Bone mineral density and depot medroxyprogesterone acetate
Kaunitz AM, Miller PD, Montgomery Rice V et al
Contraception 2006; 74: 90-9
This study aimed to plot changes in bone density during five years’ use of depot medroxyprogesterone acetate (DMPA) and for two years afterwards. Previous studies have shown a decrease during use, but results following discontinuation have been equivocal.
In the study, 248 women aged 25–35 who started DMPA were matched with 360 patients using non-hormonal contraception. At 240 weeks, mean bone mineral density (BMD) was reduced by -5.16 per cent in the DMPA group, compared with an increase of 0.19 per cent in the placebo group. Ninety-six weeks after stopping treatment, mean BMD had almost returned to normal, at -0.25 per cent.
Unfortunately, only 21 women continued the drug for the full 240 weeks, although those dropping out were monitored where possible. Even so, only 42 subjects (17 per cent) completed follow-up. Those taking DMPA for longest showed the least complete recovery after 96 weeks, so the effect on bone density may in fact be worse than it appears here.
DMPA remains effective and this study suggests that we should continue to use it with caution, but in the reasonable expectation that it will do no long-term damage.
- Dr Alison Glenesk is a GP with an interest in women’s health in Aberdeen, Scotland
Vitamins C and E in women at risk of pre-eclampsia
Poston L, Briley AL, Kelly AH et al.
Lancet 2006; 367: 1145-54
In this study, the authors tried to establish whether pregnant women at risk of pre-eclampsia could reduce the incidence of this disorder by taking vitamins C and E.
In the study, 2,024 at-risk women were randomised to take 1,000mg vitamin C and 400iu vitamin E or placebo from the second trimester until delivery, the endpoints being the development of pre-eclampsia, or low birthweight or light-for-dates infants. The incidence of pre-eclampsia was similar in both groups, but in the treated group, there was a higher incidence of low birthweight (28 per cent as opposed to 24 per cent). Numbers of light-for-dates infants were similar.
The conclusion is that vitamins C and E in these doses do not protect against pre-eclampsia and may have a detrimental effect on foetal growth.
The authors forestall anxieties about routine supplementation in pregnancy by stating that placebo patients who were using supplements had larger babies than those who were not. This may be due to the smaller doses involved.
This study was useful, despite its negative outcome. I did wonder, however, why it was necessary to use both vitamins on all of the treated patients, thereby denying us information on each vitamin alone. AG
The risk of ectopic pregnancy
Barnhart KT, Sammel MD, Gracia CR et al
Fertil Steril 2006; 86: 36-43
In this paper, the authors attempt to assess the risk of ectopic pregnancy in women who present with pain and/or bleeding in early pregnancy.
The study comprised 2,026 women presenting with these symptoms between 1990 and 1999, compared with a control population of women with intrauterine pregnancies. Of the cases, 367 (roughly 18 per cent) had an ectopic pregnancy.
Risk factors for an ectopic pregnancy were prior ectopic, history of pelvic inflammatory disease, pain at presentation, bleeding at presentation and hCG of 501-2,000miu/mL. Age under 25 and history of abortion were protective and prior non-tubal surgery, past IUD use, prior caesarean section and current cervical infection had no effect.
This study is academically interesting, particularly because previous pelvic inflammatory disease, usually thought to be strongly associated with ectopic pregnancy, actually shows a weak correlation.
I think it is unlikely to change clinical practice, however; with almost one in five women presenting with pain or bleeding actually having an ectopic pregnancy, I will continue to feel happier having a scan done than working out odds ratios. AG
Improving women’s experience in speculum examinations
Seehusen DA, Johnson DR, Earwood JS et al.
BMJ 2006; 333: 171
This US study looked at the experience of women having cervical smears with and without the use of stirrups.
One hundred and ninety-seven women were randomised into two groups. The procedure was carried out with the women fully draped in both groups, with only the perineum visible. The women were assessed for levels of physical discomfort, sense of vulnerability and sense of loss of control, and results measured on a visual analogue scale.
Women examined without stirrups experienced a reduction in mean sense of vulnerability from 23.6 to 13.1, and in physical discomfort from 30.4 to 17.2. There was no significant reduction in loss of control. The quality of smears was unaffected by method. The authors point out that embarrassment and fear of pain are barriers to women presenting for cervical screening, and it is to be hoped this study will help to put a stop to the routine use of stirrups in the US. AG
Prenatal diethylstilbestrol and risk of breast cancer
Palmer JR, Wise LA, Hatch E et al
Cancer Epidemiol Biomarkers Prev 2006; 15(8): 1509-14
Diethylstilbestrol (DES), a synthetic oestrogen, was widely used by pregnant women in the 1950s and 1960s. It is related to reproductive tract abnormalities, infertility and vaginal cancer in prenatally exposed daughters. The long-term consequences of DES exposure are attracting attention as prenatally exposed women reach postmenopausal age.
