Adverse childhood experiences and sexual dysfunction in midlife women: Is there a link?

BACKGROUND: One in 3 children has had at least 1 adverse childhood experience (ACE), and ACEs have been associated with multiple medical and psychiatric morbidities in women later in life, including greater menopause symptom burden. AIM: To evaluate the association between ACEs and female sexual dysfunction (FSD) in midlife women. METHODS: A cross-sectional analysis from DREAMS-the Data Registry on Experiences of Aging, Menopause, and Sexuality-was conducted with questionnaires completed by women aged 40 to 65 years who presented to a women's health clinic at Mayo Clinic in Rochester, Minnesota, from May 2015 to December 2016. History of ACEs was obtained with the validated ACE questionnaire. FSD was assessed by the Female Sexual Function Index and the Female Sexual Distress Scale-Revised. OUTCOMES: The association between ACEs and FSD (defined as Female Sexual Function Index score ≤26.55 and Female Sexual Distress Scale-Revised score ≥11) was evaluated via a multivariable logistic regression model, adjusting for age, menopause status, hormone therapy use, anxiety, depression, relationship satisfaction, hot flash severity, and history of abuse in the past year. RESULTS: Women (N = 1572) had a mean age of 53.2 years. Overall 59% reported having at least 1 ACE. When compared with no ACEs, a history of ≥4 ACEs significantly increased the odds of not being sexually active (odds ratio, 1.83; 95% CI, 1.30-2.57; P < .001). Among sexually active women, the proportion of women with FSD increased sequentially as the number of ACEs increased. In the univariate analysis, a history of ≥4 ACEs significantly increased the odds of FSD as compared with no ACEs (odds ratio, 2.12; 95% CI, 1.50-2.99; P < .001). The association remained statistically significant in the multivariable analysis after adjusting for confounders (odds ratio, 1.75; 95% CI, 1.15-2.68; P = .009). CLINICAL IMPLICATIONS: The findings highlight an opportunity for clinicians to screen for ACEs in women with sexual dysfunction and offer appropriate treatment and counseling as indicated. STRENGTHS AND LIMITATIONS: Strengths of the study include the large cohort, the use of validated tools for assessment of ACEs and FSD, and the adjustment for multiple potential confounding factors. Limitations include the cross-sectional study design, recall bias in reporting ACEs and recent abuse, and the low representation of racially and ethnically diverse women in the cohort. CONCLUSION: The study demonstrates an increased risk of sexual inactivity and sexual dysfunction in midlife women who experienced childhood adversity. The sexual dysfunction in women with ACEs seems to be independent of other factors that potentially affect female sexual function in midlife.

History of infertility and sexual dysfunction in midlife women: Is there a link?

BACKGROUND: Infertility has been linked with an increased risk of sexual dysfunction in reproductive-aged women, with longer periods of infertility associated with a greater risk. AIM: The study's aim was to examine whether a history of infertility treatment in women is linked to sexual dysfunction during midlife. METHODS: The cross-sectional study was conducted among sexually active women, between the ages of 45 and 65 years, who sought consultation at the women's health clinics at a US tertiary care center. History of infertility treatment was assessed with a single question that asked participants if they were treated for infertility in the past. The association between a history of infertility treatment and sexual dysfunction-which was diagnosed by a combination of Female Sexual Function Index score ≤26.55 and Female Sexual Distress Scale-Revised score ≥11-was assessed in a multivariable logistic regression model that adjusted for multiple confounders. OUTCOMES: The primary outcome was sexual dysfunction in midlife women. RESULTS: The analysis included 5912 women, with a mean age of 54.1 years. Nearly 16% of women reported receiving treatment for infertility. More than half the women (55%) had sexual dysfunction: 56.3% of those with previous fertility treatments and 54.4% of those without any fertility treatment (P = .3). Receiving treatment for infertility in the younger years did not significantly increase the odds of sexual dysfunction in midlife in univariate (odds ratio, 1.08; 95% CI, 0.94-1.24; P = .3) and multivariable analyses (odds ratio, 1.11; 95% CI, 0.96-1.29; P = .17). CLINICAL IMPLICATIONS: While infertility is known to be predictive of sexual dysfunction in women during their reproductive years, there was no association between a history of infertility treatment and sexual dysfunction in midlife women in the current study. STRENGTHS AND LIMITATIONS: The study used validated questionnaires accounting for sexual complaints and distress and adjusted for multiple confounding factors. Limitations include the selection bias introduced by the study of women presenting for evaluation of sexual dysfunction, which may have been a result of factors stronger than the influence of infertility. Other limitations include the study's cross-sectional nature with suboptimal racial and ethnic representation. CONCLUSION: Although infertility is commonly associated with female sexual dysfunction in women of reproductive age, the association was not present in midlife women in the current study.

