Developmental programming: rescuing disruptions in preovulatory follicle growth and steroidogenesis from prenatal testosterone disruption

作者：Veiga Lopez A; Moeller J; Abbott D H; Padmanabhan V^*

来源：Journal of Ovarian Research, 2016, 9(1): 39.

DOI：10.1186/s13048-016-0250-y

• Steroids
• Testosterone
• Androgen antagonist
• Insulin sensitizer

Background: Prenatal testosterone (T) excess from days 30-90 of gestation disrupts gonadotropin surge and ovarian follicular dynamics and induces insulin resistance and functional hyperandrogenism in sheep. T treatment from days 60-90 of gestation produces a milder phenotype, albeit with reduced fecundity. Using this milder phenotype, the aim of this study was to understand the relative postnatal contributions of androgen and insulin in mediating the prenatal T induced disruptions in ovarian follicular dynamics.
Methods: Four experimental groups were generated: 1) control (vehicle treatment), 2) prenatal T-treated (100 mg i.m. administration of T propionate twice weekly from days 60-90 of gestation), 3) prenatal T plus postnatal anti-androgen treated (daily oral dose of 15 mg/kg/day of flutamide beginning at 8 weeks of age) and 4) prenatal T and postnatal insulin sensitizer-treated (daily oral dose of 8 mg/day rosiglitazone beginning at 8 weeks of age). Follicular response to a controlled ovarian stimulation protocol was tested during their third breeding season. Main outcome measures included the determination of number and size of ovarian follicles and intrafollicular concentrations of steroids.
Results: At the end of the controlled ovarian stimulation, the number of follicles approaching ovulatory size (>= 6 mm) were similar to 35 % lower in prenatal T-treated (6.5 +/- 1.8) compared to controls (9.8 +/- 2.0). Postnatal anti-androgen (10.3 +/- 1.9), but not insulin sensitizer (5.0 +/- 0.9), treatment prevented this decrease. Preovulatory sized follicles in the T group had lower intrafollicular T, androstenedione, and progesterone compared to that of the control group. Intrafollicular steroid disruption was partially reversed solely by postnatal insulin sensitizer treatment.
Conclusions: These results demonstrate that the final preovulatory follicular growth and intrafollicular steroid milieu is impaired in prenatal T-treated females. The findings are consistent with the lower fertility rate reported earlier in these females. The finding that final follicle growth was fully rescued by postnatal anti-androgen treatment and intrafollicular steroid milieu partially by insulin sensitizer treatment suggest that both androgenic and insulin pathway disruptions contribute to the compromised follicular phenotype of prenatal T-treated females.

• 出版日期2016-6-29