Breast cancer is a common condition with a lifetime risk (that is, up to age 85) in the UK of one in nine and most breast cancers (80 per cent) are diagnosed over the age of 50. In the UK the overall breast cancer risk in 2000 was 114 per 100,000 female population and currently, it is the most common female malignancy. Women are understandably concerned about any factors that may increase their breast cancer risk.
It has been hypothesised that breast cancer risk is influenced by prenatal hormone levels. Women who took the drug have an increased risk of breast cancer, but whether risk is also increased in daughters exposed in utero is less clear.
This prospective study used a questionnaire to assess the relationship of prenatal DES exposure to risk of breast cancer in a cohort of DES-exposed and unexposed women since the 1970s.
During follow-up, 102 incident cases of invasive breast cancer occurred; 76 among DES-exposed women (98,591 person-years) and 26 among unexposed women (35,046 person-years). The overall age-adjusted incidence rate ratio (IRR) was 1.40. For breast cancer occurring at M40, the IRR was 1.91 and for cancers occurring at M50, it was 3.00. These results suggest that women with prenatal exposure to DES have an increased risk of breast cancer after age 40.
The authors conclude that the findings support the hypothesis that prenatal hormone levels influence breast cancer risk.
- Miss Margaret Rees is a reader in reproductive medicine at the University of Oxford and consultant medical gynaecologist at the John Radcliffe Hospital, Oxford
Anderson FD, Gibbons W, Portman D
Am J Obstet Gynecol 2006; 195: 92-6
Menorrhagia and dysmenorrhoea are common causes of consultation in primary and secondary care. Menorrhagia accounts for most hysterectomies and nearly all endometrial ablative techniques. It is therefore not surprising that many women desire fewer menstrual periods.
The extended-cycle combined oral contraceptive Seasonale induces a withdrawal bleed four times a year. It was approved in the US in 2003 and contains 84 days of 30eg ethinyl oestradiol and 150eg levonorgestrel followed by seven days of placebo.
This phase III multicentre open label study followed up 189 women who took Seasonale for two years. A common side-effect of oral contraceptives is irregular bleeding. The total number of bleeding and spotting days fell from eight in the first cycle to four at the end of the study, which is reassuring. Another potential concern is that return to fertility after discontinuation of an extended-cycle contraceptive may be delayed. This was not found in this study.
The authors conclude that these findings confirm those of previous clinical trials, that Seasonale is safe and effective. Extended-cycle contraception provides a new option. But like all oral contraceptives, its efficacy relies on women taking it reliably. Also, awareness of an unplanned pregnancy may be delayed because of the reduced frequency of withdrawal bleeds. MR
Complementary therapies for the menopause
Nedrow A, Miller J, Walker M et al
Arch Intern Med 2006; 166: 1453-65
Publication of the results of the combined and oestrogen alone arms of the Women’s Health Initiative and the Million Women Study has led to reduced use of HRT to manage menopausal symptoms. Women and health professionals are concerned about the controversies surrounding breast cancer and cardiovascular disease risk and HRT.
Some women are turning to alternative and complementary therapies, believing them to be safer and ‘more natural’.
This systematic review assessed 70 randomised controlled trials. It covered 48 biologically based therapies (phytoestrogens, black cohosh, dehydroepiandrosterone, vitamin E, kava), nine mind-body therapies (exercise, relaxation breathing, progressive muscle relaxation), one manipulative or body-based therapy, two energy therapies (magnetic devices) and 10 whole medical systems (acupuncture, traditional Chinese medicinal herbs).
The authors found that the studies of phytoestrogens and other biologically based agents showed mixed results. Those using mind-body, energy, manipulative and body-based therapies, and whole medical systems showed little benefit in treating menopausal symptoms.
The authors conclude that while individual trials suggest benefits from certain therapies, data are insufficient to support the effectiveness of any complementary and alternative therapy for the management of menopausal symptoms and recommend further study in trials with rigorous scientific designs to determine benefit and safety.
Hepatotoxicity has been associated with black cohosh, leading to a recent safety warning by the MHRA. Some herbal preparations may contain oestrogenic compounds and this is of concern for women with hormone-dependent diseases, such as breast cancer. Another major concern is interaction with prescribed treatments, such as warfarin and anti-epileptics, with potentially fatal consequences. MR
Perinatal mortality in offspring of women with diabetes
Macintosh MCM, Fleming KM, Bailey JA et al
BMJ 2006; 33; 177-80
This population-based study was part of the Confidential Enquiry into Maternal and Child Health (CEMACH) programme initiated as a result of the increasing incidence of both type-1 and type-2 diabetes and the knowledge that pregnancy in women with diabetes is associated with an increased risk of congenital anomaly, perinatal morbidity and mortality in their offspring.