Oral Delivery of Nucleic Acid Therapies for Local and Systemic Action.

Nucleic acid (NA) therapy has gained importance over the past decade due to its high degree of selectivity and minimal toxic effects over conventional drugs. Currently, intravenous (IV) or intramuscular (IM) formulations constitute majority of the marketed formulations containing nucleic acids. However, oral administration is traditionally preferred due to ease of administration as well as higher patient compliance. To leverage the benefits of oral delivery for NA therapy, the NA of interest must be delivered to the target site avoiding all degrading and inhibiting factors during its transition through the gastrointestinal tract. The oral route presents myriad of challenges to NA delivery, making formulation development challenging. Researchers in the last few decades have formulated various delivery systems to overcome such challenges and several reviews summarize and discuss these strategies in detail. However, there is a need to differentiate between the approaches based on target so that in future, delivery strategies can be developed according to the goal of the study and for efficient delivery to the desired site. The goal of this review is to summarize the mechanisms for target specific delivery, list and discuss the formulation strategies used for oral delivery of NA therapies and delineate the similarities and differences between local and systemic targeting oral delivery systems and current challenges.

Sex as an independent variable in the measurement of satiation: a retrospective cohort study.

BACKGROUND: Satiation is a key component of food intake regulation as it brings an eating episode to an end. The effect of sex on satiation measurement has not been characterized. OBJECTIVE: To assess the effects of biological variables on satiation. DESIGN: Retrospective cohort study. We included 959 participants (mean age 39 [SD 12] years; 70.7% female, and BMI 33 kg/m2 [8]) who had measurements of satiation with a nutrient-drink test to assess volume to fullness (VTF) and maximum tolerated volume (MTV), and/or an ad libitum meal test to assess calories consumed to fullness (CTF). We performed univariate and multiple regression analyses to estimate the contribution of sex to VTF, MTV, and CTF, compared to other biological variables, such as age, weight, height, BMI, waist-to-hip circumference (W/H), and lean mass percentage (LM%), that are known to affect these parameters. RESULTS: Females had higher BMI, W/H, and LM%. VTF, MTV, and CTF were lower in females: 704 [323] vs. 783 [328] mL, p = 0.001; 1226 [384] vs. 1419 [410] mL, p < 0.001; and 871 [291] vs. 1086 [326] kcal, p < 0.001; respectively. Sex was a strong and independent predictor of VTF, MTF and CTF: parameter estimate [PE] = -80.8, p = 0.006; PE = -124.2, p = 0.0007; and PE = -110, p = 0.001; respectively. CONCLUSIONS: Sex has a strong effect on satiation measured by VTF, MTV, and CTF, even after adjusting for other biological factors known to affect these parameters. Females seem to integrate intra-meal inhibition signals to consume fewer calories unrelated to body size or composition. CLINICAL TRIAL REGISTRATION: None.

Polymeric Chloroquine as an Effective Antimigration Agent in the Treatment of Pancreatic Cancer.

Hydroxychloroquine (HCQ) has been the subject of multiple recent preclinical and clinical studies for its beneficial use in the combination treatments of different types of cancers. Polymeric HCQ (PCQ), a macromolecular multivalent version of HCQ, has been shown to be effective in various cancer models both in vitro and in vivo as an inhibitor of cancer cell migration and experimental lung metastasis. Here, we present detailed in vitro studies that show that low concentrations of PCQ can efficiently inhibit cancer cell migration and colony formation orders of magnitude more effectively compared to HCQ. After intraperitoneal administration of PCQ in vivo, high levels of tumor accumulation and penetration are observed, combined with strong antimetastatic activity in an orthotopic pancreatic cancer model. These studies support the idea that PCQ may be effectively used at low doses as an adjuvant in the therapy of pancreatic cancer. In conjunction with previously published literature, these studies further undergird the potential of PCQ as an anticancer agent.

