# Neuroendocrine Regulation of LH in Normal and Disease States

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $436,843

## Abstract

PROJECT SUMMARY
Androgens and obesity-related metabolic factors, such as free fatty acids (FFAs), are critical regulators of the
reproductive axis. Along with the emerging epidemic of obesity, negative impacts of high adiposity on the female
reproductive axis are becoming evident. In addition, women affected with Polycystic Ovary Syndrome (PCOS),
the most common reproductive disorder in reproductive-aged women, experience hyperandrogenism and
metabolic features including obesity. Evidence indicates that the gonadotropin luteinizing hormone (LH) is
suppressed in high body mass individuals relative to lean women, and this is true in both normal women and
women with PCOS. Recent work has also revealed, in both normal and PCOS women, a paradox in the
association of elevated LH levels with elevated testosterone, despite the well-recognized role of testosterone in
suppressing the reproductive neuroendocrine axis. Interestingly, androgen appears to influence both the
hypothalamic reproductive circuits, dictating the pace of LH secretion, as well as pituitary gonadotrope
responsiveness to incoming GnRH pulses, suggesting a complex regulation of LH secretion patterns. The overall
goal of Project II is to investigate the impact of FFA and androgen on the female reproductive neuroendocrine
axis, either individually or in combination, in both normal and PCOS-like conditions. In Aim 1, we will elucidate
how FFAs alter in vivo LH pulse dynamics as well as the pituitary LH response to GnRH pulses. We hypothesize
that FFA induce cell stress in gonadotropes and alter hypothalamic pulsatility and gonadotrope responses to
GnRH. We will test the impact of acute and chronic exposure to a panel of FFAs on GnRH pulsatility and pituitary
sensitivity to GnRH in vivo and in vitro, using new models of GnRH challenge and perifusion pituitary culture. In
Aim 2, we will test how androgens alter LH pulse generation and the in vivo pituitary response to GnRH in
females. We will assess the effects of in vivo DHT treatment on both pulsatile LH secretion and pituitary
responsiveness to GnRH pulses, and use Cre-lox technology to determine in what specific neuroendocrine cell-
types androgens act to alter LH pulses in vivo. In Aim 3, we will examine the combined interaction of FFA and
androgens in normal females and in a mouse model of PCOS. We will determine how LH pulsatility and the
gonadotrope response to GnRH pulses are altered in the face of both elevated androgens and FFAs. Because
PCOS women have elevated androgens and FFAs, but paradoxically also exhibit rapid, high LH pulses, we will
use a novel mouse model of PCOS to investigate the interaction of androgens and obesity on LH pulse pattern
and secretion in PCOS-like conditions. We will then assess gene expression changes specifically in Kiss1 and
gonadotrope cells in a PCOS mouse model and compare these changes with those induced individually by
androgen, FFA, or high BMI alone. Together, these Aims will delineate the mech...

## Key facts

- **NIH application ID:** 9916786
- **Project number:** 5P50HD012303-38
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Mark Andrew Lawson
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $436,843
- **Award type:** 5
- **Project period:** — → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916786

## Citation

> US National Institutes of Health, RePORTER application 9916786, Neuroendocrine Regulation of LH in Normal and Disease States (5P50HD012303-38). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9916786. Licensed CC0.

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