Stephanie S. Faubion

Long-term health consequences of premature or early menopause and considerations for management

Abstract Aim To review the current evidence concerning the long-term harmful effects of premature or early menopause, and to discuss some of the clinical implications. Material and methods Narrative review of the literature. Results Women undergoing premature or early menopause, either following bilateral salpingo-oophorectomy or because of primary ovarian insufficiency, experience the early loss of estrogen and other ovarian hormones. The long-term consequences of premature or early menopause include adverse effects on cognition, mood, cardiovascular, bone, and sexual health, as well as an increased risk of early mortality. The use of hormone therapy has been shown to lessen some, although not all of these risks. Therefore, multiple medical societies recommend providing hormone therapy at least until the natural age of menopause. It is important to individualize hormone therapy for women with early estrogen deficiency, and higher dosages may be needed to approximate physiological concentrations found in premenopausal women. It is also important to address the psychological impact of early menopause and to review the options for fertility and the potential need for contraception, if the ovaries are intact. Conclusions Women who undergo premature or early menopause should receive individualized hormone therapy and counseling.

Recognition and Management of Nonrelaxing Pelvic Floor Dysfunction

Nonrelaxing pelvic floor dysfunction is not widely recognized. Unlike in pelvic floor disorders caused by relaxed muscles (eg, pelvic organ prolapse or urinary incontinence, both of which often are identified readily), women affected by nonrelaxing pelvic floor dysfunction may present with a broad range of nonspecific symptoms. These may include pain and problems with defecation, urination, and sexual function, which require relaxation and coordination of pelvic floor muscles and urinary and anal sphincters. These symptoms may adversely affect quality of life. Focus on the global symptom complex, rather than the individual symptoms, may help the clinician identify the condition. The primary care provider is in a position to intervene early, efficiently, and effectively by (1) recognizing the range of symptoms that might suggest nonrelaxing pelvic floor dysfunction, (2) educating patients, (3) performing selective tests when needed to confirm the diagnosis, and (4) providing early referral for physical therapy.

Prescribing menopausal hormone therapy: an evidence-based approach

The constantly changing landscape regarding menopausal hormone therapy (MHT) has been challenging for providers caring for menopausal women. After a decade of fear and uncertainty regarding MHT, reanalysis of the Women’s Health Initiative data and the results of recent studies have provided some clarity regarding the balance of risks and benefits of systemic MHT. Age and years since menopause are now known to be important variables affecting the benefit-risk profile. For symptomatic menopausal women who are under 60 years of age or within 10 years of menopause, the benefits of MHT generally outweigh the risks. Systemic MHT initiated early in menopause appears to slow the progression of atherosclerotic disease, thereby reducing the risk of cardiovascular disease and mortality. During this window of opportunity, MHT might also provide protection against cognitive decline. In older women and women more than 10 years past menopause, the risk-benefit balance of MHT is less favorable, particularly with regard to cardiovascular risk and cognitive impairment. For women entering menopause prematurely (<40 years), MHT ameliorates the risk of cardiovascular disease, osteoporosis, and cognitive decline. Nonoral administration of estrogen offers advantages due to the lack of first-pass hepatic metabolism, which in turn avoids the increased hepatic synthesis of clotting proteins, C-reactive protein, triglycerides, and sex hormone-binding globulin. The duration of combined MHT use is ideally limited to less than 5 years because of the known increase in breast cancer risk after 3–5 years of use. Limitations to use of estrogen only MHT are less clear, since breast cancer risk does not appear to increase with use of estrogen alone. For women under the age of 60 years, or within 10 years of onset of natural menopause, MHT for the treatment of bothersome menopausal symptoms poses low risk and is an acceptable option, particularly when nonhormonal management approaches fail.

