No wonder women are confused about the safety of hormone replacement therapy (HRT). For more than 50 years, women had been taking a synthetic hormone to replace oestrogen and ease them through the menopause. But in 2002, a major study announced that HRT increased the risk of cancer. Now, just a few months ago, another study has claimed the dangers have been overstated, and that women should consider HRT again.
This is welcome news to the women who see HRT as the only answer to months—and sometimes years—of hot flushes and night sweats, mood changes, aches and pains, and loss of libido. The UK’s health-quality controller NICE (National Institute for Health and Care Excellence) agrees, and says the latest evidence puts HRT back on the table; it’s a therapy that women can start considering with their doctors again. HRT has suddenly come in from the cold.
So why has the advice been so conflicting and confusing? It’s mainly because the manufacturers of HRT have deliberately created false trails and red herrings for the past 60 years. To understand the truth about HRT, we have to follow its history—and the money.
The first brand of HRT was Premarin, made up of conjugated equine estrogens (CEE)—in fact, from horse urine—which was approved in 1942. But even as early as the 1950s, doctors were seeing an increase in uterine cancer cases in women taking the hormone. Wyeth, the manufacturer, quietly introduced a new treatment, Prempro, which added progestogen (or its synthetic form, progestin), another hormone, to the oestrogen; this was approved in 1994.
The new therapy was promoted with the message that it kept women youthful and sexy, and helped build strong bones, so countering brittle bones and osteoporosis, another problem associated with the loss of hormones after the menopause. HRT was also good for the heart.
American doctors even faced malpractice claims if they didn’t prescribe it, and conservative British doctors were encouraged to write out more prescriptions for it. Wyeth advised them to trawl through their patient records to identify all women over the age of 45 who could be offered HRT.
At its peak, doctors were writing 126 million prescriptions for HRT every year in the US alone, which were generating sales of $3 billion for Wyeth, the main manufacturer of the therapy.
Trouble at t’Pill
But there was disturbing evidence emerging over the safety of HRT, even before the landmark Women’s Health Initiative (WHI) study of 2002, which found a connection with breast cancer, pulmonary blood clots and stroke.1
In 1997, researchers discovered that HRT increased the risk of breast cancer by 2.3 per cent for every year it was used; on average, women were taking HRT for 11 years. The risk persisted for five years after stopping the treatment.2 Others agreed, with one study finding that HRT quadrupled the risk of breast cancer.3
The well-known long-term Framingham Heart Study also doubted whether HRT had protective effects against heart disease; in fact, the data seemed to indicate that it actually increased the risk.4
Wyeth and other manufacturers countered that the researchers were looking at the wrong type of HRT; instead of oestrogen-only remedies, they should be exploring the oestrogen–progestogen combination which, they said, was safer.
A US Congress hearing in 2008 discovered that Wyeth and other HRT manufacturers were using PR companies to write articles to submit to journals that leading academics were paid to put their names to, an activity that intensified after publication of the WHI study.5
Stop the trial
The WHI trial was a game-changer. Its discoveries were so alarming that the researchers stopped the study prematurely, as they feared they were jeopardizing the lives of the participants. It was designed to be a 15-year survey of HRT starting in 1991, but 10 years into the study, the researchers discovered that oestrogen–progestin HRT increased the chances of heart attack by 29 per cent, stroke by 41 per cent and breast cancer by 26 per cent among the 161,000 postmenopausal participants.
Sales of HRT plummeted precipitously. By 2003, Wyeth’s annual revenues from HRT had fallen from $3 billion to $880 million, sending its PR machine into overdrive. Adriane Fugh-Berman, a researcher at Georgetown University Medical Center in Washington, DC, discovered a cache of 1,500 ‘scientific’ papers that endeavoured to convince doctors of the safety of Prempro.
As the US congressional hearings heard, Wyeth had recruited marketing company DesignWrite to ghost-write studies and papers, and recruit academics to ‘front’ the papers as though they had written them. “Any attempt to manipulate the scientific literature, that can in turn mislead doctors to prescribe drugs that may not work and/or cause harm to their patients, is very troubling,” said Senator Charles Grassley, who was leading the investigation.
