with full biologic potency (1,80). Thus, the reduced TSH biologic activity might be due to TRH deficiency. TRH might regulate not only TSH release but also the structural features of TSH needed for appropriate receptor binding and adenylyl cyclase stimulation. In rats with hypothalamic hypothyroidism resulting from paraventricular nuclear lesions, an altered TSH carbohydrate structure was demonstrated, which could be corrected by TRH administration in parallel with the normalization of serum TSH levels (85). Abnormal TSH glycosylation, as assessed by ricin and lentil lectin affinity chromatography (86), also was reported in patients with central hypothyroidism (87) and reduced TSH biologic activity, with prevalent hybrid, high-mannose type, and biantennary oligosaccharide moieties and a reduced degree of sialylation (88). It is therefore likely that the correct glycosylation of the molecule is essential for the expression of TSH biologic activity.

The secretion of TSH-β and TSH-α subunits may be altered in patients with central hypothyroidism. An excess of circulating TSH-β was reported in five patients with idiopathic central hypothyroidism (62); whether this finding has any relevance for the assembly of an inactive molecule of TSH remains to be determined. Differences in the molecular size of TSH, as assessed by gel chromatography, were found when comparing the TSH of some patients with central hypothyroidism with normal TSH (89); normalization of the chromatographic pattern occurred after chronic oral TRH administration (84). In one patient with idiopathic central hypothyroidism, a TSH-β subunit of large molecular size was found (62). Interpretation of these observations is uncertain, however, because immunoreactive TSH of greater than normal molecular size has been found in pituitary extracts from patients with long-standing primary hypothyroidism. A circulating TSH, biologically inactive due to a mutation of a critical carboxy-terminal cysteine residue in the TSH-β subunit gene, was found in two related families with central hypothyroidism (90).

FUNCTIONAL ABNORMALITIES IN TSH SECRETION

Functional abnormalities of TSH secretion associated with concomitant abnormalities in serum thyroid hormone concentrations resembling those found in central hypothyroidism resulting from hypothalamic or pituitary lesions can be observed in several pathophysiologic conditions (Table 51.3). Transient hypothyroidism resulting from functional TSH deficiency is found in euthyroid subjects after withdrawal of long-term T4 suppressive therapy for nontoxic goiter (91). The features of pituitary hypothyroidism, including low serum thyroid hormone and TSH concentrations and subnormal or absent serum TSH responses to TRH, are observed shortly after the abrupt cessation of thyroid hormone therapy. Complete recovery of TSH secretory function and normalization of serum thyroid hormone concentrations usually require 4 to 6 weeks. A similar biochemical situation is observed in thyrotoxic patients shortly after radioactive iodine therapy or the institution of antithyroid drug treatment: serum thyroid hormone concentrations decrease, but the compensatory increase in serum TSH concentrations is delayed (8). Likewise, the initial recovery phase of subacute thyroiditis that follows the thyrotoxic phase is associated with a functional suppression of TSH secretion, despite low or normal serum thyroid hormone concentrations. This type of abnormality of the hypothalamic–pituitary–thyroid axis does not require any treatment because of its temporary nature.

TABLE 51.3. FUNCTIONAL ABNORMALITIES OF THYROTROPIN SECRETION


Use of drugs inhibiting TSH secretion

   L-thyoxine withdrawal syndrome

   Glucocorticoids

   Dopamine

   Growth hormone

Retinoid x-receptor selective ligands

Suppressed TSH secretion after thyrotoxicosis

   Antithyroid drug treatment

   Radioactive thyroiditis

   Subacute thyroiditis

Nonthyroidal illnesses

   Major medical illness

   Major surgery

   Bone marrow transplantation

   Burns and trauma

   AIDS

   Depressive disorder

   Anorexia nervosa and bulimia

   Fasting

   Again


AIDS, acquired immunodificiency disease syndrome;TSH, thyrotropin.

