Associations of Early Prolonged Secondary Amenorrhea in Women With and Without HIV

Shayda A Swann; Elizabeth M King; Davi Pang; Marcela A P Silva; Amber R Campbell; Jerilynn C Prior; Mona Loutfy; Angela Kaida; Hélène C F Côté; Melanie C M Murray

doi:10.1093/ofid/ofae493

Menstrual Cycle · Cycle Disorders

Associations of Early Prolonged Secondary Amenorrhea in Women With and Without HIV

Swann SA, King EM, Pang D, Silva MAP, Campbell AR, Prior JC, Loutfy M, Kaida A, Côté HCF, Murray MCM

Published September 2024 Open forum infectious diseases, 11(9), ofae493

DOI 10.1093/ofid/ofae493 PMID 39301109 PMC PMC11412246

Abstract

Background

The menstrual cycle is a critical indicator of women's health. Early prolonged secondary amenorrhea increases risks for morbidity and mortality. Menstrual cycle research in women with HIV is inconsistent and often lacks an adequate comparison sample. We aimed to determine whether women with HIV have a higher lifetime prevalence of amenorrhea and whether this is independently associated with HIV and/or other biopsychosocial variables.

Methods

With data from 2 established HIV cohorts, participants assigned female at birth were eligible if aged ≥16 years, not pregnant/lactating, and without anorexia/bulimia nervosa history. Amenorrhea was defined by self-reported history of (1) no menstrual flow for ≥12 months postmenarche not due to pregnancy/lactation, medications, or surgery or (2) early menopause or premature ovarian insufficiency. Multivariable logistic regression models explored biopsychosocial covariates of amenorrhea.

Results

Overall, 317 women with HIV (median age, 47.5 years [IQR, 39.2-56.4]) and 420 women without HIV (46.2 [32.6-57.2]) were included. Lifetime amenorrhea was significantly more prevalent among women with HIV than women without HIV (24.0% vs 13.3%). In the multivariable analysis, independent covariates of amenorrhea included HIV (adjusted odds ratio, 1.70 [95% CI, 1.10-2.64]), older age (1.01 [1.00-1.04]), White ethnicity (1.92 [1.24-3.03]), substance use history (6.41 [3.75-11.1]), and current food insecurity (2.03 [1.13-3.61]).

Conclusions

Nearly one-quarter of women with HIV have experienced amenorrhea, and this is associated with modifiable risk factors, including substance use and food insecurity. Care providers should regularly assess women's menstrual health and advocate for actionable sociostructural change to mitigate risks.

Topics

By this author

Luteal Phase · Luteal Phase Deficiency

The influence of the menstrual cycle on muscle injuries - a systematic review and meta-analysis

Guthardt Y et al., 2026 Sci Rep Free full text on PubMed Central

This systematic review and meta-analysis examined the relationship between menstrual cycle phases and the incidence of muscle injuries in female team sport athletes, following PRISMA 2020 and PERSiST guidelines. A comprehensive search was conducted in PubMed, Scopus, and SPORTDiscus from inception to mid-January 2024. Studies were included if they examined female team sport athletes of reproductive age with regular menstrual cycles and compared the occurrence of muscle injuries across at least two menstrual phases. Studies involving hormonal contraceptive use, medications affecting the menstrual cycle or musculoskeletal system, or menstrual dysfunction were excluded. Three studies met the inclusion criteria, involving 318 participants. Meta-analysis yielded a pooled Risk Ratio of 1.18 (95% CI: 0.75 to 1.86, p = 0.46) for injury risk between the luteal and follicular phases, suggesting no statistically significant association. However, the certainty of the cumulative evidence was rated as very low due to methodological limitations, including inconsistent phase classifications and reliance on imprecise methods for identifying menstrual phases. Consequently, no practical or clinical recommendations can be made at this time. Future research employing standardised, physiologically accurate methods for classifying and detecting menstrual cycle phases is necessary to better understand the potential links between hormonal fluctuations and injury risk.

