"Extracts from "Clinical evidence": Menopausal symptoms

DefinitionMenopause begins one year after the last menstrual period. Symptoms often begin in the perimenopausal years.Incidence/prevalenceIn the United Kingdom the mean age for the menopause is 50 years 9 months. The median onset of the perimenopause is between 45.5 and 47.5 years. One Scottish survey (of 6096 women aged 45 to 54 years) found that 84% had experienced at least one of the classic menopausal symptoms, with 45% finding one or more symptoms a problem.¹

Interventions

• Beneficial:OestrogensTibolone

• Likely to be beneficial:ProgestogensClonidine

• Unknown effectiveness:Phyto-oestrogensTestosteroneAntidepressants

PrognosisMenopause is a physiological event. Its timing may be genetically determined. Although endocrine changes are permanent, menopausal symptoms such as hot flushes, which are experienced by about 70% of women, usually resolve with time.² However, some symptoms, such as genital atrophy, may remain the same or worsen.AimsTo reduce or prevent menopausal symptoms, and to improve quality of life with minimum adverse effects.OutcomesFrequency and severity of vasomotor, urogenital, and psychological symptoms; quality of life.MethodsClinical Evidence search and appraisal December 1999. We included only randomised controlled trials (RCTs) and systematic reviews that met Clinical Evidence quality criteria.BenefitsVasomotor symptoms: We found no systematic review. We found over 40 RCTs comparing oestrogen versus placebo and various preparations and/or routes against each other. Most found that oestrogen reduced vasomotor symptoms (data from one RCT in 875 women: odds ratio 0.53, 95% confidence interval 0.31 to 0.93).³ Two RCTs found that transdermal oestrogen at a low dose of 25 μg daily reduced severity of vasomotor symptoms compared with placebo.^4,5 Urogenital system: We found one systematic review (search date 1995) and three subsequent RCTs. The review pooled data from six RCTs.⁶ It found that oestrogen improved urogenital symptoms regardless of the route of administration (no figures available). One subsequent RCT (n=136) found that low dose transdermal oestrogen (25 μg daily) combined with norethisterone acetate significantly reduced vaginal dryness and dyspareunia compared with placebo over six months.⁴ Two other RCTs (n=192) found that local administration of oestrogen using a silicone oestradiol releasing vaginal ring over 24-36 weeks improved vaginal oestrogenisation and pH compared with placebo.^7,8 One of these trials also found a significant reduction in incidence of urinary tract infection in treated women (P=0.008).⁷ Psychological symptoms: We found one systematic review (search date 1995, 14 RCTs, 12 cohort studies), which found that oestrogen reduced depressed mood among menopausal women.⁹ Duration of treatment ranged from one month to two years. Data pooling for oestrogen versus placebo (10 studies) found that oestrogen reduced depressive symptoms (no figures available). We found no RCTs of oestrogen treatment in women with clinically proved depression. We found one systematic review (search date 1996, 10 controlled trials, 9 observational studies) of the effects of oestrogen on cognitive function in postmenopausal women and women with Alzheimer''s disease.¹⁰ Studies were too weak to allow reliable conclusions. An additional crossover RCT (n=62) found a beneficial effect of oestrogen on sleep quality compared with placebo over seven months.¹¹ Quality of life: We found no systematic review. We found four RCTs (639 women, 3 RCTs placebo controlled, 3 versus progestogen), which found significant improvement in quality of life in women treated with oestrogen compared with baseline or placebo.^12–15 The largest RCT (242 women) found that oestrogen improved quality of life (P=0.0003) and wellbeing (P=0.003) compared with placebo over 12 weeks.¹²HarmsMany RCTs have found that oestrogen causes weight gain and breast tenderness in the short term. Although many women report an increase in weight when starting oestrogen, we found no evidence from RCTs that oestrogen causes significant weight gain in the long term. The most important long term adverse effects are increased risk of venous thromboembolic disease, endometrial cancer, and breast cancer.^16–18 The relation between oestrogen (as hormone replacement therapy) and breast cancer was reviewed in a reanalysis of 51 studies of more than 160 000 women.¹⁹ The review found that the risk of breast cancer increased by 2.3% (1.1% to 3.6%) each year in women using hormone replacement therapy. Five or more years after hormone replacement therapy was stopped, there was no significant excess of breast cancer.¹⁹CommentMany studies used selected populations such as women attending hospital clinics, who may be different in their behaviour, personality, and symptom profile to women of the same age seen in primary care or those who do not seek medical advice. Option: ProgestogensSummary We found good evidence from RCTs that progestogens reduce vasomotor symptoms. We found no good quality evidence on other outcomes, including quality of life.BenefitsWe found no systematic review. Vasomotor symptoms: We found five RCTs (257 women, all trials less than a year long), which found that women taking progestogens experienced a significant reduction in vasomotor symptoms compared with placebo.^20–24 The single RCT comparing oestrogen alone with progestogen (150 mg of depot medroxyprogesterone for 25 days a month) found that over three months, 18% of women taking oestrogens and 33% taking progestogen reported no vasomotor symptoms.²¹ One RCT (n=102) found that transdermal progesterone cream 20 mg daily improved vasomotor symptoms compared with placebo (P<0.001) but had no beneficial effect on bone density.²⁵ Urogenital system: We found no RCTs evaluating the effects of progestogens alone on urinary incontinence, the lower genital tract, or sex life. Psychological symptoms: We found no RCTs. Quality of life: One RCT of cyclical progestogen plus oestrogen for six months found no evidence of an effect on quality of life.