Management of Menopausal Symptoms: A Review.

Importance: Menopause, due to loss of ovarian follicular activity without another pathological or physiological cause, typically occurs between the ages of 45 years and 56 years. During the menopausal transition, approximately 50% to 75% of women have hot flashes, night sweats, or both (vasomotor symptoms) and more than 50% have genitourinary symptoms (genitourinary syndrome of menopause [GSM]). Observations: Vasomotor symptoms typically last more than 7 years and GSM is often chronic. Efficacious treatments for women with bothersome vasomotor symptoms or GSM symptoms include hormonal and nonhormonal options. Systemic estrogen alone or combined with a progestogen reduces the frequency of vasomotor symptoms by approximately 75%. Oral and transdermal estrogen have similar efficacy. Conjugated equine estrogens (CEE) with or without medroxyprogesterone acetate (MPA) were the only hormonal treatments for which clinical trials were designed to examine cardiovascular events, venous thromboembolism, and breast cancer risk. Compared with placebo, the increased risk of stroke and venous thromboembolism associated with CEE (with or without MPA) and breast cancer (with use of CEE plus MPA) is approximately 1 excess event/1000 person-years. Low-dose CEE plus bazedoxifene is not associated with increased risk of breast cancer (0.25%/year vs 0.23%/year with placebo). Bioidentical estrogens approved by the US Food and Drug Administration (with identical chemical structure to naturally produced estrogens, and often administered transdermally) also are available to treat vasomotor symptoms. For women who are not candidates for hormonal treatments, nonhormonal approaches such as citalopram, desvenlafaxine, escitalopram, gabapentin, paroxetine, and venlafaxine are available and are associated with a reduction in frequency of vasomotor symptoms by approximately 40% to 65%. Low-dose vaginal estrogen is associated with subjective improvement in GSM symptom severity by approximately 60% to 80%, with improvement in severity by 40% to 80% for vaginal prasterone, and with improvement in severity by 30% to 50% for oral ospemifene. Conclusions and Relevance: During the menopausal transition, approximately 50% to 75% of women have vasomotor symptoms and GSM symptoms. Hormonal therapy with estrogen is the first-line therapy for bothersome vasomotor symptoms and GSM symptoms, but nonhormonal medications (such as paroxetine and venlafaxine) also can be effective. Hormone therapy is not indicated for the prevention of cardiovascular disease.

The menopausal transition period and cardiovascular risk.

The menopausal transition period spans, on average, 2-8 years before the final menstrual period and is associated with an increase in clinical and subclinical cardiovascular risk. In this Review, we discuss the metabolic and cardiovascular changes that occur during the menopausal transition period and the role of ovarian ageing, chronological ageing and other ageing-related risk factors in mediating these changes. Disentangling the relative contributions of chronological and reproductive ageing to cardiovascular risk is challenging, but data from longitudinal studies in women transitioning from premenopause to post-menopause have provided valuable insights. We also discuss evidence on how cardiovascular risk is altered by premature or early menopause, surgical menopause, and vasomotor and other menopausal symptoms. Whether targeted interventions can slow the progression of atherosclerosis and subclinical disease during the menopausal transition, thus delaying or preventing the onset of cardiovascular events, remains to be determined. Furthermore, we consider the recommended strategies for cardiovascular risk reduction in women undergoing menopausal transition using the framework of the American Heart Association's Life's Essential 8 key measures for improving and maintaining cardiovascular health, and discuss the cardiovascular risks and benefits of menopausal hormone therapy. Finally, we also discuss novel therapies that might benefit this population in reducing cardiovascular risk.

Transgender patients and gender-affirming hormone therapy through the mid-life.

