Menopause in HIV-Infected Women

Osteoporosis

Menopause, with its associated estrogen deficiency, is the most important risk factor associated with increased bone turnover and bone loss and can worsen HIV associated bone loss [104]. Among HIV-infected individuals, low bone mineral density (BMD) has been described even among premenopausal women and younger men [105–107]. Evidence suggests that the decreased BMD associated with HIV stabilizes or even improves after initiation of HAART in the younger population [105–107]. However, once HIV-infected women enter menopause, they have higher rates of bone loss compared to non–HIV-infected women with significantly increased prevalence of osteoporosis compared to non–HIV-infected women [108–112].

Chronic inflammation by HIV stimulates osteoclast differentiation and resorption [113]. In addition, HAART [114–116], vitamin D deficiency [117], low BMI, poor nutrition [118], inactivity, use of tobacco, alcohol, and illicit drugs [119,120], and coinfection with hepatitis B and C [121] all appear to contribute to decreased BMD among HIV-infected men and women [118]. Among HIV-infected postmenopausal women, those taking ritonavir were found to have increased differentiation of osteoclast cells and increased bone loss [122]. Similarly, methadone use in postmenopausal women has been associated with increased BMD decline [123]. African-American, HIV-infected postmenopausal women appear to be at the greatest risk for bone loss [109].

Multiple studies focusing on HIV-infected men have demonstrated an increased prevalence of fractures compared to non–HIV-infected men [124–126]. However, current studies on postmenopausal HIV-infected women demonstrate that fracture incidence is similar between HIV-infected and non–HIV-infected postmenopausal women [108,112]. Nevertheless, given the evidence of low BMD and increased fracture risk seen during menopause among non–HIV-infected women compounded with the additional bone loss seen in HIV-infected individuals, enhanced screening in postmenopausal HIV-infected women is prudent. Although the U.S. Preventive Services Task Force (USPSTF) makes no mention of HIV as a risk factor for enhanced screening [127] and the Infectious Diseases Society of America (IDSA) only recommends screening beginning at the age of 50 years old if there are additional risk factors other than HIV [128], the more recently published Primary care guidelines for the management of persons infected with HIV recommends screening postmenopausal women ≥ 50 years of age with dual-energy X-ray absorptiometry (DEXA) scan [86]. Preventative therapy such as smoking cessation, adequate nutrition, alcohol reduction, weight bearing exercises, and adequate daily vitamin D and calcium should be discussed and recommended in all menopausal HIV-infected women [129]. If the DEXA scan shows osteoporosis, bisphosphonates or other medical therapy should be considered. Although the data are limited, bisphosphonates have been shown to be effective in improving BMD [130–132].

Cognition

The menopause transition is characterized by cognitive changes such as memory loss and difficulty concentrating [133–136]. Both HIV-infected men and women are at higher risk of cognitive impairment [137–139]. Cognitive impairment can range from minor cognitive-motor disorder to HIV-associated dementia due to the immunologic, hormonal, and inflammatory effects of HIV on cognition [137–139]. In addition, those with HIV infection appear to have increased risk factors for cognitive impairment including low education level, psychiatric illnesses, increased social stress, and chemical dependence [137].

Studies focusing on the effects of both HIV infection and menopause on cognition have been limited thus far. In a cross-sectional study of 708 HIV-infected and 278 non–HIV-infected premenopausal, perimenopausal, and postmenopausal women, Rubin et al demonstrated that HIV infection, but not menopausal stage, was associated with worse performance on cognitive measures [140]. While menopausal stage was not associated with cognitive decline, menopausal symptoms like depression, anxiety, and vasomotor symptoms were associated with lower cognitive performance [140].

Though limited, current data appear to indicate that HIV infection, not menopause, contributes to cognitive dysfunction [140]. Symptoms of menopause, however, do appear to exacerbate cognitive decline indicating the importance of recognition and treatment of menopausal symptoms. This is especially important in HIV-infected women since decrease in cognition and depression can interfere with day to day function including medication adherence [141,142].

Cervical Dysplasia

As more HIV-infected women reach older age, the effects of prolonged survival and especially menopause on squamous intraepithelial lesions (SILs) are being investigated to determine if general guidelines of cervical cancer screening should be applied to postmenopausal women.