An impaired serum TSH response to TRH frequently is found in patients with Cushing's syndrome or during prolonged glucocorticoid administration (92,93), but clinical hypothyroidism does not occur. Patients with Cushing's syndrome do not have the normal nocturnal surge in TSH secretion (92). This occurs in association with both ACTH-secreting pituitary adenomas and adrenal tumors, suggesting that the abnormal TSH secretory pattern is due to hypercortisolism itself (92). Increased cortisol secretion may account for the deficient nocturnal surge of TSH that can be observed for several days after major surgical procedures (94). An absent nocturnal TSH surge and reduced serum TSH response to TRH also were reported in six patients with adrenal incidentaloma and subclinical Cushing's syndrome (95). Serum free thyroid hormones levels were normal in these patients, suggesting that the impairment of TSH secretion may occur at an early stage.

Patients with acromegaly who have no clinical or biochemical evidence of hypothyroidism often have no serum TSH response to TRH, whereas an exaggerated or delayed serum TSH response frequently is found in children with idiopathic GH deficiency (33). Administration of therapeutic doses of GH to children with pituitary dwarfism occasionally has been associated with reversible central hypothyroidism (96), although other studies failed to confirm this finding (97,98). Thus, GH may have a suppressive effect on TSH secretion, mediated by an increase in somatostatin secretion. Dopamine inhibits TSH secretion (98), and withdrawal of this drug is followed by a prompt increase in serum TSH and thyroid hormone concentrations (63).

In patients with nonthyroidal illness (NTI), serum TSH concentrations are frequently low or normal, despite the reduction in serum T3 and, in most severe cases, also T4 concentrations (99,100,101). Indeed, many patients with NTI have suppressed TSH secretion or an attenuated or abolished nocturnal TSH surge (102,103,104). The latter finding has been related to a loss of the usual nocturnal increase in TSH pulse amplitude (105). Studies in NTI patients have demonstrated that their serum TSH has a normal or slightly increased biologic activity. Although subnormal serum TSH responses to TRH have been reported, most NTI patients have normal TRH tests. The functional abnormalities of the hypothalamic–pituitary–thyroid axis just described and resembling those found in central hypothyroidism resulting from hypothalamic or pituitary lesions are encountered in chronic renal failure treated with regular maintenance hemodialysis (103), decompensated diabetes mellitus (33,102), burns and trauma (106), after bone marrow transplantation (105), and in other serious illnesses. Normalization of the nocturnal serum TSH surge in diabetic patients after restoration of a good glycemic control appears to be related to the presence of residual pancreatic β-cell function because it does not occur in C-peptide-negative patients (107). Functional abnormalities in TSH secretion are particularly frequent in patients with depressive disorders (108), anorexia nervosa, and bulimia. The abnormalities of TSH secretion in patients with endogenous depression might be partially accounted for by increased cortisol secretion (108). Recently, interleukin-6 (IL-6) and other cytokines were reported to inhibit pituitary–thyroid function in animals and humans, causing a reduction in serum thyroid hormone and TSH concentrations (109). Increased serum IL-6 levels have been found in NTI patients (110,111). Whether this increase represents merely an epiphenomenon of NTI or plays a role in the pathogenesis of abnormalities of pituitary–thyroid function found in these patients is not known.

Reversible central hypothyroidism occurs in patients with cutaneous T-cell lymphoma treated with high doses (300–650 mg/m2) of bexarotene, a retinoid X receptor (RXR)-selective ligand (112). This may occur through suppression of the activity of the TSH-β subunit gene promoter. Animals treated with a high-affinity RXR agonist had a 50% reduction in serum TSH and T4 concentrations (113). These findings also were present in mice with deletion of the β form of the thyroid hormone receptor, suggesting that RXR agonists cause central hypothyroidism independently of this receptor (113).

In patients with acquired immunodeficiency syndrome (AIDS), during the terminal phase of the disease, serum thyroid hormone concentrations are reduced and serum TSH is normal or low, similar to patients with other causes of severe NTI (114). In human immunodeficiency virus (HIV)–positive patients who are either asymptomatic or have less severe disease, mean 24-hour TSH levels are higher because of an increase in TSH pulse amplitude associated with an increased TSH responsiveness to TRH and a normal nocturnal TSH surge (115).