The study involved a national population-based pregnancy cohort recruited from 231 maternity units in England, Wales and Northern Ireland. The main outcome measures were stillbirth rates, perinatal and neonatal mortality and prevalence of congenital abnormalities in 2,359 pregnancies to women with type-1 or type-2 diabetes who delivered between 1 March 2002 and 28 February 2003.
Results showed that of the 2,359 women, 652 had type-2 diabetes and 1,707 had type-1 diabetes. Women with type-2 diabetes were more likely to come from a black, Asian, or other ethic minority group and from a deprived area. Perinatal mortality was comparable in babies of women with type-1 diabetes (31.7 per 1,000 births) and type-2 diabetes (32.3 per 1,000 births) and was nearly four times higher than that in the general population. The prevalence of major congenital anomaly was 48 per 1,000 births in women with type-1 diabetes and 43 per 1,000 for type-2, more than double the expected figure.
The study was being carried out at the same time as the NSF for diabetes delivery strategy was released and it is hoped that the results of this research will be a reference point from which to judge the effectiveness of the framework in tackling this public health concern.
- Alyson Huntley PhD is a freelance medical writer who previously worked as a research fellow in complementary medicine at the Peninsula Medical School, Universities of Exeter & Plymouth
Strontium ranelate prevention of fractures in elderly women
Seeman E, Vellas B, Benhamou C et al
J Bone Miner Res 2006; 21: 1113-20
On the strength of evidence that strontium ranelate reduces the risk of vertebral and non-vertebral fractures, draft NICE guidelines on the treatment of osteoporosis recommend the second-line use of strontium ranelate for women in whom bisphosphonates are not suitable.
This paper reports a planned pooling of data from two international, phase II randomised, placebo-controlled, double-blind studies, the Spinal Osteoporosis Therapeutic Intervention (SOTI) and Treatment of Peripheral Osteoporosis (TRPOS), to include 1,488 women between 80 and 100 years of age. Ambulatory postmenopausal women were recruited in parallel for both studies at 75 centres in 11 European countries and Australia between 1995 and 1996.
These trials were to evaluate the antifracture efficacy of strontium ranelate (2g per day) over three years. This analysis shows that the risk of vertebral, non-vertebral and clinical (symptomatic vertebral and non-vertebral) fractures was reduced within one year by 59 per cent, 41 per cent and 37 per cent.
At the end of three years, vertebral, non-vertebral and clinical risk fracture were reduced by 32 per cent, 31 per cent and 22 per cent respectively. Strontium ranelate was well tolerated and there were no major safety concerns. These results, in combination with past studies, suggest that strontium ranelate reduces the risk of vertebral and non-vertebral fractures in women with osteoporosis. Importantly, treatment in the elderly is effective within 12 months of starting treatment and its efficacy is sustained for at least three years. AH
Raloxifene, cardiovascular events and breast cancer
Barrett-Conner E, Mosca L, Collins P et al
N Engl J Med 2006: 355(2): 125-37
The evidence for the efficacy and safety of raloxifene is relatively weak and it is therefore considered to be a secondary or tertiary treatment for postmenopausal osteoporosis to other treatments with more robust evidence.
A previous, high quality randomised controlled trial, Multiple Outcomes of Raloxifene Evaluation (MORE), noted a significantly lower incidence of breast cancer and no significant overall effect on cardiovascular events with raloxifene treatment, but suggested a reduced risk among women who were at increased risk for cardiovascular events.
This study, Raloxifene Use for The Heart (RUTH), randomly assigned 10,101 postmenopausal women at 177 sites in 26 countries (mean age 67.5 years) with CHD or risk factors for CHD to 60mg of raloxifene per day or placebo and followed them for a median of 5.6 years. The two primary outcomes were coronary events and invasive breast cancer.
Compared with placebo, raloxifene had no significant effect on the risk of primary coronary events (533 v 553 events, hazard ratio 0.95). It reduced the risk of invasive breast cancer incidence (40 v 70 events, hazard ratio 0.56). However, raloxifene was associated with an increased risk of fatal stroke (59 v 39 events, hazard ratio 1.49) and venous thromboembolism (103 v 71 events, hazard ratio 1.44). Raloxifene reduced the risk of clinical vertebral fractures (64 v 97 events, hazard ratio 0.65).
This study concludes that raloxifene did not significantly affect the risk of CHD and that the benefits of reducing the risks of invasive breast cancer and vertebral fracture should be weighed against the increased risks of fatal stroke and thromboembolism. The GP should take into account the individual woman’s risk of disease, her personal preference and the availability of alternative treatments. AH