²⁶ We found no studies of progestogen alone on quality of life.HarmsWe found two RCTs that evaluated harms of progestogens. The first compared continuous progestogen (norgestrel) and placebo in 321 women who had undergone hysterectomy and were already taking conjugated oestrogen. It found no difference in symptoms (including weight gain and bloating).²⁷ The second RCT (875 women) compared various oestrogen-progestogen combinations over three years.³ It found that additional progestogen increased breast discomfort (odds ratio 1.92, 1.16 to 3.09). Neither trial found evidence of an effect on cardiovascular events.CommentProgestogen is seldom given alone, which makes it hard to isolate its effects. When it was given without oestrogen, doses of progestogens were high, the lowest dose being 20 mg medroxyprogesterone acetate per day. Option: TiboloneSummary RCTs found that tibolone significantly improved vasomotor symptoms, libido, and vaginal lubrication.BenefitsWe found no systematic review. Vasomotor symptoms: We found three RCTs, two of tibolone versus continuous combined oestrogen/progestogen treatment over 48 and 52 weeks (672 women with menopausal symptoms)^28,29 and one versus placebo over 16 weeks (82 women with menopausal symptoms).³⁰ The first RCT found a slightly greater reduction in hot flushes with the combined regimen than with tibolone over 48 weeks (P=0.01). The second trial found a significant reduction in vasomotor symptoms from baseline in both groups (67/72 women on HRT and 58/68 women on tibolone, P<0.001) but no significant difference between groups. The third trial found tibolone reduced vasomotor symptoms by 39% compared with placebo (P=0.001). Urogenital system: We found two RCTs. The first RCT found no significant difference between tibolone and combined hormonal treatment in terms of subjective reports of vaginal lubrication; both interventions improved lubrication compared with baseline.²⁸ The second RCT (437 women) found that tibolone improved sexual satisfaction compared with oestradiol plus norethisterone (P<0.05).³¹ We found no RCTs examining effects on urinary incontinence. Psychological symptoms: We found no RCTs. Quality of life: We found no RCTs. Bone density: We found nine RCTs, which found that tibolone increased bone density over periods from 6 to 36 months compared with baseline or placebo.³²HarmsWe found no evidence on adverse effects from RCTs. One non-randomised controlled trial found that the main unwanted effect of tibolone was breakthrough bleeding, which occurred in about 10% of users.³³ We found no good evidence of androgenic adverse effects such as hair growth and greasiness of the skin. Two RCTs of short term use found a 33% reduction in plasma high density lipoproteins with tibolone,^34,35 although the long term effects on cardiovascular disease are unknown.CommentNone. Option: Phyto-oestrogensSummary Limited evidence from small RCTs suggests that soy flour, which contains phyto-oestrogens, may relieve vasomotor menopausal symptoms.BenefitsWe found no systematic review. Vasomotor symptoms: We found three placebo controlled RCTs. Two evaluated soy supplements, which contain phyto-oestrogen, using double blind designs; the other, which was not blinded, evaluated isoflavone. The first RCT (58 postmenopausal women) compared soy flour versus wheat flour for 12 weeks and found that hot flushes were reduced significantly more in the group of women using soy flour (40% v 25% reduction).³⁶ The second RCT used a crossover design to evaluate six weeks'' administration of 34 mg soy protein daily. It found reduced severity but not frequency of vasomotor symptoms.³⁷ The third RCT (n=51) used a crossover design to compare isoflavone 40 mg daily with placebo. It found benefit from placebo compared with baseline, but not with isoflavone.³⁸ Urogenital system: We found no RCTs. Psychological symptoms: We found no RCTs. Beneficial effects of treatment on quality of life: We found no RCTs.HarmsWe found no evidence of significant adverse effects.CommentNone. Option: ClonidineSummary Two RCTs found that clonidine reduced vasomotor symptoms.BenefitsWe found no systematic review. Vasomotor symptoms: We found two RCTs.^39,40 One crossover RCT (66 women) found that clonidine reduced the mean number of flushing attacks in the 14 days after crossover compared with placebo (56.8 v 64.3, P<0.05).³⁰ The second RCT (30 women) found that more women taking clonidine reported reduced flushes at 8 weeks (12/15 v 5/14, P<0.04).⁴⁰ Psychological symptoms: We found no RCTs. Quality of life: We found no RCTs.HarmsThe two RCTs found no significant difference in the incidence of unwanted effects between placebo and active treatment groups.^39,40CommentNone. Option: TestosteroneSummary We found evidence from RCTs that testosterone improves sexual enjoyment and libido. We found no studies evaluating effects on other commonly experienced menopausal symptoms.BenefitsWe found no systematic review. Vasomotor symptoms: We found no RCTs evaluating testosterone alone in women with menopausal symptoms. We found one RCT (93 postmenopausal women) comparing oestrogen alone and oestrogen plus methyltestosterone. This concluded that addition of a small dose of methyltestosterone reduced the dose of oestrogen needed to control menopausal symptoms.⁴¹ Urogenital system: We found two RCTs, one in 40 women and one crossover study in 53 women. Both found benefit from exogenous testosterone on self reported sexual enjoyment, desire, and arousal.^42,43 Psychological symptoms: We found no RCTs. Beneficial effects of therapy on quality of life: We found no RCTs.HarmsWe found no evidence from RCTs or other controlled studies on the incidence of androgenic adverse effects with testosterone.CommentNone. Option: AntidepressantsSummary We found insufficient evidence on the effects of antidepressants on menopausal symptoms.BenefitsWe found no systematic review or RCTs that specifically addressed the effects of antidepressants on menopausal symptoms or quality of life in menopausal women.HarmsWe found no evidence on adverse effects in postmenopausal women. Antidepressants as a group can cause many central nervous system adverse effects, including sedation and agitation, as well as urinary and vision problems, liver dysfunction, and cardiac dysrhythmias.⁴⁴CommentNone.     