Aging is associated with a variety of hypothalamic–pituitary–thyroid axis changes, but in many instances these are related to concomitant NTI, drug administration, or the increased prevalence of primary hypothyroidism in elderly patients. In male Fisher rats, aging has been associated with decreased synthesis of hypothalamic TRH and consequently with decreased pituitary TSH-β mRNA levels and TSH content, suggesting a defect at the hypothalamic level (116). Evaluation of the pituitary–thyroid axis in healthy elderly subjects, including centenarians, showed a complex derangement of thyroid function, probably resulting from a combination of defective peripheral metabolism of thyroid hormones and of decreased thyroid hormone secretion of central origin. As a consequence, a slight but progressive decrease in serum TSH concentration was observed with age in these healthy subjects; this finding might be related to a resetting of the pituitary threshold of TSH suppression (117). Alcoholism has been associated with varying hypothalamic–pituitary–thyroid axis abnormalities (118).About 60% of subjects with chronic alcoholism have a blunted serum TSH response to TRH, which was more frequent after a short period of abstinence (118).

CLINICAL FEATURES

The clinical picture of central hypothyroidism varies widely, depending on the severity of the thyroid failure, the extent of the associated hormone deficiencies, the age of the patient at the time of onset, and the nature of the underlying lesion (101). The clinical features of thyroid insufficiency resulting from TSH deficiency are similar to those of primary hypothyroidism, although generally less pronounced. Patients may complain of cold intolerance, constipation, fatigue, lethargy, and mental dullness. 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 sexual maturation and bone development. Dwarfism and cretinism occur in the rare patient with familial inherited TSH deficiency. Several differentiating features, largely related to hyposecretion of other pituitary hormones, help to distinguish central hypothyroidism from primary hypothyroidism. The skin is pale and cool but not as coarse and dry as in primary hypothyroidism. The face is characteristically covered with fine wrinkles, but periorbital and peripheral edema are uncommon in patients with central hypothyroidism (Fig. 51.1). Loss of axillary, pubic, and facial hair and thinning of the lateral eyebrows are usually more pronounced, and the texture of the remaining hair is thinner than in primary hypothyroidism. The tongue is not enlarged, and hoarseness of the voice is not prominent in patients with central hypothyroidism. The heart tends to be small, and blood pressure is low. Pericardial, pleural, and peritoneal effusions are rare in these patients (119). Atrophic breasts and amenorrhea, rather than metrorrhagia, are found in premenopausal women. Body weight is more likely to be reduced than increased. The severity of the hypothyroid state ranges from mild to severe, but, in general, is mild. Although residual hormone secretion from the unstimulated thyroid gland may account for the mild degree of hypothyroidism in most patients, early recognition is also an important factor. In fact, most patients have other endocrine and nonendocrine manifestations of the hypothalamic or pituitary disease that lead them to seek medical attention before their hypothyroidism becomes severe.

FIGURE 51.1. Patient with central hypothyroidism caused by a nonfunctioning pituitary tumor. The patient had low serum thyroid hormone and thyrotropin (TSH) concentrations; no serum TSH response to thyrotropin-releasing hormone; and corticotropin, growth hormone, and gonadotropin deficiency.

Defects in GH and gonadotropin secretion usually precede TSH deficiency as hypopituitarism develops, and ACTH secretion is usually the last to be affected. Growth failure with delayed skeletal maturation is the result of GH deficiency in children, but it has few manifestations in adults. Hypoglycemia may occur, especially if hypocortisolism is also present. In diabetic patients, GH deficiency decreases insulin requirements. Gonadotropin insufficiency results in impotence, loss of libido, diminished beard growth, and testicular atrophy in men; amenorrhea, infertility, and atrophy of the breasts in women; and loss of pubic and axillary hair in both sexes. Delayed sexual maturation is the result of gonadotropin insufficiency in children. ACTH deficiency leads to weakness, postural hypotension, and depigmentation of the areolae and other normally pigmented areas of the skin. Dangerous and potentially lethal adrenal crisis may be precipitated by trauma, intercurrent infection, or surgery.