The menopause transition and post-menopause period marks a time of dynamic physiological and hormonal change. Cisgender women commonly experience vasomotor symptoms, genitourinary symptoms, and changes in bone health. The transgender population, including those assigned female at birth (AFAB) and those assigned male at birth (AMAB), has been understudied in terms of experiences through the menopause transition and midlife. Additionally, there is no formal recommendation or guidance on continuation of gender-affirming hormone therapy (GAHT) through midlife. While gender-affirming therapies for transgender patients are well defined and supported by organizational guidelines, including from the World Professional Association for TGD Health (WPATH) (Standards of Care 8, SOC8) and from the Endocrine Society (2017), evidence on continuation of therapy and dose adjustments into mid-life are lacking. Data from a few large cohort studies and small cross-sectional studies suggest increased risk of venous thromboembolism (VTE), stroke and myocardial infarction in those AMAB on GAHT. For those AFAB on testosterone therapy, risks of cardiovascular disease and stroke and to bone health are not well defined, given inconsistent findings from large cohort studies. Currently, the decision to continue GAHT for transgender patients is guided by patient preference along with clinician guidance. Further research is warranted regarding risks of continuing GAHT into mid-life for both AMAB and AFAB patients. Given the significant benefit of GAHT in this population, however, this data would be most helpful for counseling on risks along with appropriate monitoring and prevention for related morbidities during mid-life in the setting of GAHT use.

Menopausal Hormone Therapy in Older Women: Examining the Current Balance of Evidence.

Menopause occurs in all women. During the menopause transition, 80% of women experience vasomotor symptoms that can last an average of 7-10 years or longer, sometimes into the seventh and eighth decades of life. Understanding how to manage vasomotor symptoms (VMS) in older menopausal women is important since these symptoms can negatively impact quality of life. This review provides a practical guide on how to approach VMS treatment either with menopausal hormone therapy or non-hormone options. When initiating, as well as continuing hormone therapy, the factors clinicians should consider as they weigh risks and benefits include assessing a woman's risks related to cardiovascular disease, breast cancer, and osteoporosis. Utilizing a shared decision-making approach in regard to menopausal symptom management should aim to support women and help them maintain health and quality of life.

Kidney Transplant Outcomes in Recipients Over the Age of 70.

BACKGROUND: Patients older than 70 years are the fastest-growing age group of patients requiring renal replacement therapy. This has resulted in a corresponding increase in the number of elderly transplant recipients. We hypothesized that graft survival in this population would be comparable to that seen in the literature on kidney transplant recipients under 70 years of age. METHODS: This was a retrospective, single-center review of outcomes of kidney transplant recipients aged ≥70 years. Patients were dichotomized based on whether their allograft originated from a living or deceased donor. RESULTS: A total of 59 recipients aged ≥70 years underwent kidney transplantation. Of these, five (8.5%) were lost to follow-up within the first year post transplant and excluded from the analysis. History of cerebrovascular accident (p = 0.003), coronary artery disease (p = 0.03), postoperative return to the operating room (p = 0.03), and readmission within one year of transplant were predictive of graft loss (p = 0.003). Overall graft survival in our cohort declined from 92.6% at one year to 53.8% at five years. Death-censored graft survival was 100% at one year and decreased to 80.8% at five years. There were no differences seen in patient, graft, or death-censored graft survival based on donor type. CONCLUSIONS: Kidney transplant patients over 70 years, as seen in our cohort, had good short-term outcomes. Graft survival is similar to rates seen in younger cohorts but the decline in this rate over time is steeper in the older age group, possibly due to decreased patient survival. These findings could be validated further in larger multi-center studies.

A Comparison of Perceived Lifetime Breast Cancer Risk to Calculated Lifetime Risk Using the Gail Risk Assessment Tool.

