Developmental Programming: Deficits in Reproductive Hormone Dynamics and Ovulatory Outcomes in Prenatal, Testosterone-Treated Sheep1

Abstract

Prenatal testosterone excess leads to neuroendocrine, ovarian, and metabolic disruptions, culminating in reproductive phenotypes mimicking that of women with polycystic ovary syndrome (PCOS). The objective of this study was to determine the consequences of prenatal testosterone treatment on periovulatory hormonal dynamics and ovulatory outcomes. To generate prenatal testosterone-treated females, pregnant sheep were injected intramuscularly (days 30-90 of gestation, term=147 days) with 100 mg of testosterone-propionate in cottonseed oil semi-weekly. Female offspring born to untreated control females and prenatal testosterone-treated females were then studied during their first two breeding seasons. Sheep were given two injections of prostaglandin F2alpha 11 days apart, and blood samples were collected at 2-h intervals for 120 h, 10-min intervals for 8 h during the luteal phase (first breeding season only), and daily for an additional 15 days to characterize changes in reproductive hormonal dynamics. During the first breeding season, prenatal testosterone-treated females manifested disruptions in the timing and magnitude of primary gonadotropin surges, luteal defects, and reduced responsiveness to progesterone negative feedback. Disruptions in the periovulatory sequence of events during the second breeding season included: 1) delayed but increased preovulatory estradiol rise, 2) delayed and severely reduced primary gonadotropin surge in prenatal testosterone-treated females having an LH surge, 3) tendency for an amplified secondary FSH surge and a shift in the relative balance of FSH regulatory proteins, and 4) luteal responses that ranged from normal to anovulatory. These outcomes are likely to be of relevance to developmental origin of infertility disorders and suggest that differences in fetal exposure or fetal susceptibility to testosterone may account for the variability in reproductive phenotypes.

Sex differences in developmental programming models

“…It is unclear whether exposure to sex steroids may have similar adverse effects. Evidence from human populations suggests that the prevalence of insulin insensitivity and polycystic ovarian syndrome is higher in the presence of excess androgen hormones (Veiga-Lopez et al 2008, Moulana et al 2011, and it has been suggested that exposure to excess androgen in childhood influences the development of the metabolic syndrome and polycystic ovarian syndrome (Idkowiak et al 2011). In adult humans, male subjects show an increased propensity to at least some aspects of the metabolic syndrome compared with females, possibly as a primary effect of ambient sex steroid levels (Regitz-Zagrosek et al 2006).…”

Developmental Programming: Postnatal Estradiol Amplifies Ovarian Follicular Defects Induced by Fetal Exposure to Excess Testosterone and Dihydrotestosterone in Sheep

“…It is not uncommon to find subluteal cycles in prenatal T females. 14 Considering that luteinization process is triggered by LH, 50 subluteal cycles are likely the result of the dampened LH surges observed in prenatal T-treated females.…”

“…12 For instance, in the prenatal T-treated sheep, the severity of the reproductive defects is enhanced by postnatal overfeeding. 13 The progressive loss of cyclicity that occurs in prenatal T-treated sheep may also be the consequence of postnatal endocrine changes (''second hit''), namely, increased exposure to continuous high E levels 14 or reduced exposure to progesterone due to oligo-or anovulation (P 4 ). 7,14 Similarly, the shift in the rate of follicular depletion observed after puberty in prenatal T-treated sheep, by the slowing of depletion rate and stockpiling of growing follicles, 5 may relate to the altered steroid milieu.…”

Accelerated Episodic Luteinizing Hormone Release Accompanies Blunted Progesterone Regulation in PCOS-like Female Rhesus Monkeys (Macaca Mulatta) Exposed to Testosterone during Early-to-Mid Gestation

“…Numerous studies have since demonstrated fetal T or dihydrotestosterone (DHT) programming of LH hypersecretion as a consequence of elevated episodic release of GnRH/LH in PA adult female sheep [37][38][39], rats [40,41], and mice [42,43]. Such elevated LH is associated with insensitivity to estradiol-or progesterone-mediated negative feedback [37,[43][44][45], likely mediated within the hypothalamus [46,47]. Such neural origins for LH excess, and diminished LH sensitivity to estradiol/progesterone-mediated negative feedback, however, have yet to be demonstrated in PCOS-like, female nonhuman primates.…”