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).
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
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
Parallel
Micronized progesterone in continuous combination with oral estrogen
DrugCapsule 100 mg mP (Utrogestan®) orally per day in continuous combination with 1 mg encapsulated estradiol (Estrofem®)
Norethisterone acetate in continuous combination with oral estrogen
DrugCapsule 0.5 mg NETA/ 1 mg estradiol (Activelle®) orally per day (encapsulated and identical to Estrofem® and one matched placebo to Utrogestan
Mammographic breast density
Percentage change in mammographic density
Endometrial pathology
The incidence of endometrial pathology (hyperplasia or cancer)
Breast cell proliferation
Percentage change in breast cell proliferation (proliferation marker Ki-67)
Endometrial histology and cell proliferation
Percentage change in endometrial cell proliferation (histology classification and proliferation marker Ki-67)
Endometrial thickness
Change in endometrial thickness by ultrasound
Bleeding pattern
Bleeding patterns registered in diary (number of days of bleedings)
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Angelica Lindén Hirschberg
Lead sponsor
Karolinska University Hospital
Sponsor institution
