Menopause Presentation

Introduction

In this module, we provide an overview of the wide spectrum of symptoms associated with the menopausal transition (i.e., peri- and postmenopause) and briefly discuss the diagnostic approach for menopause, including possible differential diagnoses.

Symptoms of Menopause

As many as 90% of women experience symptoms during menopause. Even though most women associate menopausal symptoms with the cessation of menstrual periods, they often occur before changes in menstrual cycles or even before detectable changes in hormone levels. The most symptomatic years are typically in the perimenopause. Furthermore, women who experience menopausal symptoms during this period are highly likely to experience multiple symptoms. The most prominent symptoms of menopause – at least in the best-studied, Western populations – are related to the central nervous system (CNS)-related symptoms (including vasomotor symptoms [VMS], sleep disturbances, anxiety, depression) and urogenital symptoms. Other symptoms may include skin, mucosal and hair changes, weight and metabolic changes, musculoskeletal issues and sexual dysfunction (Figure 2-1).

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Vasomotor Symptoms

Vasomotor symptoms include hot flashes (HFs) and night sweats, occasionally followed by trembling and a feeling of coldness. Throughout menopause, as many as 75% of women will experience VMS, with 30% of them experiencing moderate to severe symptoms. These symptoms can appear as early as 10 years prior to the final menstrual period, and may persist well into the postmenopausal stage. One study conducted in Australian women aged 65-79 reported that one-third of participants still reported VMS at that age. Individuals who experience VMS earlier during menopause appear to be more likely to have persistent VMS late into postmenopause as well. However, VMS typically last around 7.4 years, with about 4.5 of those year being after the final menstrual period. The total duration of VMS varies significantly by race and ethnicity, being longest in African American women (median 10.1 years) and shortest in Chinese (median 5.4 years) and Japanese (median 4.8 years) women.

The majority of women experiencing menopausal symptoms report having HFs, which are characterized by episodic sensations of heat, often accompanied by sweating, skin reddening and palpitations. Hot flashes typically start in the upper body, most commonly in the chest and progress upward (to the neck, face and hairline) and downward, spreading throughout the body. In a study of US women in menopause who were experiencing HFs, 87% reported having at least one HF on a daily basis; one-third of participants with HFs reported having more than 10 daily.

Hot flashes can occur during the day or night, with some women waking up several times each night. They can be spontaneous or triggered by various factors such as stress, environment temperature changes and certain substances (including commonly consumed substances like alcohol and caffeine). The duration of an HF can be variable, with episodes lasting from 30 seconds to 1 hour; a typical episode often lasts no longer than 5 minutes. Hot flashes commonly occur in late perimenopause and the initial postmenopausal years, and, for most women, persist as a symptom for 6 months to 2 years. However, some studies suggests that an extended duration of the period when HF can occur, lasting up to 10 years after the final menstrual period.

Surgical menopause, early menopause and smoking represent significant risk factors for the onset and severity of HFs. Surgical menopause is associated with a very high probability (around 90%) of HFs in the first year. Declining levels of estrogens and inhibin B, along with increased FSH levels, are traditionally seen as the root cause for these episodes. However, while hormonal changes offer partial insight into thermoregulation dysfunction, additional mechanisms such as alterations in brain neurotransmitters and peripheral vascular reactivity play an important role. Core body temperature (Tc) is regulated within upper and lower thresholds for sweating and shivering, respectively, with a neutral zone in between. When Tc surpasses the upper threshold, a HF is triggered; when Tc goes below the lower threshold, shivering occurs. Thermoregulation is under catecholaminergic and serotonergic control, with the hypothalamus playing a central role. The kisspeptin-neurokinin B-dynorphin (KNDy) signaling system in the hypothalamus, which is responsible both for stimulating gonadotropin-releasing hormone secretion and for regulating Tc, undergoes hypertrophy after menopause. The hormone imbalance (reduction in estrogen) leads to increased activity of KNDy neurons, which exacerbates heat dissipation responses, leading to HFs and night sweats. Norepinephrine (NE) plays an important role in thermoregulation as well, acting through α₂-adrenergic receptors. It is hypothesized that elevated levels of NE in the brain contribute to the narrowing of the thermoneutral zone, thereby making HFs more easily triggered. Gonadal steroids also influence central NE tone by modulating brain adrenergic receptors.

Sleep Disturbances

Sleep disturbances stand out as one of the most commonly reported and bothersome issues for women in menopause. An estimated 40-60% of menopausal women experience sleep difficulties, of which nocturnal awakenings are particularly common. The multiethnic Study of Women’s Health Across the Nation (SWAN) demonstrates a clear escalation of sleep disruptions among perimenopausal and postmenopausal women compared to their premenopausal counterparts, showing a specific association between menopausal status and sleep quality.

