The identification of naturally occurring genetic mutations of the FSH receptor has led to a better understanding of the role of FSH in folliculogenesis and has allowed to identify the cause of several syndroms. Inactivating mutations of the follicle stimulating hormone (FSH) receptor have been described in rare cases of premature ovarian failure (POF). We have studied a new patient presenting a complete POF phenotype, with high plasma FSH levels, very low estrogen and inhibin B levels and complete lack of biological response to high doses of recombinant FSH. A novel homozygous mutation was found in this patient. The mutation totally impairs adenylate cyclase stimulation in vitro. Histological studies of the patients ovaries showed an increase in the density of small follicles when compared to age-matched normal women. A complete block in follicular maturation after the primary stage was also observed. This observation supports the concept that FSH seems mandatory for the initiation of follicular growth in humans only after the primary stage. Complete FSH resistance provokes infertility in our patient, remarkably associated with persistence of a high number of small follicles.
Spontaneous ovarian hyperstimulation (OHSS) is a syndrome occurring during pregnancy. It is a rare event in contrast to iatrogenic OHSS, although mild forms may be underestimated. We describe here a familial case of recurrent spontaneous OHSS. A heterozygous transmembrane mutation of the FSH receptor gene segregated with OHSS in this family. The mutated FSH receptor displayed an abnormal sensitivity to hCG. Broadening of specificity of G Protein-coupled receptors is not a common pathogenic mechanism. Molecular elucidation of this case also enlightens possible pathophysiological mecanisms in iatrogenic OHSS induced by gonadotropins used in assisted reproduction medicine.