On menstrual bleeding with hormone replacement therapy

Objective: To study 10 years compliance with oral hormonal replacement therapy (HRT). Methods: One hundred and fifty-one early postmenopausal women were initially randomly allocated to three groups in a double blind, 2-year placebo controlled trial. Fifty women received continuous combined therapy, 50 were placed on sequential therapy, while the last 51 women were given placebo for 2 years and after that no therapy. After the trial, the women were followed in an open investigation for a total of 10 years. Results: One hundred and twenty-six women (83%) out of 151 came to a 10-year interview, 4% had died and the remaining did not want to participate. None of the women in the combined group had changed to other regimens (42% were still in treatment after 10 years). Twenty-four percent from the original sequential group were still in sequential therapy; another 24% of the group had changed to other HRTs (mainly because the women disliked the monthly bleedings). Fifty-three percent of the women from the placebo group had not received any HRT. Eighteen percent were on HRT. Eighty-seven percent of the women who had taken combined therapy for 8 years were still being treated at the tenth years’ visit. Conclusion: Long-term compliance was excellent for continuous combined therapy and better than for sequential after 10 years.

Objectives: Two randomized open-label studies were performed to evaluate fully transdermal hormone replacement therapy (HRT) with oestradiol (E₂) and norethisterone acetate (NETA) in postmenopausal women. Methods: Both hormones were delivered by transdermal matrix patches changed twice weekly. Subjects received E₂, 50 μg/day and NETA, 170 μg/day or 350 μg/day, either continuously or sequentially. A one-year study (13 cycles of 28 days), including a reference regimen of transdermal E₂ and sequential oral progestogen, was followed by a continuation study for a further year in 367 women. Results: All regimens were highly and equally effective in the prevention of hot flushes. The fully transdermal regimens were associated with beneficial changes in the lipid profile. The sequential regimens provided effective scheduling of bleeding around the end of the progestogen phase. The continuous regimens were associated with irregular bleeding, which was rarely severe, and a gradually increasing incidence of amenorrhoea. With sequential or continuous therapy, bleeding was less severe at the lower dose of progestogen than at the higher dose. No endometrial hyperplasia was detected by biopsy in any treatment group. One serous endometrial carcinoma and one endometrial adenocarcinoma were detected. An endometrial thickness >5 mm did not predict the presence of hyperplasia at biopsy. Hormone-related adverse events were typical of those expected for HRT and dermal tolerability of the patches was good. Conclusions: Fully transdermal sequential or continuous HRT is effective and well tolerated in postmenopausal women. The lower dose of NETA may be preferable, because it confers adequate endometrial protection at a lower dose of progestogen.

To study the prevalence and determinants of consultation for climacteric complaints and the prescription, commencement, and continuation of hormone replacement therapy (HRT) among women aged 45–65 years.

A cross-sectional national survey was conducted in Denmark in November 1994 among 1459 women. A total of 1015 women (response rate 69.6%) agreed to participate and provided questionnaire data.

Of the women who had experienced climacteric complaints, 67.4% (95% confidence interval [CI] 63.3, 71.4%) had consulted a physician. More women consulted if their complaints were severe rather than slight-to-moderate (odds ratio [OR]6.46). Within the total sample, 33.4% of the women had been prescribed HRT at some time, and 94.1% of these women actually had started the treatment. Of the women who started the treatment, 66.3% reported that they still were using HRT at the time of the survey. The current HRT use rate among all respondents was 18.4% (95% CI 16.1, 20.9%). Women with severe or slight-to-moderate climacteric complaints more often reported having had HRT prescribed than women without complaints (OR 23.2 and 5.80, respectively). Furthermore, women who had had a hysterectomy with bilateral oophorectomy more often reported use than women with an intact uterus (OR 10.0). Hormone replacement therapy prescription was associated only weakly with osteoporosis concerns (OR 1.74). Its continuation decreased with age, was higher after hysterectomy and among women who regularly participated in sports or exercised, but was not (P > .05) related to osteoporosis concerns. Age-specific HRT continuation rates decreased among users who reported withdrawal bleeding (P < .05) but not among users who did not experience such bleeding (P > .05).

