Susan S. Girdler - US grants

This study is designed to address the possible role of altered adrenergic and beta-endorphin activity in premenstrual syndrome (PMS) / premenstrual dysphoric disorder (PDD).After prospective confirmation of diagnosis, 30 women with PMS/PDD and 30 matched controls will undergo multidimensional evaluation of adrenergic function during both the follicular and luteal phases using 24-hour urinary 6-sulphatoxymelatonin, plasma catecholamines at baseline and afterstressors, cardiovascular reactivity to stressors, and cardiovascular responsivity to isoproterenol. Pain sensitivity between PMS and control groups will also be compared at both phases, via determination of ischemic pain threshold and tolerance. Beta-endorphin levels and responsivity of beta-endorphins to stressors and pain stimuli will also be compared. In a second study, 20 of these confirmed PMS/PDD women and 10 controls will participate in a double-blind, randomized crossover comparison of the possible benefits of clonidine (a central alpha-adrenergic agonist with analgesic effects) versus a control treatment with similar perceptible signs (dry mouth). Subjects will take oral medications daily for two menstrual cycles on each treatment, providing daily ratings of physical, emotional, behavioral and pain symptoms. During the second luteal phase on each treatment, the same assessments of adrenergic and beta-endorphin activity and pain sensitivity described above will be made. Thus, this study is expected to provide new insights in regard to the physiological dysregulation involved in PMS and in assessing symptoms alleviated and the mechanisms involved in any improvements associated with clonidine treatment.

The purpose of this study is to extend previous, research suggesting that dysregulation in sympathetic nervous system function, particularly adrenergic function, may underlie and contribute to the disorder of Bulimia Nervosa. An additional purpose is to investigate whether women with bulima exhibit dimished arm pain, suggesting alterations in endogenous opioid activity.

Although epidemiological data indicate that the postmenopausal use of estrogen is associated with significant reductions in risk for coronary mortality, analyses of these data separately by smoking status reveal that the protective effects of hormone replacement therapy (HRT) may be eliminated in women smokers. Alterations in the hepatic metabolism of estrogen have been demonstrated in female smokers and this may be the mechanism rendering oral estrogen ineffective is postmenopausal smokers. Thus, the primary purpose of this study is to examine the differential effectiveness of transdermally administered estrogen (plus progesterone) versus orally administered estrogen (plus progesterone) in 108 postmenopausal women smokers. A secondary goal of this study is to insure the inclusion of an undeserved population of women, thus one half of the investigators~ sample will represent postmenopausal women smokers residing in rural North Carolina, yielding a more diverse study population in areas of socioeconomics as well as cultural and social factors. Using a randomized, placebo controlled trial, each will be initially tested for cardiovascular stress reactivity, including cardiac output and total peripheral resistance, for beta-adrenergic receptor responsivity and for measures of blood flow and vascular hypertrophy and resistance. Then, women will be randomly assigned to either 4 months of transdermal estrogen plus progesterone (n=36), or 4 months of transdermal or oral placebo (n=36). Each will be retested at the end of this intervention period. Since transdermal estrogen delivery avoids the hepatic "first-pass" effect, the investigators hypothesize that transdermal estrogen will be significantly more effective for smokers in reducing vascular tone, increasing beta-adrenergic receptor responsivity and reducing blood pressure than oral administration. Thus, this study is expected to have clinical implications for effective hormone treatment in women smokers.

The addition of progesterone to estrogen has been shown in some studies to decrease its vasodilatory effects and also to diminish beneficial changes in lipids. Although concurrent use of progesterone is commonly recommended for women on estrogen replacement because of concerns in regard to enhancing risk of endometrial cancer, use of unopposed estrogen for periods of less than one year. It is desirable to clarify whether addition of estrogen replacement to lower fat diet may produce greater than individual treatment of itself.

This project seeks to determine whether the cardiovascular responses to psychological stress differ between men and women, and whether the responses of women vary with menstrual cycle status and presence of pre- menstrual syndrome.