Evaluating the Link Between Self-Reported Endometriosis and Female Sexual Dysfunction.

BACKGROUND: Studies have found that women with endometriosis have a higher risk of female sexual dysfunction (FSD). AIM: To evaluate the relationship between self-reported endometriosis and FSD utilizing validated surveys. METHODS: A cross-sectional analysis was conducted among sexually active women aged 18-90 who presented to 3 Mayo Clinic sites from 2015 to 2021. FSD was determined utilizing a combined endpoint of Female Sexual Function Index score ≤ 26.55 and Female Sexual Distress Scale-Revised score ≥ 11. Associations between history of endometriosis and FSD were evaluated by fitting 3 multivariable logistic models and were stratified by menopause status. In the first model, the association was adjusted for age, BMI, race/ethnicity, marital status, and education. The second model adjusted for the variables in Model 1 and hormone therapy, hormonal contraceptive use, self-reported history of abuse within the last year, and co-morbidities including the history of diabetes, heart disease, hypertension, osteoporosis, and stroke. The third model adjusted for the variables in Model 1, Model 2, and anxiety, depression, relationship satisfaction, and SSRI/SNRI use. OUTCOMES: The outcomes included self-reported endometriosis and female sexual dysfunction determined utilizing a combined endpoint of Female Sexual Function Index score ≤ 26.55 and Female Sexual Distress Scale-Revised score ≥ 11. RESULTS: Of 7118 patients (mean age 51.3), 92.2% were white, 78.4% were peri- or postmenopausal, 8.7% reported endometriosis history, and 57.2% met the criteria for FSD. Women with endometriosis were more likely to be overweight or obese, be smokers, have had a history of heart disease and osteoporosis, have had anxiety and depressed mood, have had a hysterectomy and bilateral salpingo-oophorectomy, and have used hormone therapy. Compared to those without endometriosis, women with endometriosis were significantly more likely to have FSD only among premenopausal women (74.2% vs 57.4%). Similarly, in multivariable analysis the relationship was only seen for premenopausal women in all 3 models (Model 1: OR 2.74 (95% CI 1.43-5.27); Model 2: OR 2.55 (95% CI 1.30-5.04); Model 3: OR 2.30 (95% CI 1.13-4.68)). CLINICAL IMPLICATIONS: These findings highlight the opportunity for healthcare practitioners to evaluate sexual function in premenopausal women with endometriosis. For peri and postmenopausal women with endometriosis, the risk of FSD was lower than for premenopausal women with endometriosis. STRENGTHS AND LIMITATIONS: This study analyzed the association between endometriosis and FSD in women by menopause status using validated tools that included a measure of distress associated with sexual dysfunction. Limitations include its cross-sectional design which does not allow for determination of the direction of this association. CONCLUSION: The risk for FSD associated with endometriosis depends on menopause status. Endometriosis increased the odds of FSD only in premenopausal women. Kling JM, Ghaith S, Smith T, et al. Evaluating the Link Between Self-Reported Endometriosis and Female Sexual Dysfunction. J Sex Med 2022;19:1533-1561.

Association Between Body Mass Index and Female Sexual Dysfunction: A Cross-sectional Study from the Data Registry on Experiences of Aging, Menopause, and Sexuality.

