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Among WWH in the REPRIEVE trial, more advanced reproductive
age is associated with metabolic dysregulation and region of residence
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Additional research on age at menopause among WWH is needed.
Theoretically, cessation of menses among WWH (women with HIV) of more advanced reproductive age could be contributing to the association we observed. Additional work is needed to determine whether the relationships between reproductive aging milestones and cardiometabolic parameters observed in our study are causal, and, if so, the direction of causality.
STUDY RESULTS:
As expected, higher chronologic age was associated with more advanced reproductive age (OR, 1.49 per year older; 95% CI, 1.44-1.54; P < .01). Controlling for chronologic age, the following cardiometabolic parameters were associated with more advanced reproductive age: waist circumference (>88 vs ≤88 cm) (OR, 1.38; 95% CI, 1.06-1.80; P = .02) and hemoglobin (≥12 vs <12 g/dL) (2.32; 1.71-3.14; P < .01).
Analysis of baseline data from a prospectively recruited, global cohort of midlife WWH enrolled in the REPRIEVE trial yielded the following insights regarding reproductive aging. First, among the full cohort of WWH, select cardiometabolic risk factors were associated with more advanced reproductive age, controlling for chronologic age. These included waist circumference >88 cm and hemoglobin levels ≥12 g/dL.
Second, residence in sub-Saharan Africa or Latin America and the Caribbean (vs high-income regions) was associated with higher relative odds of more advanced reproductive age, while controlling for chronologic age.
Finally, among postmenopausal WWH, the median age at FMP was 48 years, correlating with an age at menopause of 49 years. When estimated across the full group of WWH, the median predicted distribution of age at FMP was 49 or 50 years, depending on the censoring strategy applied, corresponding to an age at menopause of 50 or 51 years, respectively.
In this group of WWH, cardiometabolic parameters, including high waist circumference >88 cm and hemoglobin level ≥12 g/dL, were associated with more advanced reproductive age, controlling for chronologic age. Previously published physiology studies among women in the general population have suggested relationships between reproductive aging and increased adiposity [33], as well as increased ectopic fat deposition (heart, viscera) [34, 35]. A small study has also highlighted an association between reproductive aging and ectopic fat deposition (heart) among WWH [36]. Intriguingly, a general-population study by Papadakis et al [37] revealed hormone replacement therapy decreased ectopic (visceral) fat volume among menopausal women, implying that reduced endogenous estrogen production may prompt ectopic fat deposition. By contrast, our finding that hemoglobin levels ≥12 g/dL are associated with advanced reproductive aging among WWH is unexpected, given that hemoglobin typically declines with age among women in the general population [38]. Theoretically, cessation of menses among WWH of more advanced reproductive age could be contributing to the association we observed. Additional work is needed to determine whether the relationships between reproductive aging milestones and cardiometabolic parameters observed in our study are causal, and, if so, the direction of causality.
Our current work illustrates that, among midlife WWH, waist circumference >88 cm and hemoglobin level ≥12 g/dL are associated with more advanced reproductive age after controlling for chronologic age. Furthermore, in our study, WWH from sub-Saharan Africa and/or Latin America and the Caribbean demonstrated higher odds for more advanced reproductive age, compared with WWH from high-income regions. Finally, our estimates of median age at menopause varied depending on sampling and the analytic approaches used. Overall, our findings may help clinicians anticipate the menopausal transition in WWH and promote early engagement in efforts to characterize and mitigate cardiometabolic risk and other reproductive-age associated risks. In addition, through this investigation, we extend the application of a reproductive aging staging scheme potentially relevant to future studies focused on endocrine or cardiometabolic risks among midlife women. Our baseline characterization of reproductive aging among cisgender women in the REPRIEVE trial will enable future assessment of whether reproductive age influences the risk and timing of major adverse cardiovascular events, controlling for chronologic age.
Overall, the earlier the menopausal transition, the higher a woman’s reproductive age-associated risk for comorbid conditions [3]. With respect to cardiometabolic risk, earlier menopause and/or reduced number of cycling years have been associated with increased risk for ischemic heart disease, stroke, and heart failure [4-6].
