The Stress Phenotyping Framework: A multidisciplinary biobehavioral approach for assessing and therapeutically targeting maladaptive stress physiology.

Although dysregulated stress biology is becoming increasingly recognized as a key driver of lifelong disparities in chronic disease, we presently have no validated biomarkers of toxic stress physiology; no biological, behavioral, or cognitive treatments specifically focused on normalizing toxic stress processes; and no agreed-upon guidelines for treating stress in the clinic or evaluating the efficacy of interventions that seek to reduce toxic stress and improve human functioning. We address these critical issues by (a) systematically describing key systems and mechanisms that are dysregulated by stress; (b) summarizing indicators, biomarkers, and instruments for assessing stress response systems; and (c) highlighting therapeutic approaches that can be used to normalize stress-related biopsychosocial functioning. We also present a novel multidisciplinary Stress Phenotyping Framework that can bring stress researchers and clinicians one step closer to realizing the goal of using precision medicine-based approaches to prevent and treat stress-associated health problems.

The effect of adverse childhood experience training, screening, and response in primary care: a systematic review.

Background: Adverse childhood experiences (ACEs) can have harmful, long-term health effects. Although primary care providers (PCPs) could help mitigate these effects, no studies have reviewed the impacts of ACE training, screening, and response in primary care. Methods: This systematic review searched four electronic databases (PubMed, Web of Science, APA PsycInfo, CINAHL) for peer-reviewed articles on ACE training, screening, and/or response in primary care published between Jan 1, 1998, and May 31, 2023. Searches were limited to primary research articles in the primary care setting that reported provider-related outcomes (knowledge, confidence, screening behavior, clinical care) and/or patient-related outcomes (satisfaction, referral engagement, health outcomes). Summary data were extracted from published reports. Findings: Of 6532 records, 58 met inclusion criteria. Fifty-two reported provider-related outcomes; 21 reported patient-related outcomes. 50 included pediatric populations, 12 included adults. A majority discussed screening interventions (n = 40). Equal numbers (n = 25) discussed training and clinical response interventions. Strength of evidence (SOE) was generally low, especially for adult studies. This was due to reliance on observational evidence, small samples, and self-report measures for heterogeneous outcomes. Exceptions with moderate SOE included the effect of training interventions on provider confidence/self-efficacy and the effect of screening interventions on screening uptake and patient satisfaction. Interpretation: Primary care represents a potentially strategic setting for addressing ACEs, but evidence on patient- and provider-related outcomes remains scarce. Funding: The California Department of Health Care Services and the Office of the California Surgeon General.

Estrogen and androgen hormone therapy and well-being in surgically postmenopausal women.

BACKGROUND: Women undergoing surgical menopause experience an abrupt drop in gonadal hormones and are more likely to have symptoms that negatively impact well-being, including hot flashes, sexual dysfunction, psychological problems, and testosterone deficiency. The purpose of this review was to examine the effects of hormone therapies on well-being among surgically menopausal women. METHODS: Studies were retrieved using both Cochrane and PubMed searches. A systematic literature review was performed to identify double-blind randomized controlled trials of the effects of menopausal hormone therapies on quality of life and well-being among women who have undergone hysterectomy with bilateral oophorectomy. Two studies meeting these criteria were included for review. RESULTS: For each study reviewed, the following aspects were examined: type of hormonal therapies used, inclusion/exclusion criteria, overall changes, and changes in specific parameters of well-being. General well-being improved from baseline with certain types and doses of estrogen or estrogen plus testosterone therapy, with no serious adverse events. CONCLUSIONS: Estrogen with or without testosterone may improve general well-being in some groups of surgically menopausal women. Levels of serum estrogen achieved in these studies were within a normal range for premenopausal women. Adding testosterone to estrogen therapy may provide additional improvements in well-being in some women, but only at supraphysiological levels of total testosterone and physiological levels of free testosterone. It is recommended that the clinician discuss the potential benefits and risks with each woman and devise an individualized plan based on shared decision making.

A Description of Midlife Women Experiencing Intimate Partner Violence Using Electronic Medical Record Information.

