Recombinant human thyroid-stimulating hormone: pharmacology,clinical applications and potential uses

The major functions of pituitary thyroid-stimulating hormone (TSH) are to maintain the biosynthesis and secretion of the thyroid hormones L-thyroxine (T4) and L-3,5,3'triidothyronine (T3). The TSH core contains two apoproteins, the alpha and beta subunits. The alpha subunit is identical to that of pituitary follitropin, pituitary lutropin and placental chorionic gonadotropin, whereas the beta subunit is unique. TSH is a glycoprotein; the glycoprotein components of the alpha and beta subunits account for more than 10% of their mass and are essential for normal thyrotropic action and intravascular kinetics. The hypothalamic tripeptide, TSH-releasing hormone (TRH) is required for optimum TSH biosynthesis, particularly as far as addition of the glycoprotein components is concerned. TRH deficiency is associated with secretion of TSH molecules that are appropriately measured in most assays but have reduced bioactivity. In previous years the TSH used in clinical practice was obtained and purified from bovine pituitaries. Bovine TSH was used to test thyroid function and to augment the uptake of radioiodine in patients with thyroid cancer. Bovine TSH has been largely abandoned as a clinical agent because of adverse immune reactions. A recombinant human TSH (rhTSH; Thyrogen), has been approved by the US FDA for diagnostic use in patients with thyroid cancer. The alpha and beta subunits of Thyrogen are identical to those of human pituitary TSH. Thyrogen has a specific activity of approximately 4 IU/mg and is a potent stimulator of T4, T3 and thyroglobulin (Tg) secretion in healthy volunteers. It also increases thyroid iodide uptake in patients with thyroid cancer or multinodular goitre and in volunteers, even those exposed to large amounts of stable iodide. Thyroid cancer patients who have been treated by thyroidectomy and radioiodine ablation but are at risk of harbouring residual thyroid cancer are candidates for Thyrogen administration to prepare them for whole body iodide scans and serum Tg measurements. In thyroidectomised thyroid cancer patients who are unable to secrete pituitary TSH upon thyroid hormone withdrawal, Thyrogen is the only acceptable method to prepare them for these procedures. Thyrogen has been used on a compassionate basis to prepare patients for radioiodine ablation. rhTSH, in addition to being useful in the management of patients with thyroid cancer, is potentially useful to test thyroid reserve and to aid in thyroid-related nuclear medicine procedures. In the future, TSH analogues that have superagonist or antagonist properties may become available as therapeutic agents.     

Molecular biology and laboratory diagnosis of hypothalamic-pituitary-thyroid axis]

Recent developments in molecular biology have brought dramatic changes in laboratory medicine. Applications of molecular biology techniques have made it possible to make etiological diagnosis and produce recombinant proteins for reagents. Laboratory investigations of molecular biology in the hypothalamic-pituitary-thyroid axis include TRH gene, TRH effect, TSH gene, TSH receptor and its autoantibodies, thyroid peroxidase and thyroglobulin and their autoantibodies, thyroxine (T4) binding protein genes, deiodination of T4, thyroid hormone receptor, oncogenes of thyroid etc. The following developments are reviewed. 1) Human TSH (hTSH) beta gene and its abnormality: Two types of mutations of hTSH beta gene have been found in patients with hereditary isolated TSH deficiency. DNA diagnosis and genetic counseling are now being performed. 2) Structure and function of TSH receptor: The primary structure of hTSH receptor was identified from its gene. Relationships between its structure and function have been investigated using site specific mutagenesis and synthetic short peptides. 3) Thyroid hormone receptor gene and its abnormality: The thyroid hormone receptor gene has been successfully cloned. Several mutations of the gene have been demonstrated in patients with thyroid hormone resistance. 4) Application of recombinant hTSH (r-hTSH):r-hTSH has been produced in CHO cells. Immunological and biological properties of r-hTSH are similar to those of authentic pituitary hTSH. Clinical application of r-hTSH is now in progress.     

Hypothalamic control of thyrotrophin secretion

1. By means of the haemagglutination-inhibition technique, it has been possible to measure the plasma and pituitary levels of thyroid-stimulating hormone (TSH) following unilateral and bilateral electrolytic lesions placed in the supraoptic area of the hypothalamus of female rats.

2. Unilateral lesions after 8 and 48 hr caused a temporary decrease in the percentage of circulating TSH followed by a return to normal.