Epidemiologic as well as laboratory-based studies all document that women are more sensitive to pain than men. Involvement of the female sex hormones is indicated by animal studies that show estrogen increases sensitivity to pain, while progesterone and its metabolites (allopregnanolone and THDOC) decrease sensitivity to pain. Animal studies also indicate that the modulation of pain sensitivity by the female sex hormones involves the endogenous opioids, particularly beta-endorphins. However, whether sex hormones and other neuroendocrine factors can account for gender differences in the human pain experience has not been directly investigated. Another potential factor which may modulate pain sensitivity differently in men and women, and which may itself involve female sex hormones, involves smoking-related analgesia. Thus, the purpose of Study 1 to examine gender differences in sensitivity to a variety of experimental pain procedures as a function of female menstrual cycle phase. Also, since animal studies show that stress-induced analgesia (SIA) is modulated by the estrous cycle, Study 1 will also examine whether the female menstrual cycle influences gender differences in SIA. Using a within-subjects, randomized design, 96 healthy, non-smokers will be tested for sensitivity to tourniquet-induced ischemic pain, cold pressor pain, and thermal pain during three separate test sessions. For women, one session will occur during the early follicular phase (days 2-5; low hormones), one session during the late follicular phase (days 9- 12; high estrogen) and one session during their luteal phase (5- 10 days after ovulation; high estrogen and progestins). Men will also be tested three times. In order to examine SIA, sensitivity to experimental pain will be compared after 20 minutes of mental stress (speech and math) versus after a 20-minute rest control period, counterbalancing order of stress and rest. Relationships between pain sensitivity (i.e., threshold and tolerance levels) and cardiovascular (blood pressure and vascular resistance) and neuroendocrine factors (estradiol, progesterone, allopregnanolone, THDOC, beta-endorphins, cortisol, ACTH and catecholamines) will be examined. It is predicted that gender differences in pain sensitivity will be greatest in the late follicular, followed by the luteal phase, while gender differences will be least in the early follicular phase. Study 2 will examine gender differences in smoking-related analgesia by testing 60 healthy subjects (30 men, 30 women), with half of each group comprised of habitual smokers. Identical test procedures and dependent measures described for Study 1 will be employed. Each subject will be tested only once, however, during the high estrogen phase of the female cycle since it is hypothesized that one mechanism by which smoking reduces pain sensitivity in women is via reductions in estrogen. It is anticipated that men will show greater evidence for smoking-related analgesia since smoking will activate two pain inhibitory mechanisms in men (i.e., blood pressure-related hypoalgesia and beta-endorphin mechanisms) while, for women, smoking will activate primarily beta-endorphin mechanisms (directly and indirectly via estrogen). The results of these studies, combined, are expected to provide insight into endogenous (sex hormones, beta-endorphins, blood pressure) and exogenous (smoking) pain modulatory mechanisms that may contribute to gender differences in the experience of pain.

psychological stressor; physiologic stressor; neuroendocrine system; premenstrual syndrome; menstrual cycle; progesterone; sympathetic nervous system; blood pressure; heart rate; rest; clinical research; female; human subject; women's health;