BACKGROUND: Intimate partner violence (IPV) is an important health problem affecting women of all ages, but is often not addressed during healthcare visits. PURPOSE: To use electronic records of diagnoses and telephone advice calls to describe the clinical patterns of midlife women experiencing IPV. MATERIALS AND METHODS: Using case-control methodology, women with an ICD9 diagnosis of IPV were chosen from those enrolled in 2005-2006 in Kaiser Permanente Northern California (KPNC) and matched on visit date, age, and facility with women without such a diagnosis. The study population was divided into subsets: ages 45-53 years (318 cases, 1588 controls); ages 54-64 years (200 cases, 1000 controls). Diagnoses and symptoms reported by phone that were significantly related to the cases compared with the controls were identified using multivariate logistic regression. RESULTS: Among women aged 45-53 years, diagnoses of anxiety (odds ratio [OR] = 2.05) and of psychiatric problems (OR = 1.65) and calls for head injury (OR = 3.17), mental health problems (OR = 2.46), and sexually transmitted diseases (OR = 2.40) were associated with IPV. Among women aged 54-64 years, diagnoses of anxiety (OR = 1.74) and other psychiatric problems (OR = 1.76), injuries (other than head and neck) (OR = 1.57), urinary tract infection (UTI; OR = 2.31), headache (OR = 2.06), and calls for mental health problems (OR = 4.16) were associated with IPV. Among all women aged 45-64 years, history of prior IPV was strongly associated with subsequent diagnosis of IPV. CONCLUSIONS: Information available in the electronic health record of women who have been identified as experiencing IPV can be used to identify patterns of symptoms and diagnosis among midlife women. These patterns can potentially be used to improve identification of IPV in this age group. In addition to screening of all women for IPV, the presence of psychiatric problems, injuries, headache, and UTI and prior experience of IPV should prompt additional focused clinical inquiry about IPV in midlife women.

The effects of postmenopausal hormone therapies on female sexual functioning: a review of double-blind, randomized controlled trials.

Double-blind randomized controlled trials of estrogen and/or testosterone on sexual function among natural or surgical menopause in women are reviewed. Power, validity, hormone levels, and methodological issues were examined. Certain types of estrogen therapy were associated with increased frequency of sexual activity, enjoyment, desire, arousal, fantasies, satisfaction, vaginal lubrication, and feeling physically attractive, and reduced dyspareunia, vaginal dryness, and sexual problems. Certain types of testosterone therapy (combined with estrogen) were associated with higher frequency of sexual activity, satisfaction with that frequency of sexual activity, interest, enjoyment, desire, thoughts and fantasies, arousal, responsiveness, and pleasure. Whether specific serum hormone levels are related to sexual functioning and how these group effects apply to individual women are unclear. Other unknowns include long-term safety, optimal types, doses and routes of therapy, which women will be more likely to benefit from (or be put at risk), and the precise interplay between the two sex hormones.

Osteoporosis and health-related quality-of-life outcomes in the Alameda County Study population.

INTRODUCTION: The objective of this study was to identify physical and mental outcomes of osteoporosis that affect quality of life in women. METHODS: Data were from the Alameda County Study, a longitudinal study of health and mortality that since 1965 has followed a cohort of 6,928 American persons aged 16 to 94 years at baseline. Subjects for this analysis were women who survived until at least 1994 (N = 1,171). The variables analyzed as possible outcomes of osteoporosis included measures of physical health, quality of life, and mental health. Sequential logistic regression models were run, and associations were presented as odds ratios. RESULTS: After controlling for age, ethnicity, education, financial strain, and physical activity, subjects with osteoporosis in 1994 were more likely to report the following outcomes in 1999: frailty, difficulty with balance, weakness, problems with activities of daily living, fair/poor perceived health, never going out for entertainment, and not enjoying free time much. When controlling for chronic medical conditions, the odds ratios were reduced, but remained significant for difficulty with balance and weakness (odds ratio = 2.48) and problems with activities of daily living (odds ratio = 2.80). CONCLUSION: From this study, it appears that people with osteoporosis are at higher risk of developing problems with physical frailty and difficulties with activities of daily living, and may be at risk for reduced quality of life in terms of going out for entertainment and enjoying free time. Therefore, care should be taken to maintain the quality of life for people with osteoporosis by helping them to keep as physically functional as possible.

The menopause and sexual functioning: a review of the population-based studies.

Sexual problems are among the most frequently presented health concerns of women attending menopause clinics. We examine rigorous observational studies of the menopausal transition to determine whether there are changes in sexual functioning associated with the menopausal transition and the relative roles of aging and hormonal factors. We detail the methodological limitations of menopause research. We then review studies documenting the effects of aging on women's sexual functioning prior to reviewing studies that document both aging and menopausal status. These latter studies are divided into both cross-sectional and longitudinal studies. In summary, there is an age-related decline in sexual functioning but an added incremental decline associated with the menopausal transition. There have been relatively few studies that have been prospective, population-based, utilised a validated measure of sexual functioning, and carried out concurrent hormonal sampling. The Melbourne Women's Midlife Health Project is a prospective, observational study of a community-based sample of Australian born women aged 45-55 at baseline. There were eight annual assessments using a self-report questionnaire based on the McCoy Female Sexuality Questionnaire and blood sampling for hormone levels. From early to late menopausal transition, the percentage of women with scores indicating sexual dysfunction rose from 42% to 88%. Decreasing scores correlated with decreasing estradiol but not with androgens. By the postmenopausal phase there was a significant decline in sexual arousal and interest, frequency of sexual activities, and the Total Score. There was a significant increase in vaginal dryness and dyspareunia and women's reports of their partner's problems in sexual performance. Women with low scores of sexual functioning were more likely to be distressed on the Female Sexual Distress Scale. In conclusion, there is a dramatic decline in female sexual functioning with the natural menopausal transition.