Background: Understanding the accuracy of a woman's perceived breast cancer risk can enhance shared decision-making about breast cancer screening through provider and patient discussion. We aim to report and compare women's perceived lifetime breast cancer risk to calculated lifetime breast cancer risk. Methods: Women presenting to Mayo Clinic in Arizona and Minnesota in July 2016 completed a survey assessing their perceived breast cancer risk. Lifetime Gail risk scores were calculated from questions pertaining to health history and were then compared with perceived breast cancer risk. Results: A total of 550 predominantly white, married, and well-educated (≥college) women completed surveys. Using lifetime Gail risk scores, 5.6% were classified as high risk (>20% lifetime risk), 7.7% were classified as intermediate risk (15%-20%), and 86.6% were classified as average risk (<15%). Of the 27 women who were classified as high risk, 18 (66.7%) underestimated their risk and of the 37 women who were intermediate risk, 12 (32.4%) underestimated risk. Women more likely to underestimate their risk had a reported history of an abnormal mammogram and at least one or more relative with a history of breast cancer. Surveyed women tended to overestimate risk 4.3 (130/30) times as often as they underestimated risk. Conclusion: In a group of predominantly white, educated, and married cohort of women, there was a large portion of women in the elevated risk groups who underestimated risk. Specific aspects of medical history were associated with underestimation including a history of abnormal mammogram and family history of breast cancer. Overall, in our sample, more women overestimated than underestimated risk.

Risks, Benefits, and Treatment Modalities of Menopausal Hormone Therapy: Current Concepts.

Menopausal hormone therapy (HT) prescribing practices have evolved over the last few decades guided by the changing understanding of the treatment's risks and benefits. Since the Women's Health Initiative (WHI) trial results in 2002, including post-intervention analysis and cumulative 18-year follow up, it has become clear that the risks of HT are low for healthy women less than age 60 or within ten years from menopause. For those who are experiencing bothersome vasomotor symptoms, the benefits are likely to outweigh the risks in view of HT's efficacy for symptom management. HT also has a role in preventing osteoporosis in appropriate candidates for treatment. A comprehensive overview of the types, routes, and formulations of currently available HT, as well as HT's benefits and risks by outcomes of interest are provided to facilitate clinical decision making.

Development of a topical tissue cross-linking solution using sodium hydroxymethylglycinate (SMG): viscosity effect.

Hyperviscosity agents are commonly used in ophthalmic formulations for improving corneal drug penetration by increasing tissue contact time. One such viscosity agent is hydroxypropyl methylcellulose (HPMC). HPMC has been used in riboflavin solutions for photochemical UVA cross-linking (CXL). Sodium hydroxymethylglycinate (SMG) is a small molecule formaldehyde releaser that can function as a therapeutic tissue cross-linker for corneal and scleral applications. The present study was undertaken in order to study formulation factors using HPMC and SMG that could positively influence the cross-linking effect in these ocular tissues. Formulations containing 10 mM SMG and 100 mM sodium bicarbonate were prepared with varying HPMC concentrations from 0 to 4.4%. Their cross-linking effects on porcine and rabbit eyes were measured using differential scanning calorimetry (DSC), expressed as the change/difference in melting temperature (ΔTm) compared with the control. SMG in 4.4% HPMC solution resulted in ΔTm of 6.3 ± 1.21, while other concentration showed no differences in Tm shift on porcine cornea. In ex vivo rabbit cornea, there was a trend toward an increasing cross-linking effect with higher viscosity albeit mild differences. While a significant Tm shift was observed in porcine and rabbit sclera, there was no difference in effect of cross-linking between four HPMC concentrations. Increasing the HPMC concentration does not negatively affect the cross-linking efficacy attributed by SMG and could still be a positive cross-linking enhancer by virtue of increasing tissue contact time in a dynamic biological system. This information will be useful for planning further animal and human studies.

The Timing Hypothesis: Hormone Therapy for Treating Symptomatic Women During Menopause and Its Relationship to Cardiovascular Disease.