BACKGROUND: Obesity and female sexual dysfunction (FSD) are prevalent conditions, and both are associated with significant adverse effects on health and well-being. AIM: To investigate the association between body mass index and FSD, as well as potential moderators. METHODS: This cross-sectional study was performed by analyzing medical records of 6,688 women seeking consultation for menopause-related or sexual health-related concerns at women's health clinics at Mayo Clinic Rochester, MN, and Scottsdale, AZ, between May 1, 2015, and September 15, 2019. OUTCOMES: Female sexual function was assessed by the Female Sexual Function Index, and sexual distress was assessed by the Female Sexual Distress Scale-Revised. RESULTS: Being overweight or obese was associated with a lack of sexual activity. Among sexually active women, those who were overweight or obese had lower Female Sexual Function Index total scores and sexual function domain scores (indicating worse sexual function), including sexual arousal, lubrication, satisfaction, orgasm, and pain, and higher levels of sexual distress than those with normal weight. However, on multivariable analysis, these associations were found to be mediated by other factors, including age, level of education, reproductive stage, medication use, and mood disturbances, which are known to impact body weight and sexual function in women. CLINICAL IMPLICATIONS: Overweight and obesity were associated with sexual inactivity and greater odds of having FSD, which should prompt proactive assessment of sexual function. STRENGTHS AND LIMITATIONS: The strengths of this study include the large cohort size and assessment of sexual problems in addition to sexual distress, a key component of the definition of sexual dysfunction. This study also took into account multiple potential moderating factors. Limitations include the cross-sectional design, which precludes determination of causality as well as lack of diversity in the cohort, potentially limiting generalizability of results. In addition, sexual function was not assessed in women reporting no recent sexual activity, which may confound results. CONCLUSION: Overweight/obesity and FSD are highly prevalent conditions, which appear to be indirectly associated. These results highlight the need to identify and address FSD in all overweight and obese women, with particular attention to potential contributing factors. Faubion SS, Fairbanks F, Kuhle CL, et al. Association Between Body Mass Index and Female Sexual Dysfunction: A Cross-sectional Study from the Data Registry on Experiences of Aging, Menopause, and Sexuality. J Sex Med 2020;17:1971-1980.

Diagnostic Thresholds for Androgen-Producing Tumors or Pathologic Hyperandrogenism in Women by Use of Total Testosterone Concentrations Measured by Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Previously defined thresholds for total testosterone (TT) concentrations to screen for androgen-producing tumors (APTs) have used RIA, which can be less accurate in women. We aimed to define diagnostic thresholds to screen for APTs or postmenopausal pathologic hyperandrogenism using TT concentrations measured by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). METHODS: We performed a retrospective cohort study on all women with TT ≥3.5 nmol/L and all postmenopausal women presenting with hyperandrogenism between 2004 and 2014 at the Mayo Clinic in Rochester, MN. RESULTS: Of the 369 women with TT ≥3.5 nmol/L, 89 were included and subdivided into 3 groups based on their clinical diagnosis [21 (24%), APT; 16 (18%), postmenopausal pathologic hyperandrogenism; 52 (58%), polycystic ovary syndrome]. The source of the APT was more frequently ovarian (81%, n = 17) than adrenal (19%, n = 4). The diagnostic threshold using ROC analysis for TT to identify APT in women with severe biochemical hyperandrogenemia was ≥5.1 nmol/L (sensitivity, 90%; specificity, 81%). In a second analysis of a cohort of postmenopausal women only presenting with symptoms or signs of hyperandrogenism, median TT was significantly higher in the postmenopausal pathologic hyperandrogenism group (APT and ovarian hyperthecosis) vs the idiopathic hyperandrogenism group (4.9 vs 0.8 nmol/L; P < 0.01). In postmenopausal women, the diagnostic threshold for pathologic hyperandrogenism was TT ≥2.2 nmol/L (sensitivity, 100%; specificity, 86%). CONCLUSIONS: The diagnostic threshold for TT concentration as measured by LC-MS/MS to identify APT in women with biochemical severe hyperandrogenemia was TT ≥5.1 nmol/L. In postmenopausal women, the diagnostic threshold for pathologic hyperandrogenism was lower (TT ≥2.2 nmol/L).

Menopausal Hormone Therapy in Gynecologic Cancer Survivors: A Review of the Evidence and Practice Recommendations.

Gynecologic cancers are common in the United States and represent a significant health burden. Treatment of these cancers often causes premature cessation of ovarian function, with resultant symptoms that are often more severe than those associated with natural menopause. Hormone therapy is the most effective treatment for menopausal symptoms, but the decision-making process about its use can be complex for survivors of gynecologic cancer. In this review, we provide evidence-based recommendations about the use of hormone therapy after gynecologic cancer.

