Androgen effects on the reproductive neuroendocrine axis - PROJECT SUMMARY This R01 proposal responds to “Notice of Special Interest in Research on the Health of Sexual and Gender Minority (SGM) Populations” (NOT-MD-19-001) which calls for research describing “clinical, behavioral, and social processes affecting the health of SGM individuals and their families” that will promote development of appropriate interventions to improve SGM health and fertility care. This proposal includes clinical studies of transgender individuals and the effects of androgen treatment on their reproductive health. Androgens can have significant inhibitory effects on neuroendocrine reproductive hormone secretion in both sexes, yet the mechanisms and cell types by which androgens suppress GnRH and LH pulsatile and surge secretion in females are poorly studied and remain unknown. Indeed, high levels of exogenous androgens fundamentally contribute to reproductive disruption seen in otherwise healthy women and transgender men (female sex individuals taking high levels of androgens), but the mechanisms, time course, and target neuroendocrine site(s) of action for these inhibitory androgen effects are poorly understood. Our overall hypothesis is that male levels of exogenous androgens can inhibit the female reproductive neuroendocrine axis by acting through androgen receptor (AR) in hypothalamic kisspeptin neurons to modulate endogenous LH pulse secretion and impede generation of the estrogen-generated preovulatory LH surge. We test this hypothesis in two complementary Aims that study the role of high exogenous androgens in both a clinical setting in transgender male (female sex) human subjects and corresponding transgenic female mouse models. Aim 1 investigates the effects of exogenous androgens in a clinical setting, studying transgender men taking gender affirming testosterone therapy. This clinical Aim assess the inhibitory effects and time-course of androgen treatment on a wide suite of reproductive neuroendocrine parameters, with a focus on in vivo LH pulse and LH surge secretion, coupled with analyses of menstrual cyclicity and ovarian measures. Aim 2 utilizes transgenic mice to test whether male-level androgens acting via AR specifically in kisspeptin neurons are necessary and/or sufficient for androgen inhibition of in vivo LH pulse parameters, including pulse frequency, and the estrogen-induced LH surge. This Aim also elucidates whether elevated androgen action directly in kisspeptin cells is necessary for AR inhibition of reproductive gene expression in the female brain, and uses innovative methodology to analyze androgen-induced changes in the transcriptome of specific kisspeptin neural populations in females, identifying how exogenous androgens impact these neurons to impede LH secretion. Together, these two complementary Aims will elucidate the cellular, molecular, and physiological mechanisms of androgen inhibition on female neuroendocrine reproductive hormones. This project will advance our understanding of fundamental mechanisms of androgen action in neuroendocrine control of reproduction and inform upon future clinical interventions for rescuing reproductive function in females or currently understudied SGM transgender males exposed to exogenous androgens.
