To the Editors:
As result of the large availability of antiretroviral therapy (ART), many HIV-infected women are now surviving into the fifth decade of life and beyond and will or have already experienced menopause.1 To the extent that menopause exacerbates the risks of diseases of aging, it is important to consider whether natural menopause occurs earlier in HIV-infected women. Several investigators have studied gynecologic issues in midlife HIV-infected women and the effect of HIV on the age at which women reach menopause. The studies available, however, fail to provide conclusive data permitting confirmation that the age of HIV-positive women at menopause is younger than that of uninfected women.2–9 A variety of additional factors have been implicated in causing earlier menopause, including smoking, drug use, African ethnicity, and lower education level; all of which are common among many HIV-infected populations.10,11 In addition, menopause might be difficult to ascertain in this population because of amenorrhea secondary to coexisting conditions and wasting syndrome. Furthermore, the role of HIV-related immunodeficiency on the onset of menopause is still debated.2–5,9
The present study aimed to evaluate the prevalence of prolonged amenorrhea in women aged 40 years or younger and 45 years or younger and to identify its correlates in a large population of women living with HIV in Italy enrolled in the Donne con Infezione Da HIV (DIDI) Study. DIDI is an Italian multicenter study based on a questionnaire survey performed in 585 HIV-positive women between November 2010 and February 2011. Health care workers gave the anonymous in-depth questionnaire to all women aged 18 years or older, with a fair understanding of the Italian language, and cared for in one of 16 Infectious Diseases Centers. Women were asked to report the characteristics of their menstrual flow. Women who reported “absent” menstrual flow in the last 12 months were retrospectively considered postmenopausal, in accordance with the World Health Organization definition.12 Early menopause (EM) was defined by amenorrhea occurring before the age of 46 years,11 and premature menopause (PM) was considered when menstruations were ceased in women aged 40 years or younger. Information about the age of amenorrhea onset was not available from the questionnaire; hence, women aged 46 years or older were excluded from the analysis, as were those with secondary menopause (related to surgery or anticancer radio/chemotherapy). Premenopausal and postmenopausal women were compared for demographic and clinical characteristics by Wilcoxon and χ2 test when appropriate. Factors associated with the binary outcome variable of EM were identified by multivariable logistic regression. Variables associated with PM were not analyzed because outcome was too rare.
A total of 352 of 585 women were included. Women's median age at time of questionnaire was 40 years [interquartile range (IQR): 34–43], 17% were migrants, 18% reported current illicit drug use, and 49% were current smokers. Median years from HIV diagnosis were 11 (IQR: 6–18) years, median CD4 cells nadir was 220 cells/μL (IQR: 106–300), and 19% were classified in CDC group C. Most of the included women (86%) were on effective ART. Compared with the 233 participants in the DIDI study who were not included in the present analysis, the 352 included women were younger by definition, more frequently in a less advanced stage of HIV disease, less likely to be active or former drug users, and more often migrants (data not shown). Twenty-seven of all 352 women reported absent menstrual flow during the last 12 months, determining an EM prevalence of 7.7%. As compared to premenopausal women, women with EM were older [median 42 (IQR: 39–44) vs 40 (IQR: 34–43) years; P = 0.02] and self-reported lower level of global health [median 50 (IQR: 30–55) vs 60 (IQR: 50–80), P = 0.001], psychological health [median 50 (IQR: 30–65) vs 60 (IQR: 50–80), P = 0.007], and physical health [median 42 (IQR 20–55) vs 50 (IQR 30–80), P = 0.05) on a 0-100 scale. EM women were characterized by longer history of HIV infection [median 18 years (IQR 10–22) vs 10 (IQR 6–18), P = 0.002] and more advanced clinical stage of disease (CDC group C vs group A/B: 41% vs 17.1%, P = 0.003). Bone density screening was reported by 51.9% of EM women and by 23.4% of the premenopausal women (P = 0.001); similarly, mammography was more frequently performed by EM women (74.1% vs 42.2%, P = 0.003).
After adjusting for potential confounders in the multivariable logistic regression model, having experienced an AIDS event (CDC group C) was the only predictor of EM in our study population [adjusted odds ratio (AOR): 3.33, 95% CI: 1.14 to 8.69]. No significant association emerged between risk of EM and education, age at menarche, drug use, or smoking habits. Mammography and bone density screening resulted independently associated with EM (AOR: 3.07, 95% CI: 0.94 to 9.98, P = 0.06 and AOR: 3.44, 95% CI: 1.09 to 10.8, P = 0.03, respectively). Selecting only the 173 women aged 40 years or younger, prolonged amenorrhea was reported by 9 interviewed participants, for a prevalence of PM of 5.2%.