[unreadable] DESCRIPTION (provided by applicant): Prior research indicates that women with premenstrual dysphoric disorder (PMDD) have alterations in sympathetic nervous system (SNS) and adrenergic receptor (AR) function. Our work suggests that PMDD women with histories of sexual and physical abuse, especially childhood abuse (CA) show even greater adrenergic dysregulation, since they exhibit greater heart rate and blood pressure levels, greater B-AR responsivity and lower plasma norepinephrine (NE) relative to non-abused PMDD women. Animal studies clearly indicate a role for B-AR activation in producing hyperalgesia, while NE pathways and HPA-axis activation are involved in pain inhibition. Thus, alterations in B-AR function and diminished NE and cortisol output in PMDD women with abuse may have implications for the hyperalgesia that has been documented in PMDD. It is hypothesized that increased B-AR responsivity coupled with blunted NE will contribute to worse premenstrual symptoms and to hyperalgesia to experimental pain in PMDD women with prior CA. Sixty PMDD and 90 non-PMDD women will be tested in the luteal phase of the menstrual cycle for SNS (e.g., plasma NE, blood pressure) and HPA-axis (cortisol, ACTH, B-end) activation at rest and during stress, B-AR responsivity, and pain sensitivity to ischemic, thermal heat, and cold pain. Five groups will be compared for differences in pain sensitivity and relationship to physiological measures: 1) PMDD women with prior CA (n=30); 2) never abused PMDD women (n=30); 3) non-PMDD women with prior CA (n=30); 4) never abused non-PMDD women (n=30); and 5) non-PMDD women with no abuse and no psychiatric histories (n=30) as a healthy control group. Since our prelim studies show that all women with abuse have lower cortisol and non- PMDD women with CA show some degree of adrenergic dysregulation, we predict a rank order of effects PMDD/CA+>non-PMDD/CA+>PMDD/CA->non-PMDD/CA- for adrenergic dysregulation and hyperalgesia. Following this testing, using double-blind, placebo-controlled, cross-over procedures, all women will be retested in 2 subsequent luteal phases for SNS measures, pain sensitivity, and dysphoric mood; once during a low dose, i.v. propranolol session (0.1 mg/kg) and once during placebo. Since propranolol is a B-AR blocker, we intend to use propranolol as a pharmacological probe to investigate SNS and adrenergic factors that contribute to hyperalgesia and dysphoric mood in PMDD. We hypothesize that propranolol will be associated with differentially greater normalization of SNS, NE and hyperalgesia measures, and greater reductions in dysphoria in PMDD women with CA. These results are intended to provide important insights into the pathophysiological significance of altered adrenergic activation in the subgroup of PMDD women with CA. [unreadable] [unreadable] [unreadable]

ABSTRACT Our prior work indicates that women with premenstrual dysphoric disorder (PMDD) may be more vulnerable to dysphoric mood states induced by changes in gonadal hormones and their neuroactive metabolites, and not resulting from absolute levels per se. One objective of the proposed research is to determine if a continuous oral contraceptive (OC) regimen that eliminates the pill free interval (PFI) and produces stable, low endogenous hormone levels will prevent the expression of PMDD symptoms. A second objective is to demonstrate that changing hormones trigger affective symptoms in PMDD, and to establish which gonadal hormones and their neuroactive metabolites are associated with symptoms. Eighty one women with prospectively confirmed PMDD will be randomized and complete one of three, 13 week treatment arms: Treatment #1) continuous administration of 20 ug ethinyl estradiol/3mg drospirenone [EE/P]; Treatment #2) interrupted EE/P, substituting placebo for EE/DRP during weeks 4, 8, & 12; Treatment #3) continuous placebo. The primary outcome measure will be the total PMDD symptom score assessed daily at baseline and throughout the treatments. Secondary measures will include Response Rate, mood and social adjustment scales. Serum levels of estradiol (E2) and P, as well as plasma levels of neuroactive steroids, allopregnanolone, allotetrahydroDOC, pregnanolone and pregnenolone sulfate, all potent modulators of the GABA receptor will be sampled on cycle days 17, 21, 25, 2, & 5 at pretreatment and also during treatment A month 3. Primary predictions are: 1) Continuous EE/P (arm #1) will be associated with a significant reduction in PMDD symptoms relative to pretreatment levels, and will be associated with lower symptom levels in months 2 and 3 of treatment relative to both placebo and interrupted EE/P (arms #2 and #3); 2) Women treated with interrupted OC (arm #2) will show symptom severity similar to women treated with placebo (arm #3), and will continue to show cyclicity of symptoms though there will be a shift in peak symptoms to the follicular phase, corresponding primarily to the changes in E2 induced during the PFI; 3) the increase in E2 during the PFI in women treated with interrupted OC (arm #2) will predict the development and severity of symptoms in that group; and 4) since OCs suppress the synthesis of neurosteroids, the magnitude of the change in neuroactive steroids from days 17 25 to days 2- 5 will predict PMDD symptoms in the placebo group, but not in the women treated with OCs (arms #1 and #2). The results of this study are expected to advance our knowledge on the pathophysiology of PMDD and help illuminate a substrate for affective dysregulation in women. Confirmation of the role of hormonal change in precipitating PMDD will suggest therapeutic targets for future research. Premenstrual Dysphoric Disorder (PMDD), characterized by the cyclic recurrence of affective symptoms and resultant impairment in function, has substantial morbidity and the identified treatments are of limited effectiveness. Evidence indicates that dysphoric mood states in PMDD are induced by normal changes in gonadal steroid hormones (estradiol and progesterone), rather than by exposure to elevated hormone levels. By extension, eliminating changes in gonadal hormones with continuous oral contraceptive administration, as the planned research intends, should prevent the appearance of dysphoric symptoms. The results of this research are expected to increase our knowledge regarding the causes of PMDD and to inform the design of subsequent research establishing the use of an acceptable form of therapy with minimal side effects in PMDD.

