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.

Keywords: depression; female; hypothalamic-pituitary-adrenal (HPA) axis; perimenopause; peripartum; premenstrual; stress; trauma.

Figure 1

HPA axis physiology. Following stress the 1) hypothalamus triggers release of corticotropin releasing hormone (CRH), which in turn stimulates the 2) anterior pituitary to release adrenocorticotropic hormone (ACTH), which then stimulates the 3) adrenal glands to release cortisol. Cortisol provides negative feedback at the level of the pituitary and hypothalamus to manage excessive cortisol release. However, 4) in pregnant women, the placenta adds an additional positive feedback arm, releasing CRH in response to stimulation from cortisol. 5) Estradiol (red) and progesterone (green) across the female lifespan have varied and incompletely characterized reciprocal interactions with the HPA axis, as indicated by the double-sided dashed arrow. 6) HPA hyperactivity leading to chronically elevated cortisol can result in various metabolic, neuronal, cardiovascular, and immunological changes sometimes associated with depression. (Image created with biorender.com).

Figure 2

Normative diurnal cortisol pattern.

Figure 3

HPA function and the menstrual cycle. Changes in HPA function across the typical 28-day menstrual cycle. During the follicular phase when estradiol and progesterone levels are low, basal cortisol levels are increased while stress-induced cortisol levels are decreased versus the luteal phase. The lower basal cortisol levels in luteal phase is hypothesized to be a function of increased levels of the progesterone metabolite and neuroactive steroid, allopregnanolone.

Figure 4

Maternal cortisol stimulates placental release of HPA axis hormones that elicit further maternal cortisol secretion.