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Postpartum depression (PPD) is a common complication following delivery, though evidence-based treatment options are limited. This study explores the feasibility and efficacy of outpatient PPD treatment with transdermal estradiol (TE). In a pilot, double-blind, placebo-controlled trial, women with PPD were randomized to receive transdermal 17β-estradiol (100 mcg/day) or placebo patch. Over 6 weeks, women completed weekly ratings on the Beck Depression Inventory (BDI), Edinburgh Postnatal Depression Scale (EPDS), and Hamilton Depression Scale (HAM-D). Primary outcome measures were treatment response (> 50% decrease from baseline BDI) and remission (BDI < 10) at 6 weeks, and secondary outcome measures included severity on all scales at weeks 3 and 6. Of 12 recruited women, 6 received TE and 6 received placebo. By week 6, 5 women receiving TE responded to treatment and 4 showed symptom remission, compared to 2 responders and 1 remitter in the placebo group. This difference was not significant (p = 0.24). In a mixed-model of BDI ratings, TE was associated with a 9.2 point decrease at 3 weeks (95%CI - 19.5 to + 1.0, p = 0.074) and a 10.5 point decrease at 6 weeks (95%CI - 21.0-0.0, p = 0.049) compared to placebo, though these differences did not survive multiple comparisons correction. Analogous effects were found for HAM-D but not EPDS scores. Interestingly, no significant difference in plasma estradiol levels existed between groups. We were unable to demonstrate a significant therapeutic benefit of TE compared with placebo in PPD. Although limited by under-recruitment and loss to follow-up, our results suggest TE is a feasible option for outpatient PPD management, with preliminary evidence (based on secondary outcomes) for efficacy. Therapeutic effects may be seen as early as 3 weeks and may not directly depend on peripheral measures of estradiol.

Importance: The menopause transition and early postmenopausal period are associated with a 2- to 4-fold increased risk for clinically significant depressive symptoms. Although a few studies suggest that hormone therapy can effectively manage existing depression during this time, to our knowledge, there have been no studies testing whether hormone therapy can prevent the onset of perimenopausal and early postmenopausal depressive symptoms., Objective: To examine the efficacy of transdermal estradiol plus intermittent micronized progesterone (TE+IMP) in preventing depressive symptom onset among initially euthymic perimenopausal and early postmenopausal women. A secondary aim was to identify baseline characteristics predicting TE+IMP's beneficial mood effects., Design, Setting, and Participants: Double-blind, placebo-controlled randomized trial at the University of North Carolina at Chapel Hill from October 2010 to February 2016. Participants included euthymic perimenopausal and early postmenopausal women from the community, aged 45 to 60 years., Interventions: Transdermal estradiol (0.1 mg/d) or transdermal placebo for 12 months. Oral micronized progesterone (200 mg/d for 12 days) was also given every 3 months to women receiving active TE, and identical placebo pills were given to women receiving placebo., Main Outcome Measures: Scores on the Center for Epidemiological Studies-Depression Scale (CES-D), assessed at baseline and months 1, 2, 4, 6, 8, 10, and 12 after randomization, and the incidence of clinically significant depressive symptoms, defined as a CES-D score of at least 16., Results: Of 172 participants, 130 were white (76%), and 70 were African American (19%), with a mean household income of $50 000 to $79 999. The mean age was 51 years, and 43 developed clinically significant depressive symptoms. Women assigned to placebo were more likely than those assigned to TE+IMP to score at least 16 on the CES-D at least once during the intervention phase (32.3% vs 17.3%; odds ratio [OR], 2.5; 95% CI, 1.1-5.7; P = .03) and had a higher mean CES-D score across the intervention period (P = .03). Baseline reproductive stage moderated the effect of treatment (β, -1.97; SEM, 0.80; P for the interaction = .03) such that mood benefits of TE+IMP vs placebo were evident among women in the early menopause transition (β, -4.2; SEM, 1.2; P < .001) but not the late menopause transition (β, -0.9; SEM, 0.3; P = .23) or among postmenopausal women (β, -0.3; SEM, 1.1; P = .92). Stressful life events in the 6 months preceding enrollment also moderated the effect of treatment on mean CES-D score such that the mood benefits of TE+IMP increased with a greater number of events (β, 1.22; SEM, 0.40; P = .003). Baseline estradiol levels, baseline vasomotor symptoms, history of depression, and history of abuse did not moderate treatment effects., Conclusions: Twelve months of TE+IMP were more effective than placebo in preventing the development of clinically significant depressive symptoms among initially euthymic perimenopausal and early postmenopausal women., Trial Registration: clinicaltrials.gov Identifier: NCT01308814.

