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At the heart of general practice since 1960

Recent papers on women's health

Dr Sarah Gray looks at papers on female health that have caught her eye

Dr Sarah Gray looks at papers on female health that have caught her eye

Does metformin do anything for fat distribution in PCOS?

Background

GPs are often asked to prescribe metformin for women with PCOS. It is not licensed for this indication but a Cochrane review has confirmed that it increases ovulation rates in subfertile women with PCOS where it is used in conjunction with weight loss. Even a comparatively modest weight loss will significantly reduce visceral fat. This is implicated in the increased insulin resistance characteristic of the disorder and predisposes to metabolic syndrome. It is tempting to speculate that metformin might assist in the process of weight (and particularly visceral fat) loss.

The paper The effect of metformin on fat distribution and the metabolic syndrome in women with polycystic ovary syndrome – a randomised, double-blind placebo-controlled trial. BJOG 2006; 113:817-824.

Method Forty women who were confirmed to have PCOS and who were not ovulating at trial entry were randomised to metformin 500mg three times daily or placebo for three months. Pre-conceptual healthy diet advice was given but no weight-reducing recommendations were made. Fat distribution was measured by a slice CT scan at the midpoint of L2 using the lowest possible radiation dose and by body measurements. Biochemical parameters of the metabolic syndrome and of ovulation were also assessed. Results There was no difference in fat distribution between the two groups. The metformin group showed an improvement in lipid profile but no difference in androgens, insulin, insulin resistance, ovulation or pregnancy.

Conclusion

Metformin is not a weight-loss drug and would have to be used in conjunction with lifestyle modification in women with PCOS.

What I will do now I will remember that metformin should be prescribed alongside increased aerobic exercise and a weight-reducing diet: there is no free lunch!

Recurrent pregnancy loss: are there any options?

Background

We will all know at least one couple who have had recurrent early pregnancy loss with hopes raised by the high sensitivity of modern tests only to be dashed with the onset of a delayed, heavy and often painful bleed. Research has shown one possible explanation to be thrombosis in decidual vessels and both hereditary thrombophilias and antiphospholipid antibodies have been implicated by this route. Once all known factors have been excluded, are there any options for our patients?

The paper

A randomised study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages. Fertil Steril 2006; 86: 362-6

Method

This was a multicentre trial of 107 women with proven recurrent miscarriage who were enrolled after thorough exclusion of all known aetiological factors. They were randomised to fixed dose 40mg enoxaparin (self injected subcutaneously) or 100mg aspirin, from the time of detection of a fetal heart (six to 12 weeks). All received folic acid and iron supplements and continued treatment to 37 weeks or delivery, whichever occurred first. Primary outcome was live births with obstetric complications included in secondary outcomes. Maternal and fetal safety were monitored. The trial lacked a placebo arm as this was not felt to be ethical.

Results

The live birth rate exceeded 80 per cent in both groups. Those women with no previous live birth had a 94 per cent (17/18) rate with enoxaparin and 81 per cent (18/22) with aspirin, though this is not a statistical difference due to small sample size. It was not felt to be feasible to continue to recruit the 866 patients necessary to achieve significance. There was no increase in late pregnancy complications. One aspirin pregnancy was terminated for tricuspid insufficiency and there was a slight increase in neonatal complications in this group. There were no significant maternal side-effects in either group.

Conclusion

Both aspirin and enoxaparin were associated with a high live birth rate and few late pregnancy complications.

What I will do now

I will not be prescribing in primary care but it may enable me to offer some hope, though no guarantees, to a desperate group of patients.

What is the effect of HRT on CV risk?

Background

There is much confusion surrounding the mysteries of oestrogen and its effects on the cardiovascular system. The initial Women's Health Initiative (WHI) results were widely reported to show an increased risk of CHD.This was in marked contrast to earlier observational studies. The WHI population were on average 63 at the time of randomisation and their increase in CV events occurred in the first year of use of combined regimes (oestrogen plus progestogen). Subsequent analysis has shown that the women closest to menopause (aged 50 to 59 years) did not demonstrate this increase. The investigators of the largest trial, the Nurses Health Study, have looked at their data to determine whether age and time since menopause had an effect on their results.

The paper

Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Women's Health 2006; 15: 35-44

Method

The Nurses Health study began in 1976 and enrolled 121,700 female nurses aged 30-55. They were mailed detailed questionnaires about their health, menopausal status and hormone use every two years until 2000. Cohort follow up exceeded 90 per cent. Coronary events were 'confirmed' when WHO diagnostic criteria applied and 'probable' if they involved hospitalisation and interviewers blinded to the hormone status agreed but no records were available. Re-analysis looked at the influence of all identified risk factors, the potential for missed early diagnosis and the effect of a population that matched the WHI.