Breast Health · Benign Breast Conditions

MON-154 Breast areolar diameter in healthy menstruating women—a single cycle cross-sectional study of associations with body size and ovulatory characteristics

Baaske AV et al., 2025 Journal of the Endocrine Society Free full text on PubMed Central

Tanner Breast Stage 3 (TB3, at menarche) and Tanner 5 (TB5, once ovulatory cycles established), despite being similar with an “upstanding” nipple, are different. Evidence suggests that steady and high ovulatory-level progesterone exposure accounts for the larger areolar diameter in TB5. Progesterone levels indicate whether the menstrual cycle is ovulatory and have crucial implications for women’s reproductive, metabolic, cardiovascular, and bone health. However, few data show average areolar diameter in regularly cycling women in whom SES, body size, and reproductive variables have been documented. As a step towards better understanding the role of areolar diameter in reflecting estradiol-progesterone balance, this study aims to document the average mean bilateral lateral areolar diameter (AD) in a cohort of regularly menstruating, premenopausal women in whom ovulation was documented in one cycle. We also aim to describe relationships between AD and demographic, anthropometric, and reproductive/ovulation variables. Women were eligible if aged 19-35 years with about month-apart cycles and no exogenous hormone use in the last 3-months. Participants completed one cycle with a daily Menstrual Cycle Diary© (cycle length, CL) and first morning temperatures for Quantitative Basal Temperature© (QBT©) ovulation analysis (normal luteal phase length ≥10 days). Questionnaires gathered SES, ethnic, general health, and reproductive characteristics. Bilateral horizontal areolar diameters were measured by a woman researcher with the participant supine in a warm room. From February 2020 to September 2022 (during the SARS-CoV-2 pandemic), 73 women from Metro Vancouver, British Columbia participated. Women were of median (min-max) age 30 (19-35) years, BMI 24.5 (17.1-41.4) and most identified as White (61.6%) with a median of 16 years of education. Median CL was 29 days (n=65) and QBT data showed 39.3% were normally ovulatory, 34.4% had short luteal phases and 26.2% were anovulatory. Median within-woman bilateral AD was 3.85 (2.35-8.00) cm. Left AD exceeded right (L 3.8 [2.3,8.2]; R 3.7 [ 2.4,7.8]; P=.003). Larger AD (≥3.85cm) was associated with greater body size (BMI r=.534), weight and waist circumference. However, earlier age at menarche (P=.02) was also significantly associated. No other reproductive variables (cycle length, luteal phase length, parity, ever use of CHC) were related to AD before body size adjustments. This study is the first to document, and describe demographic, anthropomorphic and reproductive associations with, AD in community dwelling, regularly cycling, premenopausal women. Future steps will determine the most influential of the anthropometric variables; adjustment for these will facilitate assessments of associations with ovulation related characteristics.

Breast Health · Benign Breast Conditions

SAT-128 Prospective 1-year Menstrual CycleBreast Tenderness and Swelling Experiences—data from healthy regularly cycling women initially proven normally ovulatory on two consecutive cycles

Wood M et al., 2025 Journal of the Endocrine Society Free full text on PubMed Central

Breast tenderness and swelling are associated with premenstrual symptoms but have not been well described in healthy, normally cycling women with known ovulatory status. There are documented negative health risks (in bone, the cardiovascular system and cancers) in association with ovulatory disturbances within normal-length cycles. Identifying breast changes across a predictable, month-apart cycle but with Subclinical Ovulatory Disturbances (SOD, short luteal phase [<10 days] and anovulation (with normal estradiol but lower or absent progesterone levels) could advance our understanding of menstrual cycle physiology, women’s health education and identification of those with chronic SOD who may benefit from cyclic progesterone therapy. Our objective was to determine whether within-woman breast tenderness and swelling experiences differed between normally ovulatory and ovulatory-disturbed cycles. In this 1-year prospective observational study, we examined daily breast tenderness (0-4) and swelling (1-5 change from usual = 3) experiences recorded via the Menstrual Cycle Diary© over ≥8 cycles (mean=13/woman) in 53 women. Ovulatory status was documented by the twice-validated Quantitative Basal Temperature© (QBT©) analysis. Cycle and ovulatory data were previously reported (Prior NEJM, 1990); Diary data were unreported. Participants were healthy, community-dwelling women, mean age 34 (32.4:35.5 years), BMI 22.0, primarily White, and about two-thirds were runners (for health or were marathon-training). Comparison of breast parameters in all normally ovulatory (n = 495) vs all SOD cycles (n = 199) (mean cycle length 28.1 [27.5-28.8 days]), showed significantly higher Breast Tenderness Score [intensity X days; 6.0 (range 1.0, 14.0) vs. 3.0 (0.0, 11.0) (P = .001)] and increased breast size [4.0 (2.0, 4.0) vs. 4.0 (0.0, 4.0) (P = .034]) in normally ovulatory cycles. However, in within-woman analysis (n = 47 women with both normally ovulatory and SOD cycles), breast tenderness/swelling did not significantly differ by ovulatory status. We plotted all ovulatory cycles (n=676) centred on ovulation; this revealed parallel timing of increases in breast tenderness and swelling in the late luteal phase. These 1-year prospective data documented that mild breast tenderness and swelling occurred before flow in cycles with normal ovulation; symptoms were less in SOD cycles. Breast changes were totally absent during the follicular phases.

