Infectious Diseases Board Review: Menopause in Women Living With HIV

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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Amenorrhea

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

Because these factors associated with amenorrhea are common in WLWH, it is not surprising that amenorrhea and anovulation are frequently found in this population. However, HIV infection itself also appears to be an independent risk factor for amenorrhea. A recent meta-analysis of 8925 women showed a significant association between HIV status and amenorrhea, even when women with and without HIV had similar rates of substance abuse and smoking and similar socioeconomic status.⁹ The impact of HIV on an increased frequency of amenorrhea was strongest in women with low BMI. Some, but not all, of the studies included in the meta-analysis found a negative association between CD4 cell count and amenorrhea. In addition, a study comparing amenorrhea frequency within subgroups of WLWH also found a higher rate of amenorrhea in women with lower CD4 cell counts.¹⁰

“Prolonged” amenorrhea, defined as amenorrhea lasting 1 year or more, also occurs at a high frequency in WLWH.⁶ This has made determination of age of menopause extremely challenging, since it is likely that many studies defining menopause are misidentifying “prolonged” amenorrhea as menopause. The Women’s Interagency HIV Study (WIHS), a multicenter observational study of women of similar socioeconomic status living with and without HIV, found that more than 50% of WLWH with “prolonged” amenorrhea had serum follicle-stimulating hormone (FSH) levels in the premenopausal range.⁸ In a later study from the same cohort, 37% of 660 WLWH with “prolonged” amenorrhea had documented resumption of menses.⁶

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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.

It is also necessary to accurately define menopause. The World Health Organization defines natural menopause as the permanent cessation of menstruation for 12 consecutive months without any obvious pathologic or physiologic causes.¹⁵ Most studies have used this definition, and many have found that the age of menopause is earlier in WLWH and is associated with immunosuppression.^14,16,17 The Ms Study found that women with CD4 cell counts < 200 cells/μL had an increased risk of amenorrhea lasting at least 12 months, when compared to women with CD4 cell counts ≥ 200 cells/μL. The median age of menopause was 42.5 years in women with CD4 cell counts < 200 cells/μL, 46.0 years in women with CD4 cell counts between 200 cells/μL and 500 cells/μL, and 46.5 years in women with CD4 cell counts > 500 cells/μL.¹⁴ Similarly, in a cohort of 667 Brazilian WLWH, among whom 160 were postmenopausal, Calvet and colleagues found that 33% of women with CD4 cell counts < 50 cells/μL had premature menopause, as compared to 8% of women with CD4 cell counts ≥ 350 cells/μL.¹⁷ In De Pommerol and colleague’s study of 404 WLWH, among whom 69 were found to be postmenopausal, women with CD4 cell counts < 200 cells/μL were more likely to have premature menopause, as compared to women with CD4 cell counts ≥ 350 cells/μL.¹⁶

Despite these findings, given the data from WIHS showing that many women with amenorrhea for at least 12 consecutive months had FSH levels in the premenopausal range⁸ and that 37% of WLWH have resumption of menses after 12 consecutive months of amenorrhea,⁶ it is probable that the conclusions about the age of menopause in WLWH are invalid, since many of the participants likely had prolonged amenorrhea, not menopause. WIHS found no significant difference in the median age of menopause when WLWH were compared to women without HIV. The median age of menopause was 47.7 years in WLWH and 48.0 years in women without HIV.¹⁸

Menopause-Associated Symptoms

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

It can be difficult to determine which symptoms are caused by the physiologic changes of menopause in WLWH, as these women have multiple potential reasons for these symptoms, such as ART, comorbidities, and HIV infection itself.²⁵ However, several studies show that there are symptoms that occur more commonly in the perimenopausal period and that WLWH experience these symptoms earlier and with greater intensity.^26-30 In addition, the burden of commonly reported HIV symptoms, such as fatigue and muscle aches/joint pains, is higher in women after menopause, suggesting this burden may be exacerbated by menopause.³¹

Vasomotor

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

Genitourinary

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.

Genitourinary symptoms are most common among women who are African American, have an increased BMI, are of lower socioeconomic status, use tobacco, have a prior history of pelvic inflammatory disease, and have anxiety and depression.^11,42,43 Similar to hot flashes, many of these predisposing factors are more common in WLWH. Fantry and colleagues found that 49.6% of WLWH had vaginal dryness.²⁷ Although 56% of postmenopausal women and 36% of perimenopausal women complained of vaginal dryness, in a multivariate analysis only cocaine use, which can decrease estradiol levels,⁴⁴ was associated with a higher frequency of vaginal dryness.²⁷

Dyspareunia is also common among WLWH. In a cross-sectional study of 178 women without HIV and 128 WLWH between 40 and 60 years of age, Valadares et al found a high prevalence of dyspareunia in WLWH: 41.8%.⁴⁵ However, this was not significantly higher than the prevalence of dyspareunia in women without HIV: 34.8%.⁴⁵ HIV infection itself was not associated with the presence of dyspareunia.

