This is a cohort study based on yearly follow-up questionnaires sent to control women of a trial comparing combined hormone therapy to either placebo or nothing (the control groups) . Women were recruited in Estonia from 1999–2001, and followed by annually mailed questionnaires in 2000–2004. Detailed descriptions of the recruitment, inclusion and exclusion criteria, trial treatment, adherence, follow-up and trial outcomes as well as the content of information leaflets and trial questionnaires have been published elsewhere [21–24]. In the following the main features relevant to this study are described.
A recruitment questionnaire was mailed in 1998–1999 to all women aged 45–64 in two Estonian counties (n = 39 713); the identification was through the Estonian Population Registry. Of the 14 743 women who returned the questionnaire, 6606 respondents were interested in participating in a randomised trial, of which 4295 women were found to be eligible according to the preliminary assessment. The eligibility criteria included age of 50 to 64 and an elapsed time of 12 months or more since the last period at the randomisation stage .
A personal invitation was mailed to eligible women in 1999–2001. A total of 2323 women responded to the invitation to visit the trial doctor. After a secondary assessment of eligibility, 1778 women proved to be eligible and were willing to join the trial; 404 women were randomized into the blind hormone therapy (HT) arm, 373 into the placebo arm, 494 into the non-blind HT arm and 507 into the non-treatment arm [21, 22]. The 46 women who participated in the pilot study are not included in the present analysis. The women in the blind arms received their drug bottles with coded labels (otherwise identical bottles). Women in the non-blind HT arm had their drug bottles marked with HT.
Only data on women in blind placebo group and non-treatment group aged 50–59 at recruitment (n = 486) are used in this study. Throughout the trial, about 90% of women in the non-treatment group and 95% in the placebo group did not start hormone therapy . The power calculations were made for the main study [21–23], but not for this cohort study based on the trial data.
All participants were mailed annual questionnaires that included questions about their current life situation, health, and use of health services. The response rate was 75% for the first annual survey, 69% for the second annual survey, and 81% of the participants for the final survey mailed at the end of the trial and followed by one reminder. On average, the final survey was completed 3.6 years after the recruitment. Each of the survey questionnaires had a list of 18 symptoms experienced in the previous two weeks and an additional question asking women to specify which they had found bothersome. The questions concerning symptoms that were related to menopause (translated into English) are given in Additional file 1: Appendix 1.
All participants gave written informed consent. The study protocol was approved by the Committee of Medical Ethics in Tallinn, Estonia and by the Ethics Committee of the University Clinic of Tampere, Finland.
The non-compliant women (about 9% of women used hormone therapy for some time during the trial in the control group) were included in this analysis. Results were analyzed separately for those aged <55 years and 56–59 years old at recruitment, and as a combined age group. For the longitudinal analysis, women were grouped into 6 groups by the timing and order of follow-up surveys they completed. The aim was for surveys to be completed at 12-month intervals. However, postal dispatch was done according to groups and the time could be somewhat more or less than 12 months. Furthermore, some women answered after some delay. Thus, we first calculated for each woman the months between the recruitment and the different surveys using the date of filling in the questionnaire. We then grouped the surveys as follows: 6–18 months = 1-year follow-up, 19–28 months = 2-year follow-up, 29–42 months = 3-year follow-up, 43–59 months =4-year follow-up. Women who left one or more follow-up surveys unanswered formed a separate group (intermittent surveys).
We classified women into those who had or had not had symptoms in the following symptom groups: 1) vasomotor symptoms (cold sweats, hot flashes), 2) psychological symptoms (feeling blue or depressed, irritability), 3) pains (backache, headache, stomach ache, stiffness or joint pain). If a woman mentioned at least one of the symptoms from a group, the woman was categorized as having the symptoms of that group. If at least one of these symptoms was said to be bothersome, the woman was categorized as having bothersome symptoms of that group.