Estradiol for Diabetes mellitus | Perimenopause | Early postmenopause

Inclusion criteria

• {"criterion_text":"- Late perimenopausal, defined as changes in the menstrual cycle with an interval of amenorrhea of >= 60 days (STRAW+10 stage –1) OR early postmenopausal (STRAW+10 stage +1), defined as final menstrual cycle more than 1 years prior to inclusion."}
• {"criterion_text":"- Final menstrual cycle < 5 years prior to inclusion"}
• {"criterion_text":"- One or more menopause-associated symptoms. For example: vasomotor symptoms (hot flushes and sweats), musculoskeletal symptoms (joint and muscle pain), effects on mood (low mood), sexual difficulties (low sexual desire)"}
• {"criterion_text":"- Additionally, for T1DM: Diabetes Mellitus type 1 diagnosed before menopause, and at least 6 months prior to the study"}
• {"criterion_text":"- Additionally, for T2DM: Diabetes Mellitus type 2 diagnosed before menopause, and at least 6 months prior to the study"}
• {"criterion_text":"- Additionally, for T2DM: Use of insulin, at least 1 time daily"}

Exclusion criteria

• {"criterion_text":"- Contra-indication for transdermal estrogen and/or progesterone therapy: Presence or sus-picion or history of breast cancer, endometrial cancer, ovarian cancer, presence or history of venous thromboembolism (unless the individual is using anticoagulation therapy), active arterial thrombosis or in the past 6 months (e.g. myocardial infarction, angina pectoris) in-herited or acquired thrombophilia, acute liver disease, or a history of liver disease as long as liver function values have not normalized, untreated endometrial hyperplasia, abnormal vaginal bleeding, porphyria, uncontrolled or severe hypertension."}
• {"criterion_text":"- Chronic kidney disease defined as eGFR < 30 mL/min/1.73m2"}
• {"criterion_text":"- Additionally, for T1DM: Use of glucose-regulating medications other than insulin, such as metformin, GLP-1/GIP re-ceptor agonists, sulfonylureas, SGLT2 inhibitors, and DPP4 inhibitors"}
• {"criterion_text":"- Additionally, for T2DM: Changes to glucose-regulating medications (metformin, GLIP-1/GIP receptor agonists, sulfonylureas, SGLT2 inhibitors, DPP4 inhibitors) other than insulin, including starting, stopping or altering the dosage, in three months prior to the study period. (Note that these medications may be used, provided they are not changed three months prior to the study.)"}
• {"criterion_text":"- Participants with BRCA1 or 2 gene or PTEN mutation"}
• {"criterion_text":"- Participants with a first degree relative with (a history of) breast cancer"}
• {"criterion_text":"- Known hypersensitivity to the excipients in the estradiol patch: acrylate copolymer, poly-ethylene terephthalate, α-tocopherol, or progesterone capsule: soy allergy or peanut aller-gy"}
• {"criterion_text":"- Hysterectomy"}
• {"criterion_text":"- Premature menopause (menopause age < 40 years)"}
• {"criterion_text":"- Hormonal contraception or hormone replacement therapy use (estradiol with or without progesterone) within three months before inclusion"}
• {"criterion_text":"- Use of systemic glucocorticosteroids less than 1 month prior to the study or anticipated need for systemic steroids during the study period (e.g., for Crohn’s disease or astma/COPD). Incidental use of topical agents is allowed."}
• {"criterion_text":"- Active malignancy or history of treated cancer within 24 months of enrollment"}

Primary endpoints

• {"endpoint_text":"- The main endpoint is the difference in the 14-day glucose time-in-range (TIR) during the final two weeks of treatment with estradiol/progesterone compared to the control period.","definition_or_measurement_approach":"Difference in 14-day glucose time-in-range (TIR) during the final two weeks of treatment with estradiol/progesterone versus control period (measured as 14-day TIR)."}

Secondary endpoints

• {"endpoint_text":"- Glucose regulation parameters: change in time-below –range (TBR, %), time-above-range (TAR, %), glycaemic variability (coefficient of variation [CV]), and mean glucose measured using 14 days of blinded CGM after 12 weeks of estradiol/progesterone versus 12 weeks of no intervention.","definition_or_measurement_approach":"Measured using 14 days of blinded continuous glucose monitoring (CGM) after 12 weeks."}
• {"endpoint_text":"- Change in serum HbA1c, carbohydrate-insulin ratio (CIR), daily insulin dose","definition_or_measurement_approach":"Laboratory measurement of serum HbA1c; calculation/assessment of carbohydrate-insulin ratio and daily insulin dose from participant records."}
• {"endpoint_text":"- Insulin sensitivity (whole body and adipose tissue) measured by hyperinsulinemiceuglycemic clamp. Whole body insulin sensitivity will be expressed as the ratio of M – value and insulin concentration: M / I. M – value in mg / kg / min and I in uIU/uL. Adipose tissue insulin sensitivity will be expressed as the suppression of plasma free fatty acid concentration in %.","definition_or_measurement_approach":"Measured by hyperinsulinemic-euglycemic clamp; whole-body expressed as M/I (M in mg/kg/min and I in uIU/uL); adipose tissue as % suppression of plasma free fatty acid concentration."}
• {"endpoint_text":"- Cardiovascular risk: change in lipid profile and 24-hour blood pressure","definition_or_measurement_approach":"Change from baseline in lipid profile (laboratory assays) and 24-hour ambulatory blood pressure measurement."}
• {"endpoint_text":"- Change in liver steatosis using the CAP score assessed with fibroscan and for participants with T2DM total liver fat assessed with MRI-PDFF","definition_or_measurement_approach":"Liver steatosis assessed by CAP score via FibroScan; in T2DM participants total liver fat assessed by MRI-PDFF."}
• {"endpoint_text":"- Change in handgrip strength using handgrip dynamometry","definition_or_measurement_approach":"Measured by handgrip dynamometry."}
• {"endpoint_text":"- Change in climacteric symptoms (Greene Climacteric Scale questionnaire), quality of sleep (Insomnia severity index), depressive symptoms (Hospital Anxiety and Depression Score), diabetes distress (Problem Areas In Diabetes), and quality of life (WHO-5).","definition_or_measurement_approach":"Assessed by validated questionnaires: Greene Climacteric Scale, Insomnia Severity Index, HADS, PAID, and WHO-5."}

Netherlands

Earliest CTIS Part Ii Submission Date

28-11-2025

Latest Decision Or Authorization Date

15-12-2025

Processing Time Days

17

Number Of Sites

1

Number Of Participants

48

Primary sponsor

Full Name

Amsterdam UMC Stichting

Organisation Type

Patient organisation/association

Country Of Registered Address

Netherlands