The oestrogen debate

Dr Anna Fenton believes women are hamstrung by the entrenched argument. Picture / Simon Baker

Rosalie Dean was on the verge of despair when she arrived at Christchurch Oxford Clinic's Women's Health. For 16 years, after a total hysterectomy at age 36 to counteract extensive endometriosis, she had battled the effects of fluctuating hormone levels. First came the headaches that throbbed for days, the aching bones that woke her in the night, the extra weight and high blood pressure that resulted from her sudden, surgical menopause.

After four years of oestrogen capsules implanted in the lining of her stomach, she tried another doctor who diagnosed over-high oestrogen levels. Smaller doses, by mouth, made her feel better but then in 2002, after reading and hearing disturbing reports about hormone replacement therapy, she decided to go off the medication.

She felt exhausted. Her self-esteem plummeted and the bone pain gnawed away at her. "But I'd started to feel worried about the oestrogen," she says. "All I'd heard and read were the negatives - especially what it does to your heart."

It is no surprise that Dean stopped HRT. There was a 49 per cent fall in HRT use that year and a further 30 per cent drop the next, as doctors and health advisers encouraged patients to quit the hormones, and in some cases, turn to natural remedies.

The negative publicity came from several major international studies. Most important was the Women's Health Initiative (WHI) which was divided into five major studies that looked at the effect of everything, from diet and supplements to hormones, in the ageing process. Two groups of women, 10,739 on oestrogen-alone therapy and 16,000 on combined oestrogen/progesterone, volunteered to test hormone replacement therapy. After five years, the combined HRT study was abandoned because of the "unacceptable" risk of breast cancer, heart attack and stroke.

Newspaper headlines at the time struck fear into HRT users: Wonder drug's dark downside; New dangers in HRT; Increased breast cancer risk forces HRT study to end.

The New Zealand Guidelines Group circulated extensive guidelines for busy GPs to study before making an informed decision about prescribing
HRT. There was a countrywide road show and a pamphlet prepared by Women's Health Action. Their advice: HRT should be taken at the lowest dose, for the shortest period of time necessary to control symptoms. The need for continuing treatment should be reviewed six-monthly.

For people like Dean, who took that advice, problems compounded. By the time she arrived at the door of endocrinologist Anna Fenton, in the summer of 2005, chronic exhaustion was driving her to bed early most days. An earlier scan showed her bone density had deteriorated to that of a 65-year-old.

"I'd decided my body was better off without anything," she says. "But it was awful. My self-esteem was affected more than anything."

What Fenton, one of New Zealand's four gynaecological endocrinologists, told her would have been welcome - if Dean hadn't been so confused. "Now," said Fenton, "new data, released in mid-2004, shows that oestrogen-alone HRT results in a significantly lower risk of both heart disease and breast cancer."

But what about the 2002 findings that said the opposite? As a specialist in women's hormones, Fenton has an expert grip on the research. "That was only half the story,"she said. "Some of the data was wrongly interpreted, leading to the media making basic mistakes about the increased risk of stroke, heart attack and cancer. When they read 'stroke increased by 41 per cent', the average person went home and thought; 'Hell I've got a 50 per cent chance of a stroke'. What the research actually meant was that an extra eight women in 10,000 had a stroke. It puts a different complexion on the risk."

The findings also pointed to "a clear difference between the risks of taking oestrogen-alone therapy (ERT) [the preferred therapy for women who have had a hysterectomy or don't tolerate progesterone] and what happens when you add the progesterone (the second hormone in combined HRT) to it."

Progesterone, a hormone which was added to HRT 20 years ago to combat an increased risk of endometrial cancer, now looked more dangerous than straight oestrogen.

The new findings about oestrogen, which come from the oestrogen-alone arm of the WHI study, are not only measured against women taking combined HRT, but also against those taking no HRT. In other words, the prognosis for breast cancer and heart disease risk is better for women on oestrogen therapy than those taking nothing.

The oestrogen-alone study was stopped a year after the combined HRT study, because of an increased risk of stroke. "The downside," says Fenton, "is that the risk of stroke and leg clots is increased slightly [for people taking ERT], but primarily in women over 65 years and, in the case of deep vein thrombosis, mainly in those who are overweight. What the data actually tell us is that an extra eight women in 10,000 will suffer a stroke and an extra 18 in 10,000 suffer a leg clot."

Fenton started her new patient on wild yam-based oestrogen - a quarter patch to begin with, building up to a full patch as her body began to respond to the hormone.

