Developmental Programming: Role of Androgen and Insulin in Advancing Placentome Differentiation in Testosterone-Treated Sheep.

Abstract

Testosterone (T) administration from gestational days (d) 30-90 induces intra-uterine growth retardation (IUGR), low birth weight, and adult reproductive and metabolic dysfunctions. IUGR was evident in d140 T fetuses, but not in d65 or d90 fetuses. Advanced placental differentiation in T females, which was reflected as an increase in proportion of type C placentomes and their weights during d65 and d90 of gestation, may have overcome IUGR at these fetal ages. Gestational treatment with dihydrotestosterone (DHT), a non-aromatizable androgenic metabolite of T, elicited similar effects at the placental level, suggesting that advanced placental differentiation may be mediated through androgenic programming. Confirmation that DHT effects are mediated by androgenic programming and not estrogenic programming (DHT can be converted to 3β-diol and act via estrogen receptor 2) would require documentation that progression of placental differentiation can be prevented by negating androgen action. Since gestational diabetes and type 1 diabetes induce histological/gross morphological changes in human placenta, it is conceivable that placental effects of T are mediated via changes in insulin sensitivity. We hypothesized that gestational T excess advances placental differentiation via its androgenic action by altering insulin sensitivity. Pregnant Suffolk sheep were administered 1) T propionate (100 mg, twice weekly, i.m.), 2) T plus flutamide, an androgen antagonist (TF; 15 mg/kg/day oral), 3) T plus rosiglitazone, an insulin sensitizer (TR, 8 mg/day oral), or 4) vehicle (n=6-18/group) beginning d30 of gestation. Distribution and weights of placentome types (type A, B, C, D) and placentome efficiency (ratio of fetal to placental weight) were determined. There were no differences in number or weight of placentomes across treatments, although considerable differences existed in the distribution and weights of placentome types. Number and weight of type B placentomes were lower in T animals compared to controls (control vs. T; number: 44 ± 10.6 vs. 12.7 ± 7.6, p<0.05; weight: 333.8 ± 80.6 g vs. 96.9 ± 45.2 g, p<0.05). In contrast, number and weight of type C placentomes were higher in T animals compared to controls (control vs. T; number: 2.2 ± 0.9 vs. 31.8 ± 9.8, p<0.001; weight: 30.1 ± 14.4 g vs. 217.7 ± 70.3 g, p<0.01). There were no differences in type A or D placentomes between control and T groups. Androgen antagonist co-treatment reversed the effects of T on types B and C placentome number and weight. In contrast, co-treatment with insulin sensitizer did not reverse T effects. Paradoxically, number and weight of type D placentomes were higher in TR females compared to controls (control vs. TR; number: 12.3 ± 7.5 vs. 61 ± 18.6, p<0.05; weight: 192 ± 109.4 g vs. 957.5 ± 361.6 g, p<0.05). Placentome efficiency was similar across groups. These findings provide unequivocal evidence that advanced placental differentiation indeed stems from androgenic programming and that this is not mediated via compromised insulin sensitivity. On the contrary, advancement of placental distribution in the TR group suggests an optimal range of insulin sensitivity requirements. Similar placental efficiency across treatment groups is suggestive that advancement in placental differentiation is able to compensate for IUGR at fetal day 90. Supported by NIH P01 HD44232. (poster)