Results

Women starting hormone therapy within four years of menopause had a significantly reduced risk of coronary heart disease (CHD), RR=0.66 (95 per cent CI 0.54-0.80) for oestrogen alone (E) and RR=0.72 (95 per cent CI 0.56-0.92) for oestrogen plus progestogen (E+P). The small group that matched the WHI starting hormone therapy 10+years after menopause showed no effect on risk (RR=0.87, 95 per cent CI 0.69-1.10 for E and RR=0.9, 95 per cent CI 0.62-1.29 for E+P). Starting over the age of 60 had no effect for E alone (RR=1.07, 95 per cent CI 0.65-1.78) and a tendency to decrease for E+P (RR=0.65, 95 per cent CI 0.31-1.38). The current user benefit could not be explained by incomplete data capture.

Conclusion

Timing of hormone initiation in relation to age or age at menopause may influence coronary risk.

What I will do now

This will help me to reassure the symptomatic perimenopausal women who I counsel most frequently about risks and benefits of hormones.How do you explain the risks of HRT?

Background

Our female patients look for good information on which to base their decision regarding management of their menopause.

How can we express this accurately and clearly and relate the evidence to their situation?

The paper

Hormone replacement therapy: time to move on? J Brit Meno Soc 2006; 12: 75-80

Method

This is a review article. The author discusses the need to communicate risks to patients in the terms used by the WHO where <1/10,000 is very rare, >1/10,000 but <1,000 is rare and >1,000 is appreciable. These numbers relate to the absolute attributable risks of the effect in question occurring in a year. Calculations based on the published figures from the WHI indicate that risks and benefits depend on the age of the patient, the age at which menopause occurred, the delay after menopause before initiation of HRT and the duration of therapy. Dose effects are not shown as a single regime was used.

Results

The overall results of the oestrogen plus progestogen arm of the trial showed an appreciable increase only in VTE risk and an appreciable decrease in total fracture risk. The E only arm had an appreciable increase in stroke and a decrease in total fractures. Age analysis showed an appreciable increase in stroke over the age of 70 with E+P but over 60 with E alone. The VTE risk was appreciable in women of all ages taking E+P but only over 70 in the E only arm. CHD risk in women over 70 taking E+P was appreciable at 2.3/1000 pa.

Conclusion

There is now sufficient information to enable each woman, with the help of her medical adviser, to come to a reasoned and balanced decision.

What I will do now

The advice previously issued by the Committee on Safety of Medicines was largely based on the WHI figures. This will help me to explain risks of hormone therapy in terms that make sense to patients.

What is the best way to start the investigation of postmenopausal bleeding?

Background

Postmenopausal bleeding (PMB) is common and UK consultation rates are of the order of 14.3/1,000 population. Between 3-10 per cent will be shown to have endometrial cancer. This has high rates of cure by hysterectomy in early stage disease but advanced disease has a poor prognosis. There have been no substantial improvements in treatment and reduced mortality depends on timely diagnosis. Ninety-five per cent of endometrial cancer presents as PMB. This is one of the criteria to justify an appointment within the two-week wait scheme.

What should happen next?

The paper

Investigating postmenopausal bleeding for endometrial cancer: cost effectiveness of initial diagnostic strategies. BJOG 2006; 113: 502-510

Method

12 strategies for investigating PMB were derived. These ranged from waiting to see if bleeding recurred to combinations of ultrasound (USS) using double endometrial thickness cut-offs of both 4mm and 5mm, endometrial biopsy (EB) and out-patient hysteroscopy (OPH). The patient journey was modelled to include treatment of positive findings, subsequent re-investigation of false negatives and in-patient procedures for failed EB. Costs used were derived from those of the Birmingham Women's Hospital and national sources and were those borne by the NHS and not the patient. Sensitivity analyses to determine the effect of different incidence and pick-up rates were performed.

Results

These were expressed in terms of cost per life year gained. There was no quality of life input as used by NICE.

Conclusion

USS using a 5mm cut-off was least expensive but both a 4mm cut-off or EB came acceptably close, particularly at high disease prevalence rates. Initial investigation with test combinations or hysteroscopy was not cost effective. The authors conclude that the choice should depend on the nature of the clinician's practice (including endometrial cancer prevalence in the local population), the woman's age, the availability of high quality USS and patient preference.

What I will do now

I can and do perform endometrial biopsy in the surgery environment. In cases where the need for two-week rule referral is not clear, I will be happy to continue to do this knowing it to be a cost effective option. I will also use this information in relation to the development of practice-based commissioning.

Sarah Gray is a GP in Cornwall – she is the primary care lead for women's and sexual health and runs the menopause referral service for the Cornwall and Isles of Scilly PCT

Competing interests

Sarah Gray regularly lectures at academically accredited meetings that are supported by the pharmaceutical industry with unreserved grants. She has been involved in one phase III trial of a hormonal product and is currently developing an audit based project with financial support from Wyeth. She has received grants towards attendance at international scientific meetings from a number of pharmaceutical companies.

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