1,2-Benzenediol, 4-(2-amino-1-hydroxyethyl)-, (R)-; 2-Propanol, 1-((1-methylethyl)amino)-3-(1-naphthalenyloxy)-; 4-(1-Hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol; Adrenergic Agents; Adrenergic Agonists; Adrenergic Drugs; Adrenergic Receptor; Adrenergic Receptor Agonist; Adrenergics; Adrenoceptors; Adrenomimetics; Aeroseb-HC; Blood Plasma; Blood Pressure; CRISP; Cardiovascular; Cardiovascular Body System; Cardiovascular system; Cardiovascular system (all sites); Cetacort; Child Abuse; Childhood Abuse; Chronotropism, Cardiac; Chronotropisms, Cardiac; Computer Retrieval of Information on Scientific Projects Database; Cort-Dome; Cortef; Cortenema; Cortisol; Cortispray; Cortril; Dermacort; Eldecort; Endorphins; Funding; Grant; HPA; Heart; Heart Rate; History; Hydrocortisone; Hydrocortone; Hytone; Infusion; Infusion procedures; Institution; Investigators; Isoprenaline; Isopropyl Noradrenaline; Isopropylarterenol; Isopropylnoradrenaline; Isopropylnorepinephrine; Isoproterenol; Isuprel; Laboratories; Levarterenol; Levonorepinephrine; NIH; National Institutes of Health; National Institutes of Health (U.S.); Noradrenaline; Norepinephrine; Nutracort; Organ System, Cardiovascular; PBO; Pain; Painful; Placebos; Plasma; Pregn-4-ene-3,20-dione, 11,17,21-trihydroxy-, (11beta)-; Proctocort; Propanolol; Propranolol; Purpose; Rate; Receptor Protein; Receptors, Epinephrine; Recording of previous events; Recruitment Activity; Regulation; Research; Research Personnel; Research Resources; Researchers; Resources; Reticuloendothelial System, Serum, Plasma; SNS; Serum, Plasma; Sham Treatment; Source; Speech; Stress; Sympathetic Nervous System; Testing; Therapeutic Hydrocortisone; United States National Institutes of Health; Vascular, Heart; Visit; Woman; Work; adenoreceptor; adolescent trauma; adrenergic; biological adaptation to stress; childhood trauma; circulatory system; hypothalamic-pituitary-adrenal (HPA) axis; hypothalamic-pituitary-adrenal axis; hypothalmus-pituitary-adrenal axis; indexing; pediatric trauma; premenstrual dysphoric disorder; reaction; crisis; receptor; receptor function; recruit; response; sham therapy; stress response; stress; reaction

