Hypoandrogenism in women with low functional ovarian reserve (LFOR, defined as an abnormally low number of small growing follicles) adversely affects fertility. The
androgen precursor
dehydroepiandrosterone (
DHEA) is increasingly used to supplement treatment protocols in women with LFOR undergoing in vitro fertilization. Due to differences in
androgen metabolism, however, responses to
DHEA supplementation vary between patients. In addition to overall declines in steroidogenic capacity with advancing age, genetic factors, which result in altered expression or enzymatic function of key steroidogenic
proteins or their upstream regulators, might further exacerbate variations in the conversion of
DHEA to
testosterone. In this Review, we discuss in vitro studies and animal models of polymorphisms and gene mutations that affect the conversion of
DHEA to
testosterone and attempt to elucidate how these variations affect female
hormone profiles. We also discuss treatment options that modulate levels of
testosterone by targeting the expression of steroidogenic genes. Common variants in genes encoding
DHEA sulphotransferase,
aromatase,
steroid 5α-reductase,
androgen receptor,
sex-hormone binding globulin,
fragile X mental retardation protein and
breast cancer type 1 susceptibility protein have been implicated in
androgen metabolism and, therefore, can affect levels of
androgens in women. Short of screening for all potential genetic variants, hormonal assessments of patients with low
testosterone levels after
DHEA supplementation facilitate identification of underlying genetic defects. The
genetic predisposition of patients can then be used to design individualized fertility treatments.