World-renowned menopause experts summarize the state of menopause knowledge and advocate for further research

By Vijay Kumar MalesuReviewed by Danielle Ellis, B.Sc.Sep 6 2023

In a recent review published in Cell, a group of authors delved into the complexities of menopause, assessed its global impacts on health, and evaluated the effectiveness and safety of current treatments, emphasizing the importance of further research.

Background

Menopause, commonly experienced by women past midlife, marks the end of ovarian function and fertility. This review acknowledges that some transgender men and non-binary individuals might also undergo menopause.

While traditionally linked to a woman's last menstrual cycle, its definition broadens for those with irregular menstruations. Individual and cultural perceptions of menopause vary, ranging from significant discomfort to a mere inconvenience.

Despite being a natural phase, interventions can alleviate symptoms, and while post-menopausal hormonal changes heighten chronic disease risks, menopausal hormone therapy might reduce these risks. Further research regarding the biology, effects, support, and treatments of menopause is necessary.

Biology of menopause and diagnostic approaches

Menopause traditionally denotes a year without menstruation due to oocyte depletion. However, this does not apply to all women, especially those with irregular periods or who have undergone certain medical procedures. The Stages of Reproductive Aging Workshop +10 (STRAW+10) offers a detailed profile of the menopausal transition.

Physiological stages and symptoms

Reproductive aging is marked by missed menstrual periods, denoting the early menopause transition. As the follicle pool decreases, the duration of amenorrhea increases, leading to pronounced menopausal symptoms such as hot flashes, mood swings, and sleep disturbances.

Diagnostic measures

In cases where the onset of the Final Menstrual Period (FMP) needs prediction or confirmation, measuring hormones like prolactin, Follicle Stimulating Hormone

(FSH), and Anti-Mullerian Hormone(AMH) can be helpful. AMH indicates the ovarian follicle reserve and potential menopause onset, but its accuracy varies; menopause diagnosis should primarily rely on clinical symptoms, complemented by hormone levels.

Menopausal timing and mechanisms

Menopause typically occurs around age 49 across various ethnicities and regions. The rate of oocyte loss, starting in fetal life and persisting into adulthood, is the primary cause of menstrual cycle changes and menopause onset, with hormonal shifts in inhibin B and AMH playing significant roles.

Central role of the hypothalamus

Before menopause, the hypothalamus experiences functional modifications that affect reproductive aging. The changing release patterns of FSH and Luteinizing Hormone (LH), along with disrupted ovulation, hint at an underlying system in the central nervous system guiding reproductive aging.

Menopausal symptoms overview

Menopause varies among women: while some transition smoothly, others face disruptive symptoms like Vasomotor Symptoms (VMS), sleep disruptions, mood swings, and urogenital changes. Often starting before their 50s, the prevalence of VMS rises with age, affecting 66% of perimenopausal women. 

In some countries, joint pain surpasses VMS as a primary symptom, with socio-economic factors heightening VMS risks. Menopause exacerbates sleep problems, and mood disorders like depression have diverse origins. Post-menopausal hypoestrogenism causes progressive vaginal atrophy and urogenital symptoms, which are often underreported and require treatment.

Health implications of menopause

Menopause can elevate risks for several health issues, necessitating regular screenings. Optimal postmenopausal care requires a balanced lifestyle, with an emphasis on health screenings, physical activity, and a balanced diet.

Silent health consequences of menopause

Systemic effects of menopause

Irrespective of the presence of symptoms, hormonal changes during menopause have systemic impacts, increasing the risk of cardiovascular diseases (CVD), diabetes, certain cancers, and bone fragility. Menopause induces metabolic system changes, resulting in increased body fat, especially visceral fat. Decreased physical activity and muscle atrophy at this stage lead to insulin resistance and poor lipoprotein profiles, escalating risks for several cancers and possibly linking to estrogen withdrawal.