Hormonal Agents · Progesterone and Progestins

"SUN-109 Feasibility of Cyclic Progesterone and Spironolactone for PCOS-specific Health-Related Quality of Life—a six-month, Phase II, single arm, single center, open-label study"

Nelson K et al., 2025 J Endocr Soc Free full text on PubMed Central

Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disorder that significantly decreases health-related quality of life (HRQoL). Combined hormonal contraceptives (CHC) are standard-of-care for PCOS but do not mitigate the neuroendocrine cause nor women’s primary concerns. Treatment options need expansion. We hypothesized cyclic oral micronized progesterone (CyclicP4) and spironolactone (Sp) would improve HRQoL, decrease LH, and acne. This Phase II, open-label single-arm pilot study evaluated the 6-month cyclicP4 and Sp treatment feasibility and safety in androgenic PCOS. Our primary outcome was within-woman change in PCOS-HRQoL (PCOSQ). No sample size calculation was possible; 40 was considered feasible. Eligible women were 19-40 years with physician-diagnosed androgenic PCOS. Exclusion criteria included HbA1c > 6.4%, use of metformin or CHC in the last month. Participants received progesterone (300 mg/bedtime 14 days/month); spironolactone (200 mg/day) began in cycle two. Adherence was tracked daily (Menstrual Cycle Diary©) and by pill counts. Safety was assessed by post-study potassium (K+). Feasibility by women’s post-trial treatment intention. PCOSQ, serum LH, calculated bioavailable testosterone (cBAT), HbA1c, hsCRP, and AMH were measured at baseline and trial end. We also assessed perceived acne and sleep changes (-5 to +5), K+ and therapy intent at study end. Six-month change by paired t-test or Wilcoxon signed-rank assessed P < .05 as important. Of 109 expressing interest, 41 enrolled, 36 began therapy (5 did not), and 26 provided final questionnaire data (19 with complete lab data). Completing women were mean age 29 (SD 4.9) years, BMI 30.3 (8.1), 61.5% White and 73.1% with university degrees. Total PCOSQ scores within-woman increased from 3.5±1.0 to 4.9±1.1 (95% CI 3.1-3.8, 4.6-5.3; P<.0000001). Each PCOSQ domain significantly improved (at least P<.001) as did acne and sleep. Weight was unchanged but waist circumference decreased 1.1 cm (NS). LH, cBAT, and AMH each decreased: LH 10.0±5.4 to 8.5±5.2 IU/L (95% CI 7.6-12.3, 6.3-10.8; P<.4), cBAT 0.7±0.4 to 0.6±0.3 nmol/L (0.5-0.9, 0.5-0.8; P<.2), and AMH 10.5±6.5 to 9.7±5.7 ng/ml (7.4-13.7, 7.0-12.4; P<.4). hsCRP remained unchanged (2.8±3.3 to 2.7±3.6 mg/L; P<.8) as did HbA1c (5.2±0.3 to 5.2±0.3%; P<.0). K+ remained within the normal range (3.5-5.0 mmol/L) at final testing (mean 4.0). Two allergic responses to spironolactone and one frequent flow/religious practice led to discontinuation. Feasibility was confirmed and participants strongly preferred continuing therapy (median Likert score=6/7, P<.0001) CyclicP4 and Sp for 6-months was feasible and significantly improved HRQoL in a non-medicine-seeking community women cohort with androgenic PCOS. Though the small sample size limited generalizability, findings are promising. A larger randomized trial comparing CyclicP4 vs. CHC is warranted.

