Background: Sex differences in disease susceptibility might be explained by a sexual dimorphism in hypothalamic-pituitary-adrenal axis activity, which has been postulated to emerge during puberty. The aim of this study is to assess the contribution of pubertal development to sexual dimorphism in cortisol production and metabolism.
Methods: Participants, born between 1995 and 1996, were enrolled from the population-based Netherlands Twin Register. At the ages of 9, 12 and 17 years Tanner pubertal stage was assessed, and early-morning urine samples were collected. Cortisol metabolites were measured with GC-MS/MS, and ratios were calculated, representing the activities of various enzymes involved in the metabolism of cortisol. Using the Markov Model, cortisol production and metabolism parameters were compared between sexes for pre-pubertal (Tanner stage 1), early-pubertal (Tanner stage 2-3) and late-pubertal (Tanner stage 4-5) stages. In addition, changes in cortisol parameters between pubertal stages were assessed for both sexes.
Results: 218 participants were included (94 monozygotic and 124 dizygotic twins of which 38 opposite-sex twins) and 542 samples were analyzed; 213, 167 and 162 at 9, 12 and 17y, respectively. In both sexes cortisol production rate decreased with pubertal progression, albeit with few differences between sexes (females 0.581-0.577; P=0.91 and 0.577-0.448; P<0.001, males 0.571-0.512; P=0.04 and 0.512-0.487; P=0.58, from pre- till early- and early- till late-pubertal stage, respectively). A-ring reductase activity was similar in both sexes at pre- and early-pubertal stage, and decreased significantly in females in late pubertal development. A-ring reductase activity was significantly discordant between sexes at late-pubertal stage (being lower in females, 5α-reductase activity: THF/cortisol 5.50 vs 8.56; P<0.001, 5β-reductase activity: THF/cortisol 26.10 vs 30.47; P=0.046), while cortisone metabolism was not (THE/cortisone 9.8 vs 10.7; P=0.23). In females, as compared to males, 11β-HSD type 2 activity was significantly lower (0.77 vs 0.92; P=0.027) at early-pubertal stage, and overall 11β-HSD activity ((THF+allo-THF)/THE) was lower at both early- and late-pubertal stage (0.55 vs 0.64; P=0.04 and 0.67 vs 0.79; P=0.008). Cytochrome P450 3A4 (6-OH cortisol/cortisol) activity did not differ significantly between sexes.
Conclusion: We found dynamic changes in cortisol production and cortisol metabolism activity during pubertal development. A sexual dimorphism in the activities of A-ring reductases and 11β-HSDs became manifest during pubertal development, with lower activities in females. Our findings suggest that the sexual dimorphism in cortisol production and metabolism might be attributed by gonadal steroids.
19 Sep 2019 - 21 Sep 2019