Symptoms and signs that arise directly from the hypothalamic or pituitary lesion may precede, accompany, and even obscure the manifestations of pituitary failure. Headache and visual field defects are often the presenting symptoms in patients with nonfunctioning pituitary adenomas that extend beyond the sella turcica. As a rule, hormone-secreting adenomas manifest themselves through the consequences of pituitary hormone hypersecretion before symptoms of pituitary insufficiency become apparent. This may not be the case, however, in men with PRL-secreting adenomas. In addition to headache and visual loss, diabetes insipidus occurs frequently in patients with craniopharyngioma, in association with growth failure in children and hypogonadism in adults. Diabetes insipidus is also a prominent feature of histiocytosis and of sarcoidosis involving the hypothalamus. In patients with tumors arising in the hypothalamus or in the region of the third ventricle, meningeal signs may occur early in the course of the disease. Rarely, hypothalamic lesions may cause obesity and abnormal temperature regulation. Patients with postpartum pituitary necrosis have a history of hemorrhage and shock after delivery, followed by deficient lactation, persistent amenorrhea, and other signs of hypogonadism. Severe headache is usually the predominant symptom of pituitary apoplexy, whereas a sudden decrease in insulin requirement may be the first indication of pituitary infarction in a diabetic patient. In other cases, a history of head injury, pituitary surgery, or radiation to the head or neck suggests the underlying lesion. Patients with idiopathic hypopituitarism may have a history of breech delivery or birth by vacuum extraction.

The rate of progression and the degree of central hypothyroidism are influenced markedly by the nature of the underlying disease. Clinical features of thyroid failure are usually detectable within 1 month after hypophysectomy. The development of hypothyroidism is less abrupt in Sheehan's syndrome, but in most instances it is relatively rapid compared with the slow, insidious onset of primary hypothyroidism resulting from atrophic autoimmune thyroiditis. It is not infrequent, however, that several years elapse after a postpartum hemorrhage before hypothyroidism, adrenal insufficiency, and hypogonadism become clinically apparent. A long latency period also may occur in patients who develop central hypothyroidism after a head injury or radiation. In patients with pituitary or hypothalamic tumors, the course and severity of hypopituitarism depend on the rate of tumor growth and the degree of compression of adjacent structures. Overt manifestations of central hypothyroidism are rare in patients with metastatic pituitary tumors or in infants with pituitary aplasia or hypoplasia because of the short life span.

Central hypothyroidism that results from prolonged thyroid hormone therapy is characteristically transient and is usually more evident at the biochemical than the clinical level. Similarly, clinical evidence of central hypothyroidism is rare in patients with other functional abnormalities of TSH secretion, such as endogenous depression and endogenous or exogenous hypercortisolism.

DIAGNOSIS AND LABORATORY TESTS

Central hypothyroidism must be suspected when symptoms and signs of hypothyroidism are associated with manifestations of other hormonal deficiencies or pituitary mass lesions. Because the clinical expression of thyroid insufficiency may be obscured by the features of other hormonal deficiencies or features arising directly from the underlying disease, thyroid function should be evaluated in any patient suspected of having a hypothalamic or pituitary disorder. The possibility of central hypothyroidism also should be considered in hypothyroid patients with no evidence of pituitary failure because it may be difficult, if not impossible, to clinically distinguish central from primary hypothyroidism.

The diagnosis of central hypothyroidism is based on the demonstration of low serum thyroid hormone concentrations in the presence of inappropriately low serum TSH values. Laboratory evaluation of this condition should include assessment of (a) serum thyroid hormone concentrations and TSH secretion, (b) the secretion of the other pituitary hormones, and (c) the anatomy of the hypothalamic and pituitary region.

