National Centers for Translational Research in Reproduction and Infertility

Metabolic and Neuroendocrine Responses to Androgen and Diet

Oregon National Primate Research Center

PI: R. Stouffer and J. Cameron

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 neuroendocrine and metabolic changes occurring with hyperandrogenemia and WSD.