African Americans (AA) are at risk for clinical pain, though the biopsychosocial mechanisms underlying enhanced pain in AAs are unknown. Relative to Caucasians, our prior work found that AAs show blunted responses of the hypothalamic-pituitary-adrenal (HPA) and sympathetic nervous system axes (SNS), and also lower oxytocin (OT) and allopregnanolone (AP), and the absence of relationship to pain sensitivity during activation of these stress-responsive systems. The relationship of these stress-responsive factors to pain sensitivity is thought to reflect an integrated response during the defense reaction. Blunted stress responses and an uncoupling of the relationship between stress responses and pain sensitivity in AAs are hypothesized to result from excessive activation of these stress systems resulting from chronic psychosocial stress in AAs. A total of 280 medically healthy AA men and women (18 - 45 years of age) will be recruited to reflect the entire SES spectrum. Interviews will access psychosocial stress, including cumulative trauma exposure, chronic stress (i.e., discrimination and difficulties), and recent negative life events. Also, potential stress buffers (e.g. religiosity, social support) will be assessed. Subjects will undergo one laboratory test session to assess pain sensitivity and endogenous pain regulatory mechanisms. Subjects will be tested while supine for baroreceptor reflex sensitivity, involving EKG measurement of heart rate and beat-to-beat changes in BP. Each subject will be tested for an index of central sensitization of pain processing by administration of a repetitive application of transient heat pulses for a maximum of 40 trials or until the subject rates the intensity of the stimulus at 100 (0-100 scale). The assessment of centrally-mediated pain inhibition will be conducted by repeating the application of transient heat pulses during concurrent hand cold presser stimulation to assess for diffuse noxious inhibitory controls (DNIC). Voluntary pain tolerance to tourniquet-induced ischemia will also be assessed. Each subject will also be exposed to the Trier Social Stress Test in order to assess stress-induced HPA and SNS reactivity. The relationship of psychosocial stress to endogenous pain regulatory mechanisms, central pain processing and peripheral pain sensitivity, and the role of stress buffers will be examined using structural equation modeling. This proposal is intended to forge new territory in the development of a bio-behavioral model relating to the development of clinical pain in African Americans. Project Description