Related research

Bone Mineral Density · Measurement

322. Prolonged Amenorrhea Is Associated with Decreased Hip Bone Mineral Density in Women Living with HIV

King EM et al., 2019 Open forum infectious diseases Free full text on PubMed Central

Background Women living with HIV (WLWH) have higher rates of long-term amenorrhea (no flow for ≥12 months) than HIV-negative women. However, little is known about the consequences of amenorrhea for WLWH. Both amenorrhea and HIV are associated with lower areal bone mineral density (BMD); though the combined effect of both on BMD remains unclear. In this cross-sectional study we investigated whether prolonged amenorrhea adversely affects BMD among WLWH. Methods We investigated BMD (using a Hologic bone densitometer) and prolonged amenorrhea among WLWH and HIV-negative control women of similar socioeconomic backgrounds aged 19–68 in the CARMA cohort. Participants were stratified by HIV status and history of prolonged secondary amenorrhea defined as a self-reported absence of menses for at least one year in the past or present, occurring at age <45 years and not due to surgery, breastfeeding, pregnancy or hormonal contraception. Hip and spine Z-scores (ageand racestandardized BMD values) were compared between groups using linear models, followed by multivariable analysis of BMD-related factors. Results WLWH (N = 129) had significantly lower hip (mean±SD −0.4 ± 0.9 vs. 0.3 ± 1.1; P < 0.001) and spine (−0.5 ± 1.3 vs. 0.2 ± 1.3; P = 0.001) Z-scores vs. controls (N = 129). Multivariable linear regression found prolonged amenorrhea was independently related to lower hip (P = 0.01), but not spine (P = 0.94) BMD. Within WLWH, the effect of amenorrhea was also additive to that of HIV, with hip Z-scores of -0.8±0.9for those with amenorrhea vs. -0.3±0.8for those normally cycling (P = 0.01). Amongst WLWH, those with prolonged amenorrhea had higher rates of illicit substance use, smoking, chronic opioid therapy, hepatitis C viral infection, and poorer HIV viral control than those with normal menstruation. Conclusion These data suggest that WLWH having prolonged amenorrhea of ≥1 year’s duration are at increased risk for hip bone loss, a finding influenced by comorbid, HIV-associated conditions. Screening WLWH for menstrual history will allow early discovery of osteoporosis risk, and stimulate preventative measures to mitigate bone loss. Disclosures All authors: No reported disclosures.

Bone Mineral Density · Measurement

Prolonged Amenorrhea and Low Hip Bone Mineral Density in Women Living With HIV-A Controlled Cross-sectional Study

King EM et al., 2020 J Acquir Immune Defic Syndr

Women living with HIV (WLWH) have higher rates of prolonged secondary amenorrhea (no flow for ≥1 year) than HIV-negative women. Both having amenorrhea and being HIV positive are associated with lower areal bone mineral density (BMD). However, their combined BMD effects remain unclear. Therefore, we investigated prolonged amenorrhea and BMD in WLWH and controls. This cross-sectional study enrolled WLWH and HIV-negative control women aged 19-68 years of similar backgrounds. We assessed BMD (Hologic; as ageand ethnicity-matched Z-scores) in the Children and women: AntiRetrovirals and Markers of Aging cohort. Participants were stratified by amenorrhea history defined as past/present lack of menses for ≥1 year at age 45 and younger and not because of surgery, breastfeeding, pregnancy, or hormonal contraception. Hip and spine Z-scores by amenorrhea/no amenorrhea used linear models with multivariable analysis for relationships within WLWH. WLWH (N = 129) were similar to controls (N = 129) in age, body mass index, ethnicity, and substance use. Among WLWH, 21% experienced prolonged amenorrhea vs. 9% in controls. WLWH had significantly lower total hip (mean ± SD: -0.4 ± 0.9 vs. 0.3 ± 1.1; P < 0.001) and spine (-0.5 ± 1.3 vs. 0.2 ± 1.3; P = 0.001) Z-scores than controls. Amenorrhea was independently associated with hip (P = 0.01) but not spine (P = 0.94) BMD by multivariable linear regression. WLWH with amenorrhea had lower hip Z-scores (-0.8 ± 0.9) than those without (-0.3 ± 0.8; P = 0.01). They also had higher rates of substance use, smoking, opioid therapy, hepatitis C coinfection, and lower CD4 nadir. WLWH had higher rates of prolonged amenorrhea and lower BMD than controls. WLWH with amenorrhea experienced lower hip BMD Z-scores than those without. Prolonged amenorrhea is an added osteoporosis risk in WLWH.