A predictive model to help identify intimate partner violence based on diagnoses and phone calls.

BACKGROUND: Intimate partner violence (IPV) is a significant health problem but goes largely undiagnosed, undisclosed, and clinically undocumented. PURPOSE: To use historical data on diagnoses and telephone advice calls to develop a predictive model that identifies clinical profiles of women at high risk for undisclosed IPV. METHODS: A case-control study was conducted in women aged 18-44 years enrolled at Kaiser Permanente Northern California (KPNC) in 2005-2006 using symptoms reported by telephone and clinical diagnosis from electronic medical records. Analysis was conducted in 2007-2010. Overall, 1276 cases were identified using ICD-9 codes for IPV and were matched with 5 controls each. A full multivariate model was developed to identify those with IPV, as well as a reduced model and a summed-score model whose performance characteristics were assessed. RESULTS: Predictors most highly associated with IPV were history of remote IPV (OR=7.8); calls or diagnoses for psychiatric problems (OR=2.4); calls for HIV concerns (OR=2.4); and clinical diagnoses of prenatal complications (OR=2.1). Using the summed-score model for a population with IPV prevalence of 7%, and using a threshold score of 3 for predicting IPV with a sensitivity of 75%, 9.7 women would need to be assessed to diagnose one case of IPV. CONCLUSIONS: Diagnosed IPV was associated with a clinical profile based on both telephone call data and clinical diagnoses. The simple predictive model can prompt focused clinical inquiry and improve diagnosis of IPV in any clinical setting.

Women, anxiety and mood: a review of nomenclature, comorbidity and epidemiology.

Women experience a high prevalence of mood and anxiety disorders, and comorbidity of mood and anxiety disorders is highly prevalent. Both mood and anxiety disorders disturb sleep, attention and, thereby, cognitive function. They result in a variety of somatic complaints. The mood disorder continuum includes minor depression, dysthymia, major depression and bipolar disorder. Chronobiological disorders, such as seasonal affective disorder as well as premenstrual dysphoric disorder, occur in some women, with comorbid seasonal affective disorder and premenstrual dysphoric disorder in just under half of these individuals [1] . Early life experience, heritability, gender, other psychiatric illness, stress and trauma all interact dynamically in the development of mood and anxiety disorders. The epidemiology, nomenclature and clinical diagnostic issues of these illnesses in midlife woman are reviewed.

Assessment and treatment for insomnia and fatigue in the symptomatic menopausal woman with psychiatric comorbidity.

Studies and treatments for the symptomatic menopausal woman with sleep complaints have been reviewed elsewhere. This article, as part of the clinical review series on the comorbid symptomatic menopausal woman, aims to examine the evidence for diagnosis and treatment of women who present with distressing sleep symptoms that they attribute to menopause. The etiology of these symptoms may be a psychiatric disorder, a pre- or co-existing problem with sleep, or a dynamic interaction among one of these and/or a symptomatic menopause. The relationship between sleep disturbance and cognitive complaints, mood problems, fatigue and low energy will be reviewed. The new research on sleep, clinical consequences of insomnia of various types, the impact of sleep disturbance on morbidity and functioning--in the context of the midlife woman in the menopausal transition--will be explored along with the evidence for different treatment strategies for these sleep problems.

Nomenclature and endocrinology of menopause and perimenopause.

The early and late perimenopausal transition is characterized by changing cycle length as well as by menopausal symptoms in some women, including increasing hot flashes and night sweats. Breast tenderness decreases as women enter the late transition. This review, as part of the clinical reviews on the menopausal woman with comorbidity, covers the endocrine phenomena of perimenopause, terminology and the observed clinical characteristics of the transition. It should be noted that the definitions covering this period vary between publications. The average duration of perimenopause is approximately 5A years. The earliest detectable hormonal change is a fall in ovarian secretion of inhibinA B, with a subsequent rise in follicle-stimulating hormone and maintained or increased levels of estradiol. As women transit the perimenopause, cycle irregularity increases, with the more frequent occurrence of prolonged ovulatory and anovulatory cycles. Levels of follicle-stimulating hormone and estradiol fluctuate increasingly and luteal function declines. Vasomotor symptoms tend to be most frequent around the time of final menses. The perimenopause is thus a time of cycle and hormone variability and single hormone measurements provide little useful information, with the clinical history being the most appropriate method of assessing menopausal status. This information will be very helpful to the clinician treating the concerned and symptomatic patient. It will also aid clinicians to avoid unnecessary laboratory testing and help them educate their patients about their perimenopause.