But Wyeth didn’t have only the WHI study to counter. The Oxford-based Radcliffe Infirmary’s Million Women Study was coming up with similarly disturbing findings. As the name suggests, it recruited more than one million women who were 50 or older with the primary remit to explore the safety of HRT, which was being used by half the participants. Its first report, published a year after the WHI findings, concluded that oestrogen–progestogen HRT doubled the chances of breast cancer, while the implanted oestrogen-only version increased the risk 1.6 times. But, as an earlier study had also found, the risk fell the longer the time from stopping HRT.6
But the picture became more confusing when the Million Women Study also revealed that HRT could both cause, and protect against, endometrial cancer. Oestrogen HRT increased the risk, but the oestrogen–progestogen form had a protective effect. In any case, though, the vastly increased risk of breast cancer with the two-hormone HRT more than offset any cancer-fighting benefits it might have, the researchers concluded.7
Finally, the Million Women Study researchers turned their attention to ovarian cancer and, again, they found HRT was a cause. It increased the risk 1.2 times and was linked with similar chances to develop fatal ovarian cancer too.8
At around the same time, Wyeth got some good news from an unlikely source. The WHI researchers took another look at the data and admitted they’d got it wrong: HRT didn’t increase the risk of either heart disease or stroke.9
HRT’s apologists dived in on cue. Dr John Stevenson, an endocrinologist at the Royal Brompton Hospital in London, said the WHI researchers had deprived women of a treatment that could have helped them through the menopause.
HRT’s death toll
Yet the cancer risk wouldn’t go away. The Million Women Study researchers reckoned that 1,300 women in the UK had developed ovarian cancer, and a further 1,000 had died of the cancer, as a direct result of taking HRT. Add in figures from the US and the picture is more disturbing still: since the early 1990s, 230,000 women in the US and UK had died of a cancer caused by HRT.
On the ground, oncologists were seeing a sudden, and steep, drop in cases of breast cancer, and the only difference was the fall in the use of HRT. In the US, breast cancer rates fell by 12 per cent in 2003—the year after the WHI study—and a smaller decrease was also seen in the UK. Researchers at the M.D. Anderson Cancer Center in Houston, Texas, reported that 14,000 fewer women that year had been diagnosed with the cancer. Researcher Dr Peter Ravdin said: “It is the largest single drop in breast cancer incidence within a single year I am aware of. Something went right in 2003, and it seems that it was the decrease in the use of hormone therapy.”10
Despite its persistent public pronouncements that HRT was safe, Wyeth—and then Pfizer, which took the company over in 2009—was building a war chest to settle claims of compensation for women who developed cancer while using HRT treatments like Prempro. A Securities & Exchange Commision (SEC) filing in 2011 revealed that Pfizer had set aside $772 million, although industry watchers believed far more would need to be allocated. The company agreed and said the sum was “the minimum expected costs to resolve all the outstanding claims”. By 2014, the company had paid out $1.6 billion to settle cancer claims.
At the time of the Wyeth takeover, Pfizer inherited 9,900 pending claims, including that of Donna Kendall, who was awarded damages of $6.3 million. Mrs Kendall, 66, developed breast cancer after taking Prempro and Provera for 11 years. After the trial, the findings of another case were revealed: Connie Barton was awarded $75 million in punitive damages after she contracted breast cancer from taking Prempro. The enormous award was partly due to recognition by the court that Pfizer was promoting a therapy that it knew could cause cancer.
With all the bad news swirling around HRT, Pfizer needed to change the conversation. It believes it has done that with a new generation of HRT therapies headed by Duavee—or Duavive for the UK/EU market. While it still contains oestrogen, the hormone has been combined with a drug called bazedoxifene to counter any cancer risk, Pfizer maintains. The drugs regulators agreed, with Duavee winning their approval in the US in 2013, and Duavive a year later in the UK.
Designed for short-term use in women who haven’t had a hysterectomy to treat moderate-to-severe menopausal hot flashes and postmenopausal osteoporosis, industry analysts reckon it could contribute $200 million in revenue to Pfizer’s Premarin family of HRT drugs, which still generates $1 billion in sales for the company in the US every year. Eli Lilly is achieving similar revenues with its HRT offerings, suggesting that the market was merely dented by the cancer scares.
Two failed drugs
But the product is not quite as new as Pfizer suggests. In fact, it’s a reworking of Aprela, an HRT treatment that Wyeth had been struggling with since 1999.
America’s drugs regulator, the Food and Drug Administration (FDA), was never convinced of its safety and kept refusing its approval. The other component, bazedoxifene, is another unapproved drug that was going to be marketed as Viviant for osteoporosis.
So essentially, Duavee/Duavive is a combination of two unapproved drugs which, on their own, raised safety concerns with the FDA. Pfizer may quietly agree—it has set aside $800 million to cover future lawsuits. Others have caught on to the idea of a ‘new HRT’. Noven Therapeutics launched Brisdelle, the first non-hormonal treatment for hot flashes, which uses paroxetine, the active ingredient in the antidepressant Paxil, which raises the risk of suicide. As a result, Brisdelle comes with a ‘black-box’ warning of this potential risk.
