The role of the hypothalamic-pituitary-adrenal axis in depression across the female reproductive lifecycle: current knowledge and future directions

Abstract

The aim of this narrative review is to consolidate knowledge on the role of the hypothalamic-pituitary-adrenal (HPA) axis in depression pathophysiology at different reproductive stages across the female lifespan. Despite growing evidence about the impact of gonadal hormones on mood disorders, no previous review has examined the interaction between such hormonal changes and the HPA axis within the context of depressive disorders in women. We will focus on HPA axis function in depressive disorders at different reproductive stages including the menstrual cycle (e.g., premenstrual dysphoric disorder [PMDD]), perinatally (e.g., postpartum depression), and in perimenopausal depression. Each of these reproductive stages is characterized by vast physiological changes and presents major neuroendocrine reorganization. The HPA axis is one of the main targets of such functional alterations, and with its key role in stress response, it is an etiological factor in vulnerable windows for depression across the female lifespan. We begin with an overview of the HPA axis and a brief summary of techniques for measuring HPA axis parameters. We then describe the hormonal milieu of each of these key reproductive stages, and integrate information about HPA axis function in depression across these reproductive stages, describing similarities and differences. The role of a history of stress and trauma exposure as a contributor to female depression in the context of HPA axis involvement across the reproductive stages is also presented. This review advances the pursuit of understanding common biological mechanisms across depressive disorders among women. Our overarching goal is to identify unmet needs in characterizing stress-related markers of depression in women in the context of hormonal changes across the lifespan, and to support future research in women’s mental health as it pertains to pathophysiology, early diagnosis, and treatment targets.

Rutin Treats Perimenopausal Depression Rats through Allopregnanolone Mediated mRNA Expression of Gabra4, Gabrb2 in the Prefrontal Cortex

“…While there are various hypotheses concerning the pathogenesis of PMD, there is a medical consensus that ovarian dysfunction is a crucial factor contributing to the development of PMD [26]. Hence, while estrogen has emerged as a primary research direction for PMD, the controversy surrounding its impact on female depression and the signi cant side effects of estrogen replacement therapy have impeded the progress of estrogen-focused investigations into the pathogenesis of PMD [27]. ALLO, as a metabolite of progesterone and a positive allosteric modulator of GABAAR, plays a crucial role in female neurocognitive disorders such as postpartum depression and premenstrual dysphoric disorder.…”

Gestational diabetes and risk of perinatal depression in low- and middle-income countries: a meta-analysis

“…There is also evidence suggesting that diabetes and depression may share common biological risk factors. For example, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been observed in people with either diabetes or depression ( 42 , 43 ). Women with GDM are more prone to experience increased inflammation and adipokine concentration, which are also related to depression as well ( 44 , 45 ).…”

Depressive symptoms and all-cause mortality among middle-aged and older people in China and associations with chronic diseases

“…This activation may lead to increased heart rates and vasoconstriction, thereby elevating cardiac output and peripheral vascular resistance, ultimately resulting in heightened blood pressure ( 121 ). Additionally, depressive symptoms can lead to hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis ( 122 ), which may cause elevated levels of cortisol ( 123 ). Sustained high levels of cortisol can disrupt blood pressure regulation mechanisms ( 124 ), increasing the risk of hypertension ( 125 ).…”