The impact of androgen metabolism and FMR1 genotypes on pregnancy potential in women with dehydroepiandrosterone (DHEA) supplementation

Abstract

For decades androgens have been considered detrimental to follicle maturation. Animal studies now suggest that they are essential for normal folliculogenesis. Especially in women with premature ovarian aging (POA), recent IVF data in humans are supportive. The literature also suggests an association between recently reported ovarian genotypes of the FMR1 gene and ovarian aging patterns. We, therefore, attempted to determine a potential difference in androgen concentrations and androgen interactions in women with POA who do or do not become pregnant while undergoing androgen supplementation, and whether androgen concentrations and pregnancy chances are affected by FMR1 genotypes. We longitudinally assessed androgen metabolism in 91 women with POA, following pre-supplementation with micronized dehydroepiandrosterone (DHEA) prior to IVF. IVF outcomes were assessed based on androgen levels and ovarian FMR1 genotypes. The mean age of the women was 39.8 ± 4.4 years; the clinical pregnancy rate was 25.3%. Total androgen concentrations were not associated with pregnancy; however, in women with abnormal FMR1 genotypes, but not those with the normal genotype, free testosterone significantly affected clinical pregnancy potential (β = 1.101, SE ± 0.508, P = 0.03). At the start of the IVF cycle, interactions of DHEA with total and free testosterone also significantly affected subsequent pregnancy rates (β = -0.058, SE ± 0.023, P = 0.01 and β = -0.496, SE ± 0.197, P = 0.012). Androgen interactions significantly influence IVF pregnancy rates in women with POA, with the impact of total androgens on cycle outcomes varying according to FMR1 genotypes. These observations suggest that the effectiveness of androgen supplementation in women with POA varies based on FMR1 genotypes, and defines androgen deficiency as a subset of diminished ovarian reserve.