Prolonged endometrial stimulation associated with oestradiol implants.

OBJECTIVE--To provide information on endometrial stimulation after discontinuation of treatment with oestradiol implants. DESIGN--Long term follow up of withdrawal bleeding patterns in women taking progestogens cyclically every month after oestradiol implant treatment was ended. SETTING--Specialist menopause clinic. SUBJECTS--10 Postmenopausal patients (at least 12 months'' amenorrhoea after the last spontaneous period) who were treated with oestradiol implants for typical symptoms of oestrogen deficiency. The oestradiol dose was 50 mg, reimplantation occurring roughly every six months. Patients subsequently either needed to discontinue the hormone treatment for medical reasons or expressed a desire to stop treatment. MAIN OUTCOME MEASURE--Duration of endometrial stimulation--defined as the presence of withdrawal bleeding in response to progestogen given cyclically--after insertion of the last oestradiol implant. RESULTS--Four patients eventually stopped bleeding, their mean duration of bleeding being 35 months (range 27-43 months). One patient required hysterectomy 26 months after the last implantation because of persistent irregular bleeding despite treatment with high doses of progestogen. Three patients bled for 22, 30, and 36 months and then restarted oestrogen treatment because symptoms returned. The last two patients subsequently continued to bleed 12 and 21 months after the last implantation. CONCLUSIONS--The duration of endometrial stimulation after implantation can be prolonged, up to 43 months. Insertion of oestradiol implants can carry a long term commitment to the cyclical administration of progestogen and regular withdrawal bleeding if endometrial hyperplasia and carcinoma are to be avoided.     