Accelerated reproductive aging has been postulated to contribute to heightened cardiometabolic risk among women with (vs without) human immunodeficiency virus (HIV) [7]. Nevertheless, studies have yielded conflicting results as to whether women with HIV (WWH) experience accelerated reproductive aging, including earlier age at menopause [8]. One potential explanation underlying conflicting findings relates to differing statistical methods used to describe or estimate age at menopause [9].
A total of 2002 cisgender women enrolled in REPRIEVE at non-EU sites during the evaluation period for this investigation. Among this sample, 375 women were excluded for parameters preventing accurate classification in our reproductive aging scheme (see Methods).
The median age of participants was 49 years, and just over half (51%) met the criteria for group 3 of the reproductive aging spectrum (postmenopausal). Participants were from sub-Saharan Africa (35%), high-income regions (24%), Latin America and the Caribbean (23%), and South East/East/South Asia (18%). The predominant race was black or African American (63%), followed by Asian (18%), and white (13%). Thirteen percent of participants reported current cigarette smoking (15% former), and 13% reported current or former substance use (including methamphetamine, cocaine, or intravenous drugs). The median body mass index (calculated as weight in kilograms divided by height in meters squared) was 27.0, and 31% of participants had a body mass index ≥30. The median waist circumference was 93 cm, and 62% of participants had a waist circumference >88 cm. The median time since HIV diagnosis was 13 years, and the median duration of ART use was 9 years. The median CD4 cell count was 685/mm3, and 74% of participants had a CD4 cell count ≥500/mm3. HIV-1 RNA levels were below the assay lower limit of quantification in 89% of participants (Table 1).
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Markella V. Zanni,1 Judith S. Currier,2 Amy Kantor,3 Laura Smeaton,3 Corinne Rivard,1 Jana Taron,4 Tricia H. Burdo,5 Sharlaa Badal-Faesen,6
Umesh G. Lalloo,7 Jorge A. Pinto,8 Wadzanai Samaneka,9 Javier Valencia,10 Karin Klingman,11 Beverly Allston-Smith,11 Katharine Cooper-Arnold,12
Patrice Desvigne-Nickens,12 Michael T. Lu,4 Kathleen V. Fitch,1 Udo Hoffman,4 Steven K. Grinspoon,1 Pamela S. Douglas,13 and Sara E. Looby1,14
Abstract
Background
Reproductive aging may contribute to cardiometabolic comorbid conditions. We integrated data on gynecologic history with levels of an ovarian reserve marker (anti-müllerian hormone [AMH)] to interrogate reproductive aging patterns and associated factors among a subset of cisgender women with human immunodeficiency virus (WWH) enrolled in the REPRIEVE trial.
Methods
A total of 1449 WWH were classified as premenopausal (n = 482) (menses within 12 months; AMH level ≥20 pg/mL; group 1), premenopausal with reduced ovarian reserve (n = 224) (menses within 12 months; AMH <20 pg/mL; group 2), or postmenopausal (n = 743) (no menses within12 months; AMH <20 pg/mL; group 3). Proportional odds models, adjusted for chronologic age, were used to investigate associations of cardiometabolic and demographic parameters with reproductive aging milestones (AMH <20 pg/mL or >12 months of amenorrhea). Excluding WWH with surgical menopause, age at final menstrual period was summarized for postmenopausal WWH (group 3) and estimated among all WWH (groups 1-3) using an accelerated failure-time model.
Results
Cardiometabolic and demographic parameters associated with advanced reproductive age (controlling for chronologic age) included waist circumference (>88 vs ≤88 cm) (odds ratio [OR], 1.38; 95% confidence interval, 1.06-1.80; P = .02), hemoglobin (≥12 vs <12 g/dL) (2.32; 1.71-3.14; P < .01), and region of residence (sub-Saharan Africa [1.50; 1.07-2.11; P = .02] and Latin America and the Caribbean [1.59; 1.08-2.33; P = .02], as compared with World Health Organization Global Burden of Disease high-income regions). The median age (Q1, Q3) at the final menstrual period was 48 (45, 51) years when described among postmenopausal WWH, and either 49 (46, 52) or 50 (47, 53) years when estimated among all WWH, depending on censoring strategy.
Conclusions
Among WWH in the REPRIEVE trial, more advanced reproductive age is associated with metabolic dysregulation and region of residence. Additional research on age at menopause among WWH is needed.
