In immune defense: redefining the role of the immune system in chronic disease

The recognition of altered immune system function in many chronic disease states has proven to be a pivotal advance in biomedical research over the past decade. For many metabolic and mood disorders, this altered immune activity has been characterized as inflammation, with the attendant assumption that the immune response is aberrant. However, accumulating evidence challenges this assumption and suggests that the immune system may be mounting adaptive responses to chronic stressors. Further, the inordinate complexity of immune function renders a simplistic, binary model incapable of capturing critical mechanistic insights. In this perspective article, we propose alternative paradigms for understanding the role of the immune system in chronic disease. By invoking allostasis or systems biology rather than inflammation, we can ascribe greater functional significance to immune mediators, gain newfound appreciation of the adaptive facets of altered immune activity, and better avoid the potentially disastrous effects of translating erroneous assumptions into novel therapeutic strategies

Sex Hormones and Mood in the Perimenopause

The focus of this chapter is the relationship between the onset of depression in women and the reproductive events of the menopause transition. Epidemiologic studies have documented that the majority of women do not become depressed during the menopause transition. However, recent longitudinal studies suggest that in some women, the reproductive events related to the menopause transition could play a role in the onset of depression. No abnormality of ovarian hormones has been identified that distinguishes women with depression from those who remain asymptomatic during the menopause transition. Nonetheless, several findings suggest a role of ovarian hormones in the onset of these depressions. First, episodes of depression cluster during the stage of the menopause transition that is accompanied by estradiol withdrawal. Second, randomized controlled trials have documented the short-term (3–6 weeks) antidepressant efficacy of estradiol in depressed perimenopausal women. Third, experimentally induced estradiol withdrawal triggers mood symptoms in some women. Thus, although depression is not a uniform accompaniment of the menopause transition, in some women, age-related changes in ovarian estrogen production may alter central nervous system function and predispose them to develop depression

Cognitive performance in healthy women during induced hypogonadism and ovarian steroid addback

Background—Gynecology clinic-based studies have consistently demonstrated that induced hypogonadism is accompanied by a decline in cognitive test performance. However, a recent study in healthy asymptomatic controls observed that neither induced hypogonadism nor estradiol replacement influenced cognitive performance. Thus the effects of induced hypogonadism on cognition might not be uniformly experienced across individual women. Moreover, discrepancies in the effects of hypogonadism on cognition also could suggest the existence of specific risk phenotypes that predict a woman’s symptomatic experience during the menopause. In this study, we examined the effects of induced hypogonadism and ovarian steroid replacement on cognitive performance in healthy premenopausal women. Methods—Ovarian suppression was induced with a GnRH agonist (Lupron) and then physiologic levels of estradiol and progesterone were re-introduced in 23 women. Cognitive tests were administered during each hormone condition. To evaluate possible practice effects arising during repeated testing, an identical battery of tests was administered at the same time intervals in 11 untreated women. Results—With the exception of an improved performance on mental rotation during estradiol, we observed no significant effects of estradiol or progesterone on measures of attention, concentration, or memory compared with hypogonadism. Conclusions—In contrast to studies in which a decline in cognitive performance was observed in women receiving ovarian suppression therapy for an underlying gynecologic condition, we confirm a prior report demonstrating that short term changes in gonadal steroids have a limited effect on cognition in young, healthy, women. Differences in the clinical characteristics of the women receiving GnRH agonists could predict a risk for ovarian steroid-related changes in cognitive performance during induced, and possibly, natural menopause

Estradiol variability, stressful life events, and the emergence of depressive symptomatology during the menopausal transition

To examine the role of estradiol fluctuation in triggering depressive symptoms in the menopause transition and assess the role of recent very stressful life events (VSLEs) as a moderating factor in this relationship

Cardiovascular, hemodynamic, neuroendocrine, and inflammatory markers in women with and without vasomotor symptoms

Vasomotor symptoms (VMS) may be associated with an increased risk of cardiovascular disease. One candidate mechanism may involve alterations in physiological responses to stress. The current study therefore examined the relationship between self-reported VMS bother and cardiovascular, hemodynamic, neuroendocrine and inflammatory responses to an acute psychosocial stress protocol

Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression

Preclinical evidence indicates that rapid changes in levels of allopregnanolone, the predominant metabolite of progesterone, confer dramatic behavioral changes and may trigger postpartum depression (PPD) in some women. Considering the pathophysiology of PPD (i.e., triggered by reproductive steroids), the need for fast‐acting, efficacious treatments and the negative consequences of untreated PPD, there is an increasing focus on developing PPD therapies. Brexanolone (USAN; formerly SAGE‐547 Injection), a proprietary injectable allopregnanolone formulation, was evaluated as a treatment for severe PPD in a proof‐of‐concept, open‐label study

Allopregnanolone as a mediator of affective switching in reproductive mood disorders

Reproductive mood disorders, including premenstrual dysphoria (PMD) and postpartum depression (PPD), are characterized by affective dysregulation that occurs during specific reproductive states. The occurrence of illness onset during changes in reproductive endocrine function has generated interest in the role of gonadal steroids in the pathophysiology of reproductive mood disorders, yet the mechanisms by which the changing hormone milieu triggers depression in susceptible women remain poorly understood