In a retrospective analysis of Papanicolaou smear results of 245 HIV-infected women, Kim et al noted that menopausal women had a 70% higher risk of progression of SILs than premenopausal women [143]. Similar results were found in a smaller retrospective study of 18 postmenopausal HIV-infected women in which postmenopausal women had a higher prevalence of SILs and persistence of low-grade SILs [144].

Although studies on progression to cervical cancer in postmenopausal HIV-infected women remain limited, current data suggest that postmenopausal HIV-infected women should continue to be monitored and screened similarly to the screening recommendations for premenopausal women. Nevertheless, further studies examining the natural course of cervical lesions are needed to establish the best practice guidelines for screening postmenopausal women.

HIV Acquisition and Transmission

The incidence of new HIV infections in older American women has increased. HIV acquisition from heterosexual contact appears to be higher in older women compared to younger women, with a study suggesting that women over age 45 years had almost a fourfold higher risk of HIV acquisition compared to those under the age of 45 years [145]. While the lack of awareness of HIV risk and less frequent use of protection may contribute to increases in new HIV infection in older women, hormonal changes associated with older age, specifically menopause, may be playing a role. Vaginal wall thinning that occurs during menopause may serve as a risk factor for HIV acquisition.

In a study by Meditz et al, the percentage of endocervical or blood CD4 T cells did not differ between premenopausal and postmenopausal women, but postmenopausal women had greater percentage of CCR5 expression. As CCR5 serves as an entry point of HIV into target cells, this suggests the possibility that postmenopausal women may be at increased risk for HIV acquisition [146]. More recently, Chappell et al also revealed that anti-HIV-1 activity was significantly decreased in postmenopausal compared to premenopausal women, suggesting that there may be an increased susceptibility to HIV-1 infection in postmenopausal women [147]. Hence there appears to be menopause-related immunologic changes of the cervix that may contribute to an increased risk of HIV acquisition in postmenopausal women.

In contrast, although data is limited, postmenopausal HIV-infected women do not appear to be at increased risk of transmitting HIV to non–HIV-infected individuals. Melo et al compared the intensity of HIV shedding between premenopausal and postmenopausal women and found that HIV shedding did not differ between premenopausal or postmenopausal women [148].

HIV Progression

Several studies have focused on the effects of HIV infection on menopause, but minimal data are available on the effects of menopause on the progression of HIV infection. With prior data suggesting that younger persons experience better immunological and virological responses to HAART [149–151], it has previously been hypothesized that virologic and immunologic responses to HAART can decline once HIV-infected women reach menopause. However, current evidence suggests that treatment responses to HAART, determined by the median changes in CD4 cell counts and percentages and viral load, in HAART-naive patients did not differ between premenopausal and postmenopausal women [152]. In addition, there appears to be no significant changes in CD4 cell counts as HIV-infected women progress through menopause [153]. These studies suggest that menopause does not affect the progression of HIV and that HAART-naive women should respond to HAART regardless of their menopausal status.

Conclusion

As HIV-infected individuals live longer, increasing number of women will enter into menopause and live many years beyond menopause. HIV-infected women experience earlier and more severe menopausal symptoms, but knowledge is still lacking on the appropriate management of these symptoms. In addition, current evidence suggests that immunosuppression associated with HIV contributes to an early onset of menopause which leads to increased risks of cardiovascular disease, osteoporosis, and progression of cervical dysplasia. These conditions require proper surveillance and can be prevented with improved understanding of influences of menopause on HIV-infected women. Furthermore, although there is some evidence suggesting that menopause has no effect on HIV transmission and progression, further studies on the immunologic and virologic effects of menopause are necessary.

There still remain significant gaps in our understanding of menopause in HIV-infected women.  As practitioners encounter an increasing number of perimenopausal and postmenopausal HIV-infected women, future studies on the effects of HIV on co-morbidities and symptoms of menopause and their appropriate management are necessary to improve care of women living with HIV.

Corresponding author: Lori E. Fantry, MD, MPH, 29 S. Greene St., Suite 300, Baltimore, MD 21201, lfantry@medicine.umaryland.edu.

Financial disclosures: None.