Objective: Premenstrual dysphoric disorder (PMDD) symptoms are eliminated by ovarian suppression and stimulated by administration of ovarian steroids, yet they appear with ovarian steroid levels indistinguishable from those in women without PMDD. Thus, symptoms could be precipitated either by an acute change in ovarian steroid levels or by stable levels above a critical threshold playing a permissive role in expression of an underlying infradian affective "pacemaker." The authors attempted to determine which condition triggers PMDD symptoms., Method: The study included 22 women with PMDD, ages 30 to 50 years. Twelve women who experienced symptom remission after 2-3 months of GnRH agonist-induced ovarian suppression (leuprolide) then received 1 month of single-blind (participant only) placebo and then 3 months of continuous combined estradiol/progesterone. Primary outcome measures were the Rating for Premenstrual Tension observer and self-ratings completed every 2 weeks during clinic visits. Multivariate repeated-measure ANOVA for mixed models was employed., Results: Both self- and observer-rated scores on the Rating for Premenstrual Tension were significantly increased (more symptomatic) during the first month of combined estradiol/progesterone compared with the last month of leuprolide alone, the placebo month, and the second and third months of estradiol/progesterone. There were no significant differences in symptom severity between the last month of leuprolide alone, placebo month, or second and third months of estradiol/progesterone. Finally, the Rating for Premenstrual Tension scores in the second and third estradiol/progesterone months did not significantly differ., Conclusions: The findings demonstrate that the change in estradiol/progesterone levels from low to high, and not the steady-state level, was associated with onset of PMDD symptoms. Therapeutic efforts to modulate the change in steroid levels proximate to ovulation merit further study.

Background: Controversy regarding the antidepressant efficacy of hormone replacement therapy (HRT) stems almost from its inception and reflects the same methodological inconsistencies that have compromised efforts to determine whether the perimenopause is accompanied by an increase in mood symptoms or depression. Methodologic differences of note (other than study design) include menopausal state (perimenopause vs. postmenopause), determination of state (earlier studies used age as a proxy measure), baseline symptomatology (asymptomatic vs. depressive symptoms vs. syndromic depression), route of hormone administration (transdermal vs. oral), and symptom or syndrome measure. Zweifel and O'Brien's 1997 meta-analysis included 26 studies of the effects of menopausal HRT on depressed mood and revealed an overall effect size of 0.68. This moderate to large effect size, showing lower ratings of depressed mood in treated patients compared with controls, implicated HRT as a potential treatment of or prophylactic for depression in menopausal women. Since this publication, multiple studies have aimed to discern the relationship between HRT and menopausal mood., Methods: The purpose of this systematic review is to examine the findings and quality of the evidence amassed since Zweifel and O'Brien's meta-analysis., Results: Of the 24 studies meeting criteria for review, only five RCTs examined depressed subjects, and only two of the study samples were solely perimenopausal., Conclusions: One can generalize from the studies reviewed here only with great caution, but there is little evidence to support the use of estradiol to improve mood in nondepressed patients (not surprisingly) and some evidence to support the antidepressant efficacy of estradiol in perimenopausal but not postmenopausal women., (© 2015 Wiley Periodicals, Inc.)

Importance: Perimenopause is accompanied by an increased risk of new and recurrent depression. The coincidence of declining ovarian function with the onset of depression led to the inference that "withdrawal" from physiologic estradiol levels underpinned depression in perimenopause. To our knowledge, this is the first controlled systematic study to directly test the estrogen withdrawal theory of perimenopausal depression (PMD)., Objective: To examine the role of estradiol withdrawal in PMD., Design, Setting, and Participants: Initial open-label treatment with estradiol followed by randomized, double-blind, placebo-controlled, parallel-design evaluation of continued estradiol treatment was evaluated at an outpatient research facility at the National Institutes of Health Clinical Center. An intent-to-treat analysis was performed between October 2003 and July 2012. Participants included asymptomatic postmenopausal women with past PMD responsive to hormone therapy (n = 26) and asymptomatic postmenopausal women with no history of depression (n = 30) matched for age, body mass index, and reproductive status who served as controls. Data were analyzed between November 2012 and October 2013 by repeated-measures analysis of variance., Interventions: After 3 weeks of open-label administration of transdermal estradiol (100 µg/d), participants were randomized to a parallel design to receive either estradiol (100 µg/d; 27 participants) or matched placebo skin patches (29 participants) for 3 additional weeks under double-blind conditions., Main Outcomes and Measures: Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale (completed by raters blind to diagnosis and randomization status), self-administered visual analog symptom ratings, and blood hormone levels obtained at weekly clinic visits., Results: None of the women reported depressive symptoms during open-label use of estradiol. Women with past PMD who were crossed over from estradiol to placebo experienced a significant increase in depression symptom severity demonstrated using the Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale, with mean (SD) scores increasing from estradiol (ie, 2.4 [2.0] and 3.0 [2.5]) to placebo (8.8 [4.9] and 6.6 [4.5], respectively [P = .0004 for both]). Women with past PMD who continued estradiol therapy and all women in the control group remained asymptomatic. Women in both groups had similar hot-flush severity and plasma estradiol levels during use of placebo., Conclusions and Relevance: In women with past PMD that was previously responsive to hormone therapy, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that normal changes in ovarian estradiol secretion can trigger an abnormal behavioral state in these susceptible women. Women with a history of PMD should be alert to the risk of recurrent depression when discontinuing hormone therapy., Trial Registration: clinicaltrials.gov Identifier: NCT00060736.

