Sexual Dimorphism in Testosterone Programming of Cardiomyocyte Development in Sheep

Perturbed in-utero hormone milieu leads to intrauterine growth retardation (IUGR), a known risk factor for left ventricular (LV) dysfunction later in life. Gestational testosterone (T) excess predisposes offspring to IUGR and leads to LV myocardial disarray and hypertension in adult females. However, the early impact of T excess on LV programming and if it is female-specific is unknown. LV tissues were obtained at day 90 gestation from days 30-90 T-treated or control fetuses (n=6/group/sex) and morphometric and molecular analyses were conducted. Gestational T treatment increased cardiomyocyte number only in female fetuses. T excess up-regulated receptor expression of insulin and insulin-like growth factor. Furthermore, in a sex-specific manner, T increased expression of Phosphatidylinositol 3-kinase (PI3K) while down regulating phosphorylated mammalian target of rapamycin (pmTOR) /mTOR ratio suggestive of compensatory response. T excess 1) upregulated atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), markers of stress and cardiac hypertrophy 2) upregulated estrogen receptors1 (ESR1) and 2 (ESR2) but not in androgen receptor (AR). Thus, gestational T excess upregulated markers of cardiac stress and hypertrophy in both sexes while inducing cardiomyocyte hyperplasia only in females, likely mediated via insulin and estrogenic programming.