Resistance to thyrotropin and thyrotropin-releasing hormone

INTRODUCTION — Resistance to thyroid-stimulating hormone (RTSH) is characterized by elevated serum TSH of normal biologic activity in the absence of goiter. Affected patients may be euthyroid or hypothyroid. It is caused by one of several genetic defects that impair function of the TSH receptor.

Resistance to thyrotropin-releasing hormone (TRH) is a rare disorder that manifests as central hypothyroidism. It is caused by inactivating mutations in the TRH receptor (TRHR) gene.

The syndromes of resistance to thyrotropin (TSH) and resistance to TRH will be discussed here. Disorders of reduced sensitivity to thyroid hormone, including resistance to thyroid hormone, are discussed separately. (See "Resistance to thyroid hormone and other defects in thyroid hormone action" and "Genetic defects in thyroid hormone transport and metabolism".)

GENERAL MECHANISMS OF HORMONE RESISTANCE SYNDROMES — Hormone resistance syndromes can be broadly defined as reduced or absent end-organ responsiveness to a hormone. Several general mechanisms have been identified:

●Impaired biologic activity of the hormone – Impaired activity of the hormone is caused by mutations or post-transcriptional modifications that result in production of an abnormal hormone molecule. Since response to the authentic hormone is normal, this circumstance is a "pseudo-resistance."

●Impaired function of hormone receptor – Impaired receptor function is caused by mutations in the receptor gene, leading in defective or absent receptor protein. Receptor defects result in impaired or absent ability to bind the hormone, defective transmission of the signal produced by hormone binding, defective targeting to the site of action, or lack of receptor synthesis.

●Quantitative reduction in receptor in the absence of receptor gene defect – Reduced quantity of the receptor may be caused by decreased synthesis or accelerated degradation. These can occur in an absence of a defect in the receptor gene or molecule proper but involve substances that control such functions.

●Post-receptor abnormalities – Cell membrane hormone receptors, such as the thyrotropin (thyroid-stimulating hormone [TSH]) receptor, mediate hormone action by activating second messengers through interaction with guanine nucleotide-binding (Gs or Gq) proteins. Because these second messengers are activated by multiple hormones, some defects in post-receptor signaling pathways can give rise to impaired action of several hormones, as is the case in McCune-Albright syndrome. (See "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.)

RESISTANCE TO THYROID-STIMULATING HORMONE — Resistance to thyroid-stimulating hormone (RTSH) is broadly characterized by high serum TSH (hyperthyrotropinemia) with normal TSH biologic activity, in the absence of goiter.

Affected individuals have normal or hypoplastic thyroid glands, high serum TSH concentrations, and normal or low serum thyroxine (T4) and triiodothyronine (T3) concentrations. They are often identified at birth through neonatal screening for congenital hypothyroidism. (See "Clinical features and detection of congenital hypothyroidism".)

Mechanism of TSH action — TSH is the predominant regulator of thyroid growth and T4 and T3 synthesis and secretion. These actions are mediated through TSH-binding to the TSH receptor located on the plasma membrane of thyroid follicular cells. Activation of the TSH receptor results in activation of G proteins and then of the adenylyl cyclase-cyclic AMP pathway of signal transduction (figure 1). At higher concentrations of TSH, the phospholipase C-phosphatidylinositol pathway is activated. The result is stimulation of thyroid follicular cell growth and function [1].

The TSH receptor belongs to a superfamily of G protein-coupled receptors that have an extracellular amino-terminal domain, seven transmembrane segments, and a cytoplasmic carboxyl terminus [2]. It has some constitutive activity, so that thyroid function does not cease entirely in the absence of TSH. Expression of the TSH receptor gene is under the control of several factors, including thyroid transcription factor 1 (TTF1, also known as NKX2-1), thyroid transcription factor 2 (TTF2, also known as FOXE1), and PAX8 [3].

Prevalence and inheritance — The precise prevalence of RTSH is not known. However, partial RTSH must not be uncommon as one-third of infants born in the state of Illinois with high blood TSH levels (>30 mU/L) maintain normal levels of T4 (>8 mcg/dL) and ongoing elevations of TSH when measured two to three weeks later (from the records of the Illinois State Laboratory) (see "Clinical features and detection of congenital hypothyroidism", section on 'High TSH, normal free T4 or total T4'). RTSH is inherited in either an autosomal recessive [4] or dominant manner [5].