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 menopause. In this study, we examined the effects of induced hypogonadism and ovarian steroid replacement on cognitive performance in healthy premenopausal women. Ovarian suppression was induced with a GnRH agonist (Lupron) and then physiologic levels of estradiol and progesterone were reintroduced 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. 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. 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.

Context: During conditions of ovarian suppression, women with premenstrual dysphoria (PMD) experience abnormal behavioral responses to physiological levels of ovarian steroids. Although hypothalamic-pituitary-adrenal (HPA) axis dysregulation frequently accompanies depression, and ovarian steroids regulate HPA axis responsivity, the role of HPA axis dysregulation in PMD is not known. We hypothesized that women with PMD would show abnormalities of HPA axis function analogous to those reported in depressive illness, and that ovarian steroids would differentially regulate HPA axis function in women with PMD compared with asymptomatic controls (AC)., Objective: Our objective was to characterize the HPA axis response to physiological levels of estradiol and progesterone in women with PMD and AC., Design and Setting: We conducted an open-label trial of the GnRH agonist depot Lupron with ovarian steroid replacement administered in a double-blind crossover design in an outpatient clinic., Participants: Forty-three women (18 with prospectively confirmed PMD and 25 AC) participated., Interventions: Women received Lupron for 6 months. After 3 months of hypogonadism, women received 5 wk each of estradiol (100-μg patch daily) or progesterone (suppositories 200 mg twice daily). During each condition, combined dexamethasone-suppression/CRH-stimulation tests and 24-h urinary free cortisol levels were performed., Main Outcome Measures: Plasma cortisol and ACTH levels were evaluated., Results: HPA axis function was similar in PMD compared with AC. In all, progesterone significantly increased the secretion of cortisol compared with estradiol [area under the curve (t(74) = 3.1; P < 0.01)] and urinary free cortisol (t(74) = 3.2; P < 0.01) and ACTH compared with hypogonadism [area under the curve (t(74) = 2.4; P < 0.05)]., Conclusions: HPA axis regulation is normal in PMD, suggesting that the pathophysiology of PMD differs from major depression. As observed previously, progesterone but not estradiol up-regulates HPA axis function in women.

Studies fail to find uniform effects of age-related or induced hypogonadism on human sexual function. We examined the effects of induced hypogonadism on sexual function in healthy men and women and attempted to identify predictors of the sexual response to induced hypogonadism or hormone addback. The study design used was a double-blind, controlled, crossover (self-as-own control). The study setting was an ambulatory care clinic in a research hospital, and the participants were 20 men (average+/-SD age=28.5+/-6.2 years) and 20 women (average+/-SD age=33.5+/-8.7 years), all healthy and with no history of psychiatric illness. A multidimensional scale assessing several domains of sexual function was the main outcome measure. Participants of the study received depot leuprolide acetate (Lupron) every 4 weeks for 3 months (men) or 5 months (women). After the first month of Lupron alone, men received (in addition to Lupron) testosterone enanthate (200 mg intramuscularly) or placebo every 2 weeks for 1 month each. Women received Lupron alone for 2 months, and then, in addition to Lupron, they received estradiol and progesterone for 5 weeks each. The results of the study: in women, hypogonadism resulted in a significant decrease in global measures of sexual functioning, principally reflecting a significant decrease in the reported quality of orgasm. In men, hypogonadism resulted in significant reductions in all measured domains of sexual function. Testosterone restored sexual functioning scores in men to those seen at baseline, whereas neither estradiol nor progesterone significantly improved the reduced sexual functioning associated with hypogonadism in women. Induced hypogonadism decreased sexual function in a similar number of men and women. No predictors of response were identified except for levels of sexual function at baseline. In conclusion, our data do not support a simple deficiency model for the role of gonadal steroids in human sexual function; moreover, while variable, the role of testosterone in sexual function in men is more apparent than that of estradiol or progesterone in women.

Perimenopausal depression affects a considerable number of women and is associated with significant disability and morbidity. Major and minor depressions are the two most prevalent forms of acute depressive illness. Major depression has an estimated lifetime prevalence of 17% and affects approximately twice as many women as men. While the relationship between the onset of depressive illness and reproductive senescence is controversial, epidemiological and clinic-based studies that have distinguished between the perimenopause and the postmenopause have documented that, for some middle-aged women, the perimenopause is associated with an increased vulnerability to depression. Future studies of perimenopausal depression should identify the number of women affected, individual risk factors and the role of hormonal therapies in this condition.

