A dose-ranging study of the use of cyclical dydrogesterone with continuous 17 beta oestradiol.

OBJECTIVE: To establish the lowest dose of cyclical dydrogesterone that protects against endometrial hyperplasia induced by continuous 2 mg 17 beta oestradiol, and to study the dose effect on vaginal bleeding and side effects. DESIGN: Double-blind, prospectively randomised dose-ranging study. SETTING: Menopause clinics in the UK and The Netherlands. SUBJECTS: Three hundred and seventy-one postmenopausal women with intact uteri, aged 40 to 60. INTERVENTIONS: Administration of six 28-day treatment cycles of continuous daily micronised 17 beta oestradiol with a randomly allocated dose of 5 to 20 mg of dydrogesterone added for the last 14 days of each. MAIN OUTCOME MEASURES: Histological assessment of adequate progestational endometrial response, bleeding patterns and adverse effects. RESULTS: The study was completed by 320 subjects (86%). Endometrial transformation occurred in over 94% of those taking 5 mg of dydrogesterone, and in over 97% of those on higher doses, without significant differences between the 10, 15 and 20 mg groups. Acceptable bleeding patterns were found at all doses, with the incidence of withdrawal bleeding rising with increasing dose. The day of onset of bleeding was predictable from cycle to cycle, and occurred later in the 20 mg group than in the others. The incidence of noncyclic bleeding was about 6% at all doses. Withdrawal occurred in 3.3% due to unacceptable bleeding and in 5.4% due to side effects. There was no relation with dose. CONCLUSIONS: A dydrogesterone-17 beta oestradiol combination hormone replacement therapy confers endometrial protection with an acceptable bleeding pattern and few side effects At least 10 mg of dydrogesterone for 14 days is required for acceptable endometrial protection.

Fluvoxamine: an open pilot study in moderately obese female patients suffering from atypical eating disorders and episodes of bingeing.

The results of a small pilot study using Fluvoxamine (Faverin) in the treatment of non-vomiting bingeing female patients and women with bulimia nervosa is presented. Ten non-vomiting subjects and six with bulimia nervosa were treated on an open basis with Fluvoxamine 100-200 mg daily. Assessment was made using established questionnaires for severity of eating disorder and abnormality of mood. Five non-vomiting patients and three with bulimia nervosa completed the study. Non-vomiters showed a significant weight loss; a significant reduction in number of binges; a significant reduction in the scores on the BITE and the EAT; and a significant reduction in anxiety. Those with bulimia nervosa had a significant reduction in hunger and a reduction in depression which tended towards significance. Firm conclusions cannot be drawn from this study as it is an open pilot study of a small number of women. However, the results indicate that Fluvoxamine may have a role in the treatment of eating disorders where bingeing is a prominent symptom and that further research would be valuable. Comments are also made on the usefulness of various questionnaires designed to assess eating disorders.

Dydrogesterone to oppose the 100 mg oestradiol implant.

Ten non-hysterectomised, post-menopausal women received the 100 mg oestradiol implant which was opposed by 20 mg dydrogesterone (nocte) for 14 days each 28-day cycle, for 6 cycles. Plasma oestradiol was measured at baseline and on three further occasions over 6 cycles. Endometrial biopsies were taken 5 weeks after implant, during the unopposed oestrogen and at week 24 during the progestogenic phase (sampling failed on both occasions in one patient). Secretory endometrium was seen in all women at the end of treatment. Cycle control was good and the mean day of onset of bleeding occurred on or after day 11 of the dydrogesterone dosage by the 5th cycle. Dydrogesterone 20 mg for 14 days every 28 days seemed to be sufficiently potent to counteract the proliferative effects of the high dose oestrogen implant.

The effects of psychomotor performance of fluvoxamine versus mianserin in depressed patients in general practice.

This study examined the psychomotor and antidepressant effects of fluvoxamine in a depressed, GP patient population, compared to those of mianserin. It was a single centre, double-blind, six-week study, preceded by a one-week pre-treatment placebo washout, in 59 patients suffering from major depressive episode (DSM III) and scoring over 24 on MADRS. The starting dose was 100 mg fluvoxamine or 60 mg mianserin daily for one week, rising to 300 mg fluvoxamine or 180 mg mianserin. Both treatment groups showed significant improvement over time with no differences between drugs in terms of efficacy. Fluvoxamine and mianserin were both shown to be effective in the treatment of depressive illness. Some psychomotor impairment in the first few days and weight gain over a longer period could affect compliance with mianserin. Fluvoxamine does not reduce psychomotor performance or cause weight gain.

Endometrial, physical and psychological effects of postmenopausal oestrogen therapy with added dydrogesterone.