Within three months the symptoms disappeared. "That appointment changed my life," says Dean. "I've no headaches, no bone pain, my blood pressure and bone density are stable. But the biggest thing is that my thoughts aren't the same. I feel energetic, happy, optimistic. My body feels right.

"I'm excited. Looking forward to new beginnings, working full-time as well."

The perplexing thing about oestrogen-only HRT is that the good news was buried for so long. Such information is normally examined and disseminated to doctors and the public by the New Zealand Guidelines Group (NZGG), a Wellington-based, largely government-funded, independent incorporated society. It is headed by Steven Caldwell, former CEO of Victim Support, run by a 12-member board and 14-member management team, plus specialist sub-groups appointed to research and advise on different medical topics.

In the case of HRT, the 12-person team included Cindy Farquhar, post-graduate professor of Obstetrics and Gynaecology at Auckland University and deputy chairperson of the NZGG and feminist Sandra Coney, the woman famous for her role in uncovering the Unfortunate Experiment on women with cervical cancer at National Women's Hospital in the mid-1980s.

Coney, who became known for her cynicism towards the medical fraternity and HRT in particular, is important to this story. Until early 2003 she headed the crusading Women's Health Action group. Her book, The Menopause Industry (1992), which asserted that drug companies had "created menopause as a disease," was published in four countries and Coney travelled to America to make women aware of the medicalisation of HRT and how to get off it.

The 2002 findings from the WHI study reinforced what Coney had been saying for years. The NZGG put together a strategy to get out the bad news. Their 2001 HRT pamphlet was updated. There were new guidelines for doctors, a major media campaign plus a discussion paper and research findings posted on the group's website.

Unsurprisingly, when new research into oestrogen-alone HRT trickled out over the next few years, it was greeted with a groan rather than enthusiasm. The group had just finished its countrywide road show explaining what the dire 2002 findings meant for HRT users. The new data, positive and contradicting the first findings, were just too much.

"It all got rather fraught," says Farquhar who can't remember the strategy for publicising the new findings. She thought there was lots in the media and a mailout with Medsafe to GPs when the new data started filtering through. On the other hand, she says, by then there was resistance from GPs to "things being mailed out" and a general fatigue with HRT in general as the layers of research and contradictions kept on coming.

By then Coney was pulling back from health activism to concentrate on her ARC and conservation ambitions. Farquhar suspected people were nervous about HRT. "I don't think the climate [to advocate ERT] would be right anywhere."

So, despite statements and press releases from gynaecological endocrinologists, the oestrogen-alone data, with its irritatingly positive results, was dismissed as of interest only to women who had had hysterectomies. No one remembers a mail-out to GPs. There were few articles in the media.

Instead there was an update to the HRT information pamphlet dated April 2004, prepared by Women's Health Action, which is still in circulation. Under breast cancer and mammography, it reads, "Previous studies have shown that oestrogen only is associated with an increased risk of breast cancer that increases the longer it is taken - though it may be less than combined HRT. Recent evidence from the WHI study has so far not confirmed this finding, but this result is uncertain."

Given Coney's attitude, it is a miracle that even this adjustment was made to the NZGG's pamphlet. "Every word of that sentence was hotly contested," she says. A lot of people were still "committed to salvage as much as they could from the wreckage of hormone replacement therapy."

A small, hard-to-find, user-unfriendly update on the group's website, alongside the original damning data, dated April 2004, is almost as negative. It says:

1) Use of ERT increases the risk of stroke.

2) Use of ERT reduces the risk of hip fracture.

3) There is no evidence of increased risk of coronary heart disease.

4) A possible (non-significant) reduction in breast cancer risk in ERT users needs further investigation.

The group was unimpressed by the new findings. Cindy Farquhar finds the risk of stroke is just as concerning as in the original results: "Many women recover from breast cancer. You don't come back from stroke." While Coney agrees oestrogen is less risky than combined HRT, "that's not to say there are no risks". Helen Roberts, the group's publicity manager and senior lecturer in Women's Health at Auckland University, had concerns about the validity of the oestrogen-alone research. "You have to extrapolate those findings to ordinary women," she says. "Most, a large majority [in the study] had had one or both ovaries removed - and that may effect the findings. Can you apply that [research] to the general population?"

Fenton is convinced you can. "Yes, 40 per cent [of women] had one or two ovaries removed, and we know that lowers the risk of breast cancer," she says. "On the other hand, the study was placebo-controlled and identically matched. In other words, half the women in the trial were on dummy pills the other half taking oestrogen. They were all matched for age, weight and general health.

