Abstract
Ten years after the Women's Health Initiative: the rumpus goes on
It's now 10 years since the first Women's Health Initiative (WHI) report sent shock waves rippling through consulting rooms and the corridors of regulatory power. Never again, it was feared, would hormone therapy be prescribed to mid-life women as a panacea for their hot flushes, crumbling bones, fibrillating hearts and waxing irritability. And so it was that this auspicious anniversary was taken as a cue by the International Menopause Society (IMS) to review the 10-year impact of the WHI in a special edition of its journal Climacteric.
Its publication, no doubt spurred on by an IMS news release, was widely picked up by the press, with most reports following the Climacteric line that ‘the evidence has changed over the last 10 years’, and thereby supports a return to a ‘rational use of HRT, initiated near the menopause’. What added strength to the IMS argument was a leading overview written by three former WHI investigators who concluded that, ‘with initiation near the menopause, the weight of evidence supports benefits over risks [of hormone therapy], with the potential to prevent or ameliorate down-stream morbidity’. 1
One of those investigators, Robert Langer, a former principal investigator of the WHI Clinical Center at the University of California, San Diego, was quoted as saying: ‘Overgeneralizing the results from the women who were - on average - 12 years past menopause to all postmenopausal women has led to needless suffering and lost opportunities for many. Sadly, one of the lessons from the WHI is that starting HT 10 years or more after menopause may not be a good idea, so the women who were scared away by the WHI over this past decade may have lost the opportunity to obtain the potential benefits’. This was the message that reverberated around the media. ‘A wasted decade’, headlined the Daily Mail in London, adding that ‘menopausal women were the victims of mass fear generated by findings from ten years ago … Many of the conclusions reached by the 2002 study, including the raised risk of breast cancer, have now been overturned’.
Elsewhere in this Climacteric special issue there were equally revisionary reviews in osteoporosis (‘restrictions on HRT use as a first-line therapy are not appropriate’), quality of life (‘the WHI underestimated the real extent of the effect of HRT’), breast cancer (‘an increase in risk with E + P HRT, but this is small … has also been exaggerated by press reports’), coronary heart disease (‘evidence now supports a window-of-opportunity for women taking HRT before the age of 60 and/or within 10 years of the menopause’) and stroke (‘a modest increase in stroke risk with HRT use if started near the menopause … This risk rises considerably in women who start at older ages’).
But, in the face of such measured reviews over time, it was not long before the epidemiologists struck back with vengeance - and where else but in the pages of the Daily Mail. 2 Just seven days after the Mail‘s ‘wasted decade’ headline, Oxford epidemiologist Professor Klim McPherson protested that ‘I've studied HRT for years - and I'm still convinced it raises women's risk of cancer’. So, McPherson went on, ‘How very sad and worrying that a newly published review - which made the headlines last week by giving HRT a clean bill of health for menopausal women - is seriously flawed’. How can Climacteric‘s ‘researchers’ have got it so wrong, he asked.
The explanation, McPherson suggested, is that the Climacteric reviewers not only presented no new evidence but also completely ignored McPherson's own studies (‘a curious omission as they were published in leading journals’) as well as those of his Oxford colleagues, notably the Million Women Study (‘a hugely relevant and internationally recognised piece of research’). Another reason, of course, was the encroaching influence of the pharmaceutical industry, which at the time of the first WHI report was lasciviously gloating over HRT as ‘on the brink of becoming a blockbuster drug, a must-have for 50-plus women’. McPherson's view of the insidious influence of the drug industry is not far removed from that of the WHI's principal investigator Rowan Chlebowski who, looking back in a 2009 interview, also said with innuendo that the greatest support for HRT came from the gynaecologists and that the HRT manufacturers were ‘big supporters of the gynecological community’. 3
The President of the IMS and BMS Chairman Nick Panay one of Climacteric's joint editors, hit back with a letter to the Daily Mail complaining about McPherson's article and his suggestion that Climacteric described the association between HRT and breast cancer as ‘simply a coincidence’. 4 This is not true, they wrote, while adding that any ‘new evidence’ was unlikely from a collection of reviews.