3. Bilateral lesions caused a fall in plasma TSH to a level 41% below normal at 10 days whereas the pituitary level increased 70%.

4. Rats with bilateral symmetrical supraoptic lesions, kept for 3 days at 4° C, had a lower plasma TSH content (23%) and a higher pituitary TSH content (16%) than the sham operated control animals but the levels of pituitary TSH did not show any significant difference (0·100 > P > 0·050).

5. Thyroidectomized rats with bilateral lesions kept at 26° C for 3 days had a much lower plasma TSH (39%) and a slightly higher pituitary TSH as compared to the normal intact animals, suggesting that the hypothalamus also influences the synthesis of TSH in the pituitary.

6. Thyroidectomized rats with bilateral lesions kept at 4° C for 3 days showed both a plasma and pituitary TSH increase compared to controls at 26° C, suggesting that when a higher demand for thyroid function is present the pituitary gland has some autonomy for both secretion and release of TSH. This autonomy appears to be slight, as there was no statistically significant difference between the pituitary TSH levels of the thyroidectomized animals bearing similar supraoptic lesions and exposed to 4 and 26° C.

     

Ultrastructure and cytochemistry of thyroid lysosomes following subtotal thyroidectomy

Following subtotal thyroidectomy, the amount of circulating thyroid hormone decreases and causes an increase in the secretion of thyrotropin (TSH) by the anterior pituitary gland. Serum levels of circulating TSH remain elevated until thyroid secretion returns to normal. In this study we have analyzed the effects of such chronic stimulation of thyroid cells by TSH, with particular emphasis on ultrastructural and cytochemical changes in the lysosomes. Weanling Sprague-Dawley rats underwent subtotal thyroidectomy and 6 weeks later the residual thyroid tissue was removed and processed for ultrastructural and cytochemical analysis. There were obvious ultrastructural signs of hyperactivity. The cells were hypertrophied and there were colloid droplets in the cells as well as extremely abundant oddly shaped lysosomes. The lysosomes reacted positively for acid phosphatase and for glycoproteins, suggesting that they are secondary lysosomes, ones which have complexed with thyroglobulin prior to release of thyroid hormones from the cells. This tremendous increase in the number of these structures in the cells is similar to that observed under normal conditions during the aging process and suggests a slowdown in the proteolytic degradation of thyroglobulin during long periods of chronic stimulation by TSH.     

Aspects pratiques des dosages de PTH

New knowledge concerning PTH biology was accumulated during the past few years. The finding that the so-called “intact” PTH assays measure a “non 1-84” PTH fragment in addition to full-length PTH has led to the development of new assays. These new assays, which were initially thought to measure 1-84 PTH only, have been shown to recognize also another PTH species called “amino-PTH”. As the various names given to the different assay methods are highly confusing, there is a need for a simplified nomenclature. A simple way would be to identify the older “intact” PTH assays as second-generation assays and the new assays (Whole, CAP, BioIntact) as third-generation assays. Although of considerable potential interest for the comprehension of PTH physiology, the third-generation PTH assays have not yet proved to be superior to the second-generation assays in clinical practice. There is thus currently no recommendation to switch from the second-generation to the third-generation assays in clinical practice, or to use a ratio derived from the concomitant measurement of PTH with both assay-generation. Because second- and third-generation PTH assays are usually highly correlated, significant differences in the clinical information provided by these methods are unlikely. However, our opinion is that more definitive bone biopsy studies in dialyzed patients selected according to their bone- and calcium-related treatment are still needed to reach a consensus. Finally, we have proposed that PTH reference values should be established in healthy subjects with a normal vitamin D status. This supposes that 25OHD is measured in the reference population beforehand, and that the subjects with vitamin D insufficiency are eliminated from the reference group. Although more complicated than the usual way to establish normative data, we have shown that it decreases the upper limit of normal by 25–35%, enhancing thus the diagnostic sensitivity for hyperparathyroidism without a decrease in specificity.     

The effects of common matrices for assay standards on performance of "ultra sensitive" immunometric assays for TSH. Report of a joint WHO/IFCC collaborative study.

