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

Abstract

Excess of prenatal testosterone (T) induces reproductive defects including follicular persistence. Comparative studies with T and dihydrotestosterone (DHT) have suggested that follicular persistence is programmed via estrogenic actions of T. This study addresses the androgenic and estrogenic contributions in programming follicular persistence. Because humans are exposed to estrogenic environmental steroids from various sources throughout their life span and postnatal insults may also induce organizational and/or activational changes, we tested whether continuous postnatal exposure to estradiol (E) will amplify effects of prenatal steroids on ovarian function. Pregnant sheep were treated with T, DHT, E, or ED (E and DHT) from days 30 to 90 of gestation. Postnatally, a subset of the vehicle (C), T, and DHT females received an E implant. Transrectal ultrasonography was performed in the first breeding season during a synchronized cycle to monitor ovarian follicular dynamics. As expected, number of !8 mm follicles was higher in the T versus C group. Postnatal E reduced the number of 4 to 8 mm follicles in the DHT group. Percentage of females bearing luteinized follicles and the number of luteinized follicles differed among prenatal groups. Postnatal E increased the incidence of subluteal cycles in the prenatal T-treated females. Findings from this study confirm previous findings of divergences in programming effects of prenatal androgens and estrogens. They also indicate that some aspects of follicular dynamics are subject to postnatal modulation as well as support the existence of an extended organizational period or the need for a second insult to uncover the previously programmed event.

Developmental programming: postnatal estradiol modulation of prenatally organized reproductive neuroendocrine function in sheep

“…There were insufficient animals to generate postnatal treatment groups from prenatal E and ED-treated animals. Changes in ovarian follicular dynamics in this cohort of animals have been reported previously (Veiga-Lopez et al 2014). …”

“…For example, postnatal overfeeding (second hit) of prenatally T-treated (first hit) sheep exacerbated the reproductive cyclicity defects, with a majority of animals ending their breeding season early (Steckler et al 2009). Similarly, postnatal exposure to E (second hit) amplified the ovarian defects induced by prenatal T excess (first hit) (Veiga-Lopez et al 2014). …”

Developmental programming: Prenatal BPA treatment disrupts timing of LH surge and ovarian follicular wave dynamics in adult sheep

“…Lack of disruption in corpora lutea of prenatal BPA -treated sheep contrasts with findings observed in sheep prenatally treated with testosterone and thought to be programmed via estrogenic actions (Steckler et al, 2007, Veiga-Lopez et al, 2014). Similarly, follicular persistence (longer than normal presence of follicles in the ovary) evidenced in prenatal testosterone -treated females shown to be programmed via estrogenic actions of testosterone (Steckler et al, 2007), was not a feature of prenatal BPA-treated females.…”

“…Ultrasonography was carried out using a scanner (Aloka SSD-900V, Aloka Co. Ltd., Wallington, CT) fitted to a 7.5 MHz linear array transducer adapted for transrectal examinations. Details of ultrasound scanning have been previously described (Veiga-Lopez et al, 2014). In brief, sheep were placed in dorsal recumbence and the probe inserted in the rectum with the transducer orientated perpendicularly to the abdomen wall to locate both ovaries.…”

Effect of maternal PCOS and PCOS-like phenotype on the offspring's health

“…Postnatal exposure to estradiol has been shown to amplify the luteal defects induced by prenatal exposure to testosterone excess in sheep (Veiga-Lopez et al, 2014), however, the impact of increased postnatal androgen action on ovarian function remains to be determined. Findings that prenatal testosterone treated sheep show progressive decline in cyclicity (Birch et al, 2003, Manikkam et al, 2006) may indicate that an imbalance in the peripubertal steroid milieu may serve as a “second hit” leading to gradual deterioration in ovarian function.…”