# ROLE OF ANDROGENS IN THE NEUROENDOCRINE DYSFUNCTION OF NASCENT PCOS

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $341,574

## Abstract

Hyperandrogenic polycystic ovary syndrome (PCOS) affects approximately 8-10% of reproductive-aged
women. PCOS is a major cause of infertility and poor gynecological health, and it is associated with obesity,
insulin resistance/hyperinsulinemia, type 2 diabetes, and endometrial cancer. The underlying causes of PCOS
remain unclear, but puberty is a critical developmental window during which the pathophysiology of PCOS
unfolds. Peripubertal hyperandrogenemia (HA) can represent a precursor to full-blown PCOS, and HA is very
common (~ 60% overall) in peripubertal girls with obesity. Thus, the study of peripubertal girls with obesity
provides an opportunity to evaluate the causes and consequences of peripubertal HA, in addition to providing
key insights into how asymptomatic HA progresses to full-blown PCOS. This proposal is designed to elucidate
how PCOS begins and develops across puberty, primarily focusing on the role of abnormal gonadotropin-
releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) secretion. More
specifically, this proposal will address the following working model regarding the emergence of neuroendocrine
abnormalities in PCOS: (1) peripubertal HA (from any source) leads to abnormal sleep-wake patterns of LH
(GnRH) pulse frequency—namely, high 24-hour frequency without normal sleep-wake changes—which
contributes to LH excess, ovarian HA, FSH deficiency, and anovulation; (2) peripubertal HA also antagonizes
estrogen- (and progesterone-) induced gonadotropin surge generation—another impediment to the
establishment of cyclic ovulatory function. Aim 1 of the proposed project involves clinical research studies
designed to assess the following: if acute progesterone suppression of wake LH pulse frequency is impaired in
girls with HA (Aim 1a); if androgen-receptor blockade (spironolactone) improves progesterone-suppression of
wake LH pulse frequency in girls with HA (Aim 1b); if spironolactone alone normalizes sleep-wake LH/FSH
secretion in girls with HA (Aim 1c); and if daily (morning) low-dose progesterone administration normalizes
sleep-wake LH/FSH secretion in girls with HA (a pilot trial of therapeutic plausibility; Aim 1d). Aim 2 of the
proposed project involves clinical research studies designed to: assess progesterone augmentation of
gonadotropin secretion in late pubertal girls with HA (Aim 2a); evaluate the ability of androgen-receptor
blockade to normalize progesterone augmentation of gonadotropin secretion in PCOS (Aim 2b); and assess
potential impairments in estradiol augmentation of gonadotropin release in PCOS (Aim 2c). These human
studies will provide insight into mechanisms underlying the development of abnormal gonadotropin secretion in
nascent PCOS. These studies will synergize with the basic studies of Projects II and III to help elucidate the
pubertal ontogeny of PCOS, all with a view to developing rational preventive and/or treatment strategies.

## Key facts

- **NIH application ID:** 10025179
- **Project number:** 5R01HD102060-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Christopher Rolland McCartney
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $341,574
- **Award type:** 5
- **Project period:** 2019-09-25 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10025179

## Citation

> US National Institutes of Health, RePORTER application 10025179, ROLE OF ANDROGENS IN THE NEUROENDOCRINE DYSFUNCTION OF NASCENT PCOS (5R01HD102060-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10025179. Licensed CC0.

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