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Androgen effects on the reproductive neuroendocrine axis

Award Number: R01HD111650
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/12/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $584,117 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	000	3	1/16/2026	NON-COMPETING CONTINUATION	$584,117
														Subtotal = $584,117

Issue Date FY: 2025 ( Subtotal = $470,251 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	000	2	10/28/2024	NON-COMPETING CONTINUATION	$581,671
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	003	2	7/4/2025	OTHER REVISION	$452,411
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	001	2	3/4/2025	TERMINATION	-$387,781
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	002	2	7/2/2025	TERMINATION	-$176,050
														Subtotal = $470,251

Issue Date FY: 2024 ( Subtotal = $647,659 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	000	1	12/12/2023	NEW	$647,659
														Subtotal = $647,659

Grand Total All Awards = $1,702,027

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Androgen effects on the reproductive neuroendocrine axis

Award Number: R01HD111650

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/12/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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