In this survey, HRT had been used by one in three women at menopause, mainly for the alleviation of climacteric complaints and hardly ever because of osteoporosis concerns. Although it might be expected that HRT users who are concerned about developing osteoporosis in later life would be likely to continue the treatment for longer than other users, the study results did not bear this out. Continuation depended mainly on having had a hysterectomy and participation in sports and was higher among users with an intact uterus if they had had no withdrawal bleeding.

The purpose of this study was to investigate the effects of 10 years of hormone replacement therapy (HRT) in postmenopausal women on bone mineral density of the lumbar spine (L-BMD) and bone mineral content of the distal forearm (F-BMC). A total of 151 women were enrolled in the study, 100 of whom were randomized to receive oral HRT (equally divided between a continuous combined and a sequential treatment regimen), with the remaining 51 receiving placebo or no treatment. The study was double-blind for the first 24 months, followed by 8 years of open-label follow-up. Total treatment duration was 10 years. At the end of 10 years, 38% of women randomized to continuous combined HRT remained on therapy compared with 22% of those who had received sequential HRT and 49% of the untreated group. A further 18% of women originally randomized to HRT had switched to other regimens. After 10 years of therapy, LBMD was found to be significantly higher in HRT-treated women than in those who remained untreated (14.5%; p < 0.001), corresponding to an increase in L-BMD of 13.1% from baseline values on HRT compared with a reduction in L-BMD of 4.7% without therapy. L-BMD increased by 15.9% in women receiving continuous combined therapy compared with 11.1% in those on sequential HRT; however, intergroup differences were not statistically significant. FBMC decreased by 0.7% over the 10 year period in the HRT treatment groups compared with a reduction of 17.6% in untreated women (p < 0.001). Mean F-BMC was 20.3% higher in women who had received HRT than in those who had not received therapy at the end of the 10 year follow-up. In conclusion, 10 years of treatment with HRT resulted in a substantial increase in L-BMD, with F-BMC also significantly higher in the HRT group than in untreated women. These results confirm that long-term HRT exerts a continuous effect against bone loss in postmenopausal women.

Objective: Intravaginal estriol (E3) effectively improves postmenopausal genito-urinary disturbances, without stimulating endometrial proliferation. The aim of the present study was to evaluate the effect of intravaginal estriol (E3) plus nasal spray salmon calcitonin (sCT), to improve neurovegetative symptoms and to prevent the decline of bone mineral density (BMD) of postmenopausal women. Methods: Two hundred and fourteen (214) healthy postmenopausal women were treated for 12 months with: (1) E3 (0.5 mg every other day) + Ca (0.5 g/day); (2) E3 + Ca + sCT (50 IU × 2/day); (3) sCT + Ca; (4) Ca. Climacteric complaints, such as hot flushes and sweating, BMD at the distal $\text{1}\text{10}$ of the radius, analyzed by dual photon absorptiometry, urinary excretion of hydroxyproline and serum alkaline phosphatase were evaluated at baseline and every 6 months. At the same time, patient compliance and drug tolerability were evaluated. Results: E3 but not sCT, improved hot flushes and sweating. E3 blunted but not completely counteracted the BMD decline observed in women treated with only Ca, and reduced urinary hydroxyproline excretion. sCT markedly increased BMD values and reduced both urinary hydroxyproline excretion and serum alkaline phosphatase. These effects were not potentiated by E3 coadministration. All treatments were well tolerated. Conclusions: Present data indicate that the combined administration of intravaginal E3 and sCT may represent an alternative therapeutic regimen for those postmenopausal women who do not accept or have contraindications to classical hormone replacement therapy.

Coronary heart disease is the principal cause of death in postmenopausal women. Postmenopausal women have an elevated cardiovascular risk profile in the form of android obesity (increased waist/hip ratio), hyperinsulinemia, impaired glucose tolerance, increased insulin resistance and elevated plasma LDL, VLDL, serum triglyceride and lipoprotein (a). A significant decrease in the relative risk of cardiovascular disease is observed with estrogen replacement therapy. The addition of progestogens commonly used in hormone replacement regimes does not, based on present evidence, seem to affect cardiovascular protection adversely. The literature on this subject has been reviewed and recommendations made with implications for the future.