In our study, the prevalence of menopause occurring at the age of 45 years or younger was 7.7%, which seems not much different than what has been reported in HIV-uninfected Italian women (7.1%).11 Among women younger than 40 years, however, we observed a high prevalence of women with PM: this proportion is much higher than the one reported for the Italian general female population (5.2% vs 1.8%).11
The interpretation of this finding should be done with great caution, as we have no confirmatory endocrine profiles. However, HIV infection and drug abuse might interfere with the levels of reproductive hormones, suggesting the need of caution in defining menopausal status by biomarkers in this populations.6 In particular, follicle-stimulating hormone plasma levels increased in HIV-infected women during the late menopausal transition as compared to HIV-negative women.6 Some authors also suggest that HIV infection is associated with prolonged amenorrhea and menstrual irregularities,4 despite no influence on ovarian aging.3,5 Indeed, women with hypothalamic amenorrhea due to HIV might have a return of menses, especially with ART.8
Having experienced an AIDS-defining event resulted the strongest predictor of EM in our study. Some authors illustrate an association between HIV-related immunodeficiency and menopause, at least at the more severe end of the spectrum,2,4,9,13 whereas others do not confirm this finding.3,5 The precise mechanism underlying the interaction between sex hormones and the immune system has not been clearly delineated. Evidence suggests that prolactine levels are increased with lower CD4 count and with use of opiate, with a possible influence on menstrual irregularities.6 Most of the studies conducted in HIV-uninfected women suggest an active immune adaptation because of the hormonal changes occurring during menopause, rather than the opposite.14–16 Increased IL2 and CD25 levels in women <5 years after menopause have been described.16 It also has been reported that estrogen-deficient women have reduced levels of T helper cells and T helper–derived cytokines.14 These findings might have clinical implications suggesting a higher susceptibility to opportunistic infections in menopausal women: AIDS might be a consequence of the menopausal hormonal asset despite menopause a consequence of AIDS. However, no data on HIV-infected women are available to confirm this speculation. On the other hand, factors other than immune suppression, may contribute to the ovarian dysfunction in AIDS women, as weight loss, decreased muscle mass, and wasting syndrome.
The lack of association between illicit drug use and EM may be due to the fact that most of the women were not current drug users at the time of questionnaire, but only had a history of drug addiction. According to guidelines and good clinical practice, EM women more frequently underwent annual bone density and mammography screening, suggesting a good perception and management of premature age-associated complications by Italian HIV clinicians.
Our study has some limitations that need to be mentioned. First, observed proportions might be an underestimation of the phenomenon in the context of HIV infection, due to the cross-sectional nature of the study that did not allow to collect information on women older than 45 years. Second, selection bias due to language barrier may have lead to the low representation of ethnicities other than white (18%). Third, the presence or the absence of menopause was based on the women self-report method that conceals the potential for recall bias. Nonetheless, we do not think that this might have substantially influenced information collection because women are often correct about their menstrual cycles status.
In conclusion, the prevalence of EM was comparable with the one reported for the Italian general population, while we observed a higher proportion of prolonged amenorrhea in women aged 40 years or younger. Because advanced stage of disease was the main predictive factor of EM in young women with HIV-infection, earlier use of antiretroviral treatment will probably favorably impact also on the fertility preservation in the setting of HIV. At the same time, chronic infection due to HIV should be listed among the possible causes of amenorrhea in young women with ceased menstruation, and HIV antibody testing should be advised in this setting. A deeper exploration of women's health issues in clinical practice may be of profound advantage from the individual and the public health perspectives.
The authors acknowledge Women for Positive Action (WFPA), a global initiative established in response to the need to address specific concerns of women living and working with HIV. The DIDI study Group stemmed from the WFPA Italia.
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APPENDIX DIDI Study Group
Antonella d'Arminio Monforte (Milan) and Adriana Ammassari (Rome).
Enza Anzalone (Frosinone), Teresa Bini (Milano), Antonella Castagna (Milano), Anna Maria Cattalan (Rovigo), Gabriella D'Ettorre (Roma), Fiorella Di Sora (Roma), Daniela Francisci (Perugia), Miriam Gargiulo (Napoli), Nicoletta Ladisa (Bari), Giuseppina Liuzzi (Roma), Tiziana Quirino (Busto Arsizio), Raffaella Rosso (Genova), Maria Paola Trotta (Roma), and Francesca Vichi (Firenze).
Antonella Cingolani (Roma) and Rita Murri (Roma).
Statistician and Data Manager
Paola Cicconi (Milano) and Paola Pierro (Roma).