Serum Thyroid Hormone Concentrations and Thyrotropin Secretion

The prerequisite for the diagnosis of central hypothyroidism is the finding of low serum total and free T4 concentrations. Measurements of serum total and free T3 concentrations are much less useful because they are frequently within the normal range. The reduction of serum thyroid hormone concentrations in central hypothyroidism usually is less pronounced than in primary hypothyroidism, although extremely low concentrations are found occasionally in patients with severe, long-standing central hypothyroidism. In newborns, a low serum reverse T3 concentration may help to distinguish infants with central hypothyroidism from sick and well infants (120).

Basal serum TSH values are inappropriately low with respect to the low serum thyroid hormone concentrations and are either undetectable or within the normal range in most patients (8,121,122). Serum TSH values may be slightly high in some patients (100,123), but not to the levels commonly found in patients with primary hypothyroidism who have a comparable reduction of serum T4. This finding may be explained by the secretion of immunoreactive but biologically inactive TSH, as discussed previously. Considerable overlap exists in basal serum TSH values between the two types of central hypothyroidism. Thus, determination of basal serum TSH is essential for the differentiation between primary and central hypothyroidism but does not allow the distinction between hypothalamic and pituitary hypothyroidism.

Measurements of the serum TSH response to TRH (200–500 µg or 5 µg/kg administered intravenously) have been used in an attempt to identify the site of the primary lesion. On the basis of the classic concept of the control mechanism of TSH secretion, it was anticipated that the serum TSH response to TRH would be impaired in pituitary hypothyroidism but preserved in hypothalamic hypothyroidism. However, as noted previously, serum TSH responses to TRH differ little in patients with hypothalamic or pituitary disorders. As shown in Figure 51.2, serum TSH responses to TRH may be subdivided into several categories according to the magnitude of the increase in serum TSH after TRH administration and the pattern of the response curve (64). Although absent and impaired responses have been encountered more frequently in hypothyroid patients who have pituitary lesions (64), they also have been found in some patients with hypothalamic disorders who have no apparent pituitary involvement. Conversely, normal or even exaggerated serum TSH responses are found in some hypothyroid patients with hypothalamic disorders (64,124) and in occasional patients with documented primary pituitary disease with no apparent hypothalamic involvement (64). Thus, it appears that the pattern of the serum TSH response to TRH does not reliably distinguish between hypothalamic and pituitary lesions. For this reason, analysis of the entire clinical picture and the results of other tests of pituitary function are required. Some euthyroid patients with hypothalamic–pituitary disorders (e.g., empty sella) also have abnormal serum TSH responses to TRH, for which there is no satisfactory explanation. Whether these abnormalities predict the subsequent development of central hypothyroidism remains to be clarified (64). The usefulness of the TRH test was further questioned in a recent report (125). A normal TRH test was found in 23% of patients with central hypothyroidism; brisk, absent-blunted, and delayed responses were present in the remaining 77%. In addition, the response to the TRH test did not differentiate between hypothalamic and pituitary disease (125).

FIGURE 51.2. Patterns of serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) (200 µg administered intravenously) in patients with central hypothyroidism. Type of TSH response: a, absent;b, impaired;c, delayed;d, exaggerated;e, prolonged;f, delayed and prolonged (and exaggerated). The shaded area represents the normal response.

In normal subjects, TSH secretion is characterized by a nocturnal surge that begins in the evening and reaches a peak at the time of onset of sleep (68,69,70,126). This surge does not occur in central hypothyroidism. A reasonable assessment of the nocturnal surge of TSH may be obtained by measuring serum TSH in samples taken every 30 minutes from 11:00 p.m. to 2:00 a.m. (68,69). Evaluation of the nocturnal TSH peak is a more reliable test for confirming the diagnosis of central hypothyroidism than is the TRH test (68, 69). Finally, TRH is no longer available in the United States for clinical use.

