Menopause International >
Volume 14, Number 4 >
Pp. 140-143
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However, there were some notable differences detected between the two groups. For example, when relative risks (RR) were stratified according to age (in five-year age bands), current users in the youngest band (51–54 years) had a higher RR of myocardial infarction (MI) than never-users (RR 1.24). This higher risk – as well as an increasing risk with longer duration of use – was not seen in any of the other age bands. This finding, therefore, does not support the timing hypothesis (the ‘window of opportunity’) that perimenopausal HRT is associated with a reduced risk of cardiovascular disease.
The study, which was based on prescription data and the national health register of Denmark, was a six-year follow-up of all healthy Danish women (n = 698,098) aged between 51 and 69 years in 1995. It therefore provided data not just on HRT use but also on the type of HRT used. And significantly, the study also found that the highest RR of MI was associated with continuous combined HRT (RR 1.35 when compared with never-use); no increase in risk was seen with unopposed estrogen, tibolone or cyclical HRTs. These principal findings, the authors concluded ‘were comparable with estimates in the randomized clinical studies’ – even though cyclical HRT types were not included in the WHI.
However, perhaps the most notable result was the significantly decreased risk of MI (RR 0.62) associated with transdermal estrogen compared with never-users. Moreover, the risk associated with transdermal estrogen was significantly lower than that found with oral estrogen. This effect, the authors suggest, may be because of ‘reduced activation of the haemostatic system’. However, in women on combined therapy no difference in MI risk was detected between oral and transdermal administration.
Dr Ellen Løkkegaard, a gynaecologist at the Rigshospitalet in Copenhagen, who led the study said: ‘Our study does not change indications and duration recommendations for HRT. But the main message is that when hormone therapy is indicated for a woman, then a cyclic combined regimen should be preferred, and that application via the skin or the vagina is associated with a decreased risk of myocardial infarction. From the previous studies on HRT we have no reason to believe that these recommendations increase the risk of other diseases influenced by hormone therapy, such as breast cancer, venous thromboembolism and stroke.’
She added that this is the first big observational study to address the influence of different HRT regimens, doses and routes of administration. ‘In this postrandomised era’. She said, ‘where randomised studies on HRT are not easily performed, it provides important new information.’
These fears have now been addressed in a new case-control study in Canada, which compared the use of HRT in 236 breast cancer patients matched with 236 controls; all cases and controls carried a mutation in BRCA11.
Results showed that 68 (29%) of the control subjects had used HRT at some time, as had 47 (20%) of the women in the breast cancer group, an adjusted odds ratio (OR) for breast cancer associated with constant use of HRT compared with never use of 0.58 (95% CI, 0.35–0.96). This OR did not depend on age at diagnosis, age at menopause or duration of use – and the association was similar for current and past users, and for women who used estrogen alone or combined. Moreover, say the authors: ‘The magnitude of the association appeared to be as great, or even greater, for women after surgical menopause than it was for women after natural menopause. This information should be reassuring to women who wish to undergo preventive oophorectomy before menopause, but it needs to be confirmed in subsequent studies.’
In an accompanying editorial, Rowan Chlebowski, best known from the WHI trial, and Ross Prentice from the Fred Hutchinson Cancer Research Center in Seattle caution that observational studies have previously misled this contentious field. They – not surprisingly – remind readers that, while the earlier observational studies suggested that HRT was not associated with an increased risk of breast cancer recurrence, randomized trials found a statistically significant increase in risk.
‘The results presented ... provide some evidence for safety but are insufficient to reliably inform routine clinical practice,’ they write. ‘As a result, continued caution in prescribing hormone therapy to women with BRCA1 mutations who are at high risk for breast cancers remains prudent.’
The journal editors also note that the study was relatively small, women who had undergone preventive mastectomy or used tamoxifen were excluded, and the results depended on the participants' recall of HRT use.
The almost forgotten WISDOM trial had aimed to evaluate the long-term benefits and risks of HRT in postmenopausal women over a 10-year period. It randomized 5692 healthy women over 50 years old from general practices in the UK, Australia and New Zealand to receive either combined HRT or placebo.
All women were monitored for an average of 12 months, and, in addition to the main clinical outcomes of cardiovascular disease, fractures and breast cancer, the impact of HRT on quality of life was recorded. This was measured using a modified version of the Women's Health Questionnaire, which included such physical and emotional components of health as depressed mood, memory and concentration, sleep problems and sexual functioning, and a symptoms questionnaire.
Results showed that significantly fewer women in the HRT group reported hot flushes (9% vs. 25%), night sweats (14% vs. 23%), aching joints and muscles (57% vs. 63%), insomnia (35% vs. 41%) and vaginal dryness (14% vs. 19%), but more reported breast tenderness (16% vs. 7%) and vaginal discharge (14% vs. 5%). Other menopausal symptoms, depression and overall quality of life were not significantly different in the two groups.
The authors propose that their findings are consistent with the WHI, and – particularly with respect to depression – other randomized trials.2
The authors claim that their findings may have important benefits for many symptomatic women, but caution that the health-related quality of life benefits must be weighed against the risk of increased cardiac events, venous thromboembolism and breast cancer. And they add that even ‘statistical significance does not imply clinical significance’.
