A NOVEL PHENOTYPE RELATED TO PARTIAL LOSS OF FUNCTION MUTATIONS OF THE FOLLICLE-STIMULATING-HORMONE RECEPTOR

A single natural loss of function mutation of the follicle stimulating hormone receptor (FSHR) has been described to date. Present in the Fi nnish population it markedly impairs receptor function, blocking folli cle development at the primary stage and presenting as primary amenorr hea with atrophic ovaries. When Western European women with this pheno type were examined for FSHR mutations the result was negative, suggest ing that other etiologies corresponding to this clinical pattern are m arkedly more frequent. We now describe a novel phenotype related to mu tations provoking a partial loss of function of the FSHR. A woman with secondary amenorrhea had very high plasma gonadotropin concentrations (especially FSH), contrasting with normal sized ovaries and antral fo llicles up to 5 mm at ultrasonography. Histological and immunohistoche mical examination of the ovaries showed normal follicular development up to the small antral stage and a disruption at further stages. The p atient was found to carry compound heterozygotic mutations of the FSHR gene: Ile160Thr and Arg573Cys substitutions located, respectively, in the extracellular domain and in the third intracellular loop of the r eceptor. The mutated receptors, when expressed in COS-7 cells, showed partial functional impairment, consistent with the clinical and histol ogical observations: the first mutation impaired cell surface expressi on and the second altered signal transduction of the receptor. This ob servation suggests that a limited FSH effect is sufficient to promote follicular growth up to the small antral stage. Further development ne cessitates strong FSH stimulation. The contrast between very high FSK levels and normal sized ovaries with antral follicles may thus be char acteristic of such patients.