SAT-017 Exogenous Androgen Inhibition of the Reproductive Neuroendocrine Axis in Females

Abstract Disclosure: L.A. Esparza: None. M. Real: None. A. Kelton: None. A. Hudson: None. J. Rodriguez: None. M. Pradhan: None. J. Yang: None. K. Iwata: None. E. Lhuillier: None. V. Duong: None. E.A. Coutinho: None. A.J. Duleba: None. T. Harrison: None. A.S. Kauffman: None. Although endogenous androgens are normally low in healthy females, elevated androgens from exogenous or endogenous sources can negatively impact reproductive hormone secretion in both sexes, lowering gonadotropin levels and decreasing gonad function. This can occur with anabolic steroid abuse, adrenal tumors, or in genetic females identifying as males that take androgen supplementation. The neuroendocrine mechanisms by which exogenous androgens alter gonadotropin release, including pulsatile and surge modes of LH secretion, remain unknown. Here, we studied neuroendocrine effects of elevated androgens in the male physiological range, including testosterone (T) or DHT, on the female reproductive axis. First, in a pilot clinical study of transgender men beginning T supplementation, we determined that both menstrual cyclicity and endogenous LH pulse secretion were significantly inhibited after 3 and 6 months of male-level T treatment versus pre-T baseline measures. To study possible underlying mechanisms, we chronically treated young adult female mice with male levels of T or DHT and studied reproductive neuroendocrine outcomes. Compared to control females, androgen-treated female mice exhibited markedly reduced in vivo LH pulsatility, including decreased pulse frequency and mean LH; estrous cycles were also impeded by androgens, matching prior reports. We hypothesized that kisspeptin neurons, potent upstream stimulators of GnRH neurons, are candidate targets to mediate inhibitory androgen effects on LH secretion. Indeed, correlating with reduced LH levels, androgen-treated female mice exhibited decreased expression of arcuate nucleus Kiss1 and Tac2 genes, critical players in GnRH/LH pulse generation. Additionally, we found that male-levels of T in female mice severely impaired generation of estrogen-induced LH surges, critical for ovulatory function. This inhibitory effect was mimicked by chronic DHT, a non-aromatizable androgen that acts specifically via androgen receptor (AR), suggesting that exogenous androgens may act via AR pathways to block pre-ovulatory processes. Corresponding brain analyses determined that female preoptic kisspeptin neurons, participants in LH surge generation, were strongly inhibited by either T or DHT treatment. Moreover, female mouse brains expressed AR in both preoptic and arcuate kisspeptin populations, suggesting these neurons may be direct targets of androgens. Indeed, preliminary evidence in transgenic conditional AR knockout mice supports this possibility for inhibition of LH pulses. Collectively, our findings demonstrate potent inhibitory effects of male-level androgens on LH secretion in both humans and female mice, and implicate inhibited kisspeptin neurons in this process. These findings have implications for understanding how androgens suppress reproductive function in females Presentation: Saturday, July 12, 2025