Nevertheless, in noting the older mean age range of both the WHI and HERS (Heart and Estrogen/Progestin Study) trials, they speculate that results in these studies are likely to underestimate ‘the positive effects of combined HRT on health related quality of life for women with symptoms’.
Their findings, they add, support the premise that women with menopausal symptoms will derive the greatest benefit in quality of life from treatment with combined HRT. ‘This is an important message,’ they add. ‘Chronic disease outcomes should not be considered in isolation from outcomes of health related quality of life in this age group.’
Now, the effect of estrogen on one important risk factor for CVD – the so-called metabolic syndrome of raised levels of C-reactive protein, triglycerides and LDL, insulin resistance, hypertension and excess body weight – has been shown to be much less important than levels of bioavailable testosterone.1 Thus, according to the SWAN study (Study of Women's Health Across the Nation), the prevalence of metabolic syndrome in women does increase with their transition into menopause, but more as a result of ‘progressive androgenicity of the hormonal milieu’ than from declines in estrogen levels per se.
The SWAN study is a ‘multiethnic’ longitudinal study of the natural history of the menopause in 3302 women; the 949 women in this nine-year arm of the study had all reached the menopause naturally, had never used hormone replacement therapy and were free of both type 2 diabetes and symptoms of metabolic syndrome at baseline.
However, by the time of the last menstrual period (LMP), symptoms of the syndrome had occurred in 13.7% of the cohort – with an occurrence odds ratio (OR) throughout the six years before and six years after the LMP of 1.45 (95% CI, 1.35–1.56) and 1.24 (1.18–1.30), respectively. The increases were independent of other risk factors, including age at LMP, ethnicity, marital status, education, smoking and baseline body mass index.
What struck the investigators, however, was that the onset of metabolic syndrome was not associated with levels of either total estradiol or total testosterone, but was significantly associated with changes in bioavailable testosterone, defined as a function of the level of sex-hormone-binding globulin (SHBG), a molecule which binds to and carries testosterone to target organs. The study found that, for every one standard deviation increase in bioavailable testosterone levels, the odds of developing metabolic syndrome increased by 10%. The onset of the syndrome was also significantly associated with changes in SHBG.
Commenting on the study, its lead author Dr Imke Janssen from Chicago said: ‘We know that estrogen levels do go down, they take a real nose dive [around the time of the LMP]. It's the most dramatic change, it's the hallmark of the menopausal transition, but in this analysis we didn't find that metabolic syndrome or its components are directly related to it. So it must be more complicated than that. The whole change of hormones with menopause is a very dynamic process, and we're just beginning to understand it. This study is part of the solution to the puzzle.’
What they do suggest, however, is that the change in estrogen level is, at best, a weak and non-significant predictor of metabolic syndrome risk – and more likely that progressive testosterone dominance in sex-hormone metabolism is related to CVD risk.
Conventionally, ovarian reserve has been measured by a combination of endocrine and ovarian markers, notably blood levels of estradiol, inhibin B and follicle stimulating hormone (FSH), and antral follicle count as detected by ultrasound. More recently, a further hormone – anti-Mullerian hormone (AMH) – has been added to the list, and studies over the past few years suggest that AMH may yet be the hot molecule in reproductive ageing. Indeed, a study reported by the fertility group from Utrecht, the Netherlands, in 2005 suggested that serum AMH represents the best endocrine marker yet for assessing the age-related decline of reproductive capacity.1
AMH, which cannot be detected in women until puberty, is expressed by the granulosa cells of the ovary throughout reproductive life and controls the formation of follicles by inhibiting excessive follicular recruitment by FSH. It therefore has an important role in folliculogenesis throughout the entire reproductive lifecycle.
A study from Utrecht this year now suggests that the predictive value of AMH indeed stretches from puberty to the menopause, with close correlation between the observed distribution of age at menopause (in a cohort of 144 women) and that predicted from declining AMH levels.2
And at an Edinburgh workshop hosted by ESHRE (European Society of Human Reproduction Embryology), Dr Frank Broekmans from the same Utrecht group proposed that a ‘counselling centre’ for girls of around 20 might, with a measurement of AMH, a sampling for genetic markers, and a dash of good advice about smoking, predict the whole of a woman's reproductive lifespan. In such a way those at risk of premature ovarian failure (POF) might be identified in good time, or those planning to start their families later reassured.
At the same workshop Dr Philippe Bouchard from Paris reported that 90% of POF cases are still of unknown aetiology, with their cause likely to be genetic. Whole genome studies have started within the past few years and several candidate genes – such as BMP15 and FMR1 – have been identified on the X chromosome. Other studies have looked at families with very rare genetic disorders – such as blepharophimosis epicanthus inversus syndrome, whose phenotype is characterized by narrow eyelids and an early menopause and is associated with mutations in FOXL2. In May last year researchers from Baylor College in Texas announced that mutations in the FIGLA gene, a transcription factor known to control oocyte development in the ovary, would explain POF in around 1% of cases.
Such gene detection, added to the predictive ability of AMH, may yet make the menopause – and especially a premature menopause – less of a mystery, and, at least for the young women in the Utrecht counselling centre, a reproductive road map to the menopause and beyond is not entirely fanciful.
When current smoking was compared with never smoking in a model that included pack years and all other variables, the OR for abdominal aortic aneurysm events was 8.73. However, for up to five years current or past-HRT, the OR was 0.69, and for more than five years' use was 0.52.
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