Pathogenesis of RTSH — Three genetic causes of RTSH have been so far identified. They involve two distinct genes and linkage to a gene locus [4].

Inactivating mutations in the TSH receptor gene located on chromosome 14 — This disorder was first described in 1995 [6]. The precise number of families with this defect is unknown but is likely in the thousands, involving approximately 100 different mutations [7,8]. A TSHR mutation database that is periodically updated is available. The inheritance is mostly recessive, equally split between homozygous and compound heterozygous gene mutations [7]. Decreased action of TSH results in reduced T4 and T3 synthesis and secretion, with compensatory increase in TSH secretion. The absence of goiter and the presence of thyroid hypoplasia in these patients are compatible with the dominant role of TSH on the growth of the thyroid gland [9]. Though not uncommon, TSH receptor gene mutations rarely cause severe congenital hypothyroidism [10]. To a certain degree, the magnitude of serum TSH elevation and the thyroid status of the patient vary with the severity of the functional impairment of the mutant TSH receptor.

With some of the mutations, heterozygotes may have higher serum TSH values, on average, usually in the upper limit of normal or just above normal [11]. In one series, 20 percent of young subjects with nonautoimmune hyperthyrotropinemia were heterozygotes for inactivating mutations of the TSH receptor [7]. In a sampling of a Japanese population, the frequency of heterozygous mutations of the TSH receptor was approximately 1:172 and the prevalence of homozygotes was approximately 1:118,000 [12]. The mild RTSH in individuals heterozygous for TSHR gene mutations is a dominant negative effect, due to entrapment of the normal receptor by oligomerization with the mutant [13]. A complex phenotype of congenital hypothyroidism and pseudohypoparathyroidism has been described in the presence of a combination of inactivating mutations of the TSH receptor and mutations of the downstream G protein (GNAS) [14].

Most loss-of-function mutations in the TSH receptor that have been identified are located in the extracellular domain of the TSH receptor, in contrast to the gain-of-function mutations that cause hyperthyroidism, which are located principally in the transmembrane and intracellular domains of the receptor [15]. Approximately one-half of the mutant TSH receptors have partial impairment of function, and in one-third of cases, affected subjects could maintain a euthyroid state by an appropriate increase in serum TSH levels (fully compensated RTSH).

PAX8 gene mutations located on chromosome 2 — Although the first reported cases of PAX8 gene mutations were associated with thyroid dysgenesis [16], these mutations also can cause RTSH. Patients often are indistinguishable clinically and by thyroid tests from those with loss-of-function mutations in the TSH receptor gene [17]. Inheritance is autosomal dominant. The impaired association of the mutant PAX8 with other transcription factors regulating the TSH receptor, thyroglobulin, and thyroperoxidase genes appear to be responsible for the RTSH phenotype.

Defect in the long arm of chromosome 15 — Some patients with similar clinical findings have no detectable TSH receptor or PAX8 gene mutations, nor do they have inactivating mutations in G protein [5,18,19]. The defect is inherited in an autosomal dominant manner. Although the precise cause of their RTSH is not known, it is linked to a 2.9 Megabase interval on chromosome 15q25.3-26.1 [20].

Classification and clinical manifestations — RTSH should be suspected in patients, particularly infants, who have high serum TSH concentrations, normal or low serum free T4 and T3 concentrations, and a normally located thyroid gland.

Three phenotypes of resistance to TSH have been identified, representing different degrees of resistance to TSH. In subjects with TSH receptor gene defects, the phenotype correlates with the magnitude of functional impairment of the mutant TSH receptor (figure 2). This does not appear to be the case in RTSH caused by PAX8 gene mutations and those linked to the locus on chromosome 15. In such individuals, wide variations in both TSH and free T4 and T3 are observed in affected individuals with the same mutation and within the same family (figure 2) [5,17,20].

