Hormonal Regulation of Cardiometabolic Health Study

Change from Baseline in RAND-36 Item Health Survey (RAND-36) Total Score

The RAND-36 Item Health Survey is a 36-item health-related quality of life instrument with eight domains: Physical Functioning, Role Limitations due to Physical Health, Bodily Pain, General Health, Vitality, Social Functioning, Role Limitations due to Emotional Problems, and Emotional Well-Being. Each domain is scored on a 0-100 scale; higher scores indicate better health status. The RAND-36 total score is computed as the arithmetic mean of the eight domain scores (range 0-100; higher = better). The reported measure is the change from baseline to follow-up (follow-up minus baseline); positive values indicate improvement. Scoring follows the instrument manual and the Statistical Analysis Plan (SAP). A prespecified sensitivity analysis may use a reduced/composite RAND-36 score (e.g., a domain subset with documented performance advantages); details are specified in the SAP. This sensitivity analysis is supportive and does not replace the prespecified analysis of this primary outcome.

Change from Baseline in Menopause Rating Scale (MRS) Score

The Menopause Rating Scale (MRS) is an 11-item questionnaire assessing menopausal symptom burden across three domains: Somatic (4 items), Psychological (4 items), and Urogenital (3 items). Each item is scored 0-4 (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe), yielding a total score range of 0-44, where higher scores indicate worse symptom severity/health-related quality of life. The outcome is the change from baseline to the specified follow-up time point (follow-up minus baseline); positive values indicate worsening and negative values indicate improvement. Scoring follows the instrument manual and the Statistical Analysis Plan (SAP). A prespecified sensitivity analysis may use a reduced MRS score that excludes items with documented suboptimal performance; details are specified in the Statistical Analysis Plan. This sensitivity analysis is supportive and does not replace the prespecified analysis of this primary outcome.

Change from Baseline in Resting Energy Expenditure (REE, kcal/day) Measured by Indirect Calorimetry

Resting energy expenditure (REE) is measured by indirect calorimetry (ventilated hood; overnight fast 10-12 h; supine, thermoneutral room). After stabilization, VO2 and VCO2 are recorded for ≥20-30 min; a steady-state segment (e.g., ≥5 min with CV \<10% and physiologic RQ) is used to compute REE (kcal/day) via the Weir equation, higher values = higher energy expenditure. Outcome is change from baseline to follow-up (follow-up - baseline); higher positive values = higher increase in energy expenditure. Procedures/quality criteria follow the device manual and the Statistical Analysis Plan (SAP). Per SAP, supportive analyses may adjust for body composition (FFM/FM) or express REE relative to FFM; these do not replace the prespecified analysis of this primary outcome.

Change from Baseline in Total Fat Mass (kg) Measured by Bioelectrical Impedance Analysis

Total fat mass (FM) will be measured by bioelectrical impedance analysis (BIA; InBody) under standardized conditions, including a 10-12 h fast before assessment. FM is reported in kg; higher values indicate higher fat mass. The outcome is the change from baseline to the specified follow-up (follow-up - baseline). Measurement procedures, quality criteria, and handling of missing/outliers follow the device manual and the Statistical Analysis Plan (SAP). Per SAP, a prespecified sensitivity analysis will estimate FM using DXA (where available); this analysis is supportive and does not replace the prespecified analysis of this primary outcome.

Change from Baseline in Women's Health Questionnaire (WHQ) Total Score (36-item)

The Women's Health Questionnaire (WHQ) is a 36-item instrument assessing midlife women's emotional and physical health across multiple domains (e.g., depressed mood, somatic symptoms, vasomotor symptoms, anxiety/fears, sleep problems, menstrual symptoms, sexual functioning, and memory/concentration). Domain scores are transformed to a 0-100 scale and averaged to a total score (range 0-100), where higher scores indicate worse health-related quality of life. The reported measure is the change from baseline to the specified follow-up time point (follow-up minus baseline); positive values indicate worsening. Scoring follows the instrument manual and the Statistical Analysis Plan (SAP). A prespecified sensitivity analysis may use a reduced WHQ total score that excludes items with documented suboptimal performance; details are specified in the SAP. This sensitivity analysis will not replace the prespecified analysis of this secondary outcome and will be interpreted as supportive.