Effects of Progestogen Oral Contraception with Norethisterone on Blood Clotting and Platelets

The effects on clotting tests and platelet function of six months'' continuous administration of the 19-norsteroid, progestogen-only contraceptive, norethisterone, have been studied in four groups of women. In a group of women who have not previously taken oral contraceptive no acceleration of clotting or platelet factors was found, but in contrast a tendency to reduced coagulability was observed. Women who had previously been taking combined oestrogen-progestogen preparations showed reduced clotting and platelet parameters when norethisterone was substituted. No changes in clotting or platelets were found in women who changed from 17-acetoxysteroid progestogen chloramadinone acetate or in a group of women started postpartum.     

Peripheral blood flow in menopausal women who have hot flushes and in those who do not.

OBJECTIVE--To compare blood pressure, heart rate, and peripheral vascular responsiveness in menopausal women who have hot flushes and in those who do not, and to assess the effect on these variables of treating women who have hot flushes with oestriol, a natural oestrogen, given vaginally. DESIGN--An open, non-randomised cohort study of flushing and non-flushing menopausal women. A before and after investigation of the effects of vaginal oestriol treatment on the circulation. SETTING--Referral based endocrinology clinic. PATIENTS--88 Consecutive menopausal women, 63 complaining of frequent hot flushes and 25 who had not flushed for at least a year. INTERVENTION--Treatment with vaginal oestriol 0.5 mg at night for six weeks in 18 of the women who had hot flushes. MEASUREMENTS AND MAIN RESULTS--Peripheral blood flow was measured by venous occlusion plethysmography at rest and in response to stressful mental arithmetic and anoxic forearm exercises. Blood flow in the forearm and its variability were significantly higher in flushing than in non-flushing women (4.1 (SD 1.7) and 3.1 (0.9) ml/100 ml tissue/min and 17% and 13% respectively). Blood pressure, heart rate, and blood flow in the hand were, however, similar in the two groups. No difference was found in the peripheral incremental response to either stress or anoxic exercise. Vaginal oestriol significantly lowered forearm blood flow from 4.4 (1.5) to 3.3 (1.1) ml/100 ml tissue/min but dilator responsiveness was unaffected. CONCLUSIONS--The peripheral circulation is different in menopausal women who have hot flushes compared with those who do not, with selective vasodilatation in the forearm. The lowered blood flow in the forearm after vaginal oestriol in flushing women may be relevant to the alleviation of vasomotor symptoms induced by oestrogen treatment.     

Oestrogen/Progestogen Oral Contraception and Blood Clotting: A Long-term Follow-up

In a long-term study of women taking the combined oestrogen/progestogen oral contraceptives Ortho-Novin and Norinyl-1 the follow-up has been continued for three years and four years respectively.Acceleration of both “intrinsic” and “extrinsic” clotting tests and of specific factor VII and X assays, reported previously at the nine-month stage, persisted throughout the period of study. Acceleration of Chandler''s tube platelet aggregation and hypercoagulable thrombelastographic patterns were recorded. There was, however, no evidence of a cumulative effect after the first nine months.     

Effect of oestrogen on the sleep,mood, and anxiety of menopausal women.

A double-blind controlled study of the effect of piperazine oestrone sulphate on sleep, depression, anxiety, and hot flushes was performed in 34 perimenopausal women. Half of the patients were given six weeks'' placebo followed by eight weeks'' oestrogen, and half remained on placebo throughout. Sleep was recorded electrophysiologically every week, and mood and anxiety were rated daily by means of visual analogue scales. Hot flushes were counted daily. Observer rating scales of anxiety and depression were complete at intervals. During the first month of active treatment the amount of intervening wakefulness in the first six hours of sleep decreased significantly more in the oestrone group than in those on placebo. Between the baseline period and the second treatment month the oestrone group showed a significantly greater decrease in the total amount of intervening wakefulness and in the frequency of awakenings. Their total amount of rapid eye movement sleep increased. Mood and anxiety improved and the number of hot flushes decreased to a similar degree in both groups. Although oestrogen did reduce the number of episodes of wakefulness in perimenopausal women complaining of insomnia, its effects on their psychological symptoms were little different to those of placebo.     