The risks and benefits of menopausal hormonal therapy (HT) have been evaluated extensively over the past three decades. While the efficacy of HT for management of menopausal symptoms, including vasomotor symptoms and vaginal dryness is well established, its relationship to cardiovascular outcomes is complex. The timing hypothesis, which posits that the cardiovascular effects of HT depend on the timing of initiation of HT in relation to menopause, has helped shape our understanding of the cardiovascular outcomes related to HT. Based on results from female monkey studies, the timing hypothesis provides a framework to explain discrepancies in results between multiple observation studies and the Women's Health Initiative (WHI) hormone therapy trials. The WHI trials closed early in 2002 in part because of increased cardiovascular events seen in women on treatment. Subanalysis of the WHI results by age group, and more recent randomized control studies, including the Kronos Early Estrogen and Prevention Study (KEEPS) and Early Versus Late Intervention Trial (ELITE), demonstrate that the risk of adverse cardiovascular events for HT are low for women <60 years of age or within 10 year from menopause. Although current data does not support using HT for primary prevention of cardiovascular disease, it does suggest that HT can be safely used to treat symptoms in appropriately selected women close to menopause.

Breast Cancer Screening: Women's Attitudes and Beliefs in Light of Updated United States Preventive Services Task Force and American Cancer Society Guidelines.

BACKGROUND: In recently updated breast cancer screening guidelines, the American Cancer Society (ACS) and United States Preventive Services Task Force (USPSTF) recommended increasing mammography screening intervals for various age groups. In addition, ACS does not recommend clinical breast examination (CBE) for routine screening among average-risk women. Our study explores women's attitudes regarding screening mammography and CBE and evaluates the impact of the updated USPSTF and ACS guidelines on these attitudes. MATERIALS AND METHODS: Six hundred fourteen patients presenting to Mayo Clinic, Arizona and Minnesota, in July 2016 completed a self-administered survey, which included a summary of the updated guidelines. RESULTS: A majority of the 555 women who fit the inclusion criteria reported that CBE and mammogram are useful in detecting breast cancer and should be performed annually, and 51% of participants were unaware of the updated guidelines. Before reviewing the guidelines, 77% believed yearly CBE and 76% believed yearly mammogram was needed for routine screening. After reviewing the guidelines, the percentage of women who planned to continue with yearly CBE and mammogram decreased significantly to 61% and 64%, respectively (p < 0.001 and p < 0.001). Nearly half the participants (48%) believed the most influential reason for the guideline change was to decrease healthcare spending. CONCLUSION: Breast cancer screening is well received among patients, and a majority of surveyed women were unaware of recent guideline changes. After reviewing the guidelines, there was a significant downward shift in intended screening frequency, although the majority still planned to undergo annual screening. Informing women about updated evidence-based guidelines may influence their knowledge, preferences, and opinions.

The female athlete triad: It takes a team.

The female athlete triad is a syndrome consisting of low energy availability (ie, burning more calories than one is taking in), menstrual dysfunction, and low bone mineral density, although all 3 components need not be present. Many providers, physical therapists, and coaches are unaware of it and thus do not screen for it. Early intervention using a team approach is essential in patients with any component of the female athlete triad to prevent long-term adverse health effects.

Choke Attack: Atypical Cardiomyopathy Subsequent to Postnasal Drip.

Midventricular ballooning syndrome, an atypical presentation of takotsubo cardiomyopathy (TCM), presents with transient wall motion abnormalities of the midsegment of the left ventricle with apical sparing. In midventricular TCM, apical contractility is unaffected or may be hyperkinetic in contrast to the typical form of TCM. We report a case of atypical TCM, wherein the patient presented with chest pain following choking and coughing spells due to a postnasal drip.

Incidence and severity of pancreatogenic diabetes after pancreatic resection.

