SAT-LB062 Adrenal Sexual Dimorphism Is Abolished by Tissue-Targeted Deletion of the Androgen Receptor

Introduction: Sex differences in mouse and human tissues can affect cancer risks, cardiovascular, kidney and liver diseases. Mouse adrenals have several sexually dimorphic traits, but their role in physiology remain poorly understood. Differences include larger adrenals in females and earlier regression of the X-zone (the mouse fetal adrenal) in males. The X-zone regresses at puberty in males and at pregnancy in females. There are also clear sex-differences in expression of adrenal mRNA and proteins. These include higher female levels of Dax-1 (Nr0b1), a nuclear receptor critically involved in adrenal development/steroidogenesis, whereas male adrenals exhibit higher levels of the androgen-metabolizing enzyme, 5α-reductase (Srd5a2). Determining the factors that drive adrenal sexual dimorphism may provide insight into the potential impact of these differences on adrenal physiology. One potential regulator of adrenal sexual dimorphism is exposure to sex steroids, particularly androgens and estrogens. Herein, we test the hypothesis that androgens, through the adrenal androgen receptor (AR), are responsible for sexually dimorphic traits of mouse adrenal glands. This hypothesis was tested through specific disruption of adrenal cortex Ar expression. Methods: Adrenal targeted deletion of Ar was accomplished in male mice by crossing heterozygous aldosterone synthase-Cre mice to floxed Ar mice (mAdARKO). Mice were sacrificed at 25 weeks of age and comparisons were made to wild type male (mWT) and female (fWT) litter mates. Adrenals were weighed, processed for histology (H&E), immunofluorescence (IF) for AR, and whole adrenal mRNA levels analyzed using quantitative RTPCR. Results: mAdARKO mice decreased adrenal Ar mRNA by 90% compared to mWT mice (p < 0.01) and AR protein was undetectable in the adrenal cortex using IF. mAdARKO adrenals were larger than adrenals of mWT mice (1.6-fold increase in weight, p < 0.01) but comparable to that of fWT animals. Nr0b1 transcripts in mAdARKO mice increased by 8-fold compared to mWT (p < 0.01) and were not significantly different from fWT adrenals. Adrenal Sdr5a2 expression was significantly downregulated in mAdARKO (0.16-fold compared to mWT; p < 0.01) and analogous to the levels seen in fWT mice. Histological analysis revealed the retention of an X-zone in post-pubertal mAdARKO which was not present in age-matched mWT animals. Moreover, mRNA for the X-zone marker, 20α-HSD (Akr1c18), increased by 140,000-fold (p < 0.01) in mAdARKO adrenals compared to mWT, and was 20 times that seen in fWT mice. Conclusion: The current study suggests that deleting adrenal Ar is sufficient to cause male adrenal phenotypic sex-reversal including retention of the X-zone. Finally, adrenal sexual dimorphism highlights the necessity to include both sexes in mouse adrenal studies and the mAdARKO model provides a novel model to determine the impact of sex on adrenal biology. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.