Effects of danazol on incidence of progesterone and oestrogen receptors in benign breast disease.

Results from a continuing clinical trial in benign breast disease indicate that danazol may induce progesterone receptors and that this effect persists after treatment. In women given danazol the number of biopsy specimens that were positive for progesterone receptors rose from 14 out of 31 before treatment to 23 out of 30 at the end of six months'' treatment and remained raised at 21 out of 31 six months later. The number of biopsy specimens that were positive for oestrogen receptors rose transiently from eight out of 31 to 12 out of 30 and then fell to six out of 31. A satisfactory clinical response was achieved in 26 of the 31 patients but was maintained in only 11 six months or more after the end of treatment. It was only in this group that a significant and long-standing increase in progesterone receptors was observed. These findings suggest that in some women with benign breast disease who have been treated with danazol changes occur that may have long term benefit.     

Treatment of urinary incontinence in women in general practice: observational study.

OBJECTIVE--To examine what is attainable when treating urinary incontinence in women in general practice. DESIGN--Observational study with 12 months'' follow up. Interview and clinical examination before, during, and after treatment of women seeking help for urinary incontinence in general practice. SETTING--General practice in the rural district of Rissa, Norway. SUBJECTS--105 women aged 20 or more with urinary incontinence. INTERVENTIONS--Treatment with pelvic floor exercises, electrostimulation, oestrogen, anticholinergic drugs, bladder training, and protective pads. MAIN OUTCOME MEASURES--Subjective and objective measures of urinary incontinence; number of patients referred to a specialist. RESULTS--After 12 months'' follow up 70% (69/99) of the women were cured or much better; the mean score on a 100 mm visual analogue scale decreased from 37 to 20 mm; and the proportion of women who were greatly bothered by their incontinence decreased by 62%. 20% (20/98) of women became continent, and the percentage of women with severe incontinence decreased from 64% (63/99) to 28% (27/98). Mean leakage per 24 hours measured by a pad test decreased from 28 g at the start of treatment to 13 g after 12 months. The number of light weight pads or sanitary towels decreased from 1.6 to 0.6 a day. In all, 17/105 (16%) patients were referred to a specialist. CONCLUSIONS--Urinary incontinence in women can be effectively managed in general practice with fairly simple treatment. Most women will be satisfied with the results.     

Metabolic consequences of atenolol and propranolol in treatment of essential hypertension.

A six-month study of triglyceride, cholesterol, free fatty acid (FFA), glucose, insulin, growth hormone, and glucagon concentrations was carried out in asymptomatic hypertensive normal-weight men randomly allocated to treatment with atenolol or propranolol. A highly significant increase in the basal plasma triglyceride concentration was observed in propranolol-treated patients after three and six months'' treatment, with a smaller but significant increase in atenolol-treated subjects after six months'' treatment. The changes in triglyceride concentration could not be ascribed to variations in plasma insulin, growth hormone, or glucagon concentrations. Basal FFA concentrations were reduced during the first three months of treatment in both groups but returned to pretreatment levels after six months. Plasma cholesterol concentrations were unchanged by either agent.     

Efficacy of tacrine and lecithin in mild to moderate Alzheimer's disease: double blind trial.

OBJECTIVE--To assess the efficacy of tacrine and lecithin in treating Alzheimer''s disease over nine months. DESIGN--Double blind randomised controlled trial. SETTING--Outpatients clinic of university department of geriatric medicine. SUBJECTS--53 subjects (26 women, 27 men) with probable Alzheimer''s disease. 41 completed the dose finding phase and were randomised to treatment. 32 (14 tacrine, 18 placebo) completed nine months'' treatment. INTERVENTIONS--Lecithin and tacrine or lecithin and placebo for 36 weeks. MAIN OUTCOME MEASURES--Scores on neuropsychological tests sensitive to deficits in the cholinergic system; mini-mental state score; behaviour change; mood; functional state; and stress in carers. RESULTS--The tacrine and placebo groups were similar except that the tacrine group had a longer duration of disease (mean 5.4 v 2.5 years in placebo group; P = 0.003). Only 17 of the 32 patients could tolerate the maximum dose of tacrine (100 mg). No significant difference was found between the groups for any of the tests after nine months'' treatment except for the digit backwards test, which is insensitive to cholinergic deficit. Analysis of subjects taking the maximum dose of tacrine and of subjects with mild dementia also found no differences. CONCLUSIONS--Tacrine produces no clinically relevant improvement over 36 weeks at the doses tolerated by these patients.     

