A remarkable case of thyrotoxicosis initially caused by graves' disease followed by a probable TSHoma - a case report.

BACKGROUND: Graves' disease is the commonest cause of thyrotoxicosis whilst thyrotropin (TSH)-producing pituitary adenomas (thyrotropinomas, TSHomas) are very rare and account for just 1-2% of all pituitary adenomas. Coexistence of a TSHoma and Graves' disease has been very rarely reported. Here, we report a case of a patient whose initial presentation with primary thyrotoxicosis due to Graves' disease, was subsequently followed by a relapse of thyrotoxicosis due to a probable TSHoma. CASE: A sixty-eight year old woman was referred to our department with classical features of thyrotoxicosis. Initial biochemistry confirmed hyperthyroxinaemia [free thyroxine (fT4) 20.4 pmol/L (reference range 7.0-16.0)] and a suppressed TSH [< 0.02mIU/L (0.50-4.20)]. A technetium pertechnetate uptake scan was consistent with Graves' Disease. She was treated with carbimazole for 18 months and remained clinically and biochemically euthyroid. After stopping carbimazole her fT4 started to rise but TSH remained normal. Laboratory assay interference was excluded. A TRH stimulation test demonstrated a flat TSH response and pituitary MRI revealed a microadenoma. Remaining pituitary hormones were in the normal range other than a slightly raised IGF-1. An 11C-methionine PET/CT scan coregistered with volumetric MRI (Met-PET-MRICR) demonstrated high tracer uptake in the left lateral sella region suggestive of a functioning adenoma. The patient declined surgery and was unable to tolerate cabergoline or octreotide. Thereafter, she has elected to pursue a conservative approach with periodic surveillance. CONCLUSION: This is a very unusual case of thyrotoxicosis caused by two different processes occurring in the same patient. It highlights the importance of considering dual pathology when previously concordant thyroid function tests become discordant. It also highlights a potential role of Met-PET-MRICR in the localisation of functioning pituitary tumours.

Functional and morphological changes in the adenohypophysis of dogs with induced primary hypothyroidism: loss of TSH hypersecretion, hypersomatotropism, hypoprolactinemia, and pituitary enlargement with transdifferentiation.

From case studies in humans it is known that primary hypothyroidism (PH) may be associated with morphological and functional changes of the pituitary. There is no insight into the time scale of these changes. In this study, seven beagle dogs were followed up for 3 years after the induction of primary hypothyroidism. Three of these dogs were followed up for another 1.5 years while receiving l-thyroxine. Adenohypophyseal function was investigated at 2-month intervals with the combined intravenous injection of CRH, GHRH, GnRH, and TRH, and measurement of the plasma concentrations of ACTH, GH, LH, PRL, and TSH. In addition, after 2 years of hypothyroidism a single TRH-stimulation test and a somatostatin test were performed, with measurements of the same pituitary hormones. Every 6 months the pituitary gland was visualized by computed tomography (CT). Induction of PH led to high plasma TSH concentrations for a few months, where after concentrations gradually declined to values no longer significantly different from pre-PH values. A blunted response to stimulation of TSH release preceded this decline. Basal plasma GH concentrations increased during PH and there was a paradoxical hyperresponsiveness to TRH stimulation. Basal GH concentrations remained elevated and returned only to low values during l-thyroxine treatment. Basal PRL concentrations decreased significantly during PH and normalized after several months of l-thyroxine treatment. The pituitary gland became enlarged in all dogs. Histomorphology and immunohistochemical studies in 4 dogs, after 3 years of PH, revealed thyrotroph hyperplasia, large vacuolated thyroid deficiency cells, and decreased numbers of mammotrophs. Several cells stained for both GH and TSH. In conclusion, with time PH led to a loss of the TSH response to low T4 concentrations, hypersecretion of GH, and hyposecretion of PRL. The enlarged pituitaries were characterized by thyrotroph hyperplasia, large vacuolated thyroid deficiency cells, and double-staining cells, which are indicative of transdifferentiation.

Secretory granules and granins in hyperstimulated male rat gonadotropes.

Granins are acidic proteins co-localized with peptides in secretory granules of many endocrine cells. They are thought to participate in certain steps of the regulated secretory pathway. This is of particular interest in rat pituitary gonadotropes, which in most cases contain both gonadotropins (follicle-stimulating hormone, FSH and luteinizing hormone, LH) and two granins (chromogranin A, CgA and secretogranin II, Sg II). Therefore, we investigated male rat gonadotropes ultrastructurally and for the cellular and subcellular localization of gonadotropins/granins under normal conditions and after stimulation by luteinizing hormone-releasing hormone (LHRH) or castration. Typical gonadotropes of controls contained differently composed secretory granules: small granules showed immunoreactivity for LH and SgII and larger granules were immunoreactive for FSH and CgA and to a lesser extent, for LH. Stimulated gonadotropes showed hypertrophy or hyperplasia and RIA for plasma LH levels showed a 30-70-fold increase. In stimulated cells a third type of secretory granule became prominent. These "intermediate" granules had an electron-dense core immunoreactive for LH and SgII, whereas CgA labeling was confined to a less electron-dense outer region. (In stimulated gonadotropes, FSH immunoreactivity could be shown effectively only at the light microscopic level.) Intermediate granules developed from structures resembling condensing vacuoles. They began to exhibit their typical double structure as they budded off from the trans-Golgi network. It therefore appears that CgA and SgII participate in establishing two different routes of the regulated pathway in gonadotropes. Therefore, immunocytochemistry of the granins seems to be a suitable approach to investigating secretory pathways in these endocrine cells.

Volume of sella turcica in normal subjects and in patients with primary hypothyroidism and hyperthyroidism.

In an attempt to assess a possible relationship between pituitary size and TSH secretion, the volume of sella turcica was measured in 570 subjects, 26 primary hypothyroid patients, and 34 thyrotoxic patients. The volume of sella turcica, measured by a 3-dimensional approach, increased progressively with age until 20 years of age and was rather constant thereafter in normal subjects. In thyrotoxic patients, the volume of sella turcica was normal in spite of decreased plasma TSH concentration. In contrast, 81% of primary hypothyroid patients had an abnormal enlargement of the sella turcica. The magnitude of an increase of sella turcica inversely related with a decrease in serum T4 and T3 concentrations. On the other hand, the magnitude of an increase of sella turcica correlated well with an increase of circulating TSH. We suggest that an increase of sella turcica indirectly reflects an increase in pituitary size and TSH-secreting capacity, possibly due to hypertrophy and hyperplasia of TSH cells in primary hypothyroid patients.