Meanwhile, just days after Climacteric's publication, a systematic review of HRT published in the Annals of Internal Medicine to update ‘evidence’ from the government-backed US Preventive Services Task Force (USPSTF) concluded that combined and unopposed HRT ‘decreased risk for fractures but increased risk for stroke, thromboembolic events, gallbladder disease and urinary incontinence’, while combined HRT ‘increased risk for breast cancer and probable dementia, whereas estrogen alone decreased risk for breast cancer’. 5 The update included all studies published between January 2002 and 2011, and therefore included the whole catalogue from the WHI. ‘Only the WHI trials were designed and powered to evaluate the effectiveness of hormone therapy for primary prevention of several conditions that were the focus of this review’, the authors stated. Based on the new analysis, USPSTF issued preliminary recommendations that postmenopausal women should not use hormone therapy to prevent certain chronic conditions.
Women benefit as much as men from secondary prevention effects of statins, despite lower representation in trials
Now a substantial meta-analysis of 11 placebo-controlled clinical trials with more than 40,000 participants also suggests that women have as much to gain from statin therapy in the prevention of recurrent cardiovascular events as men. 2 The analysis showed that overall statin therapy was associated with a similarly reduced risk of cardiovascular events for women (Relative risk (RR), 0.81) as for men (RR, 0.82). The authors thus concluded that ‘this meta-analysis supports the use of statins in women for the secondary prevention of cardiovascular events’.
However, the analysis did not find a comparably reduced risk of all-cause mortality or stroke in women as it did in men - and this they attributed not to the discriminatory effect of the statins but to the inadequate presence of women in the original trials. ‘Women represented only a fifth of the studied sample’, the authors noted, ‘limiting the strength of our conclusions. In our results, the benefit associated with statin administration in women did not reach statistical significance compared with placebo in at least two outcomes, all-cause mortality and any stroke type. The reason for this difference is uncertain. One possibility is that the small sample size of women limits the power of the study.’
This was a point taken up in an invited commentary to the study, in which the epidemiologist commentators too suggested that the effect of statins ‘on stroke and all-cause mortality in women is consistent with the effect in men’. ‘We suggest that statins work just as well in women as in men’, they concluded.
Early menopause linked to increased risk of cerebral aneurysm
As background to the study they report that over the past 20 years the prevalence of subarachnoid haemorrhage has remained largely unchanged despite increasing detection and treatment of unruptured and often incidentally discovered cerebral aneurysms. Mortality rates for ruptured cerebral aneurysms continue to average around 50%, while 20% of victims have severe disability.
However, the authors also note that, unlike all other causes of stroke, subarachnoid haemorrhage occurs twice as frequently in women as in men, peaking in the mid-life decades with an estimated frequency of six to eight per 100,000 people. ‘The putative role of estrogen in these epidemiologic findings,’ they add, ‘is further supported by the finding that hormone replacement therapy (HRT) seems to reduce the risk of [subarachnoid haemorrhage] in postmenopausal women, possibly via the effects of estrogen on blood vessel walls, inflammation and homeostasis of the vascular wall matrix.’
Their own study, based on information from 76 consecutive postmenopausal women with cerebral aneurysms who were treated by a single physician, showed that later menopausal age was significantly associated with a lower aneurysm incidence. A premature menopause (<40 years) was seen in 26% of cases and 19% of controls, and each five-year increment in menopausal age decreased the likelihood by 21%.
The control group was taken from more than 4500 women participants in the 2002 National Institute of Child Health and Human Development Contraceptive and Reproductive Experiences Study, and were matched for age and educational attainment. The average age at which women in both groups had started the menopause was similar, and analysis of the results showed that later menopause and use of hormone HRT protected against the risk of a cerebral aneurysm, lessening the risk by 21% and 77%, respectively.