Endocrine Abstracts

JOINT1612

Background: Exogenous androgenic steroid applied to pregnant sheep, or directly to developing sheep fetuses, programmes a PCOS-like metabolic phenotype in female offspring. We hypothesised that such androgen excess during development would alter postnatal adrenal steroidogenic capacity.

Methods: Using both indirect androgenic overexposure (Prenatal androgen excess; PA) (maternal testosterone propionate treatment (100 mg twice weekly) from day (d)62 to d102 of gestation; maternal injection – M-PA) and direct fetal androgen treatment (from d62, F-PA), we examined postnatal female adrenal gland function. A subset of animals directly treated during fetal life with estrogen receptor agonist DES (F-DES), or synthetic glucocorticoid dexamethasone (F-DEX) were studied to examine specificity of androgenic effects observed. Adrenal function testing, and qPCR measurement of adrenal steroidogenic genes were the outcome measurements.

Results: During fetal life, in terms of a panel of steroidogenic and related genes examined in the adrenal cortex, we observed some sexual dimorphism, but there was no evidence of prenatal androgen excess causing masculinisation of the developing female adrenal. Prior to puberty, (11 weeks postnatal age), we observed no functional alterations in terms of either cortisol or testosterone secretion in response to synthetic (Synacthen) ACTH stimulation. However, in post-pubertal female offspring (11 months old) from both M-PA and F-PA models, we observed increased expression of StAR, HSD3B1 and HSD17B mRNA in animals exposed to excess androgens during fetal life (P <0.05 – 0.001 compared to vehicle treatment). These post-pubertal adrenal gene expression changes were accompanied by a markedly exaggerated testosterone secretory response to ACTH stimulation in M-PA and F-PA animals as compared to vehicle controls (P <0.05), in the absence of any alterations in cortisol secretion. This effect was specific to prenatal androgen excess alone.

Conclusion: We conclude that the postnatal, post pubertal adrenal gland develops a hyperandrogenic phenotype as a consequence of prenatal androgen excess. The adrenal cortex may be a secondary source of increased androgens found in PCOS due to excess androgen exposure during development.