Oral vs Transdermal Estrogen Therapy and Vascular Events: A Systematic Review and Meta-Analysis

BACKGROUND Menopausal hormone therapy is widely used to alleviate climacteric symptoms but may increase the risk of venous and arterial vascular events. OBJECTIVE The objective was to synthesize the evidence about the risk of vascular events in postmenopausal women who use oral estrogen therapy (ET) and transdermal ET. METHODS We searched bibliographical databases through August 2013 for longitudinal comparative studies that enrolled postmenopausal women using either oral or transdermal ET and reported the outcomes of interest: venous thromboembolism (VTE), pulmonary embolism, deep venous thrombosis (DVT), myocardial infarction (MI), and stroke. Two reviewers independently selected and appraised studies. Outcomes were pooled using random effects meta-analysis and were reported as risk ratio (RR) and 95% confidence interval (CI). RESULTS We included 15 observational studies at moderate risk of bias with follow-up of 3 to 20.25 years. When compared to transdermal ET, oral ET was associated with increased risk of a first episode of VTE (RR, 1.63; 95% CI, 1.40-1.90; I(2) = 53%), DVT (RR, 2.09; 95% CI, 1.35-3.23; I(2) = 0 %), and possibly stroke (RR, 1.24; 95% CI, 1.03-1.48; a single case-controlled study), but not MI (RR, 1.17; 95% CI, 0.80-1.71; I(2) = 74%). CONCLUSION Observational evidence warranting low confidence suggests that compared to transdermal ET, oral ET may be associated with increased risk of VTE and DVT, but not MI.

Accelerated Accumulation of Multimorbidity After Bilateral Oophorectomy: A Population-Based Cohort Study

Objective To study the association between bilateral oophorectomy and the rate of accumulation of multimorbidity. Patients and Methods In this historical cohort study, the Rochester Epidemiology Project records-linkage system was used to identify all premenopausal women who underwent bilateral oophorectomy before age 50 years between January 1, 1988, and December 31, 2007, in Olmsted County, Minnesota. Each woman was randomly matched to a referent woman born in the same year (± 1 year) who had not undergone bilateral oophorectomy. We studied the rate of accumulation of 18 common chronic conditions over a median of approximately 14 years of follow-up. Results Although women who underwent bilateral oophorectomy already had a higher multimorbidity burden at the time of oophorectomy, they also experienced a significantly increased risk of subsequent multimorbidity (P=.XX). After adjustments for 18 chronic conditions present at baseline, race/ethnicity, education, body mass index, smoking, age at baseline, and calendar year at baseline, women who underwent oophorectomy before age 46 years experienced an increased risk of depression, hyperlipidemia, cardiac arrhythmias, coronary artery disease, arthritis, asthma, chronic obstructive pulmonary disease, and osteoporosis. In addition, they experienced an accelerated rate of accumulation of the 18 chronic conditions considered together (hazard ratio, 1.22; 95% CI, 1.14–1.31; P<.001). Several of these associations were reduced in women who received estrogen therapy. Conclusion Bilateral oophorectomy is associated with a higher risk of multimorbidity, even after adjustment for conditions present at baseline and for several possible confounders. However, several of these associations were reduced in women who received estrogen therapy.

Menopausal Hormone Therapy and Mortality: A Systematic Review and Meta-Analysis

OBJECTIVES The objective was to assess the effect of menopausal hormonal therapy (MHT) on all-cause and cause-specific mortality. METHODS We conducted a comprehensive search of several databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus) from inception until August 2013. We included randomized controlled trials (RCTs) of more than 6 months of duration comparing MHT with no treatment. Pairs of independent reviewers selected trials, assessed risk of bias and extracted data. We estimated risk ratios (RRs) and 95% confidence intervals (CIs) using the random-effects model. RESULTS We included 43 RCTs at moderate risk of bias. Meta-analysis showed no effect on mortality (RR 0.99 [95% CI, 0.94-1.05]), regardless of MHT type or history of preexisting heart disease. No association was found between MHT and cardiac death (RR 1.04 [95% CI 0.87-1.23]) or stroke (RR 1.49 [95% CI 0.95-2.31]). Estrogen plus progesterone use was associated with a likely increase in breast cancer mortality (RR 1.96 [95% CI 0.98-3.94]), whereas estrogen use was not. MHT use was not associated with mortality of other types of cancer. In 5 trials, MHT was likely started at a younger age: 2 RCTs with mean age less than 60 and 3 RCTs with MHT started less than 10 years after menopause. Meta-analysis of these 5 RCTs showed a reduction of mortality with MHT (RR 0.70 [95% CI 0.52-0.95]). CONCLUSION The current evidence suggests that MHT does not affect the risk of death from all causes, cardiac death and death from stroke or cancer. These data may be used to support clinical and policy deliberations about the role of MHT in the care of symptomatic postmenopausal women.