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death in women, and currently kills more women than men in the U.S. due to the greater burden of cardiovascular risk after menopause. Depression increases risk for CVD by two-fold. Understanding the depression-CVD link has particular relevance for women since they suffer from depression at a rate twice that of men. Estrogen (E2) withdrawal not only increases cardiovascular risk in women, but is also involved in depression. The planned study will examine the biological mediators of risk that are common to both CVD and depression (inflammation, endothelial dysfunction, cardiac autonomic dysregulation, and metabolic disturbance) within the context of E2 withdrawal during the perimenopause. Heightened cardiovascular, neuroendocrine and inflammatory reactivity to stress also define a profile of risk and adversely impacts the mediators of risk described above. While E2 is associated with beneficial effects on the mediators of risk common to depression and CVD and on stress reactivity, and is also effective in reducing depressive symptoms, there is substantial variance in both the cardioprotective and antidepressant responses to E2. The planned research intends to identify a profile of risk that would predict the greatest benefits of E2 in the prophylaxis of the progression of cardiovascular risk and appearance of depression in perimenopausal women. Based on the shared mediators of risk for CVD and depression, we predict that perimenopausal women with histories of recurrent depression will show greater progression of cardiovascular risk and suffer from more depression over 12 months than never depressed women, and show cardiovascular benefit of E2. A total of 320 perimenopausal women (45-55 years of age; STRAW stage-1) who are eligible candidates for E2 will be studied. Based on SCID interview, one half (n=160) will have a history of recurrent depression (2+ depressive episodes, 1+ must be major depression), but in remission (>2 yrs and with current CES-D score d 8) and 160 will be recruited as never depressed perimenopausal women (also CES-D d 8). Following medical and psychiatric evaluation, including assessment of lifetime trauma exposure, women will be tested for baseline cardiovascular risk profiles which include: 1) Cardiac Autonomic Tone - defined by baroreceptor sensitivity involving the non-invasive measurement of HR and beat-to-beat change in BP; 2) Stress Reactivity - based on a composite score involving cardiovascular (blood pressure and vascular resistance), neuroendocrine (cortisol), and inflammatory (IL-6) responses to the Trier Social Stress Test; 3) Endothelial Function - based on ultrasound measurement of flow mediated dilatation of the brachial artery during reactivity hyperemia; and 5) Metabolic Risk - determined based on meeting standard criteria for the metabolic syndrome or exhibiting insulin resistance in response to the oral glucose tolerance test. Using double-blind procedures, subjects will then be randomized to either transdermal 172-E2 (100ug/day) or placebo for 12 months, and micronized progesterone (P) will be given every 3 months to women on active ERT (placebo P given on 2 out of 3 months) and placebo P will be given every month to women on placebo ERT. Subjects will be assessed at regular intervals during the intervention for depression, compliance, vitals, and side effects. At months 6 and 12 of the treatment period, all cardiovascular procedures conducted at the baseline assessment will be repeated. This is a mechanistic study designed to examine the predictors (history of recurrent depression) and moderators (trauma exposure) of cardiovascular risk progression in untreated perimenopausal women over 12 months, and the mediators (stress reactivity profile) of the beneficial effects of E2 treatment on depression and cardiovascular risk. The results of this study are intended to identify potential targets for behavioral or biological intervention and provide mechanistic hypotheses that can be tested in depressions that occur during other stages of life as well as help advance the goals of individualized medicine.

DESCRIPTION (provided by applicant): The purpose of the proposed training program, Postdoctoral Training in Reproductive Mood Disorders is to develop researchers with expertise in both the biological basis and clinically relevant (predictive) phenotypes of reproductive mood disorders (perinatal depression, premenstrual dysphoric disorder, and perimenopausal depression). This is a two year training program for MD, PhD and MD/PhD trainees. Training will involve a broad-based and integrative perspective, involving not only psychiatry but cardiology and genetics, endocrinology, neuroscience, and obstetrics/gynecology. With this program's emphasis on training in pathophysiological mechanisms that underlie reproductive mood disorders, trainees will develop mastery in the following: reproductive hormonal physiology and signaling; methods for manipulating the reproductive system; and clinical phenomenology of reproductive mood disorders. Additionally, trainees will develop expertise in at least one of four methodological training tracks: Neurosciences, Genetics, Stress Physiology, or Clinical Trials Methodology. Fellows will have a primary research mentor (representing their training track) and a secondary mentor (from a different track), thereby providing additional exposure to both the interdisciplinarity and collaborative nature of science. In addition to experiential opportunities with program faculty, didactics will be tailored to the individual fellow to ensure that each achieves competence in their chosen research track. A key element of the training as well includes an independent research project. Thus, while the training plan is multidisciplinary, an emphasis is placed on individualizing the training experience for the Fellows. However, through a number of program specific venues designed to bring the Fellows together for exchange of ideas and support, the program will ensure cohesiveness among the trainees. Fellows who complete this program will be poised to become independent researchers, having the unique requisite foundation to examine biobehavioral mechanisms in reproductive mood disorders and the ability to identify therapeutic biologic targets in their future independent research. The University of North Carolina at Chapel Hill represents an ideal setting for the proposed program because it possesses a well-known collaborative infrastructure, a vibrant women's mood disorder clinical program (which includes the first inpatient perinatal depression program in the country), and a critical mass of researchers in reproductive mood disorders with a track record of success.