Sleep difficulties associated with the menopausal transition range from transient disturbances to severe and chronic poor sleep. Notably, these disturbances are not solely attributed to hormonal changes, but are also linked to frequent arousals due to HFs and night sweats, along with psychological factors. One study found that the presence of objective (i.e., physiologically-measured) HFs can predict the number of awakenings during the night. Moreover, sleep disruption in menopause may be exacerbated by disordered breathing, such as obstructive sleep apnea, independent of factors like body weight and age. Additionally, obstructive sleep apnea tends to affect more women in postmenopause than in premenopause.

Beyond the immediate impact on sleep quality, cross-sectional and longitudinal studies draw attention to the broader health implications of menopausal sleep disturbances. Notably, an association is observed between short sleep duration and hypertension, particularly in middle-aged adults and in women. Short sleep duration is also identified as a risk factor for type 2 diabetes, and obesity, as an association between short sleep duration and an increased body mass index (BMI) has been found.

Psychological and Psychosomatic Symptoms

Most women experience some form of psychological and/or psychosomatic symptoms during peri- and postmenopause, as this can be a challenging period. In a trial of US women 40-55 years of age and of different racial/ethnic backgrounds (White, Black, Chinese, Japanese and Hispanic), headache and stiffness were common symptoms in all racial/ethnic groups, as were feelings of tension, depressed mood and irritability.

Depression is a highly prevalent psychological symptom in menopausal women. Data from the SWAN cohort, which used a questionnaire evaluating sadness, loss of interest, appetite, sleep, concentration, feelings of guilt, tiredness, agitation and suicidal ideation, revealed that women in early perimenopause, late perimenopause and postmenopause were substantially more likely to report high symptom scores compared to premenopause. Specifically, women in late perimenopause exhibited a higher likelihood for a depressive disorder than those in early perimenopause. Women with a history of major depression are at increased risk of relapse during perimenopause and the first two years of postmenopause. Furthermore, women with a history of depression are nearly five times more likely to be diagnosed with major depression during the menopausal transition, while those without a history of major depression are two to four times more likely, compared to premenopausal women, to report depressed mood. Women experiencing sleep problems in early menopause are also at increased risk for persistent or recurrent depression, compared to women without sleep problems, surpassing the increased risk associated with a lifetime history of depression.

Menopause is an important period for women susceptible to anxiety disorders as well. The SWAN cohort data suggests that women with high premenopausal anxiety levels tend to continue experiencing anxiety during the menopausal transition, while those with low premenopausal anxiety are more likely to develop high anxiety levels during and after the transition. Anxiety is often linked with depression, stress and sleep disturbances, creating a complex interplay of symptoms during menopause. Anxiety-related mood changes such as feeling less capable of coping, increased worry and experiencing panic attacks are also prevalent. The onset of anxiety is partially attributed to the change in progesterone levels during and after menopause. Progesterone and its metabolites act through GABA-A receptors to alleviate anxiety symptoms, so as the hormone levels diminish toward the end of menopausal transition, this anxiolytic effect diminishes as well.

Estrogens play a crucial role in various cognitive functions, affecting areas of the central nervous system (CNS) associated with learning, judgment, evaluation and language skills. They also help limit inflammatory responses in the CNS, preventing potential damage that could lead to dystrophy and a susceptibility to dementia. Studies suggest that menopause has an impact on cognitive function, particularly affecting aspects related to verbal memory and verbal fluency. Women often report cognitive changes during the menopausal transition, including difficulties with memory and concentration, commonly referred to as "brain fog". However, data from the SWAN cohort suggest that this change in cognitive function is limited to the perimenopausal stage, with improvement observed post-menopause.

Urinary and Sexual Symptoms

During perimenopause and postmenopause, women commonly experience changes in sexual and urinary function. A global study involving nearly 14,000 women 40 years of age and above from 29 countries revealed that approximately 40% of mid-life women worldwide reported sexual concerns, such as low desire, difficulty reaching orgasm and lubrication issues. These concerns are greatly contributed by decreasing levels of estrogen during the menopausal transition, leading to urogenital atrophy and related symptoms, collectively known as genitourinary syndrome of menopause (GSM). This syndrome typically manifests 4-5 years after the menopausal transition is over and it progresses with age.

Urogenital atrophy results in various urinary symptoms, whose effects on a woman’s life range from slightly bothersome to seriously impactful. The occurrence and severity of these symptoms are influenced by age, sexual activity, ethnicity and attitudes towards menopause. Urinary incontinence (UI), increased urinary frequency during the day and night, and recurring urinary tract infections are common GSM symptoms. Urinary incontinence encompasses stress urinary incontinence (urine leakage during activities that increase pressure on the bladder, urethra and pelvic floor muscles, such as coughing or exercising), urge urinary incontinence (a sudden urge to urinate followed by involuntary leakage), or mixed urinary incontinence (the previous two combined). However, menopausal status alone is not a determinant of UI; the risk varies with factors such as obesity, parity, age and some surgical procedures.⁴ Research indicates that an increase in body weight correlates with a higher incidence of UI in women undergoing peri- and postmenopause. Additionally, mixed incontinence is positively correlated with higher BMI and hysterectomy. Another possible consequence of urogenital atrophy is pelvic organ prolapse. As the connective tissues deteriorate and the pelvic floor muscle weakens, pelvic organs (bladder, urethra, rectum, intestines, vagina, cervix) can descend into the vagina or outside the rectum.

