Developmental programming: gestational testosterone excess disrupts LH secretion in the female sheep fetus

Prenatal testosterone (T) excess

These findings demonstrate that prenatal T-treatment results in reduced fetal LH secretion, reduced fetal pituitary weight, and altered protein levels of several regulators of gonadotropin secretion. The observations that flutamide co-treatment prevented these changes suggest that programming during fetal development likely occurs via direct androgen actions.

Pregnant sheep were treated from gestational day (GD) 30 to 90 with either: 1) vehicle (control); 2) T-propionate (~ 1.2 mg/kg); 3) T-propionate and flutamide (15 mg/kg/day); and 4) T-propionate and rosiglitazone (8 mg/day). At GD 90, LH concentrations were determined in the uterine artery (maternal) and umbilical artery (fetal), and female fetuses were euthanized. Pituitary glands were collected, weighed, and protein level of several key regulators of LH secretion was determined.

Fetal pituitary weight was significantly reduced by prenatal T-treatment. Flutamide completely prevented the reduction in pituitary weight, while rosiglitazone only partially prevented this reduction. Prenatal T markedly reduced fetal LH concentrations and flutamide co-treatment partially restored LH to control levels. Prenatal T resulted in a marked reduction in LH-β protein level, which was associated with a reduction in GnRH receptor and estrogen receptor-α levels and an increase in androgen receptor. With the exception of androgen receptor, flutamide co-treatment completely prevented these alterations in the fetal pituitary, while rosiglitazone largely failed to prevent these changes. Prenatal T-treatment did not alter the protein levels of insulin receptor-β and activation (phosphorylation) of the insulin signaling pathways. Conclusions: These findings demonstrate that prenatal T-treatment results in reduced fetal LH secretion, reduced fetal pituitary weight, and altered protein levels of several regulators of gonadotropin secretion. The observations that flutamide co-treatment prevented these changes suggest that programming during fetal development likely occurs via direct androgen actions.