DESCRIPTION (provided by applicant): Early life abuse (ELA) impacts neurobiological systems that regulate stress, arousal and emotion. As such, ELA represents an environmental event altering fundamental mechanisms that cut across a variety of psychopathologies. Menstrually related mood disorders (MRMDs), including premenstrual dysphoric disorder (PMDD), are defined by the cyclic recurrence of affective and somatic/pain symptoms and impairment during the luteal phase of the menstrual cycle. MRMDs are associated with high rates of ELA and represent a model of psychopathology whose pathophysiologic underpinnings are linked to ELA. The primary objective of this application is to test predictors and biobehavioral mechanisms of efficacy of a behavioral intervention for MRMDs. Mindfulness based stress reduction (MBSR) is a promising intervention with evidence for beneficial modulation of stress, arousal and emotion. We hypothesize, based on the evidence that MRMD women with ELA have more severe symptoms, dysregulation in stress reactivity, and greater pain sensitivity than MRMD women without ELA, that MBSR will be efficacious in reducing symptoms, functional impairment and pain sensitivity in women with MRMD, especially in those with ELA. Our secondary objective is to examine biopsychosocial mediators of efficacy, thus advancing our understanding of pathophysiological mechanisms in MRMD and other disorders with high rates of ELA and aiding in the identifying therapeutic targets. 120-130 women meeting prospective criteria for a MRMD will be randomized (stratified on ELA and baseline premenstrual depression severity) to either the 8-week MBSR program or to an 8-week Health Education Program (HEP) Control Group. Primary outcome measures are: 1) premenstrual depression symptomatology assessed prospectively throughout the intervention; 2) functional impairment; and 3) sensitivity to cold pressor pain. If hypotheses for primary outcomes are supported, secondary outcome measures involving premenstrual anxiety, irritability and total symptom severity as well as sensitivity to the temporal summation of heat pain procedure (indexing central pain processing) will be examined. In the laboratory (before and after the intervention), predicted biological mediators of MBSR efficacy will be assessed at rest and in response to mental stress: 1) sympathetic nervous system (blood pressure, heart rate, plasma norepinephrine and epinephrine); 2) hypothalamic-pituitary-adrenal (plasma ACTH and cortisol); 3) inflammatory (plasma IL-6); and 4) cardiac autonomic control (baroreceptor reflex sensitivity). Predicted psychological mediators of treatment efficacy are: 1) trait mindfulness; 2) acceptance; and 3) rumination, assessed before, at the mid-point, and after the intervention. Following the 8 week intervention, women will be followed for 6 months to assess sustainability of beneficial outcomes. Outcomes will be as for the intervention phase: daily symptom ratings, function and pain sensitivity (tested at months 3 and 6), as well as adherence.

