Menopause in HIV-Infected Women
Effect of HIV on the Menstrual Cycle
Menstrual irregularities, including amenorrhea and anovulation, are more frequently found in women of low socioeconomic class who experience more social and physical stress like poverty and physical illnesses [3]. In addition, women with low body mass index (BMI) have decreased serum estradiol levels which lead to amenorrhea [3,4]. Furthermore, several studies have demonstrated that methadone, heroin, and morphine use are associated with amenorrhea. Opiate use inhibits the central neural reproductive drive leading to amenorrhea even in the absence of menopause [5–7].
As these demographics, body habitus, and lifestyle characteristics are frequently found among HIV-infected women, it is not surprising that amenorrhea and anovulation are common in this population [8–14]. In fact, studies show that there is an increased prevalence of amenorrhea and anovulation among HIV-infected women when compared to non–HIV-infected women [8]. Some studies suggest that women with lower CD4 cell counts and higher viral loads have increased frequency of amenorrhea and irregular menstruation compared to those with higher CD4 cell counts and lower viral loads [9,10]. However, it remains unclear if HIV infection itself, instead of the associated social and medical factors, is responsible for the higher frequency of amenorrhea [11–13]. For example, in a prospective study comparing 802 HIV-infected women with 273 non–HIV-infected women, there was no difference in the prevalence of amenorrhea when controlling for BMI, substance use, and age [13].
The World Health Organization (WHO) currently defines natural menopause as the permanent cessation of menstruation for 12 consecutive months without any obvious pathological or physiologic causes [15]. However, given the increased prevalence of amenorrhea in HIV-infected women, amenorrhea seen with HIV infection can be mistaken for menopause. The Women’s Interagency HIV Study (WIHS), a multicenter, observational study of HIV-infected women and non–HIV-infected women of similar socioeconomic status, found that more than half of HIV-infected women with prolonged amenorrhea of at least 1 year had serum follicle-stimulating hormone (FSH) levels in the premenopausal range of less than 25 mIU/mL [16]. Hence, this implies that some of these women may have had prolonged amenorrhea rather than menopause [17]. The traditional definition of menopause may need to be altered in this population.
Age at Menopause
Natural menopause, retrospectively determined by the cessation of menstrual cycles for 12 consecutive months, is a reflection of complete, or near complete, ovarian follicular depletion with subsequent low estrogen levels and high FSH concentrations [18]. In the United States, studies have found the mean age of menopause to be between 50 to 52 years old [19,20]. These studies, however, focused predominantly on menopause in middle class, white women. Early menopause, defined as the permanent cessation of menstruation between 40 to 45 years of age, affects 5% of the women in the United States, while premature menopause or primary ovarian insufficiency, which occurs at younger than 40 years of age, affects 1% of the women [21].
As earlier menopause is associated with increased risks of diabetes [22], cardiovascular disease [23], stroke [24], and osteoporosis [25], identifying the mean age of menopause is important in the management of HIV-infected women. Among women in the United States, early menopause has been observed in women who are African American, nulliparous, have lower BMI, smoke tobacco, and have more stress, less education, and more unemployment [26–29]. Unhealthy lifestyles can also contribute to an earlier age of menopause. Smoking is one of the most consistent and modifiable risk factors associated with an earlier onset of natural menopause, accelerating menopause by up to 2 years [26,30]. Substances present in cigarettes are associated with irreversible damage of ovarian follicles and impaired liver estrogen metabolism [30]. Cocaine use has also been associated with lower estradiol levels, suggesting possible ovary-toxic effects [7,31].
Many of these characteristics and unhealthy lifestyles are prevalent among HIV-infected women. Prevalence of current smoking among HIV-infected persons is found to be approximately 42% [32] in comparison with the 19% seen in the general population in the United States [33]. Specifically, among women participating in WIHS, 56% of the women were found to be current smokers with an additional 16% of the women found to be prior smokers [34]. In addition, African Americans account for the highest proportion of new HIV infections in the United States with an estimated 64% of all new HIV infections in women found to be in African Americans [35]. Furthermore, HIV-infected women are of lower socioeconomic status, with increased prevalence of substance use than that typically found in women enrolled in studies on the age of menopause [36]. Hence, when examining the influence of HIV on the age of menopause, one needs to have a comparator of non–HIV-infected group with similar characteristics. Studies without comparison groups have reported the median age of menopause in HIV-infected women to be between 47 and 50 years old [37–42].
There are only few studies that have focused on the age of menopause in HIV-infected women with a similar comparative non–HIV-infected group.Cejtin et al studied the age of menopause in women enrolled in the WIHS [43]. HIV-infected women partaking in the WIHS were primarily African American and of lower socioeconomic status with heterosexual transmission rather than injection drug use as the major HIV risk factor [44]. They found no significant difference in the median age of menopause when HIV-infected women were compared to non–HIV-infected women. Median age of menopause was 47.7 years in HIV-infected women and 48.0 years in non–HIV-infected women [43].
In contrast, in the Ms Study, a prospective cohort comparing 302 HIV-infected with 259 non-HIV-infected women, HIV-infected women were 73% more likely to experience early menopause than non-HIV-infected women [45]. Similar to the WIHS, there was a high prevalence of African Americans but unlike the WIHS the majority of participants had used heroin or cocaine within the past 5 years. The high prevalence of drug use and current or former cigarette use in the Ms Study likely contributed to the relatively early onset of menopause. Furthermore, the WIHS and Ms Study used different definition of menopause. The WIHS defined menopause as 6 consecutive months of amenorrhea with an FSH level greater than 25 mIU/mL while the Ms Study defined menopause as the cessation of menstrual period for 12 consecutive months [43,45]. Given the fact that 52% of the women in the Ms Study had high-risk behaviors associated with amenorrhea and that menopause was defined as 12 months of amenorrhea without corresponding FSH levels, it is possible that the Ms Study included many women with amenorrhea who had not yet reached menopause. On the other hand, although the 6 months’ duration of amenorrhea used in the WIHS to define menopause had the potential to include women who only had amenorrhea without menopause, the use of FSH levels to define menopause most likely eliminated women who only had amenorrhea.
HIV-infected women have several factors associated with early menopause which are similar to that in the general population, including African American race, injection drug use, cigarette smoking, and menarche before age of 11 [37,41]. In addition, multiple studies have shown that a key factor associated with early age of menopause among HIV-infected women is the degree of immunosuppression [37,41,45]. The Ms Study found that women with CD4 cell counts < 200 cells/mm3 had an increased risk ofamenorrhea lasting at least 12 months when compared to women with CD4 cell counts ≥ 200 cells/mm3. The median age of menopause was 42.5 years in women with CD4 cell counts < 200 cells/mm3, 46.0 years in women with CD4 cell counts between 200 cells/mm3 and 500 cells/mm3, and 46.5 years in women with CD4 cell counts > 500 cells/mm3 [45]. Similarly, in a cohort of 667 Brazilian HIV-infected women, among whom 160 women were postmenopausal, Calvet et al found 33% of women with CD4 cell counts < 50 cells/mm3 to have premature menopause, compared to 8% of women with CD4 cell counts ≥ 350 cells/mm3 [41]. De Pommerol et al studied 404 HIV-infected women among whom 69 were found to be postmenopausal. They found that women with CD4 cell counts < 200 cells/mm3 were more likely to have premature menopause compared to women with CD4 cell counts ≥ 350 cells/mm3 [37].
Besides the degree of immunosuppression, another factor contributing to early menopause unique to HIV-infected women is chronic hepatitis C infection [41].
