Androgens During the Reproductive Years: What Is Normal for Women?

Marina A. Skiba; Robin J. Bell; Rakibul M. Islam; David J. Handelsman; Reena Desai; Susan R. Davis

Disclosures

J Clin Endocrinol Metab. 2019;104(11):5382-5392. 

In This Article

Abstract and Introduction

Abstract

Objective: Whether serum androgen levels can identify women with "androgen insufficiency" or "androgen excess" is unresolved; thus, what constitutes "normal" remains uncertain. We sought to determine whether androgens, including 11-oxygenated C19 steroids, vary with age, menstrual cycle, or body mass index (BMI), during the reproductive years.

Design and Setting: Cross-sectional study recruited from eastern Australian states.

Participants: A total of 588 women, aged 18 to 39 years, who were not pregnant, lactating, or using systemic hormone therapy, with regular menstrual cycles and no previous diagnosis of polycystic ovarian syndrome.

Main Outcome Measures: Sex steroids measured using liquid chromatography-tandem mass spectrometry.

Results: Testosterone and androstenedione concentrations were significantly higher during the menstrual cycle mid- and luteal phases than in the early follicular phase, with median values across the cycle of 0.34 nmol/L (range, 0.04 to 1.01) and 1.97 nmol/L (range, 0.53 to 7.89), respectively. No cyclical variations were found in dehydroepiandrosterone (DHEA; 4.91 nmol/L; range, 0.08 to 23.51), 11-ketoandrostenedione (11KA; 7.99 nmol/L; range, 0.07 to 31.67), or 11-ketotestosterone (11KT; 1.27 nmol/L; range, 0.03 to 7.61). Overweight women had lower median testosterone (P < 0.05), DHEA (P < 0.05), and 11KA (P < 0.01) levels than normal-weight women. All C19 steroids were significantly lower (P < 0.01) in those aged 35 to 39 years than in those aged 18 to 25 years. The median 11KA/androstenedione (4.3:1) and 11KT/testosterone (3.9:1) ratios did not change with age, after adjustment for BMI and cycle stage.

Conclusions: We have demonstrated that 11KA and 11KT are stable across the menstrual cycle and make major quantitative contributions to the circulating androgen pool. All C19 androgens declined with age before menopause; hence, age-specific reference ranges are required for the interpretation of androgen levels in premenopausal women.

Introduction

Despite evidence that androgens are essential for female reproductive function[1] and health,[2] numerous obstacles to elucidating androgen physiology in women have been present. Among these have been the imprecision of assays for the measurement of low circulating testosterone concentrations in women relative to men,[3,4] and the complexity of androgen action, which is mediated through intracellular aromatization and reduction to the biologically potent metabolite estradiol (E2) and the major androgens testosterone and dihydrotestosterone (DHT). Moreover, the apparent disconnect between the clinical indicators of androgen excess and insufficiency in women and the blood levels of testosterone and the classic preandrogens, androstenedione and dehydroepiandrosterone (DHEA),[5–7] might result from the presence of other circulating androgens that, until recently, have been overlooked. These include the 11-oxygenated steroids, 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT), which are made in peripheral tissues from their abundant adrenal precursors, 11-hydroxyandrostenedione, 11-hydroxytestosterone, and 11-ketoandrostenedione (11KA).[8] 11KT and 11KDHT have been reported to bind and activate androgen receptors and to exhibit similar androgenic potency to testosterone and DHT.[9] Whether these steroids account for a meaningful proportion of the clinically active circulating androgen pool in healthy women is uncertain. Steroid measurement using liquid chromatography–tandem mass spectrometry (LC-MS/MS) enables accurate quantification of these steroids. To the best of our knowledge, the present study is the first to report the physiological concentrations of these steroids by menstrual cycle stage, age, and body mass index (BMI) and the concentrations relative to testosterone and its precursors androstenedione and DHEA, and metabolites E2, estrone (E1), and DHT. We have provided age-specific validated reference ranges for the main androgens and estrogens in women and, hence, a foundation for the exploration of the consequences of a woman having circulating androgen levels outside the age-specific ranges.

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