Fully compensated defect — The impaired response to TSH is compensated by hypersecretion of TSH; this overcomes the resistance, resulting in euthyroid hyperthyrotropinemia. In an individual patient with a mutation causing resistance to TSH, the phenotype tends to be stable over time. This course contrasts to that of acquired subclinical hypothyroidism (SCH) due to autoimmune thyroiditis, which, in the presence of antithyroid antibodies, tends to worsen over time.

Partially compensated defect — This occurs when the high serum TSH cannot fully compensate for the defect; affected individuals have mild hypothyroidism. This most often occurs in patients who are homozygous for the TSH receptor mutation, who may be euthyroid initially (elevated TSH with normal free T4; compensated RTSH) but often develop hypothyroidism over time (partially compensated RTSH) [21].

Uncompensated defect — Complete lack of TSH receptor function results in severe hypothyroidism. This most often occurs when both alleles carry mutant TSH receptors with complete lack of function [9,22,23].

Differential diagnosis — RTSH should be suspected in patients, particularly infants, who have high serum TSH concentrations, normal or low serum free T4 and T3 concentrations, and a normally located thyroid gland. The differential diagnosis includes all of those conditions that mildly impair thyroid hormone synthesis such as PAX8, TTF1 (NKX2-1), DUOX2, DUOXA2, and Pendrin (SLC26A4) gene mutations [4,24,25]. Because of the important role of TSH in promoting thyroid growth, RTSH is unlikely if the patient has a goiter or ectopically located thyroid tissue. (See "Clinical features and detection of congenital hypothyroidism" and "Disorders that cause hypothyroidism".)

Subclinical hypothyroidism — SCH is included in the differential diagnosis of compensated RTSH (see "Subclinical hypothyroidism in nonpregnant adults"). Both compensated RTSH and SCH have slight to mild elevations of TSH and normal free T4 and T3 concentrations. By definition, patients with SCH are "subclinical" and typically do not have symptoms, just as patients with compensated RTSH do not usually have symptoms of hypothyroidism. In adults, the most common cause of this phenotype is autoimmune thyroid disease, in which case, the elevations of TSH reflects a mild state of hypothyroidism for that individual, although free T4 concentrations are within the normal range for the general population. By contrast, in patients with compensated RTSH, the elevated TSH is caused by reduced action of a normal TSH molecule, eg, due to mutations in the TSH receptor. This is more likely in children or in families with a history of a similar phenotype. (See 'Pathogenesis of RTSH' above.)

The presence of a mutation in a gene known to cause RTSH would distinguish the two conditions. However, since the prevalence of SCH is 4 to 15 percent of the population, it would not be practical to recommend genetic testing for all patients diagnosed with SCH. Nevertheless, it is important to distinguish these two conditions as diagnosis of compensated RTSH does not require treatment with LT4, while many argue that SCH should be treated, depending on the patient's age and level of elevation of the TSH. Therefore, we suggest genetic testing for suspected RTSH in patients with the following characteristics:

●Absence of a history of prior normal thyroid function tests

●Presence of RTSH phenotype in other family members (eg, familial occurrence without thyroid enlargement)

●Identification of thyroid hormone abnormalities during infancy or childhood (since SCH is not common in children)

Other — Other diagnoses that should be considered in patients with biochemical characteristics consistent with RTSH (slightly elevated TSH concentration and normal free T4 and T3 concentrations) include:

●Presence of human anti-mouse antibodies (HAMA) that can cause an elevated TSH with normal thyroid hormone levels. This possibility can be excluded by direct radioimmunoassay measurement after removal of suspected HAMA from the assay.

●Presence of macro-TSH, which is a large molecular weight, biologically inactive TSH species, in which TSH is complexed with immunoglobulin G (IgG). While the free T4 and T3 values are normal, TSH is high. Other tests to diagnose macro-TSH include a blunted free T3 response to TRH stimulation and the use of free T4 cutoff values for a specific TSH value [8]. Confirmation of macro-TSH can be made either by column chromatography, in which the TSH peak is eluted in the void volume and thus indicates a high molecular weight, or by polyethylene glycol precipitation [26].

Several studies have examined the role of polymorphisms in the TSH receptor gene but have been unable to fully explain the wide range of normal TSH concentrations in the "normal population." One study has shown that 13 of 116 adults with SCH but without evidence of autoimmune thyroid disease were heterozygous for TSH receptor gene mutations, most of which were proven to result in loss of function [27].