GLUCOCORTICOID REPLACEMENT REGIMENS IN CHRONIC ADRENAL INSUFFICIENCY: A SYSTEMATIC REVIEW AND META-ANALYSIS.

OBJECTIVE: Various glucocorticoid (GC) regimens have been used in the treatment of patients with adrenal insufficiency, yet the differences between such regimens on health outcomes are unclear. We performed a systematic review and meta-analysis to compare the effects of GC regimens on quality of life (QoL), bone density, incidence of adrenal crisis, and death. In pediatric studies, we also searched for final adult height. METHODS: We searched 6 databases through July 2016. Studies were selected and appraised by independent reviewers. Data were pooled using the profile likelihood random-effects model. RESULTS: We included 34 studies. We found no difference in QoL scores between higher (≥30 mg/day of hydrocortisone [HC] equivalence) vs. lower daily doses (<30 mg/day of HC equivalence) (P = .15) or based on frequency of daily dosing (once, twice or thrice daily). Extended-release (1 study), dual-/modified-release (3 studies), and continuous subcutaneous (3 studies) forms of GCs were associated with higher QoL scores. There was no significant association between dose and type of GC and the incidence of adrenal crises. The effect on bone mineral density was heterogeneous. No data were available on mortality or final adult height in children. The quality of evidence was low due to increased risk of bias, imprecision, and heterogeneity. CONCLUSION: Extended-/dual-release, and continuous subcutaneous forms of GC may be associated with higher QoL scores. However, this is derived from short-term and imprecise evidence, warranting low confidence. ABBREVIATIONS: AI = adrenal insufficiency BMD = bone mineral density GC = glucocorticoids HC = hydrocortisone QoL = quality of life RCT = randomized controlled trial.

Expression Profile of Markers of Apoptosis, Injury and Oxidative Stress in Human Lung Epithelium Cells-A5449 Receiving Chronic Exposure of Potential Anti-Tubercular Drug-trans-Cyclohexane-1, 4-Diamine Derivative-"9u".

Earlier, we had reported the synthesis of a library of symmetrical trans-cyclohexane-1,4-diamine derivatives and evaluated them for their anti-mycobacterium activity in the H37RV strain of Mycobacterium tuberculosis. A range of efficacy was recorded in different derivatives and the compound "9u" having an i-propyl group substitution at the p-position was found to be the most effective. The compound "9u" was found to be safe for cytotoxic and genotoxic responses in human lung epithelium cells-A549, even up to many fold higher than that required to kill M. tuberculosis. Hence, compound "9u" was inferred to be a potential anti-tuberculosis drug of choice. However, the biological safety of compound "9u" upon chronic exposure was still to be answered because anti-tuberculosis (TB) treatment requires a minimum of 6 months' exposure of host systems and most of the available anti-TB drugs are known to induce apoptosis, oxidative stress and injury during such exposures. Thus, the present investigations were aimed to study the alterations, if any, in the expression profile (mRNA and protein) of markers associated with apoptosis, injury and oxidative stress in human lung epithelium cells-A549 receiving a chronic exposure of the potential anti-TB compound "9u." Our findings demonstrate that there was a statistically insignificant transient shift (until 3 weeks) in the markers of apoptosis, injury and oxidative stress, after which expression changes were similar to baseline, when compared with unexposed cells of respective time periods. The studied markers showed linearity in the trend at both mRNA and protein level, indicating the suitability of the test system selected in the study. The data confirm the therapeutic potential of compound "9u" for even long-term treatment against M. tuberculosis without having any significant apoptosis, injury and oxidative stress.

Cyto-genotoxicity Assessment of Potential Anti-tubercular Drug Candidate Molecule-trans-cyclohexane-1, 4-diamine Derivative-9u in Human Lung Epithelial Cells A549.

