News and views

How journalism works: A minor study upholds the safety of HRT

To the relief of many, 2015 ended with the apparent rehabilitation of postmenopausal hormone therapy. Not just in the eventual publication of the long-awaited guidelines from the UK’s National Institute for Health and Care Excellence (NICE) but also in a sprinkling of other studies which made headlines far greater than their results might merit.

Among the latter was a 10-year observational study of just 80 patients presented at the annual meeting of the American Society of Reproductive Medicine (ASRM) in October, an unlikely forum for game-changing research in the menopause.¹ The study, however, was reported prominently by The Times, Mail, Telegraph and Guardian as vindication of HRT’s safety (‘Using HRT to treat menopause is safe, says study’), and widely followed-up elsewhere. ‘It’s official’ was the Mirror headline, ‘HRT is NOT a danger to women as experts conclusively dismiss worries over safety.’

The ASRM meeting, like that of ESHRE, is a diary item for the UK press, but usually for fertility stories, not menopause. The abstract itself – which was not flagged up by the ASRM’s own press programme at the Baltimore meeting – actually summarised a study of the effect of HRT on body composition as determined by DXA measurement. Among its incidental findings was the fact that ‘there was no increased prevalence of medical co-morbidities between the treated and control groups’.

How did this modest American-based abstract gravitate to such bold-type headlines in the UK? We now know, thanks to research by the Guardian itself, that this was in fact ‘the first salvo’ of a public relations campaign apparently designed to promote a survey of HRT use carried out on behalf of a pharmaceutical company and aiming to ‘put the [HRT] issue back on the agenda’ just before NICE published its menopause guidelines. So we can now imagine the scene in Baltimore of a few UK journalists drumming their fingers in frustration and desperate for a story to file back to their waiting news desks in London. Add together the survey’s findings (‘a staggering 85% of women are avoiding HRT’), the US study (no co-morbidities after 10 years’ HRT) and a little controversial comment from prominent UK cheer-leaders and those news desks back home would be more than happy.

So John Studd was quoted by the Telegraph as saying that ‘most GPs are frightened of HRT – they will have learned as medical students that it is linked to health risks’, and former BMS Chairman Nick Panay that ‘the right HRT preparation, in the right woman, has low overall risks and has significant benefits’.

Lila Nachtigall, lead investigator of the US study, condemned the UK press coverage as ‘ridiculous’, insisting in the Guardian that the co-morbidity findings ‘were just an observation’. And Panay complained to the paper that his comments had been taken out of context, that he had not read the fine detail of the study. ‘I was asked to discuss the menopause, hormone therapy and the directions in which we were going in general,’ he said. ‘I did not make a comment about the data from the study.’

However, any rift in the interpretation of HRT data which the NICE guidelines might have hoped to heal was now once more exposed as a gaping chasm. Cancer Research UK, branding the UK headlines as ‘extremely misleading’, issued its own statement saying it was ‘deeply concerned for women’s health amid headlines that taking hormone replacement therapy is safe’. And Valerie Beral of the Million Women Study added her fears ‘that women will be misled into thinking the drugs are completely safe’. Panay himself downplayed the rift, telling the Guardian that ‘gynaecologists were not at odds with the cancer epidemiologists’, and that the most important thing was that women and doctors were aware of the options. Yet by the time the NICE guidelines appeared less than two weeks later those odds seemed as great as ever. The epidemiologists were furious that they had not been included in the NICE development committee, that the guidelines themselves – even if not explicitly stated – looked like an official endorsement of HRT, and that many of those involved in their development were, as the Daily Mail reported, ‘in the pay of the drug firms’. As response to the NICE guidelines would show yet again, controversy and the menopause seem never far apart.

References

Bayer AH, Goldman KN, Mauricio R, et al. Long term hormone replacement therapy (HT) does not affect post-menopausal total body composition. Fertil Steril 2015; 104 (Suppl): e5–e6.

NICE menopause guidelines: A war of words and a war of numbers

Although the 63 recommendations of the NICE clinical guidelines on the menopause were clearly written for healthcare professionals (‘give information about contraception …’, ‘consider testosterone supplementation …’, ‘advise women with vaginal dryness …’), the press release announcing its publication in mid-November was clearly aimed not at the pros but at the public: a guideline ‘to stop women suffering in silence’. So the development group members quoted in the press release all had earnest messages for women, not doctors. ‘The message to women is clear – talk about the menopause with your clinician if you need advice on your symptoms – it’s very important to discuss the options to find what might help you,’ said one. The press release was also festooned with numbers, mounted within the text like commemorative plaques on a wall of bricks. ‘1.5 million’ women having menopause symptoms, ‘51’ the average age of menopause …

One can understand NICE’s nod to tabloid news, but this was a marked change of direction, justified only by the guidelines’ underlying theme of clarity, accurate information and informed choice. ‘The guideline aims to improve the consistency of support and information provided to women in menopause,’ said NICE. Indeed, the guideline was accompanied on its website by a considerable patient information version.