Hormonal manipulation strategies in the management of menstrual migraine and other hormonally related headaches.

Menstrual migraine and other hormonally related headaches are common in women. Falling estrogen levels or estrogen withdrawal after periods of sustained higher levels can trigger migraine. It makes sense to target this trigger for management of hormonally related headaches, particularly when nonhormonal strategies have been unsuccessful. Decision making regarding the use of hormonal contraception and menopausal hormone therapy is complex and commonly driven by other factors, but hormonal manipulation can potentially improve the course of migraine. Providers caring for migraineurs are appropriately concerned about stroke risk. Estrogen-containing hormonal contraceptives are relatively contraindicated for women who have migraine with aura. Postmenopausal hormone therapy is acceptable for women with a history of migraine. For these women, transdermal estradiol is recommended. Estrogen replacement is important for women who undergo an early menopause, whether natural or induced. Practical strategies for hormonal manipulation in the management of migraine and other hormonally related headaches are presented.

Bilateral Oophorectomy and Accelerated Aging: Cause or Effect?

Background The cause-effect relationship between bilateral oophorectomy and accelerated aging remains controversial. We conducted new analyses to further address this controversy. Methods The Rochester Epidemiology Project records-linkage system was used to identify all premenopausal women who underwent bilateral oophorectomy for a noncancerous condition before age 50 years between 1988 and 2007 in Olmsted County, MN. Each woman was randomly matched to a referent woman born in the same year (±1 year) who had not undergone bilateral oophorectomy. We studied the rate of accumulation of 18 common chronic conditions over a median of approximately 14 years of follow-up (historical cohort study). Analyses were restricted to women free of any of the 18 chronic conditions at the time of oophorectomy (or index date). Results After adjustments for race/ethnicity, education, body mass index, smoking, and age and calendar year at the index date, women who underwent oophorectomy before age 46 years experienced an accelerated rate of accumulation of the 18 chronic conditions considered together (hazard ratio = 1.24; 95% confidence interval: 1.12, 1.37; p < .001). The single-year incidence rate of new conditions was most different in the first 6 years after oophorectomy but the difference attenuated thereafter. Findings did not vary by surgical indication for the oophorectomy. Conclusions Bilateral oophorectomy is associated with a higher risk of multimorbidity among women who did not have any of the 18 selected conditions at baseline. The association did not vary by surgical indication for oophorectomy. Our findings suggest that bilateral oophorectomy is causally linked to accelerated aging.

Caring for the breast cancer survivor's health and well-being.

The breast cancer care continuum entails detection, diagnosis, treatment, and survivorship. During this time, focus on the whole woman and medical concerns beyond the breast cancer diagnosis itself is essential. In this comprehensive review, we critically review and evaluate recent evidence regarding several topics pertinent to and specific for the woman living with a prior history of breast cancer. More specifically, we discuss the most recent recommendations for contraceptive options including long-acting reversible contraception and emergency contraception, fertility and pregnancy considerations during and after breast cancer treatment, management of menopausal vasomotors symptoms and vulvovaginal atrophy which often occurs even in young women during treatment for breast cancer. The need to directly query the patient about these concerns is emphasized. Our focus is on non-systemic hormones and non-hormonal options. Our holistic approach to the care of the breast cancer survivor includes such preventive health issues as sexual and bone health,which are important in optimizing quality of life. We also discuss strategies for breast cancer recurrence surveillance in the setting of a prior breast cancer diagnosis. This review is intended for primary care practitioners as well as specialists caring for female breast cancer survivors and includes key points for evidence-based best practice recommendations.

Sex Differences Research, Precision Medicine, and the Future of Women's Health

Abstract The National Institutes of Healths (NIH) commitment to improving health outcomes for women and men through rigorous science has been compromised by the lack of basic science evidence obtained from female animals. To correct this limitation, in June 2015 the NIH announced expectations that “sex,” as a biological variable, be included into research design and analysis in studies of vertebrate animals and humans (NOT-OD-15-102). Scientists must take the responsibility to implement this directive. However, in doing so, there is a risk that attention could be restricted to only studies of direct comparison between female/women and male/men. By contrast, understanding how sex influences health and disease needs to take a programmatic approach that includes the study of sex-specific conditions. A programmatic approach will assure the advancement of knowledge to improve womens health.