Cardiovascular and metabolic implications

Menopausal women experience body fat redistribution and a decline in insulin efficiency in muscle tissues. Estrogen plays a pivotal role in maintaining insulin sensitivity and vascular function, safeguarding against CVD and diabetes. Menopause elevates risks for cardiac and cerebrovascular events due to estrogen loss and subsequent vascular dysfunction.

Bone and muscle health during menopause

Bone and muscle health are intertwined, with muscle proteins influencing bone turnover. Menopause leads to rapid bone loss due to estrogen's decline, causing an imbalance in bone resorption. Estrogen's protective effect against bone loss diminishes, increasing the risk of osteoporosis and fractures. Estrogen also affects muscle health, and its decline can cause muscle deterioration.

Cognition and sleep

Menopausal women often report cognitive issues like memory lapses and impaired problem-solving. Sleep disruptions, prevalent during menopause, can further affect cognition. While early menopause's link to cognitive impairment is debated, it is unclear if symptoms result from estrogen decline or secondary factors. Guidelines discourage menopause hormone therapy for cognitive issues or dementia prevention.

Menopause in the workplace: implications and needs

Menopausal symptoms, especially in unsupportive environments, can diminish work performance and result in negative outcomes, particularly among Black and Hispanic women. With economic costs spanning medical expenses to lost productivity, there is an urgent need for holistic workplace support and expanded research that includes home-based workers.

Therapeutic options for menopause-associated symptoms 

Many women do not require treatment for menopausal symptoms. Lifestyle improvements and managing Non-Communicable Disease (NCD) risks are initial steps. Yet, a significant percentage of women, especially in high-income countries, do not get effective regulator-approved treatments. Common prescriptions include sex hormone therapies and compounds influencing hormone receptors.

Complementary and alternate medicines (CAMs)

CAMs for menopausal relief, like phytoestrogen supplements and black cohosh, are popular but often lack scientific evidence of efficacy. Black cohosh, distinct from toxic blue cohosh, has limited efficacy with safety concerns. Acupuncture has not outperformed placebos, while cognitive behavioral therapy offers symptom relief and additional mood and sleep benefits.

Non-Hormonal prescription therapies

Several non-hormonal drugs have incidentally been found effective against VMS. Medications like selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors (SSRI/SNRIs), gabapentin, and clonidine are commonly prescribed. Notably, the discovery of neurotransmitters in the hypothalamus led to the development of neurokinin 3B (NK3B) antagonists, which show significant promise against VMS.

Sex hormone therapy

Estrogen, administered alone or with progestogen, is the primary treatment for menopausal symptoms, commonly delivered through oral or transdermal methods. Each has specific metabolic impacts, with oral routes affecting lipid profiles and coagulation proteins. Concomitant progestogen therapy is essential for non-hysterectomized women to prevent endometrial issues. The impact of hormone therapy on conditions like breast cancer remains controversial.

Treatment considerations in perimenopause

Managing symptoms during perimenopause can be more challenging due to intermittent ovarian function. Approaches vary globally but often involve hormonal contraceptives. Recommendations suggest initiating Menopausal Hormone Therapy (MHT) for women up to age 59 or within 10 years of menopause onset. This guidance has its complexities, as shown in long-term follow-up studies.

Selective estrogen receptor modulators (SERMs) and their use

SERMs are synthetic hormones that target specific tissues, aiding menopause management. Key ones include raloxifene, which can reduce the risk of certain fractures and breast cancers. However, they may come with side effects like leg cramps and an increased risk of some severe conditions.

Ovarian tissue preservation

Fertility preservation techniques, such as cryopreservation of ovarian tissue, can postpone menopause and increase the chances of pregnancy in certain situations. The ethics and implications of such treatments remain debated.

Treatment of urogenital atrophy

Urogenital atrophy can be treated with various approaches like vaginal estrogen, Dehydroepiandrosterone (DHEA) therapies, and SERMs. However, some treatments might come with side effects or lack comprehensive long-term studies.