A total of 59 women were recruited between May and March , when recruitment was stopped due to time constraints, at which time there were 15 women in each treatment group and 29 in the no treatment group. Demographic characteristics of the participants are shown in Supplemental Table 1. The trial was completed in April The flow of participants with timing of drop-outs and reasons is shown in Figure 1.
Numbers included in each analysis are shown in Supplemental Table 2. One participant in each of these groups withdrew because she felt that the medication was contributing to symptoms of depression and wished to change medication. One participant in each treatment group withdrew due to side effects. There was one serious adverse event, which was a pregnancy in the no treatment group resulting in a live birth.
Participants were reminded of visits by their preferred choice of letter or e-mail and a phone call. Every attempt was made to contact women who did not attend and reasons for withdrawal sought. Another indirect measure of compliance was unscheduled bleeding which was considered an adverse event and was not reported in the trial, supporting high compliance rates.
Baseline comparisons between the treatment and no treatment groups did not reveal any differences in baseline bone density, age, or time since diagnosis Supplemental Table 3.
However, we noted that there were some baseline discrepancies between the 2 groups, for example, in alcohol, smoking, and parity. We therefore included these potential confounding factors in the analysis. Supplemental Table 4 illustrates the lack of effect of these factors on the results.
However, the time since the last period was similar, suggesting that there were more delays in diagnosis in the COCP group but the stage of ovarian failure was comparable. None of them approach significance. Comparisons between the HRT and no treatment groups at the lumbar spine were highly significant at all time points in favor of HRT.
Comparison of the COCP and no treatment groups revealed significant differences in favor of COCP at 6 and 12 months and a trend towards this at 24 months. A sensitivity analysis allowing for possible selective bias in missing data missing not at random showed that the results did not change significantly provided that the missing values were on average the same as the corresponding values observed in women with similar baseline levels, or no more than 0.
At the total hip, bone density was maintained in the HRT and COCP groups over 24 months, whereas in the no treatment group, there was a significant drop at all time points Figure 3 and Supplemental Table 5. At the femoral neck, there was a smaller reduction in bone density in the no treatment group over the course of the trial and no significant changes in the HRT or COCP groups Supplemental Table 4 and Supplemental Figure 4.
At the femoral neck, there was a trend at 12 months in favor of HRT, but no significant differences. Comparison between the HRT and no treatment groups at the total hip were significant at all time points in favor of HRT, whereas at the femoral neck, there were no significant differences.
Except at 6 months, there were no significant differences between the COCP and no treatment groups at the femoral neck. As expected in such a small trial the confidence intervals of the differences were large.
In the HRT group, bone density increased significantly at the lumbar spine and remained stable at the total hip and femoral neck over the course of the trial. In the COCP group bone density remained stable at all sites. In the no treatment group, there was a decrease in bone density at all sites and this became more pronounced as the trial progressed.
In the no treatment group, there were significant differences in bone markers compared with each treatment group at every time point. A major strength of this study is that it only includes women with spontaneous POF, which represent a distinct population.
There is also a high proportion of ethnic minorities represented. There are very few other trials in this area and as such this trial adds significantly to the body of evidence on treatment of spontaneous POF and paves the way for future research.
The main limitations of this trial were the small sample size and relatively high drop-out rate. The excess drop-out rate in the COCP group was due to loss to follow-up. Although every effort was made to remind women of appointments and contact those who did not attend, there were many who avoided contact.
This may in part be because of the difficult psychological aspects of the condition. Another limitation is that the no treatment group was not randomized.
However, the no treatment group illustrates the natural course of bone density in women who choose and continue to choose at each time point, with knowledge of bone density results to not take treatment. Recruitment to the treatment arm of the study was slow. This was partly due to women who were hoping for a pregnancy not being suitable to participate due to the chance of being randomized to COCP and partly due to women who were settled on treatment either not wanting to consider a different regimen or not wanting to complete a 2-month no treatment washout before participating.
The trial was open label due to a lack of funding for blinding. It is worth noting that some countries use the cut-off of 40 rather than 45 to define POF.
However, a woman who experiences POF at the age of 44 has 8 extra years of estrogen deficiency compared with a woman who has her menopause at She is exposed to all the risks of early estrogen deficiency, including bone loss. We therefore use the British Menopause Society's definition 1 both in clinical practice and for this research project. This confirms current opinion and recommendation for estrogen treatment in POF 1 , Our finding of a possible superiority of HRT compared with COCP at the lumbar spine may be surprising given the relatively higher biological potency of ethinyloestradiol compared with estradiol There are some plausible reasons for our findings.
With the COCP taken in the conventional manner, as it was in this trial, there is a 7 day break from estrogen every 28 days, whereas with HRT, the estrogen is continuous. The estrogens are different and although both act via estrogen receptors may have different tissue effects, although there is little published data on this.
Ethinyloestradiol has a longer half-life than estradiol. We did not measure estradiol, oestrone or ethinyloestradiol levels and this should be considered in future trials to aid evaluation of whether the different effects are dose related or due to the inherent effects of the different estrogens.