Increasing incidences of multiple drug-resistance (MDR) in Mycobacterium tuberculosis are emerging as one among the serious public health threats and socio-economic burden to the third world countries including India. Last couples of decades are witnesses of the dedicated and sustained efforts made toward the development of target specific and cost-effective antimicrobial agents against MDR-M. tuberculosis. However, the drugs in use are still incapable of controlling the upsurge of MDR. Thus, in order to address the issue, we synthesized a library of symmetrical trans-cyclohexane-1, 4-diamine derivatives and evaluated their anti-mycobacterium activity in H37RV strain of M. tuberculosis. A range of efficacy has been recorded in different derivatives of synthesized compounds and compound "9u" having i-propyl group substitution at p-position, was found to have more significant detrimental effects against the tested strain of M. tuberculosis. The present investigations were aimed to study whether the effective anti-mycobacterium concentrations of "9u" are biologically safe to human cells or not? The human lung epithelial cell line-A549 were exposed to a range of concentrations, i.e., at and above the anti-mycobacterium effective dose of "9u" for a period of 0-96 h. The standard endpoints of cytotoxicity viz., tetrazolium bromide salt (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide), neutral red uptake, lactate dehydrogenase release, trypan blue dye exclusion assays; and genotoxicity viz., micronucleus and chromosomal aberrations assays were used to evaluate the bio-safety of test compound. The compound "9u" shows no significant cytotoxicity and genotoxicity in A549 cells exposed to 10(-5) M for 72 h, a concentration substantially higher than the concentration kill the H37Rv strain of M. tuberculosis. The compound 9u was found to be safe up to 10(-4) M if given for 24 h. The data reveal the therapeutic potential of compound 9u against M. tuberculosis without any having any cytotoxicity and genotoxicity responses.

Primary ovarian insufficiency: a toolkit for the busy clinician.

Primary ovarian insufficiency (sometimes known as premature ovarian insufficiency) is a result of loss of ovarian follicular activity before the age of 40 years. It is an endocrine deficiency state in women, characterized by premature estrogen deprivation. In the absence of estrogen replacement, women experience bothersome menopause symptoms and a predisposition to accelerated aging and multimorbidity accumulation. Unless a true contraindication exists, estrogen therapy is recommended at least until the age of natural menopause. This Practice Pearl summarizes the clinical manifestations, diagnostic evaluation, and management of primary ovarian insufficiency.

Association between obesity and female sexual dysfunction: a review.

INTRODUCTION: Obesity is a global health crisis that has been growing over the past few decades. The economic burden associated with obesity is substantial as it is associated with multiple disabling chronic diseases, such as cardiovascular disease, certain cancers, osteoarthritis, chronic pain, and mental illness. Obesity is known to be a risk factor for sexual dysfunction in men, but this association is less well understood in women. AIMS: To provide a narrative review of the available literature on the relationship between overweight/obesity and female sexual dysfunction, elaborate on the possible mechanisms explaining this association, and discuss the effects of weight loss on sexual function in those with obesity. METHODS: A search of the medical literature was carried out in PubMed and Medline, focusing on original research and systematic reviews of original research on obesity and sexual function in women. RESULTS: The relationship between obesity and female sexual function is not consistent across studies. While women with obesity are more likely to have worse sexual function and avoid sexual activity, many studies have failed to identify these associations. Lifestyle changes resulting in weight loss lead to better sexual function, and bariatric surgery has been shown to improve sexual function in the first couple of years following the procedure; yet, the long-term effects of weight loss and bariatric surgery are still uncertain. CONCLUSIONS: The evidence on the relationship between obesity and female sexual function is mixed. Nevertheless, weight loss has been shown to improve sexual function in women with obesity. The impact of weight loss medications and the long-term effect of bariatric surgery on female sexual function require further study.

Menopause in the workplace: Challenges, impact, and next steps.