Psychiatric

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

Persistent menopausal symptoms, especially hot flashes, also predicted elevated depressive symptoms in several studies, suggesting the importance of appropriately identifying and treating menopausal symptoms.^29,34 In addition, cognitive decline associated with menopause contributes to depression.^50,51

Other Symptoms

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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Treatment

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

For women experiencing severe hot flashes and vaginal dryness, short-term oral MRT is indicated.⁵⁶ MRT should be limited to the shortest period of time at the lowest effective dose needed to address these symptoms, as MRT is associated with increased risks of breast cancer, cardiovascular disease, and thromboembolism and increased morbidity.⁵⁶ Drug interactions between MRT and ART are of concern for non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and cobicistat, as these ARTs and MRT are metabolized by the CYP3A4 system.⁵⁹ With any PI, there is potential for an increase or decrease in estradiol or conjugated estrogen levels; an increase in medroxyprogesterone and micronized progesterone levels; and an increase in drospirenone levels. With doravirine and rilpivirine, there is no change in expected hormonal concentrations, but with other NNRTIs (efavirenz, etravirine, and nevirapine) there is a possibility of a decrease in estradiol, conjugated estrogen, medroxyprogesterone, micronized progesterone, and drospirenone levels. None of the integrase strand transfer inhibitors alone leads to changes in hormone level, but elvitegravir is only used when co-formulated with cobicistat, which may lead to increased or decreased estrogen, progesterone, and drospirenone levels.⁶⁰ Since all of these drug interactions are uncertain, and even act in varying directions, clinicians should monitor menopausal symptoms and titrate MRT to the dose that achieves relief of menopausal symptoms.

Cardiovascular Risk

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

The increased risk for cardiovascular disease seen in HIV infection is likely compounded with the increased risk associated with menopause. Postmenopausal WLWH appear to be at higher risk of cardiovascular disease compared to postmenopausal women without HIV. Modifiable risk factors for cardiovascular disease, such as decreased fitness and smoking, are more commonly seen in WLWH.⁶⁵ Even prior to menopause, WLWH experience lipodystrophy syndrome, with increased truncal visceral adiposity and decreased subcutaneous fat and muscle mass.^65,66 Microbial translocation due to HIV-related damage of the intestinal mucosa can lead to elevated levels of lipopolysaccharides, a component of the cell wall of gram-negative bacteria; this subsequently activates monocytes, macrophages, and
T cells. In a study that compared postmenopausal WLWH to age-matched women without HIV, this HIV-related immune activation was correlated with an increase in biomarkers of cardiovascular disease, suggesting WLWH are at higher risk of developing cardiovascular disease.⁶⁷ Similarly, when comparing sex hormone concentrations in premenopausal WLWH and women without HIV, WLWH had lower estrogen and androgen levels, both of which are linked to carotid artery stiffness.⁶⁸

In addition, postmenopausal WLWH are at higher risk of cardiovascular disease compared to premenopausal WLWH. WLWH with reduced ovarian reserve had increased subclinical coronary atherosclerotic plaque compared to premenopausal WLWH, even when controlling for cardiovascular disease risk factors.⁶⁹

In summary, cardiovascular disease risk is increased in postmenopausal WLWH.⁶⁹ Appropriate measures, such as lipid control, antiplatelet therapy, smoking cessation, aerobic exercise, and other lifestyle changes, should be initiated in WLWH as in any other population.

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Osteoporosis

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

Once WLWH enter menopause, they have higher rates of osteoporosis and bone loss compared to women without HIV.⁸³ Among postmenopausal WLWH, those taking ritonavir were found to have increased differentiation of osteoclast cells and increased bone loss.⁸⁴ Similarly, methadone use in postmenopausal women has been associated with increased declines in BMD.⁸⁵ African-American postmenopausal WLWH appear to be at the greatest risk for bone loss.⁸⁶

Given the evidence of low BMD and increased fracture risk that occurs during menopause among women living without HIV, and the additional bone loss observed in PLWH, current guidelines recommend screening postmenopausal women ≥ 50 years of age with dual-energy X-ray absorptiometry (DEXA) scan.⁸⁷ Preventive therapy, such as smoking cessation, adequate nutrition, alcohol reduction, and weight-bearing exercises, should be discussed and recommended to all menopausal WLWH.⁸⁸ Adequate calcium and vitamin D intake should be discussed as well, with current evidence indicating that low-dose vitamin D supplementation at 1000 IU is as effective as high-dose vitamin D supplementation at 3000 IU in increasing BMD.⁸⁹ If the DEXA scan shows a T-score < –2.5 at the femoral neck or spine, or between –1 and –2.5 with a 10-year probability of hip fracture ≥ 3% or a 10-year probability of any osteoporosis-related fracture ≥ 20%, bisphosphonates or other medical therapy should be considered. Although the data are limited in WLWH, bisphosphonates have been shown to be effective in improving BMD.⁹⁰

Cognition

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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Cervical Dysplasia

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

In contrast, although data are limited, postmenopausal WLWH do not appear to be at increased risk of vaginally transmitting HIV. The intensity of HIV shedding did not differ between premenopausal or postmenopausal women.¹⁰⁵ There was a high prevalence of low-level HIV RNA in genital secretions among perimenopausal WLWH, suggesting WLWH in menopause do not present a major public health risk for HIV transmission.¹⁰⁶

HIV Progression

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

Conclusion

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.

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