Background and objective: Mutations in bone morphogenic protein 15 (BMP15) and growth/differentiation factor 9 (GDF9) lead to altered fertility in animal models. In the human, a heterozygous point mutation of BMP15 has been associated with premature ovarian failure (POF). Subject and methods: We have directly sequenced both genes in a cohort of 203 POF patients presenting with primary or secondary amenorrhea and high FSH levels and in a control population including 54 women with regular menstrual cycles who had at least one child. Results: We have identified several heterozygous variants. One alteration in GDF9 (S186Y) and one in BMP15 (L148P) may have pathogenic effects as both positions are conserved in vertebrate species, ranging from the chicken to mammals. These variants were absent in the control samples. We also found synonymous and neutral substitutions. Conclusions: We propose that although mutations in BMP15 and GDF9 are not a major cause of ovarian insufficiency, they may be involved in POF.

Oligoanovulatory patients with PCO but without HA have mild endocrine and metabolic features of PCOS.

Karyotyping is definitely helpful in the evaluation of POF patients. No submicroscopic chromosomal rearrangements affecting Xq region were identified. Further analysis using DNA microarrays should help delineate Xq regions involved in POF.

The size of the 2-5 mm follicle pool is an independent and important contributor to the FA of PCOS. This result could be explained by an exaggerated physiological inhibitory effect from this pool on the terminal follicle growth. The metabolic derangement of PCOS that also contributes to the FA would act through a different mechanism.

These data suggest that in anovulatory women with PCOS, gently increasing the serum FSH level reduces the AMH excess, thus relieving the inhibition from the latter on aromatase expression by selectable follicles and allowing the emergence of a dominant follicle.