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INTRODUCTION
For women, reproductive aging may fuel risks of diverse cardiometabolic comorbid conditions traditionally associated with chronologic aging. Specifically, reproductive aging-characterized by depletion of primordial oocyte stores and, in turn, reduced endogenous estrogen production [1]-may predispose women to atherosclerotic cardiovascular disease (ASCVD), heart failure, dyslipidemia, glucose dysregulation, ectopic fat deposition, and bone fragility [2, 3]. General-population women’s studies exploring reproductive age-associated cardiometabolic risks typically focus on 2 key points: whether a woman is in menopause and when she reached this milestone. Overall, the earlier the menopausal transition, the higher a woman’s reproductive age-associated risk for comorbid conditions [3]. With respect to cardiometabolic risk, earlier menopause and/or reduced number of cycling years have been associated with increased risk for ischemic heart disease, stroke, and heart failure [4-6].
Accelerated reproductive aging has been postulated to contribute to heightened cardiometabolic risk among women with (vs without) human immunodeficiency virus (HIV) [7]. Nevertheless, studies have yielded conflicting results as to whether women with HIV (WWH) experience accelerated reproductive aging, including earlier age at menopause [8]. One potential explanation underlying conflicting findings relates to differing statistical methods used to describe or estimate age at menopause [9].
A second explanation underlying conflicting findings on age at menopause relates to the inherent challenge of categorizing WWH as premenopausal versus postmenopausal. World Health Organization (WHO) criteria define menopause as permanent cessation of menses, recognized after 12 months of consecutive, otherwise unexplained, amenorrhea [10]. Reference-standard “STRAW + 10” criteria define menopause analogously, while also considering levels of hypothalamic-pituitary-gonadal axis hormones (eg, follicle stimulating hormone and estradiol) [11, 12]. However, some WWH experience prolonged amenorrhea [13] followed by subsequent resumption of menses [14]. Indeed, among WWH, factors including severe concomitant illness, adherence with select psychotropic medications, and use of opioids may result in suppression of hypothalamic-pituitary hormones, provoking reversible menstrual irregularity [15].
Recent years have seen a surge in research on anti-müllerian hormone (AMH), a marker of ovarian reserve relevant to staging reproductive aging [16]. AMH is secreted by ovarian granulosa cells. Throughout a woman’s adult life, AMH levels progressively decline-in concert with oocyte stores-and drop to an undetectable level a few years before menopause [17, 18]. Levels of AMH, which tend to be consistent throughout the menstrual cycle [19], predict age at menopause, both in the general population [20-22] and among WWH [23].
Our research group previously described a classification scheme synthesizing menstrual history and AMH levels to categorize midlife WWH along a contiguous 3-group reproductive aging spectrum: premenopausal, premenopausal with reduced ovarian reserve, and postmenopausal [24]. We reasoned applying this system may help disentangle effects of reproductive versus chronologic aging on surrogates of cardiometabolic risk among WWH. We showed that in a small sample of asymptomatic WWH from the Northeast United States, more advanced reproductive age was associated with noncalcified coronary atherosclerotic plaque, even after controlling for traditional risk factors, including chronologic age. Furthermore, we demonstrated that measures of ASCVD risk increased across the reproductive aging spectrum, in advance of menopause [24].
Building on our previous work, we now apply an analogous system to explore the correlates and timing of reproductive aging transitions in a global cohort of midlife antiretroviral therapy (ART)-treated WWH enrolled in the REPRIEVE trial. As part of our REPRIEVE Women’s Objectives study, we analyzed baseline data from 1449 cisgender female REPRIEVE participants, investigating associations of cardiometabolic and demographic parameters with reproductive aging milestones (AMH <20 pg/mL or >12 months amenorrhea).
Furthermore, after excluding from our analysis cohort WWH with bilateral oophorectomy (with or without hysterectomy), we summarized age at final menstrual period (FMP) among those women deemed by our classification to be postmenopausal (group 3). We also estimated age at FMP among WWH across all 3 reproductive aging groups, using a time-to-events methods (ie, an accelerated failure-time model). Insights gleaned may have relevance for anticipating reproductive aging transitions in WWH and focusing cardiometabolic health preservation efforts on parameters related to more advanced reproductive age.