This report describes the results of a collaborative study organized by a joint working group of IFCC and WHO and involving nine manufacturers of TSH immunometric assay kits. The study was designed to determine whether a calibrator with a common matrix gives better between-laboratory agreement for calibration of serum samples than the various kit calibrators, and to assess various materials for their suitability for use as common matrices. Kit calibrators or calibrators consisting of the IRP for TSH made up in two common matrices, 1) serum from patients with untreated thyrotoxicosis or 2) serum taken from subjects treated with suppressive doses of triiodothyronine, gave similar results for the between-laboratory variation of estimates of TSH concentration for a range of serum samples. Dose-response curves for the two calibrators in 'common' matrices were similar to one another and to those fort the kit calibrator. However, the occurrence of non-specific serum effects is shown by the comparison of results for these calibrators with results for calibrators made up in a third common matrix, serum treated with wheat germ lectin. Dose response curves for this calibrator were dissimilar to those for the other calibrators and between-laboratory variation for estimates in terms of this latter calibrator showed a substantial increase. Moreover, although the between-laboratory variances for estimates of the TSH concentration in terms of each of these calibrators (except those made up in serum treated with in the wheat germ lectin) were similar for any one sample from five hyperthyroid patients, the variances were not consistent between samples, even for samples with similar mean TSH concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Methimazole interferes with the progression of experimental autoimmune myocarditis in rats

We produced experimental autoimmune hypophysitis (EAH) in rats and investigated its characteristics. Female Lewis rats were immunized by two injections with homologous pituitary homogenate and complete Freund's adjuvant. Blood was collected serially from the rats, and serum antibodies to pituitary antigens were examined. The rats were sacrificed 2 or 4 weeks after the final immunization, and histological examinations of the endocrine organs were carried out. Histological examination revealed slight, focal infiltration of mononuclear cells in the pituitary gland only in the rats immunized with the pituitary homogenate. Infiltration of mononuclear cells was not observed in the thyroid gland, pancreas, adrenal gland, or ovary. In the serological examination, antibodies to both cytosolic antigens and cytoplasmic particle antigens from the pituitary gland were detected by enzyme-linked immunosorbent assay (ELISA), and these antibody levels increased with time. Western blotting using the serum antibodies identified an immunoreactive protein of approximately 21.5 kDa among these antigens, and we confirmed that this protein was rat growth hormone (GH). Furthermore, antibodies to GH, thyrotropin (TSH), and luteinizing hormone (LH) were detected by ELISA. Antibodies to follicule stimulating hormone, prolactin, or adrenocorticotropin were not detected. These data suggest that several antigens from the pituitary gland are involved in EAH in rats, and that GH, TSH, and LH are major antigens among the pituitary antigens in this model.     

Effect of diphenylhydantoin on hypothalamic-pituitary-thyroid function in the rat

Chronic diphenylhydantoin (DPH) administration (5 mg x 100 g body wt-1 x day-1) to the normal rat is associated with a decrease in the serum thyroxine (T4) and triiodothyronine (T3) concentrations without an appropriate rise in the serum thyrotropin (TSH) concentration, suggesting a possible direct effect of DPH on TSH secretion. To further study this possibility, DPH was administered chronically to thyroidectomized, hypothyroid rats. In the hypothyroid rats treated chronically with DPH, serum TSH did not increase, pituitary TSH content was significantly decreased, and the serum TSH response to thyrotropin-releasing hormone (TRH) was decreased compared to that of diluent-treated, hypothyroid rats. Hypothalamic TRH content was similar in DPH and diluent-treated rats. These findings suggest that DPH suppresses pituitary TSH secretion, probably as a thyroid hormone agonist. The effect of a single large dose of DPH (20 mg/100 g body wt) administered to thyroidectomized rats also decreased serum tSH but, in contrast to the findings in chronically treated rats, hypothalamic TRH and pituitary TSH content and the serum TSH responses to TRH were increased. These differences may be due to the acute inhibitory effect of a large dose of DPH on hypothalamic TRH release. Furthermore, because the effect of thyroid hormone on regulating pituitary TSH synthesis and release is dose and time dependent, the effect of DPH as a thyroid hormone agonist on pituitary TSH dynamics may also be variable.     

