Developmental programing: impact of testosterone on placental differentiation.

Area of Science:

• Reproductive Endocrinology
• Developmental Biology
• Metabolic Physiology

Background:

• Gestational testosterone excess is linked to maternal hyperinsulinemia, intrauterine growth retardation (IUGR), low birth weight, and adult metabolic/reproductive issues.
• Placental insufficiency is a known cause of IUGR in sheep models.
• Testosterone's impact on placental differentiation and fetal growth warrants investigation regarding its androgenic and insulin-related mechanisms.

Purpose of the Study:

• To investigate whether excess gestational testosterone affects placental differentiation through androgenic action or altered insulin sensitivity.
• To determine if testosterone's effects on placental development are mediated by its androgenic properties or metabolic changes.
• To assess the role of insulin sensitivity in testosterone-induced placental changes and subsequent fetal growth.

Main Methods:

• Comparative study using gestational testosterone, dihydrotestosterone (non-aromatizable androgen), or testosterone with an androgen antagonist (flutamide) in sheep.
• Investigated the effect of co-treating with testosterone and an insulin sensitizer (rosiglitazone).
• Monitored placental development at specific gestational days (65, 90, 140) and recorded offspring birth weights.

Main Results:

• Gestational testosterone treatment accelerated placental differentiation from day 65, resulting in low birth weight.
• Placental advancement was significantly influenced by testosterone's androgenic actions, independent of disrupted insulin homeostasis.
• Despite enhanced placental efficiency, the advancement was insufficient to prevent intrauterine growth retardation and low birth weight in female offspring.

Conclusions:

• Gestational testosterone excess advances placental differentiation via androgenic mechanisms, contributing to intrauterine growth retardation and low birth weight.
• Altered insulin sensitivity does not appear to be the primary driver of testosterone-induced placental changes.
• These findings offer insights into the developmental origins of health and disease, potentially relevant to polycystic ovary syndrome phenotypes.