We recently discovered that a mild elevation in testosterone (T) levels in prepubertal female monkeys led to a significant increase in the frequency of pulsatile LH secretion, as well as an increase in LH response to GnRH, and concluded that chronic exposure to mild hyperandrogenemia over the course of puberty triggers changes in the neural drive to the reproductive axis that resemble those of girls with PCOS in early adulthood. Subsequently, when monkeys were 5 years of age, we fed them a Western Style Diet (WSD) and after 14 months both T-treated and control animals had a faster than normal pulse frequency in the early follicular phase, as well as decreased LH pulse amplitude. T-treated animals also showed a significant decrease in insulin sensitivity compared to control animals (2.6-fold lower), and changes in ovarian structure function, as detailed in Project II. These pilot studies demonstrate that a combination of T+WSD can lead to neuroendocrine, ovarian and metabolic abnormalities clinically associated with hyperandrogenemia and obesity. However, the specific roles that T and WSD played in the development of these abnormalities are unclear, as this pilot study did not include a T alone group, nor a normal monkey chow group. The overall goal of Project I is to use the pubertal female rhesus monkey model to further define the effects of adolescent and early adult (1) T, (2) WSD, and (3) T+ WSD treatment, compared to (4) control conditions, on function of the metabolic and reproductive neuroendocrine axes.
Aim 1 will examine the effects of these four treatments on key metabolic systems and sleep patterns, measuring metabolic substrate and hormone levels, ivGTT, ITT, measurement of metabolic rate in a metabolic chamber, hyperinsulinemic/euglycemic clamps, dexascans, and activity. Sleep disorders are linked to both elevated T and obesity in a bi-directional fashion and could be partially responsible for the metabolic pathologies associated with PCOS.
Aim 2 will examine the effects of treatments on reproductive neuroendocrine secretion (LH, FSH and responsiveness to GnRH), plus peptide levels and gene expression in KNDy (Kisspeptin, Neurokinin 8, Dynorphin) neurons in the basal hypothalamus.
Aim 3 will test whether decreasing circulating T levels by removing T implants and/or reinstating a lower calorie, low fat diet will reverse neurendocrine and metabolic changes occurring with hyperandrogenemia and WSD.

Public Health Relevance

This project builds on promising preliminary data collected in a group of female rhesus monkeys showing that a slight elevation in circulating testosterone levels plus consumption of a WSD during puberty leads to neuroendocrine, ovarian and metabolic symptoms characteristic of polycystic ovarian syndrome. This project will examine further the systemic changes in metabolic and reproductive hormones occurring with hyperandrogenemia, a high fat/caloric WSD, and their combination, plus whether their effects are reversible.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54HD071836-01A1
Application #
8510085
Study Section
Special Emphasis Panel (ZHD1-DSR-L (55))
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$248,941
Indirect Cost
$81,793
Name
Oregon Health and Science University
Department
Type
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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McGee, W K; Bishop, C V; Pohl, C R et al. (2014) Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys. Am J Physiol Endocrinol Metab 306:E1292-304
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