INTRODUCTION: Menopause is a natural part of a woman's life that coincides with a time when many women play significant roles in the workforce. Menopause symptoms, such as hot flashes, fatigue, and difficulty with concentration and memory, can have a negative effect on work productivity and efficiency. OBJECTIVES: This paper summarizes the impact of menopause in the workplace, with an emphasis on the impact of symptoms on employed women and how the workplace influences their experiences. It highlights economic implications, promotes awareness, and suggests potential next steps. METHODS: A search for papers was conducted between August and November 2023 in the PubMed and Medline databases. Papers were selected based on personal experience and interpretation of the findings. Recommendations for managing menopause symptoms in the workplace and guidance on an optimal workplace intervention strategy were provided. RESULTS: Women experiencing severe menopause symptoms are more likely to report adverse work outcomes, including absenteeism and job-related decisions such as quitting, retiring early, or declining promotions than women experiencing few symptoms. Factors such as a lack of awareness about menopause, inflexible work conditions, and high-stress jobs can exacerbate the severity of these symptoms. Additionally, unaddressed menopause symptoms contribute to both direct and indirect economic costs, including medical resource utilization and lost work productivity, resulting in a substantial economic burden. CONCLUSION: Menopause symptoms impair women's work experiences and productivity. In addition to dismantling the stigma associated with menopause, it is critical to create and implement menopause workplace policies and interventions aimed at supporting women in this universal life stage.

Weight Gain in Midlife Women.

PURPOSE OF REVIEW: To summarize the evidence and clinical implications of weight and body composition changes during midlife in women and provide an overview of weight gain prevention and management in this population. RECENT FINDINGS: Aging-related changes such as decreased energy expenditure and physical activity are important culprits for weight gain in midlife women. The hormonal changes of menopause also influence body adiposity distribution and increase central adiposity. These body changes can have health consequences including the development of cardiometabolic diseases, osteoarthritis, cancer, worsening in cognition, mental health, and menopause symptoms. Midlife women experience changes related to aging, menopause, and lifestyle which favor weight gain. Clinical practice should focus on early counseling and anticipatory guidance on the importance of dietary changes and physical activity to attenuate this phenomenon. Future research should focus on the longitudinal relationship between weight trends in midlife and health consequences and mortality.

Cardiometabolic outcomes in Kronos Early Estrogen Prevention Study continuation: 14-year follow-up of a hormone therapy trial.

OBJECTIVE: This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS). METHODS: KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17ß-estradiol (Climara, 50 µg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits. RESULTS: Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17ß-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance. CONCLUSIONS: There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years.

Premature Ovarian Insufficiency.

Natural menopause typically occurs between the ages of 46 to 55 years. Premature ovarian insufficiency or premature menopause refers to compromised ovarian follicular activity, occurring spontaneously or because of medical interventions, prior to the age of 40 years. The premature loss of estrogen leads to bothersome menopause symptoms and predisposes the women to multiple long-term health risks including a higher mortality risk. Hormone replacement therapy used until the natural age of menopause can help manage the symptoms effectively and can mitigate the long-term risk of estrogen deprivation to some extent. However, hormone replacement therapy is underutilized in this population due to the inappropriate extrapolation of potential risks that have been demonstrated with hormone therapy use in women after natural menopause. There is a large unmet need for educating patients and providers regarding the impact of premature ovarian insufficiency and the compelling need for its appropriate management.

Functional Hypothalamic Amenorrhea: Recognition and Management of a Challenging Diagnosis.

Functional hypothalamic amenorrhea is responsible for approximately a third of the cases of secondary amenorrhea. The condition is a result of disturbances in gonadotropin-releasing hormone pulsatile secretion at the level of the hypothalamus, which in turn disrupts gonadotropin secretion. It is due to psychosocial stress, disordered eating, and/or excessive exercise. Often, however, it is a combination of more than one etiology, with a possible role for genetic or epigenetic predisposition. The dysfunctional gonadotropin-releasing hormone release leads to the cessation of ovarian function, resulting in amenorrhea, infertility, and a long-term impact on affected women's bone health, cardiovascular risk, cognition, and mental health. Functional hypothalamic amenorrhea is a diagnosis of exclusion, and treatment involves identifying and reversing the underlying cause(s). The aim of this concise review is to summarize the current knowledge of functional hypothalamic amenorrhea, review its pathophysiology and the adverse health consequences, and provide recommendations for diagnosis and management of this condition. Furthermore, this review will emphasize the gaps in research on this common condition impacting women of reproductive age all over the world.