Understanding Menopause-Associated Risks

Individualized Assessment of Risk for Menopause-Related Sequelae

Women in the peri- and postmenopause are at increased risk for osteoporosis, cardiovascular disease (CVD) and cognitive impairment. In this section, we provide a brief overview of individualized risk assessment for these common conditions.

Osteoporosis Risk Assessment

Osteoporosis is the loss of bone mineral density (BMD) and bone mass that predisposes the affected individual to bone fracture. An individual’s BMD may be expressed as a T-score, which is defined as “the standard deviation of an individual’s bone mineral density (BMD) from the mean value for young normal White women.” The World Health Organization (WHO) defines osteoporosis as a T-score of -2.5 and below. Peak bone mass is achieved by age 20 in women, and is generally lower than in men. This is one of the factors that skews the sex ratio of osteoporosis, with rates of osteoporotic fracture in women (21-29% lifetime risk, depending on the fracture site) being approximately double the rates in men (5-14% lifetime risk). Other modifiable and non-modifiable risk factors for osteoporosis are shown in Table 3-1.

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Current guidelines from the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) recommend evaluating all women 50 years of age and older for osteoporosis risk. Initial evaluation should include a detailed history, physical exam and clinical fracture risk assessment using a validated risk assessment tool, such as FRAX®. FRAX®, available at the University of Sheffield’s web site (https://frax.shef.ac.uk/FRAX/tool.aspx), is a questionnaire that integrates information on risk factors to provide a 10-year major osteoporotic and hip fracture risk. The risk profile may warrant investigation of bone mineral density (BMD); the guidelines recommend using dual-energy X-ray absorptiometry (DXA) to measure BMD in the lumbar spine, hip and, if indicated, 1/3 radius. Osteoporosis is diagnosed if:

• There is a fragility bone fracture, even with a normal T-score determined by DXA
• The T-score in the lumbar spine, femoral neck, total hip, or 1/3 radius, regardless of the presence or absence of a prevalent fracture

Osteoporosis may also be diagnosed in patients with a T-score of -1.0 to -2.5 if the FRAX® score if sufficiently elevated, based on country-specific thresholds (e.g., ≥20% risk of major osteoporotic fracture or ≥3% risk of hip fracture in the US). Patients with confirmed osteoporosis should be evaluated for secondary causes and for prevalent vertebral fractures.

Cardiovascular Disease Risk Assessment

Cardiovascular disease is the leading cause of death in globally, with ischemic heart disease and stroke accounting for 16% and 11% of all deaths in 2019, respectively. Both genetic and environmental (including social) factors contribute to CVD risk, with smoking, diabetes, hypertension and elevated low-density lipoprotein cholesterol (LDL-C) being the major modifiable risk factors. The risk of CVD in women increases after menopause, particularly early menopause. This is likely due to the cardioprotective influence of estrogen. Direct action of estrogen on vascular endothelial cells promotes vasodilation, cell proliferation and cell migration, decreasing vascular resistance and increasing the regenerative capacity of the endothelium. Estrogen also acts on cardiomyocytes, reducing LDL-C and insulin resistance and limiting atherosclerosis and ischemic injury. Cardiometabolic changes that occur during the menopausal transition and increase CVD risk are shown in Figure 3-5. Briefly, the progression and severity of metabolic syndrome increase in the late premenopause and early perimenopause, carotid atherosclerosis rapidly increases in the late perimenopause and arterial stiffness increases within the first year of the last menstruation. The period around the final menstrual period is characterized by an increase in visceral adiposity and a decline in lean mass. The lipid profile typically changes in the same period, with an increase in total cholesterol and atherogenic species, including LDL-C and apolipoprotein B.

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The increase in CVD risk associated with perimenopause is highest in women who experience early menopause and decreases with increasing age at menopause onset. An international analysis of more than 300,000 women found that, compared with women who experienced menopause at age 50-51 years, CVD risk was significantly higher in women who experienced menopause at age <40 years (hazard ratio [HR] 1.55), age 40-44 years (HR 1.30) and age 45-49 years (HR 1.12) and lower in women who had menopause at age 52-54 (HR 0.96) and age ≥55 (HR 0.88).

There are no strong recommendations for CVD risk assessment specific to peri- and postmenopausal women. The 2014 North American Menopause Society (NAMS) guidelines recommend that healthcare providers apply the CVD risk assessment criteria from the American College of Cardiology (ACC) and the American Heart Association (AHA), which apply to the general population. The current (2019) ACC/AHA guidelines for the primary prevention of atherosclerotic CVD (ASCVD) recommend that a 10-year ASCVD risk assessment be performed for all patients 40-75 years of age other than those who would immediately benefit from lipid-lowering therapy. In cases of borderline (5% to <7.5%) and intermediate (7.5% to <20%) risk, CVD risk enhancers should be taken into consideration in the decision of whether to start lipid-lowering therapy; premature menopause (menopause at age <40 years) is one such risk enhancer.