Officially NICE highlighted its principal diagnostic and treatment recommendations as:

In otherwise healthy women aged over 45 years with menopausal symptoms, diagnose the following without laboratory tests: perimenopause based on vasomotor symptoms and irregular periods; menopause in women who have not had a period for at least 12 months and are not using hormonal contraception; menopause based on symptoms in women without a uterus.

Response to the NICE publication was largely approving. Heather Currie, chair of the British Menopause Society, hoped it would ‘play an important role in raising awareness of all menopausal symptoms, will encourage women to consider lifestyle changes to improve later health, and will clarify uncertainty around both prescribed and non-prescribed treatment options’. And David Richmond, President of the Royal College of Obstetricians and Gynaecologists, described the document as ‘a milestone for both healthcare professionals and women’.

The press too was mainly complimentary, with many titles (such as the BBC) taking the line that HRT should now take a greater part in these new patient conversations. ‘Women SHOULD be given HRT to fight menopause, says health watchdog because the benefits far outweigh the risks’ was the Daily Mail’s take, while the Guardian said that ‘HRT could benefit one million women’. Although reversing some of the health scares of the previous 13 years, the guidelines’ HRT emphasis as sensed by the press was no great surprise; indeed, a summary report for the British Medical Journal (whose authors included the development group chairman Mary Ann Lumsden) noted that ‘HRT is the most effective treatment for the relief of vasomotor symptoms’ and ‘for most symptomatic, menopausal women, the benefits of HRT outweigh the risks’.¹

However, even before the full guideline was publicly available, the Oxford epidemiologist Klim McPherson was quoted in the Guardian as saying he found it ‘absolutely unbelievable’ that he and colleague Valerie Beral had not been consulted on their composition, and that the decline in breast cancer incidence found in the past decade could be clearly attributed to the fall in HRT use.

Both, of course, had had the opportunity to register with NICE as stakeholders, yet the list of more than 200 stakeholders contains neither their individual names nor their institutions. Stakeholder status would have given them the opportunity to raise their concerns specifically, and to have them formally answered.

Once the guidelines were published McPherson was back in action again. He told the Independent:

This guidance leans too far in the direction of playing down the risks [of HRT] … the aftermath of accepting this new guidance stands a very good chance of increasing the breast cancer, cardiovascular disease and ovarian cancer numbers by several thousand in the next 10 years.

Two days later, McPherson described NICE as ‘irresponsible’ in the Daily Mail, and the guidelines as ‘totally misleading’.

NICE had little option but to respond, and subsequent online versions of the Daily Mail report carried the NICE statement that all relevant peer-reviewed research had been included in the evidence base, and that the guidelines do not ‘urge GPs to offer hormone replacement therapy to anyone with severe menopause symptoms’ (as the Mail had suggested). The statement also addressed the rumblings of conflict of interest raised by McPherson and pursued in detail by several newspapers (declarations of interest had been clearly set out in fine detail in Appendix C of the full guideline):

The group of independent, respected clinicians and medical experts who have developed the NICE menopause guideline have done so with integrity and in line with NICE’s strict conflict of interest policy. NICE does not allow people who have a current personal financial interest in the outcome to take part in developing its guidance.

So now a few months later, how have the guidelines been received? Controversy is meat and drink to the press, and it’s tempting to think that the McPherson storm was nothing more than Fleet Street doing its job. A survey of 500 GPs conducted by GP Online found that the majority (80%) thought the guideline would increase their confidence in dealing with the menopause. For this was, as NICE insisted, the first ever full guideline on the menopause, and not a mere update of previous recommendations. Endorsements were widespread, and none appeared to doubt the need for guidelines, accurate diagnosis or recommendations for symptom relief.