It has been suggested that at higher doses as well as having a direct stimulatory effect on osteoblasts the cells which make bone through both the progesterone and androgen receptors, levonorgestrel may bind to glucocorticoid receptors and inhibit osteoblasts A study on ovariectomized rats investigating the effect of continuous vs cyclical progesterone with estrogen replacement on bone density showed that continuous progesterone was less beneficial than cyclical, with down-regulation of bone estrogen and progesterone receptors cited as a possible mechanism However, this effect is not seen in older women taking continuous combined HRT.
Hyperlipidemia was defined as a serum cholesterol level of Subjects were classified as smokers if they reported current smoking or had stopped smoking less than 1 year previously; otherwise, they were classified as nonsmokers. Pharmacy records were collected at community pharmacies.
Because Dutch patients usually register at a single community pharmacy, use of pharmacy records provides an almost complete listing of a subject's prescribed drugs. It was determined whether subjects had been dispensed oral contraceptives or hormone replacement therapy during the year preceding the baseline investigation with the urine collections. A subject was considered using a drug if she had at least one prescription for the drug during this year.
Oral contraceptives were defined as preparations containing ethinyl estradiol and a progestin. Progestins were classified as second generation levonorgestrel, lynestrenol, and norethindrone or third generation desogestrel, gestodene, and norgestimate. Hormone replacement therapy was defined as oral preparations containing conjugated estrogens or estradiol valerate, or transdermal preparations containing estradiol. Hormone replacement therapy was subdivided into therapies with or without additional progestin.
Vaginal preparations, defined as creams or vaginal tablets containing estriol or dienestrol, were not considered hormone replacement therapy. Analyses were performed using commercially available statistical software SPSS version 9. Differences between continuous variables were tested using t tests.
Logistic regression analysis was performed to determine the association between oral contraceptive use or hormone replacement therapy and microalbuminuria, using a regression model with variables that included age; presence of hypertension, obesity, diabetes, or hyperlipidemia; and smoking status. The characteristics of women with microalbuminuria, according to their menopausal status, are shown in Table 1.
In women who were premenopausal, oral contraceptive use was significantly more prevalent in those with microalbuminuria compared with those without.
Microalbuminuria in the premenopausal group was also associated with hypertension, obesity, and higher creatinine clearance. In women who were postmenopausal, there was a tendency toward more hormone use in the group with microalbuminuria compared with those without.
Also in the postmenopausal group, those with microalbuminuria were older and had a higher prevalence of hypertension, diabetes, obesity, and hyperlipidemia compared with those without microalbuminuria. Table 2 shows the characteristics of subjects, according to menopausal status and oral contraceptive use or hormone replacement therapy.
Premenopausal oral contraceptive users were significantly younger and had a higher prevalence of microalbuminuria compared with nonusers, although the cardiovascular risk factors did not differ between the groups. In women who were postmenopausal, oral contraceptive and hormone replacement therapy users were significantly younger than nonusers. Creatinine clearance was also higher in women using oral contraceptives or hormone replacement therapy compared with nonusers. Table 3 gives the crude ORs for having microalbuminuria, ORs adjusted for age alone, and ORs adjusted for age, hypertension, diabetes, obesity, hyperlipidemia, and smoking.
Adjustment for age alone and for all factors increased the ORs for microalbuminuria in premenopausal oral contraceptive users and in postmenopausal hormone replacement therapy users. Oral contraceptive use and hormone replacement therapy were independently associated with microalbuminuria. Of the adjustment factors, age demonstrated the largest effect. In the premenopausal group using hormone therapy, we calculated ORs for different estrogen dosages, progestin types, and durations of use Table 4.
There was a tendency toward an association between microalbuminuria risk and estrogen content in oral contraceptives. Furthermore, women using oral contraceptives containing second-generation progestins had a higher risk than users of third-generation progestins. The results were similar for women using oral contraceptives longer than 5 years vs 5 years or less.
To determine whether the increased albumin excretion was related to creatinine clearance, we added this variable to the regression model. The association of oral contraceptive use with microalbuminuria, however, did not change after addition of this factor OR, 1. In the postmenopausal group, users of hormone replacement therapy and oral contraceptives showed an increased OR for having microalbuminuria.
Findings were similar in users of hormone replacement therapy with and without addition of progestins. Women using hormone replacement therapy for more than 5 years had a higher risk of having microalbuminuria compared with those using this therapy for 5 years or less.
Use of estrogens or progestins in general was also associated with microalbuminuria OR, 2. Ovarian function during hormonal replacement therapy in perimenopausal women.
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Obstet Gynecol. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab. When is it safe to switch from oral contraceptives to hormonal replacement therapy? Gebbie AE, et al. Ovulation in perimenopausal women abstract. Speroff L. Contraception for older women. This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference.
This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact afpserv aafp. Studies now show that oral contraceptives can safely be taken until menopause with no limitations.
As long as you do not smoke or have hypertension, you can take oral contraceptives for the duration of your childbearing years. However, when you start to go through menopause, your body produces less estrogen which can cause unpleasant symptoms such as hot flashes and vaginal discomfort.
Hormone replacement therapy is one treatment option for women going through menopause. Hormone replacement therapy is a medication containing estrogen, which replaces the estrogen your body is no longer producing during menopause. There are two primary types of hormone replacement therapy: systemic hormone therapy and low-dose vaginal products.
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