Transdifferentiation of pituitary thyrotrophs to lactothyrotrophs in primary hypothyroidism: case report

Primary hypothyroidism causes adenohypophysial hyperplasia via stimulation by hypothalamic thyrotropin-releasing hormone (TRH). The effect was long thought to simply result in thyroid-stimulating hormone (TSH) and prolactin (PRL) cell hyperplasia, an increase in TSH and PRL blood levels with resultant pituitary enlargement, often mimicking adenoma. Recently, it was shown that transformation of growth hormone (GH) cells into TSH cells takes place in both clinical and experimental primary hypothyroidism. Such shifts from one cell to another with a concomitant change in hormone production are termed "transdifferentiation" and involve the gradual acquisition of morphologic features of thyrotrophs ("somatothyrotrophs"). We recently encountered a unique case of pituitary hyperplasia in a 40-year-old female with primary hypothyroidism wherein increased TSH production was by way of PRL cell recruitment. The resultant "lactothyrotrophs" maintained TSH cell morphology (cellular elongation and prominence of PAS-positive lysosomes) but expressed immunoreactivity for both hormones. No co-expression of GH was noted nor was thyroidectomy cells seen. This form of transdifferentiation has not previously been described.     

Reanalysis of Antisera Specificities and Binding Characteristics of Rat Pituitary Hormone Assays

Rat pituitary hormone radioimmunoassays (RIAs) are widely used in reproductive research, yet data on specificity and binding characteristics of many of the antisera are not widely available. This report characterizes one set of rat antisera supplied by the National Institutes of Health (USA). Rat follicle-stimulating hormone (FSH) and thyrotropin-stimulating hormone (TSH) antisera appear specific, but TSH exhibited significant competition in the rat luteinizing hormone (LH) assay. In addition, statistically significant nonparallelism was demonstrable in all three assay systems. This creates further problems in characterizing antisera cross-reactivity and may make potency estimates for pituitary standards inaccurate.     

Neuroendocrinology of the pituitary gland

The hypophysial-portal chemotransmitter hypothesis of control of the anterior pituitary was first set forth in the 1940s on the basis of physiological studies of the effects of lesions of the hypothalamus, and of section of the pituitary stalk on pituitary function. Morphological demonstration of specific neuropeptide pathways in the hypothalamus, which project to the median eminence, and the chemical identification of releasing hormones in the hypothalamus have fully established this theory. Specific neuropeptides have been isolated which stimulate the secretion of ACTH (CRF, corticotrophin releasing hormone), TSH (TRH, thyrotropin releasing hormone), GH (GHRH, growth hormone releasing hormone), and the gonadotropins (LHRH, luteinizing hormone releasing hormone; GnRH, gonadotropin releasing hormone). Prolactin secretion is regulated by both an inhibitory hormone (dopamine), and by one or more releasing factors. A factor inhibitory to GH and TSH secretion has also been identified. All factors except for the prolactin inhibitory hormone (which is a biogenic amine) are peptides, all synthesized as part of large prohormones. These substances have all been introduced into medical and veterinary practice where they are useful for regulation of pituitary abnormalities, and study of normal physiology.     

Évaluation d'une nouvelle technique de dosage des immunoglobulines spécifiques E des protéines du lait de vache

TopicsDiagnosis of cow's milk intolerance (CMI) is founded upon assay of specific IgE against cow's milk proteins whose ImmunoCap technic from pharmacia diagnostics (Phadia) allows to quantify from 0.1 KUA/l. We retrospectively studied the advantages of this extent of the scale of concentrations with regard to that traditionally scale restricted at 0.35 kUA/l and we verified the forecasted threshold of 0.1 kUA/l.Material and methodsWe selected 68 serums from 63 children, 32 with CMI confirmed, 12 with probable CMI and 19 controls. Anti alpha lactalbumin, beta lactoglobulin and casein IgE had been measured for every sample on UniCap 100, with a couple of dosage protocols: the usual one which allowed to quantify IgE from 0.35 to 100 kUA/l and the new one with a scale of calibration fit for quantify from 0.1 kUA/l.ResultsThe threshold of this new protocol had been determined on 0.1 kUA/l for the three allergens. The two protocols were well correlated. For 21 among 68 samples (31%), the new calibration permitted to calculate concentrations with specific IgE but it was obtained < 0.35 KUA/l with the old one. These samples correspond with 10 confirmed CMI, 3 probable CMI, 7 controls, among which 5 isolated gastro oesophageal reflux GER.ConclusionResults of this study showed us that the new IgE dosage protocol can be a rearlier diagnosis tool of a cow's milk sensitization. Prospective study is needed to confirm. We asked about possible link between sensitization and GER.     

