Expression of the Thyroid-Stimulating Hormone Receptor in the Folliculo-Stellate Cells of the Human Anterior Pituitary

Abstract

TSH secretion from the anterior pituitary is mainly regulated by TRH and thyroid hormones. We hypothesized that in addition the pituitary itself could modulate TSH production by sensing its own TSH release, enabling fine-tuning of TSH secretion. For such an ultra-short loop control, the pituitary should contain a TSH receptor (TSH-R). To find evidence for this we screened a human pituitary complementary DNA library with a digoxigenin-labeled TSH-R probe and found 2 positive clones of 32,000 plaques. One clone was sequenced and found to be completely identical to the thyroid TSH-R. T SH IS THE major regulator of thyroid hormone synthesis and secretion. The production of TSH in the anterior pituitary is modulated by thyroid hormones via a classical negative feedback mechanism and by TRH from the hypothalamus by a positive feedforward mechanism. In concert with other circulating factors, such as dopamine, somatostatin, and some steroids, TRH and thyroid hormones are seen as the main determinants to maintain normal TSH secretion.We hypothesized that, in addition, TSH secretion might be fine-regulated in a short loop feedback at the pituitary level through the TSH receptor (TSH-R). This hypothesis was developed on two grounds. Firstly, because we were intrigued by the well known clinical observation that many patients with Graves' hyperthyroidism continue to show suppressed plasma TSH levels despite adequate antithyroid treatment, resulting in clinical euthyroidism and normal (or even low) plasma T 4 and T 3 levels (1, 2). In our experience this is less often seen in patients with other forms of hyperthyroidism. We wondered whether TSH-R-stimulating antibodies might suppress TSH secretion by direct action on the pituitary. If so, the pituitary should contain a TSH-R. Several reports have now demonstrated that the TSH-R is present at extrathyroidal sites. In the intestine, for example, it appears to be involved in a local paracrine network of hormonal regulation of T cell homeostasis in response to locally produced TSH (3).Secondly, we hypothesized that it would be more efficient for the fine-tuning of TSH secretion (i.e. to keep TSH plasma levels within a certain range) if the pituitary was able to measure and regulate its own TSH production, in analogy to modern heating boilers, which regulate their heat production through built-in temperature sensors in addition to the room thermostat.A pituitary TSH-R might be involved in TSH secretion at the pituitary level in an autocrine fashion via a TSH-R on the thyrotroph itself. Alternatively, it might be mediated in a paracrine fashion through another cell type. A likely candidate for this is the folliculo-stellate (FS) cell (4), which is known to produce various cytokines and other regulatory factors, mostly notably IL-6 (5, 6).To test our hypothesis, we set out to study the presence and cellular localization of the TSH-R in the human anterior pituitary using several, independent methods aimed at finding both TSH-R messenger ribonucleic acid (mRNA) and protein. Ma...

Novel neuroanatomical pathways for thyroid hormone action in the human anterior pituitary

“…4). The expression of the TSH receptor reported earlier in MHC-class II cells (40) and the increase in D2 activity that has been observed in TSH-producing tumors (41) suggests that D2 expression in the anterior pituitary can be influenced directly by TSH. This is further supported by a dose-dependent increase of D2 mRNA by TSH, which has been reported in human thyroid cells and the presence of a cAMP response element in the D2 promoter (42).…”

History and perspectives of pituitary folliculo-stellate cell research

“…Moreover, the detection in vitro of numerous receptors in FS cells (15) or TtT/GF cells (93 -95), as well as of [Ca 2þ ] i rises in response to certain stimuli (94), further point to the 'excitable' nature of these cells. On the other hand, the occurrence of TSH receptors in a subpopulation of FS cells also expressing MHC-class II receptors (29) points to a possible role of these receptors in the immune accessory function of this FS cell subpopulation. Functional TSH receptors are also found in TtT/GF cells; these, however, are not coupled to cAMP or inositol 1,4,5-triphosphate pathways, but probably signal through the Janus kinase/signal transducer and activator of transcription 5a pathway (30).…”

“…This electrically coupled FS cell network was suggested to provide a mechanism for long-distance communication in the anterior pituitary in response to physiological stimuli (28). The finding of thyrotropin (TSH) receptors expressed in a subpopulation of FS cells in situ and in cell lines also opened a new perspective on ultra-short feedback loop regulation by FS cells of TSH secretion (29,30).…”

Analysis of Lag Behind Thyrotropin State After Radioiodine Therapy in Hyperthyroid Patients

“…A number of studies proposed different causes of transient suppressed serum TSH level during antithyroid drug therapy. Prummel et al (2000) reported that TSH receptor was expressed in the folliculo-stellate (FS) cells of the human anterior pituitary gland, and TSH secretion might be down regulated through TSH receptor via a paracrine feedback loop (8). Delayed recovery of pituitarythyroid axis may be also from long standing thyroid hormone excess (9).…”