For Doctors in a Hurry
- Researchers investigated if adrenarchal hormones mediate the sex differences in depression and anxiety that emerge during early adolescence.
- This population-based cohort study followed 1239 children, measuring salivary hormones at age 9 and mood symptoms at age 13.
- In males, each doubling of dehydroepiandrosterone (DHEA) was associated with a 54% increased risk for depression and 57% for anxiety.
- The study found no evidence that DHEA, DHEAS, or testosterone levels mediated the higher rates of these disorders in females.
- The sex disparity in adolescent mood disorders is likely driven by factors other than the measured adrenarchal hormones.
Adrenarchal Androgens and the Adolescent Mental Health Gap
The transition into adolescence is characterized by a sharp rise in the incidence of depression and anxiety, marking the developmental point where sex differences in prevalence first emerge [1]. While psychosocial factors are often cited, clinical attention has increasingly focused on the endocrine shifts of adrenarche, the early stage of pubertal maturation involving the increased secretion of adrenal androgens [2]. Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are neurosteroids that modulate the hypothalamic-pituitary-adrenal axis, the primary system regulating the physiological stress response, and have been linked to mood regulation across various clinical populations [3, 4]. Despite these biological links, the role of early hormonal shifts in driving the sex disparity in adolescent mental health remains unclear [5]. This prospective cohort study evaluates whether these adrenal androgens serve as the primary mediators of the increased psychiatric risk observed in young females compared to their male peers.
Longitudinal Tracking of the Child to Adult Transition Study
Researchers utilized data from the Child to Adult Transition Study, a population-based cohort in Melbourne, Australia, to investigate the endocrine precursors of adolescent mood disorders. This longitudinal investigation followed 1,239 participants, including 667 females and 572 males who were initially recruited during Grade 3. The study was designed to evaluate how early endocrine shifts influence the development of internalizing symptoms, a clinical term for inward-facing emotional distress patterns, such as withdrawal or rumination, that characterize depression and anxiety. Baseline assessments were conducted when the participants reached 9 years of age, a period coinciding with the onset of adrenarche, the developmental stage where the adrenal glands begin producing higher levels of androgens. During this phase, the researchers collected salivary samples to measure concentrations of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and testosterone. These baseline levels served as the primary predictors for outcomes measured at wave 5, when the participants reached 13 years of age. This four-year prospective window allows clinicians to assess whether late-childhood hormonal markers can predict the emergence of psychiatric symptoms during the peak period for the onset of clinical depression and anxiety disorders.
Sex-Specific Risk and the Predictive Value of DHEA in Males
The study confirmed that incident depression and anxiety rise significantly by age 13, with a clear divergence between sexes. The prevalence of self-reported depression symptoms was nearly three times higher in females than in males, at 11% versus 4%, respectively. A similar disparity was observed for anxiety symptoms, which affected 10% of females compared to 3% of males. The analysis revealed a sex-specific association between DHEA levels at age nine and subsequent psychiatric symptoms in males. For every doubling of salivary DHEA concentration in males, the risk ratio (RR) for developing depression symptoms by age 13 was 1.54 (95% CI 1.04 to 2.28, p = 0.03), and the risk ratio for anxiety symptoms was 1.57 (95% CI 1.09 to 2.27, p = 0.02). In contrast, the associations between adrenarchal hormones and these psychiatric outcomes were inconclusive in the female cohort. For the practicing physician, these findings suggest that while elevated DHEA may serve as a biological marker for future internalizing symptoms in boys, it does not appear to have the same predictive utility for girls during this specific developmental window.
To determine if hormonal differences explain the higher prevalence of disorders in girls, the researchers employed causal mediation analysis, a statistical framework used to identify whether a specific biological pathway explains the relationship between an exposure and an outcome. They specifically estimated interventional indirect effects (IIEs), which are measures used to quantify how much the risk of depression or anxiety would change if the hormone levels of females were shifted to match the distribution seen in males. This hypothetical intervention had minimal impact on reducing the risk in females compared with males. Specifically, the interventional indirect effect risk ratio for depression was 1.03 (95% CI 0.92 to 1.14, p = 0.64), while the interventional indirect effect risk ratio for anxiety was 1.07 (95% CI 0.96 to 1.20, p = 0.23). These non-significant ratios indicate that adrenarchal hormone levels do not mediate the sex differences in depression and anxiety. While early DHEA levels are a significant risk marker for males, they do not account for the higher female prevalence. For clinicians, this suggests that the divergence in mental health outcomes during early adolescence is likely influenced by other biological, psychological, or social factors rather than the absolute levels of adrenal androgens measured at the onset of adrenarche.
References
1. Sajjadi H, Kamal SHM, Rafiey H, Vameghi M, Forouzan AS, Rezaei M. A Systematic Review of the Prevalence and Risk Factors of Depression among Iranian Adolescents. Global Journal of Health Science. 2013. doi:10.5539/gjhs.v5n3p16
2. Dutheil F, Vincent SDS, Pereira B, et al. DHEA as a Biomarker of Stress: A Systematic Review and Meta-Analysis. Frontiers in Psychiatry. 2021. doi:10.3389/fpsyt.2021.688367
3. Peixoto C, Grande AJ, Carrilho CG, Nardi AE, Cardoso A, Veras AB. Dehydroepiandrosterone for depressive symptoms: A systematic review and meta-analysis of randomized controlled trials.. Journal of neuroscience research. 2020. doi:10.1002/jnr.24721
4. Peixoto C, Grande AJ, Mallmann MB, Nardi AE, Cardoso A, Veras AB. Dehydroepiandrosterone (DHEA) for Depression: A Systematic Review and Meta-Analysis.. CNS & neurological disorders drug targets. 2018. doi:10.2174/1871527317666180817153914
5. Turk MC, Bakker CJ, Spencer SM, Lofgren SM. Systematic review of sex differences in the relationship between hormones and depression in HIV.. Psychoneuroendocrinology. 2022. doi:10.1016/j.psyneuen.2022.105665