Thyrotropin-releasing hormone receptors in gut tissues resemble pituitary receptors

The relative order of activity of thyrotropin-releasing hormone (TRH) and various analogs in contracting the isolated guinea pig antrum and duodenum correlated with their potencies in activating thyroid-stimulating hormone (TSH) release. The action of TRH in both tissues was selectively antagonized by the putative pituitary TRH receptor antagonist, chlordiazepoxide (10 microM). The data indicate that the contractions produced by TRH in these gut tissues are mediated by TRH receptors with similar characteristics as the pituitary TRH receptors responsible for TSH release.     

In vitro TSH and PRL secretion from eutopic and heterotopic rat pituitaries: effects of hypothyroidism

Five adenohypophyses from donors of the same strain, age, and sex were transplanted under the renal capsule of young adult female rats. At least 3 wk later, enzymatically dispersed cells from eutopic or heterotopic adenohypophyses from the same rat were perifused in vitro in a small chamber. Thyrotropin (TSH) and prolactin (PRL) secretion per 10(6) cells were significantly less from heterotopic than from eutopic cells under all conditions. In cells from euthyroid animals, TRH induced TSH secretion only in the eutopic cells but induced PRL secretion in both eutopic and heterotopic cells. Hypothyroidism increased TRH-induced TSH secretion and content in the cell lysate in both eutopic and heterotopic cells but increased TRH-induced PRL secretion only in the eutopic cells. The increase in TSH secretion induced by hypothyroidism in the heterotopic cells was of borderline statistical significance. The inability of TRH to induce TSH secretion in heterotopic pituitary cells from euthyroid rats may be due to a lower set point for thyroid hormone inhibition of TSH secretion in the heterotopic thyrotrophs. Heterotopic pituitary TSH secretion is probably suppressed by the normal plasma thyroid hormone concentration maintained by the eutopic pituitary and may be stimulated by TRH only in the presence of a subnormal plasma thyroid hormone concentration.     

Physiological Relevance of Thyroid Stimulating Hormone and Thyroid Stimulating Hormone Receptor in Tissues other than the Thyroid

Decades of research have provided strong evidence for a reciprocal relationship between the immune system and hormones of the hypothalamus–pituitary–thyroid (HPT) axis. Thyroid stimulating hormone (TSH), in particular, has been shown to have a variety of immune-regulating cytokine-like activities that can influence the outcome of T cell development in the thymus and intestine, and can affect the magnitude of antibody and cell-mediated responses of peripheral lymphocytes. Production of TSH and the expression of the TSH receptor are widely but selectively distributed across many different types of hematopoietic cells in the bone marrow, as well as among subsets of dendritic cells, monocytes and lymphocytes in the spleen and lymph nodes. In addition to their role in immunity, the involvement of TSH-producing hematopoietic cells in the microregulation of thyroid hormone activity represents a novel and potentially important aspect of the TSH-mediated immune-endocrine circuit.     

Utility of Pit-1 Immunostaining in Distinguishing Pituitary Adenomas of Primitive Differentiation from Null Cell Adenomas

Pit-1 immunostaining is not routinely used in the characterization of pituitary adenomas, and its utility in distinguishing adenomas dedicated towards the lactotroph, somatotroph, and thyrotroph lineage from null cell adenomas warrants further evaluation. Pituitary adenomas that were negative for expression of a basic panel of hormonal markers (ACTH, prolactin, and growth hormone) were further evaluated for TSH, SF-1, and Pit-1 expression using a tissue microarray. Among the 147 identified pituitary adenomas that were negative for ACTH, prolactin, growth hormone, and TSH, expression of SF-1 was present in 68 cases (46%). Of the remaining 72 cases with sufficient tissue for further analysis, four were Pit-1 positive (6% of the adenomas negative for ACTH, prolactin, growth hormone, TSH, and SF-1); the remaining 68 were potentially null cell adenomas. Two of the Pit-1-positive adenomas displayed a paranuclear CAM 5.2 staining pattern suggestive of a sparsely granulated somatotroph adenoma; however, only one case contained fibrous bodies within a majority of the adenoma cells. Our data suggests that Pit-1 can be utilized as a second tier immunostain in cases of clinically non-functioning adenomas that are immunonegative for ACTH, prolactin, growth hormone, TSH, and SF-1 in order to further segregate rare cases of Pit-1-positive adenomas from null cell adenomas. Pit-1 immunostaining can recognize rare cases of sparsely granulated somatotroph adenomas that appear immunonegative for growth hormone, as well as rare cases of other Pit-1-positive adenomas that are negative for Pit-1 lineage hormones. Overall, pituitary adenomas of the Pit-1 lineage that do not produce prolactin, growth hormone, or TSH are rare, with only four cases identified in the current study.     