Sexual symptoms that follow urogenital atrophy include vaginal dryness, pain during intercourse (dyspareunia), vulvar itching, burning and discomfort. The international Vaginal Health: Insights, Views and Attitudes (VIVA) study reported high prevalence rates for several urogenital symptoms in women with vaginal discomfort, including vaginal dryness (83%), pain during intercourse (42%) and involuntary urination (30%). The severity of these symptoms was reported as moderate or severe by 62% of women in the study. Other symptoms related to urogenital atrophy are atrophic vaginitis and vulvar dermatoses. These can mimic or be a part of GSM, leading to dyspareunia or coexisting with vulvodynia (vulvar pain lasting at least 3 months without a clear identifiable cause).

As estradiol and testosterone levels decline, sexual desire declines as well. The menopausal transition has been linked with a decrease in sexual desire, independent of aging, with up to 52% of women reporting reduced desire in the postmenopause. Pain during intercourse due to urogenital atrophy and inability to reach orgasm can contribute to diminished sexual desire, arousal difficulties and relationship problems. Additionally, a decline in general self-esteem and well-being post-menopause may further impact sexual intimacy. However, postmenopausal women report lower rates of distress associated with a lower desire. Two Australian studies found that low sexual desire associated with distress declined from 32.2% to 13.6% in women 40-64 and 65-79 years of age, respectively. Masturbation, which is not dependent on partner status, temporarily increases in early perimenopause and decreases thereafter in postmenopause.

Muscle and Joint Pain

Myalgia and arthralgia are common symptoms during menopause, believed to be linked to decreased estrogen levels. The occurrence of both muscle and joint pain are often linked to HFs and depressed mood. Research suggests that musculoskeletal pain affects a significant portion of perimenopausal women, with an estimated prevalence of 71%, presenting a significant physical and psychological health burden. Some women may report more arthralgia/myalgia than VMS during menopause. The incidence of musculoskeletal pain doubles during the menopausal transition, with the highest occurrence between 45 and 55 years of age. However, differentiating between musculoskeletal pain and arthritis in epidemiological studies poses a challenge, making it difficult to accurately assess the burden of arthralgia/myalgia.

Bone Changes

Osteopenia and osteoporosis represent conditions characterized by a progressive decline in bone mass, heightening the risk of fractures, particularly in the spine and femur. Globally, one in three women aged 50 and older will have an osteoporotic fracture, with even higher prevalence rates in the United States and Europe (around 40-50%).

The key change in the musculoskeletal system during menopause is the loss of bone mineral density. Following the peak bone mass achieved in early adulthood, the delicate balance between osteoblastic bone formation and osteoclastic bone resorption is disrupted when estrogen levels decline after menopause. This hormonal change causes an imbalance where bone breakdown exceeds bone formation during the natural bone remodeling process, leading to an overall loss of bone density. Furthermore, the decline in daily activity and skeletal muscle mass, coupled with the absence of estrogen-mediated pathways, further contribute to the reduction in bone formation during the menopausal transition.

Cardiovascular Complications

Estrogens are potent vasoactive hormones that play a crucial role in maintaining healthy blood vessels by promoting nitric oxide synthesis, vascular remodeling, flexibility and regulating inflammatory responses. Estrogen affects endothelial cells, increasing the production of nitric oxide, which widens blood vessels and promotes cell growth and migration. This results in reduced vascular resistance and supports regeneration of the blood vessel lining. Estrogen also impacts cardiomyocytes, leading to improvements in low-density lipoprotein cholesterol (LDL-C) levels, insulin resistance and mitigating various cardiovascular (CV) risks. Post-menopause, estrogen deficiency triggers changes that elevate the risk of CV events. The risk of stroke doubles in the initial decade following menopause, eventually surpassing that of men in the same age category.

Early menopause and primary ovarian insufficiency are associated with an increased risk of coronary heart disease, stroke and overall mortality. In a multinational longitudinal study involving over 300,000 women, the highest hazard ratio was observed for premature menopause (menopause before the age of 40), with the risk declining as the age of menopause approached the mean value (50.2 years). This study also found that the risk of developing CV disease (CVD) before the age of 60 was twice as high in women experiencing menopause before the age of 40 and 1.4 times higher with early menopause before the age of 45.

Another factor contributing to the increased CVD risk during menopause is the elevated production of pro-inflammatory cytokines and adipokines in visceral adipose tissue. The accumulation of visceral adipose tissue poses a higher health risk compared to subcutaneous fat and is an independent contributor to CVD development. This heightened risk is primarily linked to insulin resistance, which can also lead to the development of metabolic syndrome and type 2 diabetes. Additionally, postmenopausal women may experience increased deposition of fat in other visceral tissues such as the heart, with reports indicating significantly greater volumes of heart fat in women in the late perimenopause and postmenopause compared to their counterparts in premenopause, irrespective of age, race, obesity, or other factors.