Treatment — Individuals with fully compensated RTSH are euthyroid and need no treatment [21]. There is no evidence that in the absence of other risk factors, persistent elevation of serum TSH levels produces TSH-secreting pituitary adenomas or thyroid neoplasia.

Individuals with mutations in both alleles of the TSH receptor may be euthyroid initially (elevated TSH with normal free T4; compensated RTSH) but often develop mild hypothyroidism over time (partially compensated RTSH) [21]. Individuals with partially compensated or uncompensated RTSH should be treated with levothyroxine, like any other hypothyroid patient. Because these individuals have normal responsiveness to thyroid hormone, the goal is to normalize their serum TSH concentration.

RESISTANCE TO THYROTROPIN-RELEASING HORMONE — Resistance to thyrotropin-releasing hormone (TRH) is a rare disorder that is transmitted as an autosomal recessive trait. It is due to an inactivating mutation in the TRH receptor.

Mechanism of action of thyrotropin-releasing hormone — TRH, a tripeptide of hypothalamic origin, acts by binding to TRH receptors located on the cell membranes of the pituitary thyrotroph cells. This results in depolarization, an influx of calcium into the cytosol, and activation of the phospholipase C-phosphatidylinositol pathway that stimulates the synthesis and release of thyroid-stimulating hormone (TSH) [28].

The human TRH gene is located on chromosome 3 and contains six copies of the progenitor sequence [29]. The TRH receptor, a typical G protein-coupled receptor with seven transmembrane spanning domains, is encoded by a single gene located on chromosome 8 [28,30].

Pathogenesis — Resistance to TRH is due to inactivating mutations in the TRH receptor (TRHR) gene. This disorder was first described in 1997 in a child with compound heterozygote mutations [31]. Twelve years passed before a second family with resistance to TRH was reported; affected members were homozygous for a different TRHR mutation [32]. Heterozygotes are normal.

Clinical manifestations — The patient with resistance to TRH presented with findings of central hypothyroidism: normal serum TSH, low thyroxine (T4) and triiodothyronine (T3) concentrations, and no serum TSH or prolactin responses to the administration of TRH. (See "Central hypothyroidism".)

SUMMARY AND RECOMMENDATIONS

●Resistance to thyroid-stimulating hormone (RTSH)

•Definition – RTSH is characterized by high serum TSH (hyperthyrotropinemia) with normal TSH biologic activity, in the absence of goiter. It is caused by one of several genetic defects that impair function of the TSH receptor. (See 'Resistance to thyroid-stimulating hormone' above and 'Pathogenesis of RTSH' above.)

•Clinical manifestations – RTSH should be suspected in patients, particularly infants, who have high serum TSH concentrations, normal or low serum thyroxine (T4), free T4, and triiodothyronine (T3) concentrations, and a normally located thyroid gland that is normal size or hypoplastic. The phenotype varies depending on the degree of resistance to TSH. (See 'Classification and clinical manifestations' above.)

•Pathogenesis – RTSH has been associated with inactivating mutations in the TSH receptor gene (mostly autosomal recessive), or PAX8 gene mutations (autosomal dominant). Other cases in which these mutations are absent have been linked to a region on the long arm of chromosome 15. (See 'Pathogenesis of RTSH' above.)

•Treatment – In patients with RTSH who are euthyroid (the impaired response to TSH is fully compensated by hypersecretion of TSH), we suggest NOT treating with thyroid hormone (Grade 2B). (See 'Fully compensated defect' above.)

If the high serum TSH cannot fully compensate for the defect (partially compensated or uncompensated defects), the individual is hypothyroid and should be treated with thyroid hormone like any other hypothyroid patient. (See 'Treatment' above.)

●Resistance to thyrotropin-releasing hormone (TRH) – Resistance to TRH is a very rare disorder that is transmitted as an autosomal recessive trait. It is due to an inactivating mutation in the TRH receptor and manifests as central hypothyroidism. (See 'Resistance to thyrotropin-releasing hormone' above.)

ACKNOWLEDGMENT — Support for this topic review was provided in part with funds from the National Institutes of Health (NIH), USA grant 4R37 DK15070.