Hormonal Drivers of Perimenopausal Inflammation and Mood Symptoms

Up to one third of women, up to a billion people, experience the emergence or worsening of depressive and anxiety (mood) symptoms as their hormonal milieu shifts into perimenopause. Despite this proportion, we still do not understand what biological changes in perimenopause contribute to the increased risk of symptoms. Recent work suggests that perimenopause initiates a proinflammatory state and links both follicle-stimulating hormone (FSH) and acyl-ghrelin, two peripheral hormones that can cross the blood-brain barrier, to negative health outcomes. The roles of FSH and acyl-ghrelin extend beyond their canonical links to fertility and hunger, respectively. FSH receptors and ghrelin receptors are observed in many tissues and cells, including immune cells. FSH receptors are highly expressed in monocytes and FSH receptor activation stimulates proinflammatory cytokine production. Ghrelin receptors are expressed in the efferent vagus nerve, a well-known anti-inflammatory component of the autonomic nervous system, and acyl-ghrelin signaling increases vagal activity. Despite these observations, the hormonal mechanisms leading to mood symptoms remain elusive because the convergent hormonal pathways linking perimenopausal inflammation and mood symptoms have not been modeled. Our goal is to compare the time course of changes in FSH, estradiol, other reproductive hormones and acyl-ghrelin with the time course of changes in inflammation and mood. The study tests a mechanistic hypothesis in which elevated FSH and decreased acyl-ghrelin elevate proinflammatory markers through actions on monocytes and the autonomic nervous system, and thereby increase depressive and anxiety symptoms. This is a prospective longitudinal case-control study using a surgical menopause model, i.e. risk-reducing bilateral salpingo-oophorectomy (BSO). Surgical menopause reduces inter-individual variation in the onset and duration of perimenopause, thus facilitating our ability to measure associations between hormones, inflammation, and vagal activity pre- and post-menopause. We will recruit women seeking premenopausal risk-reducing BSO and age-matched premenopausal “controls” having non-BSO gynecological surgery. We will collect endocrine, immune and other measures pre-surgery, one week post-surgery and monthly post-surgery up to six months. Aim 1 will test the hypothesis that mood symptoms change with surgical menopause and that changes in hormones and proinflammatory markers relate to mood symptoms, specifically measuring plasma levels of FSH, estradiol, acyl-ghrelin, progesterone, liver-enriched antimicrobial peptide 2, cytokines and adipokines in basal plasma. Aim 2 will test the hypothesis that proinflammatory markers change with surgical menopause and that changes in acyl-ghrelin and vagal activity (vagal reflex, heart rate variability) relate to proinflammatory markers. Aim 3 (exploratory) will test the hypothesis that hormones relate to monocyte signaling changes with surgical menopause and that this signaling relates to proinflammatory markers. Mediation models will test for mechanistic effects across all aims.