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).
Postmenopausal women with climacteric symptoms will be randomized (1:1) to double blind treatment with oral mP or NETA in combination with oral estradiol. For the breast part, a power analysis revealed that 91 women/group would be sufficient to detect a significant difference in mammographic breast density between the groups at the 5%-level (two-sided) with 80% power. Considering the estimated rate of discontinuation and incomplete data, the target sample for the breast part is 260 patients. For the endometrial part, it is estimated that two or less women with serious adverse endometrial outcomes would result in an annual incidence of endometrial pathology of 0.67% or less with an upper bound of the one-sided 95% CI of 2.08% or less. Considering the estimated rate of discontinuation and incomplete data in the mP + estradiol group, the target sample for this part of the study is 390 patients. The total number of patients in part 1 and 2 will be 520. Mammography at baseline and after 12 months of treatment will be assessed by independent radiologists at the Karolinska University Hospital blinded to treatment. In addition to visual judgment, a computer based quantitative assessment will be performed. All mammograms will be anonymous so that the operator will be unaware of the patient's identity and type of treatment. Percentage change in mammographic density will be evaluated and compared between the groups. Endometrial biopsies at baseline and after 12 months of treatment will be evaluated by two independent pathologists at the Karolinska University Hospital for the incidence of endometrial pathology (hyperplasia or cancer) in the mP + estradiol group. Furthermore, immunostaining of the proliferation marker Ki-67, and other markers related to proliferation and apoptosis will be analyzed and compared between groups. Different validated self-assessment questionnaires will be used for screening of mood disorders like depression and anxiety, as well as quality of life and menopausal symptoms. The Patient Health Questionnaire (PHQ-9) is a tool for screening, diagnosing, and measuring the severity of depression. The Hospital Anxiety and Depression Scale (HADS) is an instrument for detecting states of depression and anxiety in the setting of a hospital or medical outpatient clinic. Health related quality of life is measured using the Psychological General Well-Being Index (PGWB). The Women's Health Questionnaire (WHQ) measures menopausal symptoms. The change in scores will be compared between the groups. Blood lipid profile, serum hormones, growth and metabolic factors, and coagulation factors will be analyzed. The gut- and vaginal microbiome will be characterized and compared between groups.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
520
Capsule 100 mg mP (Utrogestan®) orally per day in continuous combination with 1 mg encapsulated estradiol (Estrofem®)
Capsule 0.5 mg NETA/ 1 mg estradiol (Activelle®) orally per day (encapsulated and identical to Estrofem® and one matched placebo to Utrogestan
Karolinska University Hospital
Stockholm, Sweden
RECRUITINGMammographic breast density
Percentage change in mammographic density
Time frame: At baseline and 12 months treatment
Endometrial pathology
The incidence of endometrial pathology (hyperplasia or cancer)
Time frame: At baseline and 12 months treatment
Breast cell proliferation
Percentage change in breast cell proliferation (proliferation marker Ki-67)
Time frame: At baseline and 12 months treatment
Endometrial histology and cell proliferation
Percentage change in endometrial cell proliferation (histology classification and proliferation marker Ki-67)
Time frame: At baseline and 12 months treatment
Endometrial thickness
Change in endometrial thickness by ultrasound
Time frame: At baseline and 12 months treatment
Bleeding pattern
Bleeding patterns registered in diary (number of days of bleedings)
Time frame: 3, 6, 9 and 12 months
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)
Time frame: At baseline and 12 months treatment
Depression (PHQ-9)
Change in score of PHQ-9: A 4-point scale where a larger value reflects more depression.
Time frame: At baseline and 12 months treatment
Anxiety (HADS)
Change in score of HADS: A 4-point scale where a larger value reflects more anxiety.
Time frame: At baseline and 12 months treatment
Quality of life (PGWB)
Change in score of PGWBI, where a where a higher score reflects more well-being.
Time frame: At baseline and 12 months treatment
Menopausal symptoms (WHQ)
WHQ: A 4-point scale where a larger value reflects less menopausal symptoms.
Time frame: At baseline and 12 months treatment
Serum levels of hormones, growth factors, lipids and coagulation factors.
Change in serum levels of these markers
Time frame: At baseline and 12 months treatment
Gut- and vaginal microbiome
Change in microbiome diversity and relative abundance of different microbial species.
Time frame: At baseline and 12 months treatment
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