A new offering needs good marketing, and a few studies have surfaced over the past few years regarding the safety and benefits of taking HRT. But the headline-grabbing study has been that of Dr Lila Nachtigall, a professor of obstetrics and gynaecology at New York University. She and her team tracked the health of 80 postmenopausal women taking HRT for an average of 14 years and compared them with 56 women not taking it. They found no differences in the health of either group and concluded that HRT didn’t increase the risk of breast cancer, heart disease or diabetes. Nachtigall, who also works at New York’s Women’s Wellness Center, said: “We found women taking HRT over a long period of time to be in very good health. It’s now clear that women on HRT over many years can enjoy benefits. The risks of HRT have definitely been overstated. The benefits outweigh the risks.”11
Less than a month later, the UK’s NICE, which determines best-practices medical care, issued a new guideline that doctors could again start discussing HRT with women going through the menopause. It’s an effective option for treating severe menopausal symptoms, and may be recommended after doctors discuss “the risks and benefits” with their patients. Estrogen-only HRT caused “little or no increase in the risk of breast cancer” while the oestrogen-plus-progestogen form did come with a risk, but that diminished on stopping the HRT.
There are several concerns about the NICE recommendation. The first is that the Nachtigall
study involved just 80 women and would hardly seem to sufficiently counter the evidence of major studies involving more than a million women, let alone the $1.6 billion paid out so far to settle damages claims. The second is that nine of the 18-person panel that made the new HRT recommendation have financial ties to HRT manufacturers. And, third, the same can be said of Nachtigall, whose name came up in the Congressional hearings as having been recruited by Wyeth in 1999 as the author of an article extolling the benefits of HRT after the paper had been drafted by marketing ghost writers.
At best, say critics of the Nachtigall study, only women with the most severe menopausal symptoms should try HRT and, even then, only for the shortest possible time.
But, ultimately, the question every woman has to ask herself is: does one study of 80 women make HRT safe and counterbalance the mountain of evidence of harm that has accumulated over the past 12 years or so?
As life-destroying as menopause can be—and as life-enhancing as HRT may be—the answer should still be a resounding ‘no’.
What are the alternatives?
There are plenty of tried-and-tested alternatives to HRT to treat the symptoms of menopause.
Brittle bones/osteoporosis: supplement with vitamin D. One study from Addenbrooke’s Hospital in Cambridge found that even low-dose supplements can dramatically reduce the risk of fractures compared with a placebo.1 Boron can also help prevent postmenopausal osteoporosis, as it stimulates the body to make more estrogen.2
Hot flushes: try omega-3 fatty acids. Taking 2 g/day halves the severity of hot flushes, and had a positive effect in 70 per cent of women taking these supplements.3 Vitamin E can also reduce the frequency and severity of hot flushes, 4 as can acupuncture, which achieved a “marked clinical improvement” with 12 sessions compared with the usual care.5 The herbal supplement Fernal was twice as effective as a placebo in reducing flushes in one trial of 54 menopausal women.6 Also, the herb black cohosh has a long tradition of use for ‘women’s problems’, and can help with flushes and mood swings. It’s so effective that Germany’s health regulator has approved its use at 40 mg/day. There have been concerns, though, that it might worsen the spread of breast cancer, so women with a family history of the disease should perhaps think twice.7, 8
General symptoms: aromatherapy has helped women with their general menopausal symptoms after a month of at-home care and two sessions with a therapist.9 Yoga, tai chi and meditation-based programmes can also ease symptoms.10
Loss of libido: the herb Ginkgo biloba can improve your sex life within a month, according to one trial of 202 pre- and postmenopausal women complaining of low sex drives.11
Cutting HRT cancer risk
A few simple changes to your diet could offset HRT’s cancer risk, several studies have found. Implausible as it may sound, adding celery and parsley to the diet might even reverse aggressive breast cancer caused by HRT. It’s all to do with apigenin, a compound found in those foods.
Apigenin, a flavonoid, shrinks tumours stimulated by progestin, the synthetic hormone used in HRT and birth-control pills, say researchers at the University of Missouri. It kills cancer cells, stops them from spreading and interferes with the genetic codes that encourage cancer growth. However, as these tests were carried out in laboratory mice, there’s no guarantee that similar effects would be seen in humans.1
Curcumin, the spice that gives Indian food its distinctive taste and colour, seems to have a similar effect on cancer cells. The spice, derived from turmeric root, appears to slow and even stop the development of cancerous tumours in the breast.
Researchers at the University of Missouri discovered that the spice hampered the cancer-causing effects of HRT by blocking the growth factors that increase the blood supply to tumours, so effectively starving them.2