Developmental Programming: Prenatal and Postnatal Contribution of Androgens and Insulin in the Reprogramming of Estradiol Positive Feedback Disruptions in Prenatal Testosterone-Treated Sheep

Abstract

Prenatal testosterone (T) excess compromises the estradiol (E(2)) positive feedback. This study tested the hypothesis that antagonizing androgen action or improving insulin sensitivity prenatally would prevent positive feedback disruptions from developing, whereas postnatal intervention with androgen antagonist or insulin sensitizer would ameliorate the severity of disruptions in prenatal T-treated females. The E(2) positive feedback response was tested at 16 wk of age in the following groups of animals: 1) control, 2) prenatal T, 3) prenatal T plus the androgen antagonist, flutamide, 4) prenatal T plus insulin sensitizer, rosiglitazone, 5) prenatal T and postnatal androgen antagonist, and 6) prenatal T and postnatal insulin sensitizer (n = 7-21 animals/group). Prenatal T treatment involved the administration of T propionate (100 mg, im) twice weekly from d 30 to 90 of gestation. Prenatal interventions involved daily sc administration of androgen antagonist (15 mg/kg) or oral administration of insulin sensitizer (8 mg) for the same duration. Postnatal treatments began at 8 wk of age and involved daily oral administration of androgen antagonist (15 mg/kg) or insulin sensitizer (0.11 mg/kg). None of the prenatal/postnatal interventions increased number of animals responding or prevented the time delay in LH surge response to the E(2) positive feedback challenge. In contrast, the postnatal treatment with androgen antagonist or insulin sensitizer increased total LH released in response to E(2) positive feedback challenge, compared with the T animals. Overall, these interventional studies indicate that timing and magnitude of the LH surge are programmed by different neuroendocrine mechanisms with postnatal androgens and insulin determining the size and prenatal estrogen likely the timing of the LH surge.

Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions

“…On the other hand, disruptions in E 2 positive feedback were found in T- but not DHT-treated females suggesting that this defect is likely programmed via estrogenic actions of prenatal T [17, 45]. The observation that co-treatment with prenatal T and androgen antagonist failed to reverse the defects in E 2 positive feedback is supportive of this premise [51]. …”

“…At the positive feedback level, postnatal treatment with androgen antagonist or insulin sensitizer has been shown to partially improve the neuroendocrine response, increasing the magnitude but failing to prevent the delay in LH surge response to the E 2 positive feedback challenge [51]. These results indicate that timing and magnitude of the LH surge are programmed by different neuroendocrine mechanisms with postnatal androgens and insulin determining the magnitude and estrogens likely the timing of the LH surge.…”

Impact of psychosocial stress on gonadotrophins and sexual behaviour in females: role for cortisol?

“…Using a sheep model of neuroendocrine defects resulting from prenatal exposure to excess testosterone (Salloum et al 2012), Cheng et al (2010 showed that impaired E2-positive feedback, evidenced by delayed LH surge, and decreased progesterone-negative feedback, evidenced by increased pulse frequency, were correlated with a decrease in NKB and dynorphin, but not kisspeptin, in KNDy cells. In addition, exposure to prenatal testosterone resulted in decreased NK3R co-localization in KNDy cells (Ahn et al 2015).…”

Reproductive neuroendocrine dysfunction in polycystic ovary syndrome: Insight from animal models

“…In any case, it remains of interest what role these early metabolic perturbations play in potentially reprogramming the reproductive axis. A recent study found no effect of prenatal treatment with the insulin sensitizer rosiglitazone on PNA-induced disruptions in estradiol negative and positive feedback (Abi Salloum et al, 2012); however, GnRH/LH pulsatility in intact animals and other aspects of neuroendocrine function remain to be studied following this and similar prenatal interventions.…”