Chronically elevated androgen with or without a western-style diet reduces the pregnancy rate and early placental vascularization in young adult rhesus monkeys

Abstract

To determine if chronic hyperandrogenemia and/or consumption of a western-style diet (WSD) beginning near menarche suppresses pregnancy rate or early placentation in young adults. 2 by 2 factorial cohort Silastic implants containing either cholesterol (control C, n=20) or T (serum T levels ∼1.5 ng/ml; n=20) were placed sc in rhesus macaque females nearing menarche. These females were randomized to consume either a standard chow diet, or a WSD in a 2 x 2 factorial experimental design (n=9-10/group). After 3.5 years of treatment (∼6 years old), individuals were paired with a fertile male at the mid-cycle rise in serum E2 in a time-mated breeding (TMB) program [1]. Serum P4 was monitored post-TMB until levels either: a) declined below 0.5 ng/ml with concurrent menses, i.e., pregnancy did not occur, or b) remained elevated. Pregnancies were confirmed by Doppler ultrasound (DUS) on gestational day (GD) 30-36, and placental blood volume (BV) determined by contrast-enhanced US [1]. Pregnancy rates and number of TMB to pregnancy were analyzed by Generalized Linear Model function (chi-squared values), and placental BV was analyzed by Mixed Models function of SAS. Thirty-eight monkeys fulfilled the criteria for mating; 1 WSD-treated female was acyclic and did not display a rise in serum E2 levels. Similar numbers of the control (C, 7/10; 70%) and WSD (7/10; 70%) females became pregnant, whereas fewer T (4/10; 40%) and T+WSD (3/9; 33%) females achieved pregnancy (effect of steroid P<0.05) at first pairing. Also, 2 of 3 pregnancies in the T+WSD group were atypical: 1 anembryonic pregnancy miscarried by GD58-59, and 1 twin pregnancy was delivered early at GD105 due to pregnancy complications. Additional TMB (up to 3x) resulted in 100% of C, 70% of WSD, 100% of T and 69% of T+WSD females conceiving (diet P<0.004), however T-treated females required more TMB to achieve pregnancy than C or WSD groups (steroid P<0.02). At GD30-36, the BV of placentas in T, WSD and T+WSD females was reduced 1.6 (T), 2.1 (WSD), and 1.8 (T+WSD)-fold compared to controls (P<0.05). Exposure to chronically elevated androgen significantly reduced pregnancy success in young adult females at first mating with fertile male monkeys, and delayed time to pregnancy. Based on our previous studies, the subfertility could be due to: a) ovulation of immature or degenerated oocytes, or b) abnormal expression of endometrial decidualization and implantation markers detected at mid-secretory phase of the menstrual cycle in T and T+WSD treated animals. Reduced placental BV during the first trimester in T, WSD and T+WSD-treated females, may impair fetal-placental health as gestation progresses, which is currently under investigation. These data may provide insight into the etiology of subfertility in women experiencing hyperandrogenemia despite continued ovarian cyclicity.