Understanding the menopause transition in sickle cell disease: An analysis of the implementation of the adapted menopause quick 6

Abstract Background: Women with sickle cell disease (SCD) may experience accelerated reproductive aging and premature or early menopause (before age 40 or 45 respectively), compared to the typical median age of around 51 years in the general U.S. population. The menopausal transition commonly features symptoms such as hot flashes, sleep disturbances, mood changes, vaginal dryness, urinary issues, and joint aches—many of which also occur in SCD and may be masked or misattributed. Understanding symptom prevalence in women with SCD is essential, given potential short- and long-term morbidity. We hypothesized that women with SCD would report similar symptoms to those in the SWAN cohort. Additionally, we explored the relationship between SCD severity and menopause symptom burden. Methods: This single-center observational study surveyed 103 women with SCD (aged 30–65) attending an adult SCD clinic over a 9-month period. Participants completed the Menopause Quick-6 (MQ-6) symptom questionnaire, previously adapted to the SCD context. A total MQ-6 score (range: 0–7) was calculated to assess associations between symptom burden and SCD-related clinical markers. Medical chart review captured demographics, hemoglobin subtype, HbF%, markers of disease severity (LDH, reticulocyte count, ferritin, etc.), chronic disease-modifying therapies, and use of opioids or neuropathic medications. All participants were Black; two who had died prior to analysis (both HbSS, ages 40 and 45) were excluded. Descriptive statistics were compared to the Study of Women's Health Across the Nation (SWAN), a multi-site longitudinal study of midlife (42-52years) women’s health. Multivariate analyses were used to explore correlations between symptom burden and clinical variables. Results: A total of 101 women were analyzed. This convenience sample surveyed __over half __ the women in this age range. The mean age was 44.3 ± 9.8 years (range: 30–66). Treatment use included hydroxyurea (45% mean dose: 1117 ± 444 mg/day; median: 1000), chronic exchange transfusion (10%), L-glutamine (2%), and voxelotor (7%). Half reported chronic opioid use (mean: 113 ± 115 MME/day), and 21% were taking medications against neuropathic pain (e.g., gabapentin). Markers of hemolysis indicated moderate disease severity: LDH 350 ± 156 IU/L, reticulocyte count 173 ± 101 ×10⁹/L, and hemoglobin 8.97 ± 1.93 g/dL. Iron overload parameters included ferritin 829 ± 781 ng/mL, TSAT 41 ± 30%, and TIBC 280 ± 75 µg/dL. Analysis of the adapted MQ-6 indicated that symptom prevalence in our cohort was comparable to that reported by Black women in the SWAN study, with non-significant increases in several domains: hot flashes (54% vs. 46%, binomial test P=0.11), sleep disturbances (39% vs. 35%, P=0.37), menstrual changes (35% vs. 33%, P=0.47), joint pain (39%), mood disturbances (31% vs. 27%, P=0.39), bladder issues (26%), irregular periods (31%), and vaginal health concerns (14%). The mean total MQ-6 score was 1.85 ± 1.73. Exploratory analysis showed that age >40 years and higher hemoglobin levels were significantly associated with higher total MQ-6 scores. Notably, individuals with higher hemoglobin were more likely to have non-HbSS subtypes. Conversely, use of voxelotor and participation in chronic red cell exchange were associated with lower MQ-6 scores; these were all patients with HbSS subtype. In contrast, patients on “neuropathic medications” or L-glutamine had higher MQ-6 scores. Interestingly, individuals on higher average doses of hydroxyurea had lower total MQ6 score <3 (1160mg vs 1064mg). No significant associations were found between MQ-6 score and hospitalization frequency, chronic pain, or opioid dosage. Conclusions: Midlife women with SCD report a substantial burden of menopausal symptoms—particularly hot flashes, sleep disturbances, and joint pain. Symptom burden appears influenced by age and hematologic parameters, while disease-modifying therapies may mitigate reported symptoms or individuals with severe disease may not experience the typical hormonal related menopausal symptoms. These findings lay some foundational groundwork for future studies examining the interplay between disease severity, treatment, and reproductive aging in women with SCD. Routine use of menopause screening tools and menopausal biomarkers in SCD care may facilitate early detection and targeted management in this vulnerable population.