Perimenopause and Menopause

Nanette Santoro, MD: Nanette Santoro, MDMenopause is having a moment. News articles appear daily, and celebrity testimonials abound on social media. There is a renewed interest in hormone therapy. New hormonal (estetrol) and non-hormonal (NK3 receptor antagonists) treatments are coming to market. Attention to these trends is long overdue. As obstetrician–gynecologists, we are obligated to rise to the occasion. There is an enormous unmet need for dissemination of high-quality information about menopause and perimenopause. Hormone therapy, the best and most effective single treatment for most women with menopausal symptoms (and especially those with multisystem symptoms), remains at historically low levels of use (fewer than 4% of age-eligible women1) despite the high prevalence of moderate-to-severe vasomotor symptoms (16–40% depending on the population studied)2 and a clamor for more attention to workplace accommodations for perimenopausal women.3 There is much work to be done. There is more to menopause than the simple narrative of hormone loss, however. A combination of sensitivity to changing estrogen levels, susceptibility to cancer and cardiometabolic disease, and familial health risks paint an individual picture from which clinicians can help forecast the future for each of our patients. Predictive tools for common diseases such as cardiometabolic disease and fractures already exist. A 10-year predictor of disability has been developed recently for women in midlife.4 Polygenic risk scores and pharmacogenomics soon will allow us to further predict disease risks and point clinicians toward the most effective strategies to help our patients achieve healthy longevity. A narrow focus on hormone therapy as a cure-all for people in menopause misses the forest for the trees. Two important, ongoing studies have and will continue to guide us. SWAN (the Study of Women's Health Across the Nation) is entering its 30th year and has contributed a great deal of data about the natural history of the menopause transition and the health trajectories of its participants over decades of follow-up. SWAN has shown us that the 3–5 years surrounding the final menstrual period, the transmenopause, is associated with up to 10% overall skeletal bone loss.5 In addition, there is a rise in low-density lipoprotein cholesterol levels, increasing density of high-density lipoprotein particle size, accrual of carotid intimal medial thickness, and a change in body composition, with a small loss of lean body mass and its replacement with adipose tissue.6 These latter processes accelerate during the menopausal transition but restabilize after the final menstrual period and then assume a more benign trajectory, strongly implying that they are a direct consequence of menopause. In its upcoming iteration, SWAN will provide information on how or whether the menopause experience per se is associated with long-term major health outcomes such as heart disease, dementia, frailty, and fractures. The Women's Health Initiative remains a treasure trove of long-term follow-up data that can link hormone use for 6–8 years to a variety of morbidity and mortality outcomes. As we continue to accrue outcomes on participants, the data overall have provided reassurance about the use of hormone therapy; outcomes appear neither better nor worse from the typical systemic exposure that hormone users will have if they experience symptoms for their median duration. Why are we doing so poorly at eliciting and addressing common symptoms of menopause? Two main explanations have been proffered. The first of these suggests that the ability to treat menopausal symptoms with hormone therapy died with the publication of the Women's Health Initiative’s principal findings in 2002 and 20047 and the ensuing unfortunate adverse media treatment. The level of comfort and expertise in evaluation and treatment of menopausal patients reported by residents in obstetrics and gynecology and other specialties remains very low, with only 6.8% of residents surveyed reporting feeling adequately prepared to address menopausal issues8—and we are the specialists who ought to have the most expertise. The second reason is that not everything related to menopause and midlife women's health can and should be focused on hormones or symptoms. SWAN has shown us the importance of health trajectories—and how dramatically they can change with the menopause transition for some. Facility with treatment of the underlying conditions driving these risks, such as weight loss, physical activity, and lipid lowering, need to become a central part of the practice of health care for women in midlife. A final important caveat to our knowledge of the menopausal transition and beyond is that we often wind up attempting to treat perimenopause and menopause as the same condition—even though our knowledge of perimenopause remains incomplete. We do not know exactly when the process begins. We rely on menstrual-based definitions and have no adequate biochemical or imaging tools to standardize the onset. When surveys are conducted on women in their 30s, many describe symptoms identical to those of the menopausal transition. There clearly remains much to be learned. Not all women with cyclical symptoms in their 30s and 40s are perimenopausal, and it is important to distinguish what is menopause-related from what is not. The upcoming series of articles in Obstetrics & Gynecology devoted to the issues of perimenopause and menopause is therefore welcomed. It is time to bring attention back to the nearly universal symptomatology that besets women in midlife and to implement robust, evidence-based treatment options for them. In this month's issue of Obstetrics & Gynecology, two important areas of inquiry are addressed. Menegaz De Almeida et al9 (see page 253) report on the aggregate data for the new, highly effective class of nonhormone treatments for vasomotor symptoms: fezolinetant and elinzanetant. These treatments are new to market, with the former in clinical use for about 2 years and the latter pending U.S. Food and Drug Administration approval. Brown et al10 (see page 247) point out the sizeable gaps in knowledge and the urgent need for attention to the menopausal experience of military women. They highlight the multiple risk factors that augur for a more symptomatic menopausal transition for military women and describe the systemic factors that work against career advancement concurrent with menopause. A team of experts will be providing the backdrop and communicating the current state of knowledge and best practices for other issues surrounding menopause. There is much to learn and implement. Our patients deserve nothing less.