Primary Ovarian Insufficiency: Genes, hormones, and beyond

Primary ovarian insufficiency (POI) is characterized by amenorrhea in association with postmenopausal follicle-stimulating hormone (FSH) levels in women younger than 40 years. POI affects 1% of women and greatly influences a woman’s fertility potential and her overall health. The exact cause of POI remains to be elucidated in most women. In 2004, the Dutch POI consortium was established. This national collaboration is aimed at unraveling the genetic components of POI and to further describe the phenotype of women affected by POI. This thesis presents results from the ongoing research activities of the national POI collaboration. POI is nowadays regarded as a complex genetic trait. Through the common disease - common variant approach, research is focused on the identification of important new genes and non-coding alleles involved in gene expression modulation. It is of utmost importance to include a homogeneous and well-phenotyped population in this type of study. We demonstrated that women with familial POI (incidence of 29%) have no distinctive phenotype characteristics than women with sporadic POI, and conclude that familial background of POI does not necessitate a different genetic approach. Meanwhile, researches worldwide have always focused on the possibility that specific single gene mutations could explain a considerable proportion of POI, especially in familial cases. One of these candidate genes is NR5A1. In contrast to previous findings of a mutation frequency of 8% of NR5A1 in women with POI, we found an overall mutation rate of only 1.4%. NR5A1 can therefore not be considered as a major contributor to the presence of POI. Similarly, FMR1 premutations and intermediate-sized CGG repeat alleles were previously found to contribute to POI in up to 13%. In our POI cohort only 1.7% of women were FMR1 premutation carriers. Moreover, measures of POI severity did not significantly depend on CGG repeat numbers, which emphasizes that normal and intermediate FMR1 CGG repeat sizes do not play a central role in POI. While hypoestrogenemia in women with POI and the probably associated effects have been fairly well documented, the role of androgens remains to be determined. Our systematic review and meta-analysis showed that women with POI have significantly decreased total testosterone concentrations in comparison with female controls. A complicating factor in this matter is that androgen measurement in female samples is problematic due to trueness and precision problems. We assessed that, compared with a labor-intensive extraction radioimmunoassay, liquid chromatography-tandem mass spectrometry is a reliable, fast alternative for measuring androgen hormones in women. Women about to undergo gonadotoxic treatment are increasingly seeking medical help for fertility preservation. Fifteen children have now been born following ovarian cryopreservation and subsequent autotransplantation. The question remains whether this still experimental technique is sufficiently successful (possible publication bias) to offer to women about to undergo gonadotoxic treatment. We identified that ovarian reserve parameters such as AMH and inhibin B, are very low following this procedure, which indicates a low ovarian reserve status. This explains the poor pregnancy rate, and we therefore conclude that this method is not very successful.