PROJECT SUMMARY Vulnerability to the deleterious mood effects of normal changes in reproductive hormones is a likely underpinning to reproductive mood disorders. The menopause transition (MT) is associated with pronounced hormonal variability (within the context of relative E2 deprivation) and substantially increased risk for clinically impairing anxiety and anhedonia. Anxiety is characterized by cognitive bias to interpret ambiguous stimuli in a threat-related manner. Anhedonia can be defined by decreased motivation to approach rewards. The neurobiologically-based constructs of ?threat reactivity? and ?approach motivation? provide a framework for studying the pathophysiology of the clinical impairment experienced by 25% of women in the MT. Although the causes of affective symptoms in the MT remain unknown, severe life stress proximate to the MT is a strong predictor. Framed within a diathesis-stress model, the primary objective of this research is to determine the pathophysiological mechanisms of estradiol (E2) in the clinical anxiety and anhedonia seen in the MT. Specifically whether E2 variability or E2 levels predict exaggerated hypothalamic-pituitary-adrenal (HPA) axis reactivity and impaired recovery to stress and, in turn, deficits in behavioral indices of threat responsivity and approach motivation and symptoms of anxiety and anhedonia. The secondary objective of the research is to use a hormonal manipulation as a mechanistic probe to stabilize E2 variability in premenopausal ranges and determine if: a) HPA axis reactivity/recovery represents a biomarker of behavioral and symptom responses to E2 stabilization; b) whether recent severe life stress predicts the HPA axis response to hormone stabilization. A total of 170 women in the early or late MT who are eligible for the hormonal probe will be recruited to reflect the full continuum of anxiety and anhedonia symptoms based on self-report to the State-Trait Anxiety Inventory and the Snaith-Hamilton Pleasure Scale, respectively. However, we will over-represent the clinically impairing end of the anxious and anhedonic phenotype (75% of the sample). Over an 8-week baseline, anxiety and anhedonia symptoms and serum E2 measured by liquid chromatography-tandem mass spectrometry (LC- MS/MS) will be assessed on a weekly basis. At baseline week 8, HPA axis (plasma cortisol and ACTH) response to the Trier Social Stress Test and behavioral measures of threat responsivity (via Dot-Probe task) and approach motivation (Effort Expenditure for Rewards Task ?EEfRT?) will be determined. Using transdermal E2 as a pharmacological probe to stabilize variability of E2 in premenopausal ranges, women will then be randomized to transdermal E2 (0.10 mg) or placebo for 16 weeks. This is not a clinical efficacy trial. We will use an RCT design with a hormonal manipulation in order to investigate the pathophysiologic role of E2 variability (or E2 levels) in HPA axis dysregulation and, in turn, threat responsivity and approach motivation. Serum E2 will be assessed weekly during weeks 9-16, and HPA axis reactivity to stress and behavioral responses to the Dot-Probe and EEfRT tasks will be assessed every four weeks during the 16 week probe.

Abstract Large sectors of the US population, especially certain racial and ethnic groups, remain underrepresented (UR) in the biomedical research (BMR) workforce. Although the National Institutes of Health has employed diversity- focused efforts to increase the proportion of UR scientists in BMR, these efforts have been largely focused at the undergraduate and predoctoral level. Racial/ethnic underrepresentation is evident at each stage of the BMR career trajectory, though the transitions from Postdoctoral Fellow (Postdoc) to Faculty and from Assistant to Associate Professor represent points of greatest risk for attrition from BMR. Inadequate mentoring, less access to role models, and isolation are implicated in racial/ethnic underrepresentation in academia. The dyadic mentoring model for UR groups is limited because few senior UR faculty exist and because it may not address the isolation experienced by UR scientists in BMR. Peer group mentoring is a strategy that builds a mentoring community and several facilitated (by a senior faculty) peer group mentoring models for UR Postdocs and Junior Faculty have shown promising outcomes. However, that research is uncontrolled and does not permit the disentanglement of the contributions of psychosocial support from those of skills-based mentoring. The primary objective of this proposal is to determine the unique contribution that psychosocial components of peer group mentoring make, above and beyond that of skills-based mentoring, to both personal gains and objective career outcomes for UR early career biomedical researchers using a facilitated peer group mentoring approach. The University of North Carolina and Duke University together will randomize 160 UR men and women Postdocs or Assistant Professors in BMR to one of two, 9-month, peer group mentoring arms, stratified by gender and rank, and facilitated by a senior UR BMR Faculty (with 6-8 peers/group),: 1) Skills-based only to facilitate manuscript and grant writing skills and other academic products; or 2) Skills-based + Psychosocial to include semi-structured discussions on topics such as microaggressions, the imposter syndrome, and cultural capital. Participants will be assessed for short-term (self-efficacy, belonging, vulnerability to stereotype threat, and professional identity), medium-term (career satisfaction and career commitment) and longer-term outcomes (NIH grant scores, funding, publications, citations, retention, promotion) at interim time points during and for a minimum of 2 years following the peer mentoring intervention. 50% of participants will provide qualitative data (interviews, focus groups, and written narratives) to elucidate the mechanisms by which the interventions influence outcomes. This research is expected to provide the evidence base for a scalable, effective approach to mentoring early career, UR biomedical researchers at other institutions.