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Some children with juvenile hypothyroidism exhibit unexplained precocious puberty. Interaction of TSH with the human FSH receptor (hFSH-R) is a possible pathophysiological mechanism for this syndrome that has not been explored due to the lack of hFSH-free TSH preparations and the scarcity of a suitable hFSH-R-based assay system. To devise an in vitro FSH bioassay suitable for exploring this mechanism, we expressed hFSH-R complementary DNA in COS-7 cells and stimulated them with recombinant hTSH (rec-hTSH). Rec-hTSH elicited a dose-dependent cAMP response in the in vitro hFSH-R bioassay; however, the concentration of rec-hTSH required for half-maximal stimulation was several logs greater than that of hFSH. Rec-hTSH acted as a competitive inhibitor of hFSH at the hFSH-R, indicating that hTSH and hFSH are acting through the same receptor, namely the hFSH-R. This provides a potential novel mechanism for the precocious puberty of juvenile hypothyroidism.

Despite having amenorrhea and markedly elevated serum gonadotropin levels, some women with karyotypically normal spontaneous premature ovarian failure, nevertheless, have ovarian follicles that function intermittently. Graafian follicles capable of responding to these high FSH levels are faced with high serum LH levels as well, which might induce inappropriate luteinization and prevent normal follicle function. We examined this possibility using weekly blood sampling and sonography in 65 patients. Nearly 50% of our patients demonstrated ovarian follicle function [serum estradiol, > 183 pmol/L (50 pg/mL)] during a median of 4 months of observation (range, 2-6 months). However, during this observation, only 16% achieved an ovulatory serum progesterone level [> 9.5 nmol/L (3.0 ng/mL)]. We imaged an antral follicle by sonography in over 40% of patients (27 of 65), and serum estradiol was significantly greater when an antral follicle was present. The follicles in these patients were not functioning normally, however. In contrast to normal women, patients with ovarian failure had poor correlation between follicle diameter and serum estradiol. We biopsied these antral follicles in 6 patients and found luteinized Graafian follicles in all cases. Therefore, luteinized Graafian follicles account for at least 60% of the antral structures imaged (95% confidence limit). Thus, inappropriate luteinization of Graafian follicles appears to be a major pathophysiological mechanism in patients with karyotypically normal spontaneous premature ovarian failure.

Two-thirds of young women with karyotypically normal spontaneous premature ovarian failure have a femoral neck bone mineral density more than 1 SD below the mean of a reference group. These young women need early education regarding strategies to maintain their bone mass and ongoing medical evaluation to maintain compliance with these strategies.

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Some children with juvenile hypothyroidism exhibit unexplained precocious puberty. Interaction of TSH with the human FSH receptor (hFSH-R) is a possible pathophysiological mechanism for this syndrome that has not been explored due to the lack of hFSH-free TSH preparations and the scarcity of a suitable hFSH-R-based assay system. To devise an in vitro FSH bioassay suitable for exploring this mechanism, we expressed hFSH-R complementary DNA in COS-7 cells and stimulated them with recombinant hTSH (rec-hTSH). Rec-hTSH elicited a dose-dependent cAMP response in the in vitro hFSH-R bioassay; however, the concentration of rec-hTSH required for half-maximal stimulation was several logs greater than that of hFSH. Rec-hTSH acted as a competitive inhibitor of hFSH at the hFSH-R, indicating that hTSH and hFSH are acting through the same receptor, namely the hFSH-R. This provides a potential novel mechanism for the precocious puberty of juvenile hypothyroidism.