Sexual dimorphism in testosterone programming of cardiomyocyte development in sheep

Am J Physiol Heart Circ Physiol. 2022 Apr 1;322(4):H607-H621. doi: 10.1152/ajpheart.00691.2021. Epub 2022 Feb 4.


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 upregulated receptor expression of insulin and insulin-like growth factor. Furthermore, in a sex-specific manner, T increased expression of phosphatidylinositol 3-kinase (PI3K) while downregulating phosphorylated mammalian target of rapamycin (pmTOR)-to-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 and 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.NEW & NOTEWORTHY The present study demonstrates sex-specific effects of gestational T excess between days 30 and 90 of gestation on the cardiac phenotype. Furthermore, the sex-specific programming is likely secondary to perturbation in both estrogen and insulin signaling pathways collectively. These findings are supportive of the role of androgen excess to serve as early biomarkers of CVD and could be critical in identifying therapeutic targets for LV hypertrophy and predict long-term CVD.

Keywords: DOHAD; cardiovascular disease; hyperplasia; insulin signaling; left ventricle; testosterone.

MeSH terms

  • Animals
  • Atrial Natriuretic Factor / genetics
  • Female
  • Insulin / metabolism
  • Male
  • Mammals / metabolism
  • Myocytes, Cardiac / metabolism
  • Natriuretic Peptide, Brain / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Sex Characteristics*
  • Sheep
  • Testosterone* / metabolism


  • Insulin
  • Natriuretic Peptide, Brain
  • Testosterone
  • Atrial Natriuretic Factor

Associated data

  • figshare/10.6084/m9.figshare.19287437