Sensitizing effect of treatment with estrogens on TSH response to TRH in male rats.

Daily administration of estradiol benzoate (10 microgram/100 g body wt) to intact male rats led to a twofold increase of the plasma TSH (thyroid-stimulating hormone) response to thyrotropin-releasing hormone (TRH) after 4 and 7 days of treatment whereas the basal plasma TSH level was not affected. The basal plasma PRL concentration and the PRL response to TRH were both markedly increased by estrogen treatment. The TSH pituitary content remained unchanged, whereas the PRL pituitary content increased in parallel with the effect on PRL secretion. Treatment with estrogens for 1 wk sensitized the TSH secretory response to low doses of TRH (10 ng), whereas no significant effect on the response was found at high doses of the neurohormone. The present data show that the stimulatory effect of estrogens on the TSH response to TRH is due to true sensitization of the thyrotrophs to the action of the neurohormone, whereas that on prolactin secretion can result partly from increased pituitary prolactin content.     

A Plurihormonal TSH-Secreting Pituitary Microadenoma: Report of a Case with an Atypical Clinical Presentation and Transient Response to Bromocriptine Therapy

Inappropriate secretion of thyrotropin (TSH) is a rare cause of hyperthyroidism, and it is caused by either a TSH-producing pituitary adenoma (usually a macroadenoma) or to selective pituitary resistance to thyroid hormone. The case of a 31-yr-old male who presented with clinical features of thyrotoxicosis, including episodes of thyrotoxic paralysis, and a thyroid profile characterized by free hyperthyroxinemia and hypertriiodothyronemia with a nonsuppressed, inadequately normal TSH is reported. Dynamic testing showed both, lack of TSH stimulation by thyroid-releasing hormone (TRH), and lack of suppression by T3, consistent with autonomous TSH secretion. Pituitary MRI revealed a microadenoma. Seventy five percent of the patient’s serum TSH immunoreactivity eluted as α-subunit in Sephadex G-100 chromatography. A diagnosis of TSH-secreting microadenoma was established, and the patient was treated successfully with bromocriptine, which resulted in both clinical and biochemical resolution of his hyperthyroidism. Two months later, he became hyperthyroid again during bromocriptine therapy. Octreotide was started with adequate control of his symptoms and normalization of his free T4 level. He eventually underwent transsphenoidal surgery with successful resection of a chromophobic microadenoma which immunostained for TSH, growth hormone (GH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). One month postoperatively he is clinically and biochemically euthyroid on no medications.     

Long-Term Immunization Against the β-Subunit of Ovine Luteinizing Hormone (oLHβ) Has No Adverse Effects on Pituitary Function in Rhesus Monkeys

ABSTRACT: One postulated safety hazard of contraceptive methods based on immunization against gonadotropic hormones is the possibility that circulating antibodies which crossreact with pituitary hormones may impair pituitary function through the deposition of immunoglobulin and/or complement suggesting immune complexes. In order to evaluate this possibility in rhesus monkeys actively immunized against the β-sub-unit of ovine luteinizing hormone (oLHβ), we used three approaches to study the effects of long-term immunization on pituitary function: a) evaluation of pituitary responsiveness to challenge with a GnRH-agonist; b) examination of pituitary histology and immunostaining with gonadotropin antisera; and c) examination of pituitary cells for deposition of immune complexes. Our results indicate that circulating anti-oLHβ antibodies did not result in significant impairment of pituitary function in rhesus monkeys.     

Exaggerated and prolonged thyrotrophin releasing hormone (TRH) test responses in tertiary hypothyroidism.

A 60 year old man with panhypopituitarism due to a large meningioma and prolonged and exaggerated thyroid stimulating hormone (TSH) responses is described. Initial investigations showed a subnormal urinary free cortisol concentration, a low serum cortisol taken at 0900 hours, and a low free T4 concentration. The TSH was towards the upper end of the normal range. Subsequently pituitary function tests showed subnormal production of luteinising hormone in response to luteinising hormone releasing hormone (LHRH) and a short synacthen test with a low 30 minute cortisol value. Long synacthen testing showed a normal response at four days, confirming that the abnormalities were due to a pituitary or hypothalamic cause. A computed tomogram showed a large meningioma compressing the hypothalamus, pituitary, and temporal lobe. TRH testing showed a prolonged and exaggerated response, consistent with tertiary hypothyroidism.