Reproductive Aging · Ovarian Aging

Age at Natural Menopause in Women Living with HIV: A Cross-Sectional Study Comparing Self-Reported and Biochemical Data

Swann SA et al., 2023 Viruses Free full text on PubMed Central

Early menopause (<45 years) has significant impacts on bone, cardiovascular, and cognitive health. Several studies have suggested earlier menopause for women living with HIV; however, the current literature is limited by reliance on self-report data. We determined age at menopause in women living with HIV and socio-demographically similar HIV-negative women based on both self-report of menopause status (no menses for ≥12 months) and biochemical confirmation (defined as above plus follicle-stimulating hormone level ≥ 25 IU/mL). Multivariable median regression models assessed factors associated with menopause age, controlling for relevant confounders. Overall, 91 women living with HIV and 98 HIV-negative women were categorized as menopausal by self-report, compared to 83 and 92 by biochemical confirmation. Age at menopause did not differ significantly between groups, whether based on self-report (median [IQR]: 49.0 [45.3 to 53.0] vs. 50.0 [46.0 to 53.0] years; p = 0.28) or biochemical confirmation (50.0 [46.0 to 53.0] vs. 51.0 [46.0 to 53.0] years; p = 0.54). In the multivariable model, no HIV-related or psychosocial variables were associated with earlier age at menopause (all p > 0.05). Overall, HIV status per se was not statistically associated with an earlier age at menopause, emphasizing the importance of comparing socio-demographically similar women in reproductive health and HIV research.

Ovarian Hormones · Estrogen

Lower anti-Müllerian hormone levels are associated with HIV in reproductive age women and shorter leukocyte telomere length among late reproductive age women

Van Ommen CE et al., 2023 AIDS Free full text on PubMed Central

We sought to better understand factors associated with ovarian aging in women with HIV (WWH). HIV has been associated with diminished fertility, younger age at menopause, and shorter leukocyte telomere length (LTL), a marker of cellular aging. We herein examine cross-sectional and longitudinal associations between LTL, anti-Müllerian hormone (AMH), and HIV. We included WWH and HIV-negative women 12-50 years of age in the CARMA cohort with one or more study visit(s). LTL and AMH were measured by qPCR and ELISA, respectively. Women were analyzed in peak reproductive (<35 years) vs. late reproductive (≥35 years) life phases. Using multivariable mixed-effect linear or logistic regressions, we assessed factors associated with AMH and ΔAMH/year while adjusting for relevant confounders. WWH had shorter LTL and lower AMH levels compared to HIV-negative controls despite being of similar age. After adjusting for relevant factors, HIV was associated with 20% lower AMH levels in women under 35 years of age and shorter LTL was associated with AMH levels below 2 ng/ml among women aged 35 years or older. Longitudinally, ΔAMH/year was largely related to initial AMH level among older women, and to age in younger women. Factors associated with AMH change across women's reproductive lifespan. Lower AMH among peak reproductive aged WWH suggests that HIV may have an initial detrimental effect on ovarian reserve, an observation that may warrant counseling around pregnancy planning. In women aged 35 years or older, the association between shorter LTL and lower AMH suggests that the immune and reproductive aging connections are more important in this age group.

Menstrual Cycle › Cycle Disorders › Amenorrhea · Reproductive Endocrinology › Ovarian Hormones › Estrogen · Longevity and Reproductive Aging › Reproductive Aging › Ovarian Aging

Mona Loutfy, Davi Pang, Jerilynn C Prior, Marcela A P Silva, Shayda A Swann

M Loutfy, D Pang, J Prior, M Silva, S Swann

PMID 39301109 39301109 DOI 10.1093/ofid/ofae493 10.1093/ofid/ofae493 Swann et al. 2024, Swann 2024

Cite this article

Swann, S. A., King, E. M., Pang, D., Silva, M. A. P., Campbell, A. R., Prior, J. C., Loutfy, M., Kaida, A., Côté, H. C. F., & Murray, M. C. M. (2024). Associations of Early Prolonged Secondary Amenorrhea in Women With and Without HIV. Open forum infectious diseases, 11(9), ofae493. https://doi.org/10.1093/ofid/ofae493