Increased clearance of cortisol by 5beta-reductase in a subgroup of women with adrenal hyperandrogenism in polycystic ovary syndrome

Abstract

Objective: Increased peripheral metabolism of cortisol may explain compensatory ACTH-dependent adrenal steroidogenesis and hence hyperandrogenism in polycystic ovary syndrome (PCOS). Previous studies have described an increased 5alpha-reduction of cortisol or impaired regeneration of cortisol by 11beta-HSD1 in PCOS. However, these observations may be confounded by obesity. Moreover, the relationship between alterations in cortisol metabolism and the extent of adrenal androgen hyper-secretion in response to ACTH has not been established. This study aimed to examine the association between cortisol metabolism and ACTH-dependent adrenal hyperandrogenism in PCOS, independently of obesity.

Design: We compared 90 PCOS women (age 18-45 yr) stratified by adrenal androgen responses to ACTH1-24 and 45 controls matched for age and body weight.

Methods: PCOS women were stratified as normal responders (NR), intermediate responders (IR), and high responders (HR) to 250 microg ACTH1-24: NR (no.=27) had androstenedione and DHEA responses within 2 SD of the mean in controls; IR (no.=43) had DHEA responses >2 SD above controls; HR (no.=20) had both androstenedione and DHEA responses >2 SD above controls.

Results: All groups were similar for age, body weight, and body fat distribution. Basal testosterone, androstenedione, and 5alpha-dihydrotestosterone plasma levels were similarly elevated among the 3 groups of PCOS compared with controls, whereas basal DHEA-S was higher in HR (2.8+/-1.2 microg/ml) and IR (2.4+/-1.1 microg/ml) than in NR (1.8+/-0.8 microg/ml) and controls (1.7+/-0.6 microg/ml). The HR group had the lowest basal plasma cortisol levels (101+/-36 ng/ml vs IR 135+/-42 ng/ml, NR 144+/-48 ng/ml, and controls 165+/-48 ng/ml; all p<0.01), but the greatest cortisol response to ACTH1-24 (Delta(60-0)cortisol 173+/-60 ng/ml vs IR 136+/-51 ng/ml, NR 114+/-50 ng/ml, and controls 127+/-50 ng/ml; all p<0.01), and the highest urinary excretion of total and 5beta-reduced cortisol metabolites (eg 5beta-tetrahydrocortisol/ cortisol ratio 25.2+/-15.3 vs IR 18.8+/-10.7, NR 19.7+/-11.4, and controls 17.2+/-13.7; all p<0.05). There were no differences in urinary excretion of 5alpha-reduced cortisol metabolites or in 5alpha-dihydrotestosterone/testosterone ratio between groups.

Conclusions: Adrenal androgen excess in PCOS is associated with increased inactivation of cortisol by 5beta-reductase that may lower cortisol blood levels and stimulate ACTH-dependent steroidogenesis.

Figure 1

Response of androgens and cortisol to ACTH_1-24 (Δ_(60-0)) in PCOS normal responders-NR, intermediate responders-IR and high responders-HR, and in controls shown as individual values (scatter plot) and means ± SD. P< 0.001 for comparison in androstenedione and DHEA, P= 0.025 for comparison in 17OH-Progesterone, and P= 0.001 for comparison in cortisol among the three groups of PCOS (NR, IR, HR) by one-way ANOVA. To convert to SI units, multiply DHEA by 3.467 (result in nmol/L) and cortisol by 27.59 (result in nmol/L).

Figure 2

Fasting plasma DHEA-S and cortisol levels in PCOS normal responders-NR, intermediate responders-IR and high responders-HR, and in controls. Data are means ± SD. P= 0.004 for comparison in DHEA-S and P= 0.003 for comparison in cortisol among the three groups of PCOS (NR, IR, HR) by one-way ANOVA. To convert to SI units, multiply DHEA-S by 2.741 (result in μmol/L).

Figure 3

Relative 5β- (5βTHF/cortisol, 5βTHE/cortisone) and 5α- (5αTHF/cortisol) reduction of cortisol and the balance of 5β- and 5α-reductases (5βTHF/5αTHF) in PCOS normal responders-NR, intermediate responders-IR and high responders-HR, and in controls. Data are means ± SD. P= 0.049, P= 0.053, P= 0.825, and P= 0.044 for comparison in 5βTHF/cortisol, 5βTHE/cortisone, 5αTHF/cortisol, and 5βTHF/5αTHF levels, respectively, among the three groups of PCOS (NR, IR, HR) by one-way ANOVA.

Figure 4

Relationship between androstenedione or DHEA response to ACTH_1-24 and fasting plasma cortisol levels.