Sixteen postmenopausal women receiving conjugated equine oestrogens 1.25 mg/day, continuously, were randomly allocated to add dydrogesterone 20 mg/day for 12 days each calendar month for 3 months and then 10 mg/day in an identical fashion for a further 3 months, or to receive the dydrogesterone doses in reverse sequence. The effects of the two dydrogesterone doses on endometrial histology, vaginal bleeding, and the symptomatic and psychological status were compared. Endometrial samples were obtained around day 10 of progestogen addition. Dydrogesterone, 20 mg, induced uniform, late secretory transformation in all samples; with 10 mg one sample showed mixed early and late secretory features and another demonstrated late secretory changes associated with atypical hyperplasia. Both dydrogesterone doses induced an acceptable withdrawal bleed; most bleeding episodes were 'spotting' or normal in amount, and heavy bleeding was reported infrequently. There was one episode of breakthrough bleeding. There were no differences in bleeding patterns between the two dose regimens. Anxiety, and the physical and psychological status were significantly improved after 3 months of therapy. Significant benefits on depression were observed less clearly. There were no differences between the two dydrogesterone doses on anxiety, depression and the physical and psychological status, and, overall, the addition of the progestogen did not antagonize oestrogen benefits.

Effect on plasma lipids and lipoproteins of postmenopausal oestrogen therapy with added dydrogesterone.

In a prospective, randomized, cross-over study, 14 postmenopausal women completed 9 months of treatment with conjugated equine oestrogens, 1.25 mg daily. Seven women added dydrogesterone 20 mg daily for 12 days during months 2, 3 and 4, and then 10 mg daily for an identical time in months 5, 6 and 7. The other seven women added the two dydrogesterone doses in reverse sequence. No dydrogesterone was taken during months 8 and 9. Lipids and lipoproteins were measured before treatment and at the end of months 4, 7 and 9. Lipids were also estimated in an untreated (reference) group of eight postmenopausal women on two occasions 6 months apart; these showed significant changes in HDL2- and HDL3-cholesterol. In the treatment group, HDL-cholesterol and apolipoprotein (apo) A1 were significantly higher and LDL-cholesterol and apo B were significantly lower at months 4, 7 and 9 compared with baseline values. Triglyceride levels were increased significantly over baseline values, but remained within the normal range. No significant differences between the two dydrogesterone doses were observed on any lipid and lipoprotein fraction, nor were there any differences between the oestrogen-only and oestrogen/dydrogesterone treatment phases. Dydrogesterone appears to cause little, if any, lipid and lipoprotein changes and assessment in a larger population of postmenopausal women is warranted.

Anxiety neurosis in general practice. A double-blind comparative study of diazepam and clovoxamine, a novel inhibitor of noradrenaline and serotonin reuptake.

This was a multicentre prospectively randomized double-blind parallel comparison of clovoxamine (n = 37) and diazepam (n = 35) in 72 patients suffering from anxiety neurosis, in general practice. Patients were seen weekly. Treatment was for 4 weeks (50 mg clovoxamine b.d. or 5 mg diazepam b.d.) rising according to response to a maximum of 300 mg clovoxamine or 30 mg diazepam daily. Drug was tapered off in week 5 and patients were seen again in week 6 after they had been off drug for at least a week. A treatment period of 4 weeks was selected in line with WHO guidelines for the testing of anxiolytic drugs. Although more patients dropped out due to intolerance on clovoxamine (24%) compared with diazepam (11%), analysis of completed patients showed that clovoxamine was equally effective with significant improvement in both groups at week 4 (p less than .001) compared with baseline Morbid Anxiety Inventory scores and Hamilton Anxiety Scale scores. Diazepam patients had a more rapid response which levelled off, whereas those on clovoxamine continued to improve after 2 weeks. At 6 weeks after taper off the improvement on clovoxamine was sustained whereas on diazepam there was evidence of deterioration after stopping the drug. Clovoxamine appears to have potential as an alternative treatment to diazepam for anxiety in general practice.

The tolerance and antidepressive activity of fluvoxamine as a single dose compared to a twice daily dose.

A double-blind study was carried out in 62 hospital out-patients suffering from mild to moderate depression to investigate the efficacy and tolerance of fluvoxamine given as a single daily dose or in divided doses. Patients were allocated at random to receive 100 mg fluvoxamine either as a single daytime dose, a single night-time dose or as 50 mg twice daily over a period of 6 weeks after a 1 week wash-out period on placebo. Patients were assessed using the Hamilton and Montgomery Asberg depression rating scales and the Clinical Global Impression scale before and during treatment. All three dosage regimens produced significant improvement and no significant difference was found in antidepressive effect between the groups. However, patients receiving a single night-time dose experienced fewer side-effects leading to drop-out before the end of the study than in the other two groups.