Interplay of Cortisol, Testosterone, and Abdominal Fat Mass in Normal-weight Women With Polycystic Ovary Syndrome

Daniel A. Dumesic; Adina F. Turcu; Haiping Liu; Tristan R. Grogan; David H. Abbott; Gwyneth Lu; Devyani Dharanipragada; Gregorio D. Chazenbalk


J Endo Soc. 2023;7(8) 

In This Article

Abstract and Introduction


Context: Ovarian and adrenal steroidogenesis underlie endocrine-metabolic dysfunction in polycystic ovary syndrome (PCOS). Adipocytes express aldo-keto reductase 1C3 and type 1 11β-hydroxysteroid dehydrogenase, which modulate peripheral androgen and cortisol production.

Objectives: To compare serum adrenal steroids, including 11-oxygenated androgens (11-oxyandrogens), cortisol, and cortisone between normal-weight women with PCOS and body mass index- and age-matched ovulatory women with normal-androgenic profiles (controls), and assess whether adrenal steroids associate with abdominal adipose deposition.

Design: Prospective, cross-sectional, cohort study.

Setting: Academic medical center.

Patients: Twenty normal-weight women with PCOS and 20 body mass index-/age-matched controls.

Intervention(s): Blood sampling, IV glucose tolerance testing, and total-body dual-energy x-ray absorptiometry.

Main Outcome Measure(s): Clinical characteristics, hormonal concentrations, and body fat distribution.

Results: Women with PCOS had higher serum total/free testosterone (T) and androstenedione (A4) levels and a greater android/gynoid fat mass than controls (androgens P < .001; android/gynoid fat mass ratio, P = .026). Serum total/free T and A4 levels correlated positively with android/gynoid fat mass ratio in all women combined (P < .025, all values). Serum 11ß-hydroxyA4, 11-ketoA4, 11ß-hydroxyT, 11-ketoT, cortisol, and cortisone levels were comparable between female types and unrelated to body fat distribution. Serum 11-oxyandrogens correlated negatively with % total body fat, but lost significance adjusting for cortisol. Serum cortisol levels, however, correlated inversely with android fat mass (P = .021), with a trend toward reduced serum cortisol to cortisone ratio in women with PCOS vs controls (P = .075), suggesting diminished 11β-hydroxysteroid dehydrogenase activity.

Conclusion: Reduced cortisol may protect against preferential abdominal fat mass in normal-weight PCOS women with normal serum 11-oxyandrogens.


Ovarian and adrenal steroidogenesis are interwoven into the endocrine-metabolic pathophysiology of polycystic ovary syndrome (PCOS).[1–5] Within the adrenal, cytochrome P450 11ß-hydroxylase catalyzes the hydroxylation of androstenedione (A4) and testosterone (T) to 11ß-hydroxyandrostendione (11OHA4) and 11ß-hydroxytestosterone (11OHT), respectively.[4–6] 11β-hydroxysteroid dehydrogenase type 2 then converts 11OHA4 and 11OHT to their respective ketosteroids, 11-ketoandrostendione (11KA4) and 11-ketotestosterone (11KT), with 11KT also originating from reduction of 11KA4 via aldo-keto reductase 1C3 (AKR1C3; also known as 17β-hydroxysteroid dehydrogenase type 5). Although 11OHA4 is quantitatively the dominant 11-oxygenated androgen (11-oxyandrogen), its bioactivity is negligible, but it serves as substrate for 11KT, a potent androgen with bioactivity comparable to that of T.[4–6]

Elevated serum 11OHA4 levels have been reported in one-half of National Institutes of Health (NIH)-defined women with PCOS who are overweight.[1] More recently, serum 11-oxyandrogen levels have been shown to be elevated in 40% of PCOS women by Rotterdam criteria, and to positively correlate with body mass index (BMI), fasting circulating insulin levels, and insulin resistance in some,[7,8] but not all,[9] studies.

We have previously shown that normal-weight hyperandrogenic women with PCOS exhibit low-normal insulin sensitivity and metabolic alterations that accompany preferential abdominal fat accumulation.[10–14] It is unclear, however, whether adrenal steroidogenesis interacts with an elevated androgens pathway in normal-weight women with PCOS to further affect endocrine-metabolic pathophysiology related to altered body fat distribution.[15] It is also unclear whether adipocyte expression of AKR1C3 and types 1 or 2 11βHSD in these women with PCOS modulate peripheral androgen and cortisol activation/inactivation. Therefore, the present study compares serum adrenal steroids, including 11-oxyandrogens, cortisol, and cortisone, between normal-weight women with PCOS and BMI- and age-matched ovulatory women with normal-androgenic profiles (controls), and assesses whether adrenal steroids associate with preferential abdominal adipose accumulation.