Cognitive Decline Risk Assessment

Approximately 50-60% of women report symptoms of cognitive decline during menopausal transition, including verbal and numeric forgetfulness, impaired thinking and forgetting appointments or the purpose/intention of a behavior. Some data suggests that objective cognitive performance may not change in perimenopause (or, if decreased, remains within normative bounds), but subjective perception of cognitive performance may decrease. In one study, memory complaints were associated with decreased working memory and complex attention performance, but not verbal learning or verbal memory. There is data to suggest that verbal memory decline is associated with objectively measured hot flashes (HFs), but not self-reported HFs, in women who experience moderate-to-severe HFs. Longitudinal studies have revealed that overall, perimenopause has a small but statistically significant negative effect on cognitive performance. However, it currently unknown whether the cognitive decline experienced during perimenopause persists in postmenopause.

No specific screening or risk assessment for cognitive decline is indicated for women in menopause transition. If a patient complains of cognitive difficulties, it is recommended to normalize the experience, noting that a transient cognitive decline is not unusual in perimenopause. Cognitive testing may be performed, while reassuring the patient that even if an individual decline in performance is uncovered, the results are likely to fall in the normative range. If clinically significant functional impairment is discovered or if the patient reports decreased everyday functionality because of her symptoms, a referral to a neuropsychiatrist may be appropriate.

Management of Menopause-Related Sequelae

In this section, we provide a brief overview of the options for prevention and management of common menopause-associated sequelae.

Osteoporosis Management

Women in the menopause transition who have been diagnosed with osteoporosis but do not have bothersome VMS should be treated for osteoporosis only.

The current AACE/ACE guidelines recommend first correcting any calcium or vitamin D deficiency before starting patient education and pharmacologic therapy. Patient education should include discussion of lifestyle measures (keeping fit and active, ensuring adequate calcium and vitamin D intake), measures to limit fall risk (e.g., minimizing clutter at home, installing handrails, etc.) and the risk-benefit profile of medications.

The choice of pharmacotherapy depends on whether the patient is at very high risk of fractures (a category which includes persons with prior fractures and those of advanced age, frailty, on glucocorticoid therapy, with very low T-scores, or at increased fall risk) or not. For patients at very high risk, the recommended pharmacologic options include abaloparatide (a parathyroid hormone (PTH)-related protein that stimulates bone formation), denosumab (a monoclonal antibody [mAb] that inhibits bone resorption), romosozumab (a mAb that stimulates bone formation and inhibits resorption), teriparatide (a PTH fragment that increases bone growth) and zoledronate (a bisphosphonate that inhibits bone resorption); alternative options include the bisphosphonates alendronate and risedronate. For patients at high risk (i.e., not at very high risk), denosumab and the bisphosphonates alendronate, risedronate and zoledronate are the preferred options, with ibandronate (another bisphosphonate) and raloxifene (a selective estrogen receptor modulator) as alternatives. These options and yearly assessments/therapy modification strategies are presented in Figure 3-6.

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Certain formulations of menopausal hormone therapy (MHT) (including estrogen-only and combination products) are FDA-approved for the prevention of osteoporosis in postmenopausal women, but none are approved for osteoporosis treatment. Despite being FDA-approved, the use of MHT for osteoporosis prevention in the absence of other menopause-related symptoms is controversial and is recommended against by the US Preventive Services Task Force.

Cardiovascular Risk Management

In general, the management of CVD risk is not different for women in peri- or postmenopause and the general population. Primary prevention entails leading a heart-healthy lifestyle, including getting enough exercise (a weekly minimum of 150 or 75 minutes per week of moderate- or high-intensity exercise, respectively) and adopting or maintaining a healthy diet (rich in vegetables, fruits, nuts, whole grains and lean vegetable or animal protein). Patients with primary hyperlipidemia (LDL-C level of 190 mg/dL or higher), type 2 diabetes, or a 10-year ASCVD risk of ≥20% should be on pharmacologic lipid-lowering therapy (with statins as a first-line option). Lipid-lowering therapy may also be appropriate for patients with a 10-year ASCVD risk of 5 to <20%, if the calculated risk estimate and risk enhancers (which include premature menopause) favor it.

Although data from the WHI studies suggests a CVD prevention benefit for MHT in recently menopausal women, MHT should not be used for this purpose in the absence of other symptoms. In women with premature and early menopause, MHT should be used until the age of normal menopause to prevent CVD.

Cognitive Decline Management

No generally effective treatment exists for menopause-related cognitive decline. Mild attention or memory deficits may be attenuated by patient education, such as training the patient to attempt focusing attention or to use mnemonic devices. Therapy for other bothersome symptoms of menopause, including MHT and non-hormonal therapy may also secondarily improve cognitive function, as may exercise and improved sleep discipline. However, it should be noted that no clinical trials or other evidence support the use of MHT for the sole purpose of alleviating cognitive impairment (i.e., in the absence of other bothersome menopausal symptoms).