Pioglitazone improves insulin action and normalizes menstrual cycles in a majority of prenatally androgenized female rhesus monkeys

Abstract

Purpose of the study: To determine whether pioglitazone will improve menstrual cyclicity in a fetal programming model for polycystic ovary syndrome.

Basic procedures: Eight prenatally androgenized (PA) and 5 control female rhesus monkeys of similar age, body weight and body mass index received an oral placebo daily for 6-7 months followed, after at least 90 days, by daily oral dosing with pioglitazone (3mg/kg) for an additional 6-7 months. Blood was sampled thrice weekly to monitor ovulatory function, and a variety of endocrine challenges were performed to quantify changes in ovarian, gonadotropin and glucoregulatory function.

Most important findings: Pioglitazone normalized menstrual cycles in 5 out of 8 (62%) PA females (pioglitazone responsive; Pio(RESP)). Pioglitazone increased serum 17alpha-hydroxyprogesterone responses to an hCG injection in Pio(RESP) PA females, while diminishing serum progesterone, and increasing DHEA and estradiol responses to hCG in Pio(RESP) PA and all normal females.

Principal conclusions: Insulin resistance plays a mechanistic role in maintaining anovulation in a majority of PA female monkeys.

Figure 1

Serum steroid levels in PA (placebo phase: solid bars, pioglitazone treated phase: dotted bars) and control (placebo phase: open bars, pioglitazone treated phase: dashed bars) adult female rhesus monkeys following 200 IU recombinant hCG i.m. at 0h (backtransformed means and upper 95% confidence limits). Progesterone, A: p<0.05 vs placebo, a: p<0.05 vs 0h (control and PA combined), b:p<0.05 vs 48h (control and PA combined), c: p<0.05 vs 24h or 48h (control and PA combined); 17αOHP, A: p<0.01 pioglitazone vs placebo (PA only, all time point combined), a: p<0.05 vs 0h, b: p<0.05 vs 24h; DHEA, A: p<0.003 vs placebo (control and PA all time points combined); Androstenedione, A: p<0.07 vs control female monkeys (all treatment and all time points combined), a: p<0.05 vs 0h (all females all treatment phase combined); Testosterone, a: p<0.05 vs 0h (all females and all treatment phases); Estradiol, A: p<0.001 vs placebo (control and PA female monkeys combined), a: p<0.05 vs 0h (all female monkeys all treatment phases combined).

Figure 2

The ratios of hormones from the hCG test in PA (placebo phase: solid bars, pioglitazone treated phase: dotted bars) and control (placebo phase: open bars, pioglitazone treated phase: dashed bars; backtransformed means and upper 95% confidence limits). Androstenedione/DHEA, A: p<0.01 vs placebo (control and PA females combined); a: p<0.0004 vs 0 min; b: p<0.01 vs 24h (all treatments and females combined). Estradiol/Testosterone, A: p<0.001 vs placebo (all females and all timepoints combined); a: p<0.006 vs 0h; b: p<0.004 vs 24 h. Progesterone/Estradiol, A: p<0.0009 vs placebo (all females and all timepoints combined); a: p<0.001 vs 0h; b: p<0.02 vs 24h; c: p<0.005 vs 48h.

Figure 3

Serum LH:FSH ratio in PA (placebo phase: solid circle, pioglitazone treated phase: solid square) and control (placebo phase: open circle, pioglitazone treated phase: open square) adult female rhesus monkeys following 20µg GnRH i.v. at 0 min (backtransformed means and 95% confidence limits). * : p<0.03, PA versus controls (all times and treatments combined). In addition, pioglitazone values are increased (p<0.05) versus placebo (both female groups and all times combined).