Progesterone and the premenstrual syndrome: a double blind crossover trial.

A double blind, randomised, crossover trial of oral micronised progesterone (two months) and placebo (two months) was conducted to determine whether progesterone alleviated premenstrual complaints. Twenty three women were interviewed premenstrually before treatment and in each month of treatment. They completed Moos''s menstrual distress questionnaire, Beck et al''s depression inventory, Spielberger et al''s state anxiety inventory, the mood adjective checklist, and a daily symptom record. Analyses of data found an overall beneficial effect of being treated for all variables except restlessness, positive moods, and interest in sex. Maximum improvement occurred in the first month of treatment with progesterone. Nevertheless, an appreciably beneficial effect of progesterone over placebo for mood and some physical symptoms was identifiable after both one and two months of treatment. Further studies are needed to determine the optimum duration of treatment.     

Sulphasalazine in ankylosing spondylitis: a double blind controlled study in 60 patients.

Sulphasalazine has been reported to be effective in ankylosing spondylitis with peripheral arthritis, but its efficacy in spondylitis is unknown. Thus 60 patients with active ankylosing spondylitis without peripheral arthritis or gastrointestinal symptoms were randomly allocated to one of two therapeutic groups. One group received 2 g sulphasalazine daily for six months and the other a placebo. Thirteen patients (six given placebo and seven given sulphasalazine) dropped out of the trial and were considered to be treatment failures. After six months'' follow up efficacy was rated as good or very good by 15 of the 30 patients given sulphasalazine and by only six of the 30 given placebo (p less than 0.02). Furthermore, in the patients given sulphasalazine the daily consumption of non-steroidal anti-inflammatory drugs, functional index, and plasma IgG concentrations had fallen significantly. These data suggest that sulphasalazine may be a safe and effective treatment for spondylitis in ankylosing spondylitis.     

A Double-Blind,Placebo-Controlled Trial of Donepezil for the Treatment of Menopause-Related Cognitive Loss

Background: Perimenopausal and menopausal women are more likely to complain of memory loss than are premenopausal women, although the association between menopause and cognitive loss remains controversial. Recently published studies on the risks of hormone therapy have left many women and their physicians seeking effective nonhormonal treatments for menopausal symptoms, including cognitive loss.Objective: This study investigated the efficacy of the cholinesterase agent donepezil in the treatment of menopause-related cognitive loss.Methods: Community-dwelling women in natural menopause were recruited for a randomized, double-blind, placebo-controlled study of donepezil. To qualify for enrollment, the Brief Cognitive Rating Scale was used to determine cognitive symptoms, and women with depression were excluded. Subjects were randomized to receive either donepezil, commencing at 5 mg/d, or placebo. At week 6 of randomization, the dosage of donepezil was increased to 10 mg/d. Treatment continued throughout the 26-week study. The primary outcome measure was the overall change in neurocognitive test results over time. Outcome variables of test scores were analyzed before and after receipt of donepezil or placebo.Results: A total of 28 women aged 46 to 60 years were enrolled. Fourteen women were randomized to receive active drug, 14 to placebo. Two women dropped out of the placebo group. There were no statistically significant differences between treatment groups in post-/pre-dose mean score ratios. No interactions were statistically significant. The P values for tests of equal variances did not reveal a difference in the means. Subjective measures did show some trends toward improvement in memory and cognition.Conclusion: Donepezil was no more effective than placebo in treating the symptoms of menopause- related memory and cognitive loss.     

Acute and chronic arterial and venous effects of captopril in congestive cardiac failure.

