The climacteric period. Epidemiological, clinical and pharmacokinetic studies

Abstract

Objectives: To study: (1) factors influencing the prevalence and severity of climacteric symptoms and the use of hormone replacement therapy (HRT); (2) womens attitudes and knowledge about the menopause and HRT (Studies I-III); (3) clinical and lipid metabolic effects of 17b-estradiol (E2) and norethisterone acetate (NETA) administered continuously (Studies IV-V); (4) the bioavailability of 1 mg E2 and 0.5 mg NETA (Study VI). Material & methods: Studies I-III were based on a questionnaire to 5.990 middle-aged women randomly obtained from the population register (response rate 76%). Sixty postmenopausal women (Studies IV-V) were randomly allocated to 3 continuous combined HRT regimens containing : 1mg E2 + 0.25 mg NETA; 1 mg E2 + 0.5 mg NETA; 2 mg E2 + 1 mg NETA. The pharmacokinetics of 0.5 mg NETA alone or in combination with 1 mg E2 in single-dose or as multiple doses were studied in 24 postmenopausal women. Results: Vasomotor symptoms were reported in 53%, depression/ irritabi-lity 57%, sleep disturbances 52% and vaginal dryness 21% (Studies I-III). Severe climacteric symptoms were correlated to a high body mass index (BMI), dryness complaints and hysterectomy/salpingoophorectomy. Women with higher education, full-time occupation or who exercised regularly were more often symptomfree. Estrogens were used by 21% (13% HRT) and 20% had stopped therapy (14% HRT), mostly due to a fear of cancer and side-effects. HRT was associated with past oral contraceptive use. 67% preferred HRT without withdrawal bleedings. Non-hormonal treatment had been used by 45% and was effective in 31-63%, compared to 70-90% with HRT. In the Studies IV-V a similar and prompt reduction of climacteric symptoms occurred in all 3 groups. Bleedings, mainly spottings, occurred most commonly during early treatment. All endometrial biopsies showed atrophy. Serum cholesterol (ch), low density lipoprotein (LDL)-ch, high density lipoprotein (HDL)-ch and triglycerides were reduced in all 3 groups. The HDL/LDL-ch ratio was unchanged. The bioavailability of NET after 0.5 mg NETA alone was not influenced by the addition of 1 mg E2. After multiple-doses the Cmax of NET was unchanged but the AUC and t1/2 increased. An increase in Cmax and AUC of E1 and estrone sulphate (E1S) was found after 28 days combined therapy. Smoking and BMI were negatively correlated to plasma NET, E2 and E1S .