Prolactin and Adrenal Androgens During Adrenarche.

Introduction: Premature adrenarche (PremA), is associated with increased adiposity and in girls to earlier puberty and adverse metabolic profiles. Recently LC-MS/MS studies demonstrated adrenal production of more potent androgens: 11-oxygenated C19 steroids. Defining the mechanisms that regulate adrenal 11-oxygenated C19 steroids production has been elusive. We recently showed that genetic determinants of DHEAS during adrenarche differed from those during adulthood. One highly significant variant was at the prolactin receptor which is strongly expressed in human adrenal tissue. The aim of this study is to test whether an association exists between DHEAS/11-oxygenated C19 steroids and prolactin concentrations in pre-pubertal girls.

Methods: Two hundred and forty four prepubertal girls recruited within the 'the Food and Environment Chilean Cohort,' with normal birth weight (3.37 ± 0.02 Kg) were examined at 6.7 ± 0.6 years, including anthropometry and blood sampling. DHEAS and 11-oxygenated C19 steroids were measured by LC-MS/MS. Girls were categorized according to the DHEAS concentrations in normal DHEAS (ND, < 75th percentile for the population) or high DHEAS (HD, ≥ 75th percentile). This definition of adrenarche subgroups allows identification of PremA independently from other factors influencing clinical manifestations (i.e ethnicity, tissue sensitivity).

Results: None of the girls presented clinical evidence of pubarche. At this age mean DHEAS concentration was 16.4 (9.6, -25) μg/dL and the 75th percentile set at 25.0 μg/dL. Girls with HD had higher weight (1.3 ± 1.2 vs. 0.7 ± 1.1, p < 0.001), height (0.6 ± 1.0 vs. 0 ± 0.9, p < 0.001) and BMI (1.3 ± 1.2 vs. 0.9 ± 1.1, p < 0.01) SDs compared to ND. The concentrations of all 11-oxygenated C19 steroids (ng/mL) were higher in girls with HD compared to girls with ND: 11KA by 16% [0.14 (0.12, 0.16) vs. 0.12 (0.10, 0.14)], 11OHA by 43% [0.07 (0.05, 0.08) vs. 0.04 (0.03, 0.05)], 11KT by 35% [0.19(0.15, 0.25) vs. 0.14 (0.11, 0.19)] and 11OHT by 30% [0.03 (0.02, 0.05) vs. 0.03 (0.01, 0.04)]. DHEAS levels correlated with each of the 11-oxygenated C19 steroids both in the raw and in fully adjusted model. Prolactin levels [6.5 (4.4, 10.7) vs. 5.7 (4.1, 9.3)] ng/mL and insulin [7.2 (5.7, 8.7) vs. 6.8 (5.3, -9.4)] μUI/mL did not differ in HD compared to ND girls. Prolactin levels were not associated with DHEAS concentrations but significantly associated with 11KA (p < 0.001) even after adjustment by covariates and was close to the limit of significance in the fully adjusted model for 11OHA (p = 0.051).

Conclusions: Our observations confirm that 11KT is the dominant bioactive androgen in children during adrenarche and PremA. Prolactin levels are directly correlated to the concentrations of the adrenal bioactive androgens. Conditions or medications that increase prolactin concentrations during childhood could have a role in PremA.