OBJECTIVE--To determine whether captopril alters peripheral venous tone in patients with congestive cardiac failure. DESIGN--Open study of patients at start of captopril treatment and three months later. SETTING--A hospital gamma camera laboratory. PATIENTS--16 Men with congestive cardiac failure in New York Heart Association class II or III, aged 57-73. INTERVENTIONS--Patients were initially given 500 micrograms sublingual glyceryl trinitrate followed by 25 mg oral captopril. The study was then repeated after three months'' captopril treatment. MAIN OUTCOME MEASURES--Previously validated non-invasive radionuclide techniques were used to measure changes in central haemodynamic variables and peripheral venous volumes in the calf. RESULTS--After 25 mg captopril there were falls in blood pressure and relative systemic vascular resistance and increases in cardiac index and left ventricular ejection fraction. This was accompanied by a 16% increase in peripheral venous volume (95% confidence interval 13.4% to 18.4%, p less than 0.01), which compared with an 11% increase after 500 micrograms glyceryl trinitrate (10% to 12%, p less than 0.01). Eleven patients were restudied after three months'' continuous treatment with captopril. The resting venous volume was higher than it had been initially, by about 10%, and increased by a further 8.4% after 25 mg captopril (5.4% to 11.4%, p less than 0.05). CONCLUSIONS--Captopril is an important venodilator. Venous and arterial dilatation are produced short term and during long term treatment.     

Lack of effect of oral magnesium on high blood pressure: a double blind study.

Seventeen unselected patients with mild to moderate essential hypertension and whose average supine blood pressure after two months'' observation with no treatment was 154/100 mm Hg were entered into a double blind randomised crossover study of one month''s treatment with magnesium aspartate (15 mmol magnesium/day) and treatment with placebo for a further month. This preparation of magnesium was well tolerated and did not cause diarrhoea. Despite a significant increase in plasma magnesium concentration and a significant increase in urinary excretion of magnesium while taking magnesium aspartate there was no fall in blood pressure compared with either treatment with placebo or values before treatment. The results provide no evidence for a role of dietary magnesium in the regulation of high blood pressure and are contrary to recent speculations.     

Prospective double-blind trial of synthetic steroid (Org OD 14) for preventing postmenopausal osteoporosis.

A double-blind trial of Org OD 14, a synthetic steroid with an unusual endocrine profile, was conducted on 100 postmenopausal women; of these, 63 completed two years'' treatment (33 Org OD 14; 30 placebo). A dose of 2.5 mg/day successfully prevented bone loss over two years, whereas a significant reduction in bone mineral content occurred in women taking placebo, the rate being comparable to that in earlier studies (p less than 0.01). At the dosage used (2.5 mg/day) Org OD 14 also significantly reduced the severity of menopausal complaints (flushing, sweating, etc). Vabra aspiration curettage in 20 cases 6-18 months after starting active treatment showed no evidence of endometrial hyperplasia, though weak proliferation of the endometrium was seen in three. Org OD 14 may provide a new approach to hormonal prevention of bone loss in postmenopausal women without inducing appreciable endometrial stimulation; the potential value of Org OD 14 in osteoporosis and other post-climacteric complaints warrants further investigation.     

Amenorrhoea after Discontinuing Combined Oestrogen-Progestogen Oral Contraceptives

Out of 210 women seen at the Middlesex Hospital with secondary amenorrhoea the 63 who developed it after stopping oral contraceptives were fully investigated. Five had organic disease sufficient to account for the amenorrhoea (one had severe diabetes, one a pituitary tumour, and three premature ovarian failure); two patients had galactorrhoea (one of whom also had the pituitary tumour); two had anorexia nervosa.Of the 63 women 40 (63%) had suffered from amenorrhoea or prolonged or irregular menstrual cycles before taking the pill, and this suggested that combined oestrogen-progestogen oral contraceptives should be used with caution for women with irregular menstruation.Nineteen patients wished to become pregnant and 12 have so far done so after treatment with clomiphene or gonadotrophins.In another study 204 women recorded when their first menstrual cycle occurred after stopping the pill. Seventy-four had a cycle longer than five weeks but only five exceeded three months, and only one of the five had more than six months'' amenorrhoea. These results confirm that the incidence of amenorrhoea after stopping oral contraceptives is low.     

Clonidine (Dixarit) for menopausal flushing.