Biologic Assay of Serum Thyrotropin

The paradoxic finding of measurable and even slightly high serum immunoreactive TSH concentrations in patients with central hypothyroidism (see previous discussion) stimulated study of the biologic activity of circulating TSH in this condition. Bioassayable serum TSH may be determined by cytochemical assay, based on the ability of TSH to increase lysosomal membrane permeability in thyroid follicular cells (78,81). Less sensitive but more feasible assays are based on the stimulation of adenylyl cyclase activity in human thyroid membranes or cells (82,83) and in continuously cultured rat thyroid cells (FRTL-5) (82,83) or CHO-R cells (83) (Fig. 51.3). These assays require preliminary concentration and purification of serum TSH by immunoaffinity chromatography. Using these techniques, reduced biologic activity of immunoreactive serum TSH was documented in several patients with central hypothyroidism (1,80). These tests, although important for the assessment of TSH biologic activity, are not widely available.

FIGURE 51.3. The ratio between biologic (B) and immunologic(I) activities of serum thyrotropin (TSH) in patients with central hypothyroidism and in control subjects. The open circles refer to single cases, and the filled circle, triangle, and diamond refer to mean ± SD in central hypothyroidism, primary hypothyroidism, and normal subjects, respectively. The dotted line indicates the lower limit of the normal range. Patients with central hypothyroidism have B/I ratios lower than those in normal or primary hypothyroid subjects (Adapted from Persani L, Ferretti E, Borgato S, et al. Circulating thyrotropin in sporadic central hypothyroidism. J Clin Endocrinol Metab 2000;85:3631, with permission.)

Serum Triiodothyronine Response to Thyrotropin-Releasing Hormone

The release of T3 from the thyroid in response to the increase in serum TSH that follows TRH administration may provide an indirect assessment of the bioactivity of endogenous TSH. In normal subjects, serum T3 concentrations increase from 30% to 100% above the baseline values 120 to 180 minutes after intravenous injection of 200 µg of TRH. An impaired or absent serum T3 response is indicative of central hypothyroidism, provided that a primary thyroid lesion has been excluded (2). The coexistence of a normal or exaggerated serum immunoreactive TSH response with an abnormally low serum T3 response suggests the secretion of bioinactive TSH (2,80).

Measurement of Thyrotropin-Releasing Hormone

Attempts to measure serum or urine TRH by radioimmunoassay have been made by several investigators (127). TRH is widely distributed throughout the brain and several other tissues, which suggests that most of the TRH in peripheral blood is derived from nonhypothalamic sources (50,127). Thus, measurement of serum or urinary TRH cannot be used as a reliable test for the evaluation of the hypothalamic–pituitary–thyroid axis.

Other Tests

Serum antibodies against to thyroglobulin and thyroid peroxidase are present in a high proportion of patients with primary hypothyroidism (128), but they are usually undetectable in patients with central hypothyroidism (80).

Routine laboratory tests are of little value in the differentiation between primary and central hypothyroidism. Hypercholesterolemia is commonly regarded as characteristic of primary hypothyroidism, but mild to moderate elevations of serum cholesterol occur in some patients with central hypothyroidism (129).

In the rare forms of inherited TSH deficiency, recently developed molecular biology methodology allows identification of the affected subjects, identification of the mutated gene carriers, and prenatal diagnosis in at-risk pregnancies, which is of the greatest value for the early institution of T4 replacement therapy.

Tests of Other Pituitary Hormones

In hypothyroid patients with impaired TSH secretion, deficiency of other pituitary hormones should be sought by specific tests for each hormone. Evaluation of GH and PRL secretion under basal conditions and after appropriate stimulation, as well as tests of the pituitary–adrenal and pituitary–gonadal axes, should be performed. Abnormalities of various degrees in these tests are common in patients with central hypothyroidism. Caution should be used, however, in the interpretation of the results because some of these abnormalities may be due to hypothyroidism itself. A low serum GH concentration and a blunted GH response to hypoglycemia are frequent findings in central hypothyroidism, but may also occur in patients with primary hypothyroidism. In the latter condition, as in patients with isolated TSH deficiency, GH secretion is restored to normal by T4 therapy. High basal serum PRL concentrations with an increased response to TRH frequently are associated with hypothalamic–pituitary disorders, but they too may occur in primary hypothyroidism. Serum follicle-stimulating hormone and luteinizing hormone concentrations are low in most patients with central hypothyroidism, but some reduction and an impaired response to gonadotropin-releasing hormone are found in patients with primary hypothyroidism. In postmenopausal women with primary hypothyroidism, however, serum gonadotropin concentrations remain high.