Study Participants
The REPRIEVE trial (NCT02344290) enrolled 7770 individuals with HIV (31% natal female), aged 40-75 years, without prior cardiovascular disease (CVD) and with low-to-moderate traditional CVD risk. Each clinical research site obtained institutional review board/ethics committee approval, as well as any other applicable regulatory entity approvals. Participants were provided with study information, including a discussion of risks and benefits, and were asked to sign the approved declaration of informed consent. Associated publications include additional details about trial design, objectives, and methods [25, 26].
Our primary analysis on correlates of reproductive aging transitions centered on 1449 cisgender WWH (henceforth referred to as WWH) enrolled in the non-European Union (EU) component of REPRIEVE after integration of the REPRIEVE Women’s Objectives (protocol version 3, distributed to REPRIEVE sites on 2 February 2016). As noted in the article by Grinspoon et al, 213 European participants were recruited into a protocol parallel to the main REPRIEVE protocol (REPRIEVE-EU). REPRIEVE-EU participants’ data were not planned for in the original REPRIEVE Women’s Objectives proposal and were not included in this analysis.
Among women enrolled in the non-EU component of REPRIEVE after protocol version 3, participants were excluded from the analysis for parameters expected to confound classification in our reproductive scheme. Such parameters included (1) self-report of any of the following: history of hysterectomy without bilateral oophorectomy, history of uterine ablation, current use of a progesterone intrauterine device or implant, or current use of sex hormones or sex hormone blockers and/or (2) missing or invalid AMH levels (Supplementary Figure 1). For our secondary analysis on timing of (natural/nonsurgical) reproductive aging transitions, WWH who reported bilateral oophorectomy (with or without hysterectomy) were also excluded (n = 75).
DISCUSSION
Analysis of baseline data from a prospectively recruited, global cohort of midlife WWH enrolled in the REPRIEVE trial yielded the following insights regarding reproductive aging. First, among the full cohort of WWH, select cardiometabolic risk factors were associated with more advanced reproductive age, controlling for chronologic age. These included waist circumference >88 cm and hemoglobin levels ≥12 g/dL. Second, residence in sub-Saharan Africa or Latin America and the Caribbean (vs high-income regions) was associated with higher relative odds of more advanced reproductive age, while controlling for chronologic age. Finally, among postmenopausal WWH, the median age at FMP was 48 years, correlating with an age at menopause of 49 years. When estimated across the full group of WWH, the median predicted distribution of age at FMP was 49 or 50 years, depending on the censoring strategy applied, corresponding to an age at menopause of 50 or 51 years, respectively.
General-population studies have shown that staging reproductive aging by self-reported menstrual history alone may be less accurate than analogous staging achieved through a synthesis of self-reported menstrual history and hypothalamic-pituitary-gonadal axis hormones [32]. One strength of our analysis of factors related to reproductive aging milestones was that these milestones were defined not only by self-reported menstrual history but also by levels of AMH, a key biomarker of ovarian reserve. A second strength of our study includes the size and diversity of our cohort, as well as the standardized data collection methods across sites. Indeed, our study integrates menstrual history data and data on levels of AMH among nearly 1500 midlife WWH from across the globe to yield important, clinically relevant insights on correlates and timing of reproductive aging transitions.
In this group of WWH, cardiometabolic parameters, including high waist circumference >88 cm and hemoglobin level ≥12 g/dL, were associated with more advanced reproductive age, controlling for chronologic age. Previously published physiology studies among women in the general population have suggested relationships between reproductive aging and increased adiposity [33], as well as increased ectopic fat deposition (heart, viscera) [34, 35]. A small study has also highlighted an association between reproductive aging and ectopic fat deposition (heart) among WWH [36]. Intriguingly, a general-population study by Papadakis et al [37] revealed hormone replacement therapy decreased ectopic (visceral) fat volume among menopausal women, implying that reduced endogenous estrogen production may prompt ectopic fat deposition. By contrast, our finding that hemoglobin levels ≥12 g/dL are associated with advanced reproductive aging among WWH is unexpected, given that hemoglobin typically declines with age among women in the general population [38].