Clonidine, 0.05 mg twice daily, was evaluated in a multicentre, randomized, placebo-controlled, double-blind crossover study in 66 patients who had had menopausal flushing for less than 1 year. Although the placebo effect was substantial, clonidine reduced the frequency of attacks significantly more than did placebo. In three of the four trials the patients'' comparisons of symptoms before and after crossover indicated significantly greater improvement when the crossover was from placebo to clonidine rather than the reverse. The frequency, severity and duration of attacks were reduced by clonidine in 78%, 89% and 88% of the patients respectively, and by placebo in 50%, 53% and 50%. Side effects were minimal and their pattern was the same for clonidine as for placebo. Clonidine''s action as a peripheral vascular stabilizer makes it potentially useful for the treatment of menopausal flushing. It would be prudent to include clonidine at the beginning of treatment so that its efficacy could be assessed in each individual. Its use would enhance the effects of the usual management of the menopausal syndrome, which consists of explanation, reassurance and, sometimes, the use of tranquillizers. Clonidine is a symptomatic medication that makes flushing more tolerable and should reduce the number of patients who would otherwise be exposed to the risks of estrogens.     

Effect of oral gamolenic acid from evening primrose oil on menopausal flushing.

OBJECTIVE--To evaluate the efficacy of gamolenic acid provided by evening primrose oil in treating hot flushes and sweating associated with the menopause. DESIGN--Randomised, double blind, placebo controlled study. SETTING--District general hospital and teaching hospital. SUBJECTS--56 menopausal women suffering hot flushes at least three times a day. INTERVENTION--Four capsules twice a day of 500 mg evening primrose oil with 10 mg natural vitamin E or 500 mg liquid paraffin for six months. MAIN OUTCOME MEASURES--Change in the number of hot flushes or sweating episodes a month. RESULTS--56 diaries were analysed, 28 from women taking gamolenic acid and 28 from those taking placebo. Only 18 women given gamolenic acid and 17 given placebo completed the trial. The mean (SE) improvement in the number of flushes in the last available treatment cycle compared with the control cycle was 1.9 (0.4) (P < 0.001) for daytime flushes and 0.7 (0.3) (P < 0.05) for night time flushes in women taking placebo; the corresponding values for women taking gamolenic acid were 0.5 (0.4) and 0.5 (0.3). In women taking gamolenic acid the only significant improvement was a reduction in the maximum number of night time flushes (1.4 (0.6); P < 0.05). CONCLUSION--Gamolenic acid offers no benefit over placebo in treating menopausal flushing.     

Region‐specific effects of oestradiol on adipose‐derived stem cell differentiation in post‐menopausal women

The goal of this study was to determine the effect of acute transdermal 17β‐oestradiol (E₂) on the adipogenic potential of subcutaneous adipose‐derived stem cells (ASC) in post‐menopausal women. Post‐menopausal women (n = 11; mean age 57 ± 4.5 years) were treated for 2 weeks, in a randomized, cross‐over design, with transdermal E₂ (0.15 mg) or placebo patches. Biopsies of abdominal (AB) and femoral (FEM) subcutaneous adipose tissue (SAT) were obtained after each treatment and mature adipocytes were analysed for cell size and ASC for their capacity for proliferation (growth rate), differentiation (triglyceride accumulation) and susceptibility to tumour necrosis factor alpha‐induced apoptosis. Gene expression of oestrogen receptors α and β (ESR1 and ESR2), perilipin 1 and hormone‐sensitive lipase (HSL), was also assessed. In FEM SAT, but not AB SAT, 2 weeks of E₂ significantly (P = 0.03) increased ASC differentiation and whole SAT HSL mRNA expression (P = 0.03) compared to placebo. These changes were not associated with mRNA expression of oestrogen receptors α and β, but HSL expression was significantly increased in FEM SAT with transdermal E₂ treatment. Adipose‐derived stem cells proliferation and apoptosis did not change in either SAT depot after E₂ compared with placebo. Short‐term E₂ appeared to increase the adipogenic potential of FEM, but not AB, SAT in post‐menopausal women with possible implications for metabolic disease. Future studies are needed to determine longer term impact of E₂ on regional SAT accumulation in the context of positive energy imbalance.