Neurobehavioral impact of menopause on mood.

The menopausal transition is a time of risk for mood change ranging from distress to minor depression to major depressive disorder in a vulnerable subpopulation of women in the menopausal transition. Somatic symptoms have been implicated as a risk factor for mood problems, although these mood problems have also been shown to occur independently of somatic symptoms. Mood problems have been found to increase in those with a history of mood continuum disorders, but can also occur de novo as a consequence of the transition. Stress has been implicated in the etiology and the exacerbation of these mood problems. Estrogen and add-back testosterone have both been shown to positively affect mood and well-being. In most cases, the period of vulnerability to mood problems subsides when the woman's hormonal levels stabilize and she enters full menopause.

Role of stressful life events and menopausal stage in wellbeing and health.

Stress plays an essential role in the development, continuation and exacerbation of mood problems throughout a woman's life. It exacerbates somatic symptoms of menopause, increasing the risk of recurrence of mood disorders, as well as of a mood disorder de novo throughout the lifespan and specifically in the menopausal transition. Chronic stress affects the hypothalamic-pituitary axis, hypothalamic-pituitary-ovarian axis, the proinflammatory cytokines and cardiovascular risk. The current evidence for the potential interactions between acute stress, chronic stress, childhood stress and victimization, and individual susceptibility to the development of depression and/or anxiety in response to stressful life events, are reviewed in the context of the increasing data on the association of these and a symptomatic menopausal transition. Strategies for the optimal approach for clinicians to evaluate and treat the symptomatic perimenopausal patient with stressful life events and comorbid mood disorders are presented.

Arthralgias, bodily aches and pains and somatic complaints in midlife women: etiology, pathophysiology and differential diagnosis.

Somatic symptoms characterized by arthralgias, bodily aches and pains, musculoskeletal pain and joint pain have been investigated in a number of menopause and depression studies. Although depression is one of the most common causes of bodily aches and pains, and arthralgias, these same symptoms are also commonly associated with a natural menopause, surgical menopause and menopause induced by chemotherapy in breast cancer treatment. Somatic symptoms in the absence of definitive medical diagnoses result in these patients receiving various diagnoses and labels--'medically unexplained symptoms', 'worried well', as well as various Diagnostic and Statistical Manual of Mental Disorders (4th edition) somatoform diagnoses. Osteoarthritis and joint pain increase in prevalence from premenopausal- to menopausal-aged women with hormonal change implicated in their etiology. The current research on the relationships among menopause, depression, nociceptive mechanisms, perception and pain in the distressed midlife patient is discussed. The amelioration and management of pain symptoms in the menopausal and postmenopausal woman, with or without comorbid depression, have been elusive and difficult problems for clinicians. Familiarity with the differential diagnosis, pathophysiology and evidence-based treatment for such patients is crucial to their proper care.

Role of psychiatric comorbidity on cognitive function during and after the menopausal transition.

While cognitive complaints are common during the menopausal transition, measurable cognitive decline occurs infrequently, often due to underlying psychiatric or neurological disease. To clarify the nature, etiology and evidence for cognitive and memory complaints during midlife, at the time of the menopausal transition, we have critically reviewed the evidence for impairments in memory and cognition associated with common comorbid psychiatric conditions, focusing on mood and anxiety disorders, attention-deficit disorder, prolonged stress and decreased quantity or quality of sleep. Both the evidence for a primary effect of menopause on cognitive function and contrarily the effect of cognition on the menopausal transition are examined. Impairment in specific aspects of executive function is explored. Evaluation and treatment strategies for the symptomatic menopausal woman distressed by changes in her day-to-day cognitive function with or without psychiatric comorbidity are presented.

Treatment of vasomotor symptoms in the menopausal transition and postmenopausally: psychiatric comorbidity.

This article aims to educate the nonpsychiatric as well as the psychiatric clinician on the impact of vasomotor symptoms in women with comorbid psychiatric problems and the challenges of treating vasomotor symptoms in these women. The pathophysiology, prevalence and common risk factors associated with disturbing hot flashes in the menopausal transition are reviewed. Hormonal, nonhormonal and behavioral treatment options of vasomotor symptoms for these women are discussed. Special pharmacokinetic implications for hormonal treatment of those women on anticonvulsant medications for the treatment of their mood disorders, on tamoxifen and/or with high or low sex hormone-binding globulin are examined. An in-depth discussion of mood and the menopausal transition, theoretical mechanisms for mood problems with the symptomatic menopause and the impact of stress on the symptomatic menopause are found elsewhere in this clinical review series on psychiatric illness, stress and the symptomatic menopause.