More than half of the 37.9 million persons living with HIV (PLWH) worldwide are women.1 Between 2010 and 2016, 58% of women living with HIV (WLWH) in the United States were older than 45 years.2 As such, an increasing number of WLWH are entering menopause and living well beyond menopause. Despite this, health care providers expressed a lack of confidence in managing menopause in WLWH, and menopausal symptoms often are not recognized by providers.3 Enhancing our knowledge about menopause in WLWH is important, since the physiologic changes associated with menopause impact short- and long-term quality of life and mortality.
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Menstrual irregularities, including amenorrhea and anovulation, are more frequently found in women of low socioeconomic status, presumably due to associated physical and emotional stress.4 In addition, women with low body mass index (BMI) have decreased serum estradiol levels, which lead to amenorrhea.4,5 Furthermore, low parity and many legal and illegal drugs are associated with amenorrhea, including hormonal contraceptives, opiates, stimulants, antipsychotics, and chemotherapeutic agents.6-8
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Age at Menopause
In the United States, the median age of menopause is between 50 and 52 years in middle-class white women.11,12 Earlier menopause has been observed in women who are African American, are nulliparous, have a lower BMI, smoke tobacco, and have more stress, less education, and higher unemployment rates.11,13,14 Because 57% of women diagnosed with HIV in 2018 were African American and many WLWH have other risk factors associated with earlier menopause, studies examining the age of menopause in WLWH need to use a comparator group of women without HIV with similar characteristics and control for these factors to determine the influence of HIV on the age of menopause.
The perimenopausal period, which begins, on average, 4 years prior to the final menstrual period, is characterized by hormonal fluctuations leading to irregular menstrual cycles.19,20 Symptoms associated with these physiologic changes during the perimenopausal period include vasomotor symptoms (hot flashes), genitourinary symptoms (vaginal dryness and dyspareunia), anxiety, depression, sleep disturbances, and joint aches.21,22 Such menopausal symptoms can be distressing and negatively impact quality of life.23 In WLWH, severe menopausal symptoms have been associated with suboptimal adherence to antiretroviral therapy (ART).24
In the United States, the most common symptom during perimenopause is hot flashes, which occur in 38% to 80% of women.32,33 Vasomotor symptoms are most common in women who smoke, use illicit substances, have a high BMI, are of lower socioeconomic status, and are African American.11 As expected, prior studies focusing on hot flash prevalence among premenopausal, perimenopausal, and postmenopausal WLWH found that postmenopausal women experience more hot flashes than premenopausal or perimenopausal women.27,28 In addition, a comparison of women with and without HIV demonstrated a higher prevalence of hot flashes among WLWH.26,29 Vasomotor symptoms can be severely distressing, with hot flashes contributing to increased risk of depression.25,34 In a cross-sectional analysis of 835 WLWH and 335 women without HIV from the WIHS cohort, persistent vasomotor symptoms predicted elevated depressive symptoms in both WLWH and women without HIV.34 In a similar cross-sectional analysis of 536 women, among whom 54% were WLWH and 37% were perimenopausal, psychological symptoms were prevalent in 61% of the women with vasomotor symptoms.29
Estrogen deficiency, which accompanies the perimenopausal period, leads to vulvovaginal atrophy (VVA), manifesting with symptoms of vaginal dryness, itching, burning, urinary urgency, and dyspareunia (painful intercourse).33,35,36 Unlike vasomotor symptoms, which diminish with time, genitourinary symptoms generally worsen if left untreated.37 Furthermore, these symptoms are often underreported and underdiagnosed.38,39 VVA was found in 43% to 84% of postmenopausal women.36,40,41 In the AGATA study, the prevalence of VVA was associated with years since menopause. 36 Vaginal dryness and dyspareunia were common.
Anxiety and depression are also common symptoms in perimenopausal women.46-48 Studies have shown that depression is diagnosed 2.5 times more frequently among perimenopausal women than premenopausal women.48 In a study by Miller et al that focused on 536 WLWH, among whom 37% were perimenopausal, 89% reported psychological symptoms.29 Ferreira et al found that perimenopausal WLWH had an increased incidence of psychological symptoms, such as depression and anxiety, compared to women without HIV infection.26 Whether this increased prevalence of psychological symptoms seen in WLWH can be attributed to menopause is unclear, since one third to one half of men and women living with HIV experience symptoms of depression.49 However, in the WIHS, which compared findings from 835 WLWH to findings from 335 women without HIV from all menopausal stages, elevated depressive symptoms were seen in the early perimenopausal period.34 There was no increased incidence of such symptoms during the premenopausal or postmenopausal stage, suggesting that factors related to menopause contribute to depressive symptoms during the perimenopausal stage.34
Sleep disturbances are common among perimenopausal women, with an estimated prevalence between 38% and 46%.52-54 Hot flashes, anxiety, and depression appear to be factors that contribute to sleep difficulty.52-54 In a cross-sectional study of 273 WLWH and 264 women without HIV between 40 and 60 years of age, insomnia was found in 51% of perimenopausal and 53% of postmenopausal WLWH. The prevalence of insomnia in WLWH and women without HIV was the same.55 Joint aches are also commonly reported in the perimenopausal period, with a prevalence as high as 50% to 60% among perimenopausal women in the United States.22,29 Miller and colleagues found that 63% of menopausal WLWH reported arthralgia.29