BACKGROUND: While many patients experience prolonged survival after pancreatic resection for benign or malignant disease, the long-term risk of pancreatogenic diabetes mellitus (DM) remains poorly characterized. METHODS: One thousand one hundred seven patients underwent pancreatectomy at Thomas Jefferson University between 2006 and 2013. Attempts were made to contact all living patients by telephone and a DM-focused questionnaire was administered. RESULTS: Two hundred fifty-nine of 691 (37 %) surviving patients completed the survey, including 179 pancreaticoduodenectomies (PD), 78 distal pancreatectomies (DP), and 2 total pancreatectomies. In the PD group, 44 (25 %) patients reported having DM prior to resection. Of these, 5 (12 %) had improved glucose control after resection and 21 (48 %) reported escalated DM medication requirements post-resection. Of 135 PD patients without preoperative DM, 24 (18 %) had new-onset DM postoperatively. In the DP group, 23 patients (29 %) had DM preoperatively. None had improved glucose control after resection, while six (26 %) had worse control after resection. Seventeen of 55 DP patients (31 %) without preoperative DM developed new-onset DM postoperatively (p = 0.04 vs. PD). Preoperative HgbA1C >6.0 %, glucose >124 mg/dL, and insulin use >2 units per day were associated with an increased risk of new-onset postoperative DM. CONCLUSIONS: The development or worsening of DM after pancreatic resection is extremely common, with different types of resections conveying different risks for disease progression. DP places patients at a greater risk for the development of new-onset postoperative diabetes when compared to PD. In contrast, patients with preoperative diabetes are more likely to experience worsening of their disease after PD as compared to DP. Patients should be screened prospectively, particularly those at highest risk, and informed of and educated about the potential for post-resection DM.

Ovarian leydig cell hyperplasia: an unusual case of virilization in a postmenopausal woman.

Objective. To report an unusual case of ovarian Leydig cell hyperplasia resulting in virilization in a postmenopausal woman. Methods. Patient's medical history and pertinent literature were reviewed. Results. A 64-year-old woman presented with virilization with worsening hirsutism, deepening of her voice, male musculature, and male pattern alopecia. Her pertinent past medical history included type 1 diabetes, hyperlipidemia, and hypertension. Her pertinent past surgical history included hysterectomy due to fibroids. On further work-up, her serum total testosterone was 506 ng/dL (nl range: 2-45) and free testosterone was 40 pg/mL (nl range: 0.1-6.4). After ruling out adrenal causes, the patient underwent an empiric bilateral oophorectomy that showed Leydig cell hyperplasia on pathology. Six weeks postoperatively, serum testosterone was undetectable with significant clinical improvement. Conclusion. Postmenopausal hyperandrogenism can be the result of numerous etiologies ranging from normal physiologic changes to ovarian or rarely adrenal tumors. Our patient was found to have Leydig cell hyperplasia of her ovaries, a rarely reported cause of virilization.

Phenotypic expression of polycystic ovary syndrome in South Asian women.

UNLABELLED: Polycystic ovary syndrome (PCOS) occurs in 6% to 10% of women and, as the most common worldwide endocrinopathy of reproductive-aged women, is linked to a constellation of reproductive and metabolic abnormalities, including anovulatory infertility, hirsutism, acne, and insulin resistance in association with metabolic syndrome. Despite a genetic component to PCOS, ethnicity plays an important role in the phenotypic expression of PCOS, with South Asian PCOS women having more severe reproductive and metabolic symptoms than other ethnic groups. South Asians with PCOS seek medical care at an earlier age for reproductive abnormalities; have a higher degree of hirsutism, infertility, and acne; and experience lower live birth rates following in vitro fertilization than do whites with PCOS. Similarly, South Asians with PCOS have a higher prevalence of insulin resistance and metabolic syndrome than do other PCOS-related ethnic groups of a similar body mass index. Inheritance of PCOS appears to have a complex genetic basis, including genetic differences based on ethnicity, which interact with lifestyle and other environmental factors to affect PCOS phenotypic expression. TARGET AUDIENCE: Obstetricians and Gynecologists, Family Physicians Learning Objectives: After completing this CME activity, physicians should be better able to state an ethnic difference in reproductive dysfunction between South Asian and white women with polycystic ovary syndrome (PCOS), state an ethnic difference in metabolic dysfunction between South Asian and white women with PCOS, identify a genetic abnormality found in South Asian women with PCOS, and list 2 environmental factors that predispose South Asian women to metabolic dysfunction.