Androgen excess, abnormal ovarian development and associated pathologies in genetically altered FORKO female mice: a paradigm for exploring hyperandrogenism

Introduction: Androgens important for normal ovarian function and produced by the thecal and stromal compartments are used by the granulosa cells for production of estrogens. Androgen excess has adverse effects on reproduction and causes related metabolic disturbances. Methods: We examined ovarian hormones, LH levels, follicular dynamics, markers and metabolic parameters at different ages in genetically altered female mice with complete or partial disruption of the FSH-receptor gene. Results: Sterile null females (FORKO mice) produce excess androgen as early as 3 weeks with sustained high levels in adult life. Estradiol is undetectable and progesterone is also reduced. Circulating androgen excess is associated with extensive hypertrophy of the theca and stromal cells with early elevated levels of LH in circulation. Follicular dynamics are drastically altered, ranging from accelerated recruitment to eventual slow down and early loss of oocytes. These phenomena are also reproducible in haploinsufficient females that show early reproductive senescence (similar to middle-aged women). Study of developmental markers such as antimullerian hormone, transcription factor GATA-4, estrogen receptor (ER) β and androgen receptor has provided a working model to explore molecular interactions. In addition to ovarian dysfunction early androgen excess (and estrogen deficiency) led to visceral obesity, abnormal lipid profiles, glucose intolerance, hyperinsulinemia and presumptive insulin resistance in the mutants.