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Despite the increased severity of menopausal symptoms experienced among WLWH, menopausal replacement therapy (MRT) is used less frequently in WLWH than in women living without HIV.55 Topical treatment is recommended for women who are experiencing vaginal dryness. First-line treatment is topical nonhormonal therapy, such as moisturizers and lubricants.56 If symptoms are not relieved, then topical vaginal estrogen therapy is recommended.56 Randomized placebo-controlled studies have verified the safety and efficacy of topical estrogen in the general population, and there is no reason to expect different outcomes in WLWH.57,58
Estrogen deficiency that occurs during menopause leads to an increased risk of cardiovascular disease, particularly with changes in lipid profiles, insulin resistance, and body composition (eg, increased fat mass and waist circumference).61 HIV infection also is associated with a higher risk of cardiovascular disease, with studies consistently reporting a 1.5- to 2-fold increase in the rate of cardiovascular events in PLWH compared to persons without HIV.62 The inflammatory effects of HIV as well as ART exposure, specifically to PIs and abacavir, increase the risk for cardiovascular disease.62 In addition, traditional risk factors, including dyslipidemia, contribute to cardiovascular disease risk in this population.63,64
Menopause, with its associated estrogen deficiency, is the most important risk factor linked to increased bone turnover and bone loss.70 In addition, HIV is associated with bone loss, with low bone mineral density (BMD) described even among men and premenopausal women with HIV infection.71 Although decreased BMD associated with HIV stabilizes or even improves after initiation of ART in the younger population,72-74 chronic inflammation caused by HIV stimulates osteoclast differentiation and resorption.71 Other factors that appear to contribute to decreased BMD among PLWH include ART; vitamin D deficiency; low BMI; poor nutrition; inactivity; use of tobacco, alcohol, and illicit drugs; hepatitis B and C coinfection; and frailty, defined as increased vulnerability to stresses related to aging.72-80 Among ARTs, tenofovir disoproxil fumarate is associated with an increased risk of osteoporosis, and switching from this agent to tenofovir alafenamide improves bone density.81 Prolonged amenorrhea is also an added risk factor for osteoporosis in WLWH.82
Both men and women living with HIV are at higher risk for cognitive impairment, ranging from minor cognitive-motor disorder to HIV-associated dementia.91 In addition, the menopause transition is characterized by cognitive changes, such as memory loss and difficulty concentrating.92,93 Studies focusing on the effects of both HIV infection and menopause on cognition have been limited thus far. A cross-sectional study demonstrated that HIV infection, but not menopausal stage, was associated with worse performance on cognitive measures.94 While menopausal stage was not associated with cognitive decline, menopausal symptoms like depression, anxiety, and vasomotor symptoms were associated with lower cognitive performance, highlighting the importance of recognition and treatment of menopausal symptoms.94
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WLWH are at increased risk for low- and high-grade squamous intraepithelial lesions (SILs) and more rapid progression to cervical carcinoma, as compared to women without HIV.95 This increased risk of cervical disease is associated with age, human papillomavirus genotype, and degree of immunosuppression.96 In addition, menopause appears to affect the risk of cervical disease. Postmenopausal WLWH had a higher risk of progression of SILs and persistence of lower-grade SILs compared to premenopausal women.97,98 Although studies on progression to cervical cancer in postmenopausal WLWH remain limited, current data suggest that postmenopausal WLWH should continue to be monitored and screened similarly to premenopausal women.
HIV Acquisition and Transmission
Women aged 50 years and older are primarily exposed to HIV through heterosexual contact.99 While the lack of awareness of HIV risk and less frequent use of barrier protection can contribute to new HIV infection in older women, physiologic changes associated with menopause also may be playing a role.100 Vaginal wall thinning and immunologic changes of the cervix that occur during menopause may serve as a risk factor for HIV acquisition. The cervicovaginal mucosa of postmenopausal women had higher levels of p24 antigen after ex vivo HIV-1 infection, suggesting higher susceptibility to acquire HIV infection.101 Postmenopausal women have been shown to have increased cervical CCR5 expression, which serves as an entry point of HIV into target cells.102 Finally, anti-HIV-1 activity was significantly decreased in postmenopausal women compared to premenopausal women.103 In addition, ex vivo studies demonstrated reduced tenofovir disoproxil fumarate and emtricitabine triphosphate concentrations in cervical tissue of postmenopausal women, suggesting that postmenopausal women may need higher doses of pre-exposure prophylaxis to achieve protective efficacy.104
With prior data suggesting that younger persons experience better immunologic and virologic responses to ART,107-109 it had previously been hypothesized that virologic and immunologic responses to ART will decline once WLWH reach menopause. However, current studies suggest that menopause does not affect the progression of HIV and that ART-naive women should respond to ART, regardless of their menopausal status. Treatment responses to ART, determined by the median changes in CD4 cell counts and percentages and viral load, in ART-naive individuals did not differ between premenopausal and postmenopausal women.110 In addition, there appear to be no significant changes in CD4 cell counts as WLWH progress through menopause.111
As individuals with HIV infection live longer, an increasing number of women will enter menopause and live many years beyond menopause. WLWH experience earlier and more severe menopausal symptoms, but evidence on the appropriate management of these symptoms is still lacking. These conditions require proper surveillance, and can be prevented with an improved understanding of the effects of menopause on WLWH. However, there remain significant gaps in our understanding of menopause in WLWH. As practitioners encounter an increasing number of perimenopausal and postmenopausal WLWH, studies of the effects of HIV on comorbidities and symptoms of menopause and their appropriate management are necessary to improve care of WLWH.