Change from baseline in the Pelvic Floor Distress Inventory-20 (PFDI-20) total score (20-item)

The Pelvic Floor Distress Inventory-20 (PFDI-20) is a 20-item questionnaire assessing pelvic floor symptom distress across three subscales: POPDI-6 (pelvic organ prolapse distress), CRADI-8 (colorectal-anal distress), and UDI-6 (urinary distress). Each subscale is scored 0-100, and the PFDI-20 total score is their sum (range 0-300), where higher scores indicate worse symptom distress and poorer health-related quality of life. The outcome is the change from baseline to the specified follow-up (follow-up minus baseline); positive values indicate worsening. Scoring follows the instrument manual and the Statistical Analysis Plan (SAP). A prespecified sensitivity analysis will examine the three PFDI-20 subscale scores (POPDI-6, CRADI-8, UDI-6), each scored 0-100 (higher = worse). These analyses are supportive only and do not replace the prespecified analysis of the PFDI-20 total score as a secondary outcome.

Change from Baseline in Athens Insomnia Scale-5 (AIS-5) Score

The Athens Insomnia Scale-5 (AIS-5) is a 5-item validated instrument assessing sleep difficulty. Each item is scored 0-3, producing a total score of 0-15, where higher scores indicate more severe insomnia symptoms. The outcome is the change from baseline to the specified follow-up time point (follow-up minus baseline); positive values indicate worsening. Scoring follows the instrument manual and the Statistical Analysis Plan (SAP). A prespecified sensitivity analysis may examine individual AIS-5 items; these analyses are supportive only and do not replace the prespecified analysis of this secondary outcome.

Change from Baseline in Fat-Free Mass (kg) Measured by Bioelectrical Impedance Analysis

Fat-free mass (FFM) will be measured by bioelectrical impedance analysis (BIA; InBody) under standardized conditions, including a 10-12 h fast before assessment. FFM is reported in kg; higher values indicate higher fat-free mass. The outcome is the change from baseline to the specified follow-up (follow-up - baseline). Measurement procedures, quality criteria, and handling of missing/outliers follow the device manual and the Statistical Analysis Plan (SAP). Per SAP, a prespecified sensitivity analysis will estimate FFM using DXA (where available); this analysis is supportive and does not replace the prespecified analysis of this secondary outcome.

Change from Baseline in 15D Health-Related Quality of Life (15D) Index Score

The 15D is a 15-dimension health-related quality of life instrument that yields a single index score ranging from 0 to 1, where higher scores indicate better health status. The outcome is the change from baseline to the specified follow-up time point (follow-up minus baseline); positive values indicate improvement. Scoring follows the instrument manual and the Statistical Analysis Plan (SAP). This measure is prespecified as Other Prespecified Outcome and will be interpreted as supportive.

Change from Baseline in Female Sexual Function Index (FSFI) Total Score

The Female Sexual Function Index (FSFI) is a 19-item instrument covering six domains of sexual function (Desire, Arousal, Lubrication, Orgasm, Satisfaction, Pain). The FSFI total score ranges from 2 to 36, where higher scores indicate better sexual function. The outcome is the change from baseline to the specified follow-up time point (follow-up minus baseline); positive values indicate improvement. Scoring follows the instrument manual and the Statistical Analysis Plan (SAP). A prespecified sensitivity analysis may examine domain scores; these analyses are supportive only and do not replace the prespecified analysis of this outcome.

Change from Baseline in Center for Epidemiological Studies Depression Scale (CES-D) Total Score

The CES-D consists of 20 items, each scored 0-3; the total score ranges from 0 to 60, where higher scores indicate greater depressive symptom severity. The outcome is the change from baseline to the specified follow-up time point (follow-up minus baseline); positive values indicate worsening. Scoring follows the instrument manual and the Statistical Analysis Plan (SAP). This measure is listed as an Other Prespecified Outcome and will be interpreted as supportive.

Change from Baseline in Satisfaction With Life Scale (SWLS) Score

The SWLS has 5 items scored 1-7; total score 5-35, where higher scores indicate greater life satisfaction. Outcome is change from baseline to the specified follow-up (follow-up minus baseline); positive = improvement. Scoring follows the instrument manual and the Statistical Analysis Plan (SAP). Listed as Other Prespecified Outcome (supportive).