Impact of a Short-Term Western-Style Diet and Hyperandrogenism on Adult Rhesus Macaque Ovarian Function.

Abstract

Objective: To determine the effect of an obesogenic Western-style diet and hyperandrogenemia on ovarian outcomes.

Design: Experimental, controlled animal study SUBJECTS: Post-pubertal rhesus macaque females EXPOSURE: A Western-style diet (T+WSD: 36% fat, 45% carbohydrate, 18% protein) combined with exogenously administered testosterone versus a standard chow diet (Control, CTRL; 15% fat, 59% carbohydrate, 27% protein). Animals underwent controlled ovarian stimulations to assess ovarian follicle development.

Main outcome measures: Cycle length, the proportion of ovulatory cycles, and daily levels of estradiol (E2), progesterone (P4), AMH, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were compared between CTRL and T+WSD groups through one menstrual cycle. Follicular fluid was assessed for cytokine and steroid content, and retrieved oocytes were evaluated for meiotic maturation and underwent in vitro fertilization. Granulosa cells were analyzed for differential gene expression. Ovaries were removed in early luteal phase (4 days post midcycle estradiol surge) and analyzed for morphological differences.

Results: The T+WSD group demonstrated significantly decreased luteal P4 levels. We found no differences in cycle length, proportion of ovulatory cycles, day of E2 surge, total E2 synthesis, FSH, LH, or AMH. Analysis of follicular fluid retrieved from animals undergoing an ovarian stimulation protocol revealed increased vascular endothelial growth factor-A (VEGFA), elevated cortisol:cortisone ratio, and increased testosterone and progesterone levels in the treatment group (p<0.05). Granulosa cells from T+WSD demonstrated significantly up- or down-regulated genes relative to controls, including those related to cell differentiation and migration. The ovarian morphology of treatment animals demonstrated enlarged cystic follicles reminiscent of polycystic ovaries.

Conclusion: Similar to prior studies assessing long-term exposure (5-6 years) to T+WSD in female rhesus macaques beginning before menarche, a 1-year T+WSD treatment in adult, regularly cycling females led to reduced luteal-phase progesterone levels and polycystic ovarian morphology. Additionally, short-term T+WSD exposure resulted in altered granulosa cell gene expression. While 1 year of T+WSD exposure leads to altered luteal progesterone, follicular fluid steroid and cytokine content, and granulosa cell gene expression changes, insults of longer duration are required to exert additional negative effects on ovarian function.