Theoretically, cessation of menses among WWH of more advanced reproductive age could be contributing to the association we observed. Additional work is needed to determine whether the relationships between reproductive aging milestones and cardiometabolic parameters observed in our study are causal, and, if so, the direction of causality.
Of note, our data on trends in cardiometabolic parameters observed across the successive reproductive aging groups suggest that select adverse metabolic changes (eg, those related to circulating lipid levels) occur across a continuum of reproductive aging. This finding is highly intuitive, given that hormonal changes among aging women also occur along a continuum, not abruptly after 12 months of amenorrhea. Moreover, this finding resonates with those of general-population studies showing that aging women analogously experience other endocrine/metabolic comorbid conditions (eg, accelerated bone loss) en route to menopause [39, 40]. It is worth noting, however, that in modeling controlling for chronologic age, no significant associations between lipid levels and more advanced reproductive age were observed. Nevertheless, taken together, findings from our study and others suggest that clinicians should engage midlife WWH in cardiometabolic risk assessment and cardiometabolic risk prevention before these women are determined to be postmenopausal.
Among this group of WWH, residence in sub-Saharan Africa or Latin America and the Caribbean (vs residence in high-income regions) was associated with higher odds of more advanced reproductive age, controlling for chronologic age. Of note, general-population studies have also highlighted apparent regional differences in age at menopause [41, 42]. Our finding that WWH in sub-Saharan Africa or Latin America and the Caribbean (vs WWH in high-income regions) have higher odds of more advanced reproductive age has broad implications, given that the majority of WWH globally reside in these regions. Further research is required to delineate the interplay of genetic and environmental factors potentially underlying this observation.
As noted above, the median age at FMP in our study (and thus inferences on age at menopause) differed depending on the group sampled and the statistical methods used. As reflected in a meta-analysis by Imai et al [8], previous studies aiming to characterize age at menopause among WWH have yielded conflicting results. Likely explanations for inconsistent findings include (1) differences in sampling and analytic methods, (2) singular reliance on self-reported menstrual history in the absence of relevant hormonal data, (3) differences in definitions of menopause, and (4) absence of thorough investigation for parameters that may predispose to prolonged amenorrhea in the absence of menopause. In contrast to the controversy on age at menopause among WWH, there seems to be consensus across studies on the point that women with HIV have lower age-adjusted levels of AMH than those without HIV [43-45], reflective of advanced reproductive aging. Harmonization of strategies used across studies to characterize age at menopause among WWH would be valuable.
The extent to which our findings can be generalized to WWH globally remains unclear. Our findings were derived from ART-treated WWH with low-to-moderate traditional CVD risk engaged in care and enrolled in a large-scale CVD prevention trial (REPRIEVE). That is, our studied population may be expected to be healthier than the global population of midlife WWH. Also of note, the cross-sectional design of our investigation precludes definitive inferences as to whether observed associations (eg, between advanced reproductive age and select parameters) are causal and limits the ability to assess the directionality of observed associations. And finally, our approaches to estimating age at menopause among WWH are limited, in part, by participant self-report of age at LMP as well as the relatively young age of the cohort (with only 51% postmenopausal). Continued follow-up of menstrual patterns in this cohort would allow for a more precise estimation of age at menopause in future analyses.
Our current work illustrates that, among midlife WWH, waist circumference >88 cm and hemoglobin level ≥12 g/dL are associated with more advanced reproductive age after controlling for chronologic age. Furthermore, in our study, WWH from sub-Saharan Africa and/or Latin America and the Caribbean demonstrated higher odds for more advanced reproductive age, compared with WWH from high-income regions. Finally, our estimates of median age at menopause varied depending on sampling and the analytic approaches used. Overall, our findings may help clinicians anticipate the menopausal transition in WWH and promote early engagement in efforts to characterize and mitigate cardiometabolic risk and other reproductive-age associated risks. In addition, through this investigation, we extend the application of a reproductive aging staging scheme potentially relevant to future studies focused on endocrine or cardiometabolic risks among midlife women. Our baseline characterization of reproductive aging among cisgender women in the REPRIEVE trial will enable future assessment of whether reproductive age influences the risk and timing of major adverse cardiovascular events, controlling for chronologic age.
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