Biological Sex Modifies Aldosterone Secretion at a Cellular Level

3D Rendering of the Adrenal Gland

Aldosterone levels are known to differ by sex in humans and rodents. Usually, the levels are reported to be higher in females than males, but the results haven’t been consistent.

Researchers at Brigham and Women’s Hospital previously discovered production of aldosterone can be modified acutely by the level of aldosterone itself and/or the activity of the mineralocorticoid receptor (MR). However, only male rodents were included in that study, which was reported in the Journal of Endocrinology. Whether biological sex affects that novel, ultrashort negative feedback loop was unknown.

Now, expanding on their earlier work, the researchers have found sex differences in the regulatory factors that control aldosterone secretion, although not in the feedback loop. Gordon H. Williams, MD, senior physician in the Division of Endocrinology, Diabetes and Hypertension at the Brigham, Shadi K. Gholami, PhD, research fellow in the division, and colleagues report their new findings in the Journal of Endocrinology.


In male and female Wistar rats fed a low-salt diet, the researchers evaluated the effect of biologic sex on the early and late pathways of aldosterone synthesis:

  • Early pathway: Aldosterone synthesis begins in the zona glomerulosa cells in the adrenal cortex’s outermost layer. The StAR protein facilitates the transfer of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane, where the cholesterol side-chain cleavage enzyme (CYP11A1) is located
  • Late pathway: Aldosterone synthesis occurs via a series of enzymatic activities, including (a) conversion of cholesterol to pregnenolone by CYP11A1, and (b) conversion of deoxycorticosterone and/or corticosterone to aldosterone by the aldosterone synthase enzyme (CYP11B2)

Early Pathway

The researchers determined:

  • mRNA expression levels of the StAR and CYP11A1 genes was significantly higher in female than male rats
  • Basal pregnenolone levels, an indicator of the activity of the two genes, were significantly greater in females than males
  • Pregnenolone levels remained significantly higher in females in response to angiotensin II and after pharmacological interruption of aldosterone synthesis

Late Pathway

The researchers also observed:

  • mRNA expression level of the CYP11B2 gene was equivalent in females and males
  • Basal aldosterone as a biomarker of functional activities of the late pathway was significantly lower in females than males, but after angiotensin II stimulation, the levels were significantly higher in females
  • Females and males did not differ in mineralocorticoid receptor (MR) expression or the activity of the ultrashort feedback loop (assessed by measuring the aldosterone/corticosterone ratio)

Clinical Relevance

These findings suggest the clinical manifestations of aldosterone-mediated diseases may differ by sex. Understanding differences in sex-related control of aldosterone should make it possible to treat those diseases more appropriately and specifically in both men and women.

Documentation of the ultrashort feedback loop reveals that dysregulation of the aldosterone/MR pathway can result in excess mineralocorticoid effects without increased aldosterone levels. That knowledge may lead to new targeted therapeutic and diagnostic approaches.