Menopausal Symptoms Clinical Trial
Official title:
Safety of Oral Micronized Progesterone Versus Norethisterone Acetate in Continuous Combination With Oral Estrogen as Menopausal Hormone Therapy - a Double-blind Randomized Study- PROBES Study (Progesterone Breast Endometrial Safety Study)
About one third of all women during menopausal transition have significant climacteric symptoms with considerable impact on quality of life. Meta-analysis has shown a beneficial risk profile with menopausal hormone therapy (MHT) for women 50 to 60 years. Still, there is a great need to find safe MHT able to control excessive endometrial stimulation by estrogen without stimulatory effects on the breast by the combination of estrogen/progestogen. Recent observational studies indicate a lower risk for breast cancer using micronized progesterone (mP) combined with estrogen but increased risk of endometrial cancer than by standard MHT. In a randomized trial, the balance between benefits and risks of mP vs. progestogens (norethisterone (NETA)) in combination with estrogen will be explored. For apparent reasons, long-term largescale clinical trials with endometrial and breast cancer as the primary endpoints, are not feasible. However, much knowledge can be obtained using relevant surrogate markers. Mammographic breast density is a strong risk factor for breast cancer, and endometrial hyperplasia is a strong risk factor for endometrial cancer. The primary objective is to compare the effects of one year treatment with mP versus progestogen, in combination with estradiol on mammographic breast density. Furthermore, to evaluate the effect of one year treatment with mP in continuous combination with estradiol on endometrial pathology (hyperplasia and cancer).
Status | Recruiting |
Enrollment | 520 |
Est. completion date | December 2027 |
Est. primary completion date | September 2026 |
Accepts healthy volunteers | No |
Gender | Female |
Age group | 45 Years to 60 Years |
Eligibility | Inclusion Criteria: - Healthy and naturally postmenopausal women (more than one year since last menstruation or FSH > 40 IE/L) with climacteric symptoms (sweating, hot flush and/or sleep problems) that adversely affect the quality of life - Age 45-60 years - BMI > 19 kg/m2 and = 32 kg/m2 - Intact uterus - In case of previous MHT use, washout 8 weeks for oral MHT and 4 weeks for transdermal MHT or local estrogen treatment before screening - Written informed consent Exclusion Criteria: - Previous history or risk factors for breast cancer, breast cancer in situ or abnormal mammogram at baseline as assessed clinically by a radiology expert - Previous history or risk factors for endometrial cancer or hyperplasia or abnormal/proliferative endometrial biopsy at baseline - Vaginal bleeding - Any concomitant medical treatment except for well-controlled hypertension, non-insulin treated type 2 diabetes, asthma and hypothyroidism - History or presence of or risk factor for cardiovascular disease including thromboembolic disorder or cerebrovascular disease - History or presence of liver and gallbladder disease, familial hyperlipidemia, epilepsy or classical migraine with aura - History or presence of clinically significant depression or other psychiatric disorder that might in anyway compromise the performance of the trial or undermine its scientific validity - Porphyria, Systemic lupus erythematosus and otosclerosis - Current use of MHT or local estrogen treatment - Alcohol and/or drug abuse - Clinically significant findings on physical and/or gynecological examination at baseline - Hypersensitivity to any of the study treatments |
Country | Name | City | State |
---|---|---|---|
Sweden | Karolinska University Hospital | Stockholm |
Lead Sponsor | Collaborator |
---|---|
Angelica Lindén Hirschberg |
Sweden,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Mammographic breast density | Percentage change in mammographic density | At baseline and 12 months treatment | |
Primary | Endometrial pathology | The incidence of endometrial pathology (hyperplasia or cancer) | At baseline and 12 months treatment | |
Secondary | Breast cell proliferation | Percentage change in breast cell proliferation (proliferation marker Ki-67) | At baseline and 12 months treatment | |
Secondary | Endometrial histology and cell proliferation | Percentage change in endometrial cell proliferation (histology classification and proliferation marker Ki-67) | At baseline and 12 months treatment | |
Secondary | Endometrial thickness | Change in endometrial thickness by ultrasound | At baseline and 12 months treatment | |
Secondary | Bleeding pattern | Bleeding patterns registered in diary (number of days of bleedings) | 3, 6, 9 and 12 months | |
Secondary | Gene and protein expression of growth factors and apoptosis markers in breast and endometrial tissue | Change in gene and protein expression (proliferation and apoptosis markers) | At baseline and 12 months treatment | |
Secondary | Depression (PHQ-9) | Change in score of PHQ-9: A 4-point scale where a larger value reflects more depression. | At baseline and 12 months treatment | |
Secondary | Anxiety (HADS) | Change in score of HADS: A 4-point scale where a larger value reflects more anxiety. | At baseline and 12 months treatment | |
Secondary | Quality of life (PGWB) | Change in score of PGWBI, where a where a higher score reflects more well-being. | At baseline and 12 months treatment | |
Secondary | Menopausal symptoms (WHQ) | WHQ: A 4-point scale where a larger value reflects less menopausal symptoms. | At baseline and 12 months treatment | |
Secondary | Serum levels of hormones, growth factors, lipids and coagulation factors. | Change in serum levels of these markers | At baseline and 12 months treatment | |
Secondary | Gut- and vaginal microbiome | Change in microbiome diversity and relative abundance of different microbial species. | At baseline and 12 months treatment |
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