Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men

Abstract

Background: Many hormones display distinct circadian rhythms, driven by central regulators, hormonal bioavailability, and half-life. A set of 11-oxygenated C19 steroids (11-oxyandrogens) and pregnenolone sulfate (PregS) are elevated in congenital adrenal hyperplasia and other disorders, but their circadian patterns have not been characterized.

Participants and methods: Peripheral blood was collected every 2 h over 24 h from healthy volunteer men (10 young, 18-30 years, and 10 older, 60-80 years). We used mass spectrometry to quantify 15 steroids, including androstenedione (A4), testosterone (T), 11β-hydroxy- and 11-ketotestosterone (11OHT, 11KT),11β-hydroxy- and 11-ketoandrostenedione (11OHA4, 11KA4), and 4 ∆5-steroid sulfates. Diurnal models including mesor (rhythm adjusted median), peak, and nadir concentrations, acrophase, and amplitude were computed.

Results: 11OHA4 followed a rhythm similar to cortisol: acrophase 8:00 h, nadir 21:00 h and were similar in young and old men. 11KT had similar diurnal patterns, but the peak was lower in older than in young men, as was the case for A4. All four steroid sulfates were higher in young vs older men. PregS and 17-hydroxypregnenolone sulfate (17OHPregS) showed sustained elevations between 8:00 and 18:00 h, and nadirs around midnight, while DHEAS and AdiolS displayed minimal diurnal variations. All 4 11-oxyandrogens correlated tightly with cortisol (r from 0.54 for 11OHT to 0.81 for 11OHA4, P < 0.0001 for all), but very weakly with T, supporting their adrenal origin and ACTH governance.

Conclusions: 11-Oxyandrogens, PregS, and 17OHPregS display distinct circadian and age variations, which should be accounted for when used as clinical biomarkers.

Figure 1

Steroidogenic pathway focused on 11-oxyandrogen and Δ⁵-steroid sulfate synthesis. CYP11A1, cholesterol side-chain cleavage enzyme; CYP17A1, 17α-hydroxylase/17,20-lyase; HSD3B2, 3β-hydroxysteroid dehydrogenase type 2; CYB5A, cytochrome b₅ type A; CYP11B1, 11β-hydroxylase; HSD11B1, 11β-hydroxysteroid dehydrogenase type 1; HSD11B1/2, 11β-hydroxysteroid dehydrogenase type 1 or 2; HSD17B, 17β-hydroxysteroid dehydrogenases; PregS, pregnenolone sulfate; 17OH-Preg, 17α-hydroxypregnenolone; 17OH-PregS, 17OH-Preg sulfate; 17OH-Prog, 17α-hydroxyprogesterone; DHEAS, DHEA sulfate; A4, androstenedione; 11OHA4, 11β-hydroxyandrostenedione; 11OHT, 11β-hydroxytestosterone; 11KA4, 11-ketoandrostenedione; 11KT, 11-ketotestosterone; T, testosterone.

Figure 2

Circadian patterns of Δ⁴ and steroid sulfates hormones Loess smoothing curves were fitted using data from healthy men (10 young 18–30 years, and 10 older 60–80 years). The central lines represent the fitted medians, and the shaded areas represent the 95% CI. A4, androstenedione; T, testosterone; 11OHA4, 11β-hydroxyandrostenedione; 11KA4, 11-ketoandrostenedione; 11OHT, 11β-hydroxytestosterone; 11KT, 11-ketotestosterone; 17OHP, 17α-hydroxyprogesterone; DHEAS, DHEA sulfate; PregS, pregnenolone sulfate; 17OHPregS, 17-hydroxypregnenolone sulfate; AdiolS, androstenediol-3-sulfate. A full color version of this figure is available at https://doi.org/10.1530/EJE-21-0348.