As ever, the bone of contention was HRT and an interpretation of harm as allowed by the epidemiological data. With the WHI’s revision of its coronary heart disease risk in 2007, and confirmation that HRT as unopposed estrogen does not increase the risk of breast cancer, most international statements on the menopause and hormone therapy had been cautiously favourable in recent years, without actually quantifying risk. Yet here in this latest NICE guideline were tables setting out the risk estimates for coronary heart disease, stroke and breast cancer, noting for the latter that ‘HRT with estrogen and progestogen can be associated with an increase in the risk of breast cancer’ and that ‘any increase in the risk of breast cancer is related to treatment duration and reduces after stopping HRT’ (and that estrogen alone is associated with little or no change in risk). Among the statistics was the ‘estimate’ that the current use of combined HRT for 7.5 years would be responsible for five additional cases of breast cancer. Both McPherson and Valerie Beral were quoted by the Daily Mail as saying that cases of breast cancer would rise at a far greater pace than this – ‘up to 7000 extra cases of breast cancer within ten years’.

The war of words thus became a war of numbers, whose final thoughts seemed left to Paul Pharoah, Professor of Cancer Epidemiology at the University of Cambridge, who in a little used comment released through the Science Media Centre put the risk very close to NICE’s own estimates. He calculated that, of 1000 50-year-old women in the UK, 23 would be expected to be diagnosed with breast cancer before they reached 60; however, if 1000 50-year-old women took combined HRT for five years, 28 would be expected to be diagnosed with breast cancer before 60 (an increase of five per 1000). ‘In my view,’ he added, ‘the best evidence for the effect of estrogen only HRT and estrogen + progestagen HRT comes from the Women’s Health Initiative. The numbers from the observational studies are not reliable because of possible biases.’

Panay himself, as a member of the NICE development committee and former chairman of the BMS, said he hoped the guidelines would prove a basis for educating professionals and the public ‘about all aspects of the menopause, not just HRT’. He further hoped that the HRT controversy would not divert attention from the most important goal, ‘which is to put the menopause back on the health agenda in order to optimise the quality of life and welfare of women in our ageing population’.

References

Sarri G, Davies M and Lumsden MA; Guideline Development Group. Diagnosis and management of menopause: summary of NICE guidance. BMJ 2015; 351:h5746.

Guidelines reaffirm diagnosis of premature ovarian insufficiency

There was no controversy in the NICE guidelines (nor has there ever been generally) about the use of hormone therapy in young women with premature ovarian insufficiency (POI), a clearly defined condition which has now superseded the past’s misleading epithet ‘premature menopause’. The concerns, anyway, are not so much with the long-term effects of hormone treatment, but more with the long-term effects of hormone deficiency on bone and cardiovascular disease in such young people. However, the guidelines add that ‘these young women need support and holistic care with a number of psychosocial issues, such as infertility, sexuality and psychological distress’. POI, said NICE, is defined by ‘menopausal symptoms, including no or infrequent periods’ in women under 40 and with elevated FSH levels in two samples. Anti-Muüllerian hormone (AMH) testing is not advised, despite its predictive accuracy of ovarian reserve for IVF, and incidence of POI is put at one per 100 (with diagnosis often delayed).

This is largely the position taken by another recently published guideline, this time the first ever dedicated specifically to POI.¹ This European guideline, published in December by the European Society of Human Reproduction and Embryology (ESHRE), also recognises an increasing incidence of POI resulting partly from better cancer survival rates in young women (particularly from the haematological malignancies and breast cancer) and the increasing use of bone marrow and stem cell transplants for benign conditions.

The ESHRE guideline similarly sets out a clear diagnostic definition of POI based on menstrual disturbance and biochemical confirmation – that is, absent or irregular periods for at least four months and an elevated level of FSH. POI, adds ESHRE, can occur as early as the teenage years, although most cases occur between the ages of 30 and 40 years.

It is also noted that around 10% of women whose POI is of natural cause have chromosomal or genetic abnormalities, most of which are linked to the X chromosome. As a result, the guidelines recommend chromosome analysis in suspected POI cases, and testing for Fragile-X syndrome. This itself has been implicated in the causation of POI, although the guideline insists that ‘currently it is not possible to predict or prevent the onset’ of POI. There are, nevertheless, important health consequences for carriers of a Fragile-X permutation and their children.

Early initiation of HRT is ‘strongly recommended’ in women with POI to protect bones and control future risk of cardiovascular disease; ‘it should be continued at least until the average age of natural menopause,’ say the guidelines. HRT, however, will not help restore ovarian function or fertility in women with POI, for whom the chances of spontaneous pregnancy are described as ‘small’. No treatments have been shown to increase natural fertility, and egg donation is the only successful approach to childbirth. Once eggs are gone, they’re gone irrevocably – unless the tantalising prospect of Jonathan Tilley’s ‘egg precursor cells’ is truly able to rewrite biology.

Reference

Management of women with premature ovarian insufficiency. Guideline of the European Society of Human Reproduction and Embryology. See https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Management-of-premature-ovarian-insufficiency.aspx