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

Results

Participant Characteristics

A blood sample was provided by 761 participants. Of these, 752 were available for analysis (Figure 1). Of the 752 samples, 588 were included in the reference group after excluding 8 women with menopause, 4 with hyperprolactinemia, 1 who had become pregnant, 29 taking prohibited medications, 64 who had reported a previous diagnosis of PCOS, 36 with >35 days since their LMP, and 22 whose cycle phase could not be classified. Most (73.6%) had identified as Caucasian/white, and 44.4% had a normal BMI of 18.5 to 24.9 kg/m2 (Table 1). We classified 163women (27.7%) in the early follicular phase, 184 (31.3%) in the midcycle phase, and 241 (41.0%) in the luteal phase at the time of their blood sampling.

Figure 1.

Selection of reference group from women who provided a blood sample. *Identified by blood test results.

Variations in C19 Steroids Across the Menstrual Cycle

Testosterone and androstenedione levels varied across the menstrual cycle in a similar manner to the levels of E1 and E2, with statistically significant nadirs in the early follicular phase compared with the midcycle and luteal phases (Figure 2; Table 2). After adjusting for age and BMI, the median early follicular nadir for testosterone was 0.32 nmol/L (range, 0.04 to 0.85) compared with that at midcycle (0.35 nmol/L; range, 0.09 to 1.01; P = 0.003) and that at the luteal phase (0.35 nmol/L; range, 0.07 to 0.89; P = 0.024). For androstenedione, the early follicular nadir was 1.82 nmol/L (range, 0.63 to 5.37) compared with that at midcycle (2.07 nmol/L; range, 0.63 to 7.89; P = 0.002). No menstrual cycle variations were found for the levels of DHEA (median, 4.92 nmol/L; range, 0.08 to 23.51), 11KA (median, 7.99 nmol/L; range, 0.07 to 31.67), or 11KT (median, 1.27 nmol/L; range, 0.03 to 7.61).

Figure 2.

Sex steroid levels across the menstrual cycle. In the box and whisker plots, the box represents the interquartile range (IQR); the line in the box is the median. The whiskers extend to the upper and lower adjacent values. The upper adjacent value was defined as the largest data point ≤75th percentile + 1.5 × IQR. The lower adjacent value was defined as the smallest data point ≥25th percentile − 1.5 × IQR. After factorial ANOVA, adjusted for BMI and cycle stage, with Bonferroni correction: *P < 0.05, **P < 0.01. A, androstenedione.

Associations Between BMI and Levels of C19 Steroids

Testosterone, DHEA, and 11KA were each inversely associated with BMI in linear regression, adjusted for age and cycle stage (Table 3). The median testosterone level was higher for normal-weight women than for overweight women (median, 0.36 nmol/L; range, 0.04 to 1.00; vs median, 0.31; range, 0.07 to 0.89; P = 0.026). The DHEA concentration was also greater for the normal-weight women than for the overweight women (median, 5.37 nmol/L; range, 0.08 to 19.83; vs median, 4.40 nmol/L; range, 1.01 to 21.25; P = 0.034). The 11KA concentration was greater in the normal-weight women (median, 8.79 nmol/L; range, 0.69 to 31.67) than in both overweight women (median, 7.76 nmol/L; range, 0.57 to 28.84; P = 0.005) and obese women (median, 6.68 nmol/L; range, 0.07 to 27.47; P < 0.0001). BMI was not associated with circulating levels of androstenedione or 11KT.

C19 Steroids and Age

In the linear regression analysis, all C19 steroids exhibited a statistically significant decline between the ages of 18 to 25 and 35 to 39 years, adjusted for BMI and cycle stage (Table 4). The overall decline in the median levels from the youngest to oldest age groups were as follows: DHEA, −36%; androstenedione, −31%; 11KA, −28%; testosterone, −25%, and 11KT, −12%. The median 11KA/androstenedione ratio (4.3:1) and 11KT/testosterone ratio (3.9:1) did not change with age, after adjustment for BMI and cycle stage (Table 5). The between-group differences that remained statistically significant in the factorial ANOVA, adjusted for BMI and cycle stage, with Bonferroni correction, are shown in Figure 3.

Figure 3.

Levels of C-19 steroids according to age group. Raw data presented as scattergraphs with fitted locally weighted scatterplot smoothing (LOWESS) curves, with the y axis a log (base 10) scale. In the box and whisker plots, the box represents the interquartile range (IQR), the line in the box is the median. The whiskers extend to the upper and lower adjacent values. The upper adjacent value was defined as the largest data point ≤75th percentile + 1.5 × IQR. The lower adjacent value was defined as the smallest data point ≥ 25th percentile − 1.5 × IQR. Outliers are any values beyond the whiskers. After factorial ANOVA, adjusted for BMI and cycle stage, with Bonferroni correction: *P < 0.05, **P < 0.01. A, androstenedione; T, testosterone.

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