Ovarian steroids appear to alter neuronal function in women, but direct physiological evidence is lacking. In animals, estradiol enhances excitatory neurotransmission. Progesterone-derived neurosteroids increase GABAergic inhibition. The effect of weak transcranial magnetic stimulation of the motor cortex on the motor evoked potential (MEP) from transcranial magnetic stimulation given milliseconds later is changed by GABAergic and glutamatergic agents. Using this technique previously, we showed more inhibition in the luteal phase relative to the midfollicular menstrual phase, which is consistent with a progesterone effect. To detect the effects of estradiol, we have now divided the follicular phase. We tested 14 healthy women during the early follicular (low estradiol, low progesterone), late follicular (high estradiol, low progesterone), and luteal (high estradiol, high progesterone) phases, with interstimulus intervals from 2 to 10msec (10 trials at each interval and 40 unconditioned trials). We calculated the ratio of the conditioned MEP at each interval to the mean unconditioned MEP: the higher the ratio, the less inhibition and the more facilitation caused by the first stimulus. The combined ratios increased significantly from the early follicular phase to the late follicular phase and then decreased again in the luteal phase. These findings demonstrate an excitatory neuronal effect associated with estradiol and confirm our earlier finding of inhibition associated with progesterone.

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. [ABSTRACT FROM AUTHOR]

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 events related to the menopause transition could play a role in the onset of depression. In this article we review evidence suggesting a relationship between the menopause transition and depression. Additionally, we describe several findings that suggest a role of ovarian hormones in the onset of these depressions, including the clustering of episodes of depression during the stage of the menopause transition that is accompanied by estradiol withdrawal, and the therapeutic effects of short-term estradiol in depressed perimenopausal women. Finally, we discuss possible causes of affective disturbances during the menopause transition. [ABSTRACT FROM AUTHOR]

The article discusses how basic neuroscience can inform hormone therapy in women. The physiology of reproductive aging in women is reviewed. Information on studies that have evaluated the effects of the menopause transition and hypogonadism on measures of cognition, mood and sexual function is presented. The characteristics of the menopause transition are described.

This article focuses on a review of evidence related to the following 3 questions: (1) Does depression appear during the menopausal transition? (2) What factors influence the risk for depression during the menopausal transition? (3) Do age-related alterations in ovarian hormone secretion contribute to the development of depression in some middle-aged women? A brief background is provided on the importance of depressive disorders. Methodologic issues that have compromised previous studies investigating the possible relation between the menopausal transition and depression are discussed. Evidence is presented that suggests a relation between the perimenopause (the interval between the early menopausal transition and 1 year after the last menses), but not the postmenopause, and the onset of depressive illness. Finally, studies are reviewed that suggest an association between alterations in ovarian function and depression, including several randomized placebo-controlled trials examining the antidepressant efficacy of estradiol in depressed perimenopausal and postmenopausal women. [Copyright &y& Elsevier]

Women with a history of perimenopausal depression (PMD) who were withdrawn from hormonal therapy with estradiol experienced a significant increase in depressive symptom severity compared with women with past PMD who remained on estradiol and women with no PMD history, a new study has found. The findings suggest that normal changes in estradiol secretion can generate an abnormal behavioral state in women susceptible to depression. Study results were published online May 27, 2015, in JAMA Psychiatry. [ABSTRACT FROM AUTHOR]

Abstract: Premenstrual Dysphoric Disorder (PMDD) is a mood disorder affecting about 5% of women and is associated with substantial morbidity. Albeit inconsistently, PMDD is described as being characterized by heritable personality traits. Although PMDD is a heritable disorder, it is unclear whether any of the heritable susceptibility to PMDD resides in heritable personality traits. In groups of carefully characterized women with PMDD (n =68) and controls (n =56), we attempted to determine whether diagnosis-related traits could be confirmed, as well as to determine whether such traits were associated with SNPs in estrogen receptor alpha (ESR-1) that we previously demonstrated were associated with PMDD. We observed 7/25 traits to be significantly different in patients and controls and further showed that 11/12 significant associations observed between these 7 traits and 16 ESR-1 SNPs involved the intron 4 SNPs previously shown to be the locus of the association with PMDD. While several interactions between genotype and diagnosis were observed, the effect of genotype in most instances was in the same direction in patients and controls. These data demonstrate affective state-independent personality traits that distinguish patients with PMDD from controls and further support the relevance of ESR-1 polymorphic variants in the regulation of non-reproductive behaviors. [ABSTRACT FROM AUTHOR]