Serum cortisol concentrations are characteristically reduced in hypopituitarism and are usually normal in primary hypothyroidism. Measurements of serum cortisol may help to differentiate the hypothyroxinemia of central hypothyroidism (low to normal serum cortisol) from the low T4 state due to nonthyroidal illness, which generally is associated with high serum cortisol values. The response to metyrapone is frequently subnormal in hypopituitarism, reflecting diminished ACTH reserve. The response is usually normal in primary hypothyroidism, although delayed or subnormal responses occur in some patients. Similarly, the serum cortisol response to insulin-induced hypoglycemia may be impaired in hypopituitarism as well as in some patients with primary hypothyroidism (130).

Location of the Hypothalamic–Pituitary Lesion

Various imaging techniques may be used to identify lesions in the hypothalamic and pituitary region. Skull radiography and tomography have been largely replaced by more sensitive procedures, such as computed tomography (CT) and magnetic resonance imaging (MRI). Indirect signs of pituitary tumors detectable by the older techniques include enlargement of the sella, erosion of its floor, and erosion or elevation of the clinoid processes. The presence of soft tissue densities within the sphenoid sinus suggests the presence of extrasellar extension of a pituitary tumor. Suprasellar calcification is a common finding in craniopharyngioma. Long-standing primary hypothyroidism also may be associated with enlargement of the pituitary gland that can be reversed by T4 therapy (131). A normal or small sella turcica is found in patients with central hypothyroidism attributable to nontumorous lesions (132). CT and MRI have the advantage of visualizing the pituitary gland directly and therefore may provide direct evidence of pituitary tumors or other abnormalities, such as an empty sella turcica. CT and MRI are especially useful in the evaluation of extrasellar extension of pituitary tumors.

THERAPY

Therapy of central hypothyroidism should be directed toward restoring and maintaining euthyroidism. In addition, hypofunction of other endocrine glands resulting from pituitary hormone deficiencies should be corrected and the pituitary or hypothalamic cause of the central hypothyroidism treated appropriately.

Patients with central hypothyroidism should be treated with T4 in the same way as are patients with primary hypothyroidism, except when there is coexisting ACTH deficiency. Before T4 therapy is initiated, pituitary-adrenal function should be evaluated by measurement of serum cortisol and assessment of ACTH reserve. If ACTH deficiency is present, cortisol replacement should be initiated before any T4 is given because of the risk of precipitating an adrenal crisis. In addition, if gonadotropin, GH (especially in children), and antidiuretic hormone deficiencies are present, appropriate replacement therapy should be instituted after the adrenal steroid and T4 are given. Patients with isolated TSH deficiency require only T4 therapy, but should be evaluated carefully at least twice a year to detect further loss of pituitary function. Transient functional TSH deficiency usually does not require any treatment.

Although other thyroid preparations can be used, T4 is the preparation of choice (see Chapter 67). The initial dose of T4 should be based on the age and cardiovascular status of the patient. In young adults who do not have ACTH deficiency, therapy may be initiated at a daily dose of 1.4 to 1.6 mg/kg T4 for 4 to 6 weeks; the dose then may be adjusted on the basis of its peripheral effects. In patients with cardiovascular disease or ACTH deficiency and in elderly patients, therapy should be begun with 0.3 to 0.7 mg/kg of T4; after 3 to 4 weeks, the dose can be increased progressively until an optimal effect is achieved. In infants and children, the dose of T4 should be relatively higher because T4 clearance is more rapid and underreplacement may result in mental retardation and impaired physical growth.

Serum TSH measurements cannot be used as in primary hypothyroidism to determine the adequacy of T4 therapy. Instead, the correct dosage should be determined by clinical response and by measurements of serum free T4, and together with some biochemical indexes of thyroid hormone action (133).

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