Context: Rare activating mutations of the hFSHR have been reported in some women with spontaneous ovarian hyperstimulation in pregnancy, where follicular growth is inappropriately stimulated by elevated concentrations of hCG through hFSHR. It is not known if ovarian hyperstimulation in peri-pubertal girls with untreated primary hypothyroidism is caused by hFSHR mutations and/or influenced by hFSHR allelic variants rendering the hFSHR more sensitive to circulating TSH.

Objective: Determine if mutations of the hFSHR and/or hFSHR allelic variants are associated with greater sensitivity of the hFSHR to TSH.

Design: The hFSHR gene was sequenced from eight pediatric patients displaying gonadal hyperstimulation due to primary hypothyroidism. HEK293 cells expressing different hFSHR allelic combinations were studied for their responsiveness to recombinant hTSH.

Setting: University research centers.

Patients: Eight unrelated patients (7 girls and 1 boy), who exhibited primary hypothyroidism and gonadal hyperstimulation.

Interventions: None

Main Outcome Measure: DNA sequencing of the hFSHR gene. Basal, rhFSHR- and rhTSHR-stimulated cAMP levels were assayed in 293 cells transfected with the hTSHR or different hFSHR allelic combinations. Cell surface receptor numbers were also determined.

Results: No hFSHR mutations, but two known polymorphisms, were identified in the patient population. In vitro experiments demonstrated a dose-dependent and specific rhTSH-dependent increase in cAMP production in 293 cells expressing the wild-type hFSHR, regardless of hFSHR isoform.

Conclusions: Pediatric gonadal hyperstimulation associated with severe primary hypothyroidism is likely due to the actions of the elevated concentrations of TSH on the wild-type hFSHR and this response is not dependent upon the hFSHR isoform.