"And the result was the same across the two groups: a significantly reduced incidence of breast cancer and heart problems including sudden death, bypass grafting and heart attack."

There is obviously a fundamental philosophical difference between the Guidelines Group and doctors like Anna Fenton. While the NZGG leans away from medicalisation of women's health - "The best medicine is the least medicine" - doctors and endocrinologists are more inclined to use drugs if they are effective and balanced against risk.

The view of medical experts is clear. Writes esteemed Australian Professor Henry G. Burger, in the June volume of the endocrinologists' magazine: "Long term oestrogen-alone would appear very safe for at least 15 years."

So why did it take so long to get the good news into the public domain? Because, say those in the field, the political gap between doctors and medical activists here in New Zealand is so wide and so obstructive, only selected information makes it into the media. This is at odds with what happens overseas where, despite similar political jostling, the medical activists have less influence.

Fenton believes women like Dean are hamstrung by the entrenched argument. "Doctors like us are telling them one thing and health activists are telling them something different. I get many women coming in saying they spoke to their GPs about how they feel and they [the GPs] say, 'well it's dangerous. I'm just not going to use it'."

New Zealand guidelines are "not based on good quality information and certainly not regarded as appropriate guidelines by world experts. You're almost better to have no guidelines."

The progesterone factor

When her menopausal symptoms started in the early 1980s Louise* felt terrible. It wasn't simply the hot flushes and sweats. What worried her most was the dizziness and her bursts of uncontrollable temper, like the worst premenstrual tension.

A course of HRT provided blessed relief, but then she started noticing a distinct change in her symptoms during the second part of the month when she had to take progesterone tablets as well as wear the hormone patches prescribed by her GP.

"It was terrible,"she says. "Every month I'd take the first progesterone pill and tell myself that this time I'd be okay. Then, out of nowhere would surge these inexplicable rages and a feeling of total despair."

After telling her that the progesterone turned her into a fiend, her partner left for good.

But her doctor insisted she continue with the progesterone part of the therapy. Every month she dreaded taking the pills. A friendly Family Planning doctor allowed her to take them for five days rather than eight. A sympathetic GP suggested she take them every three months. "But then I really collected it - the symptoms were far worse," she remembers. "It wasn't just the depression. I got blurred vision, couldn't sleep, couldn't type properly and felt giddy."

A progesterone-implanted IUD, known as a Mirena, had the same effect. And finally Louise gave up HRT. Her menopausal symptoms are now controlled by Fluox, a form of Prozac.

Her sister, who reacted just as badly to the progesterone, now has an annual ultrasound to check the lining of her uterus for signs of cancer. She now feels fantastic on the lowest-possible dose of oestrogen.

Says endocrinologist Anna Fenton, "doctors started adding progesterone to the regime 20-odd years ago to counteract a risk of endometrial cancer. Now, if you look at the combination data you're actually potentially creating a bigger risk of breast cancer by adding the progesterone than the number of endometrial cancers you're preventing.

"There's a bit of a myth out there about progesterone," she continues. "For many women it's a depressive and suppressive hormone. They can feel a lot flatter, more fatigued and with lower motivation when they've got the progesterone added than with the oestrogen alone."

The latest data also suggests that women like Louise run a higher risk of breast cancer by taking combined HRT than the endometrial cancer they risk by taking oestrogen alone.

And Louise: "All the time my body was telling me what was good for me."

* Not her real name

What they're saying

British Menopause Society: The risk of breast cancer in the oestrogen-alone arm of the WHI study was lower than in the placebo group: four fewer cases at 50-59, five at 60-69, one at 70-79 per 1000 women.

There is no overall increased risk for coronary disease, and again oestrogen alone may actually reduce the risk.

Australasian Menopause Society: These results show no increase in breast cancer risk up until 10 years of oestrogen alone and a small increase after 20 years' use ... however, the exact influence of oestrogen on breast cells is still not clearly understood and it is better to quote "a possible increased risk of breast cancer with very long-term use".

International Menopause Society: Lancaster, UK: The initial report on the oestrogen-alone arm of the WHI study concluded that there was a non-significant decreased risk for breast cancer in oestrogen therapy (ERT) users ... overall this study carries a very clear message that ERT for postmenopausal women does not increase the risk of breast cancer and in certain subgroups may even be protective ... The risks of oestrogen therapy have been overstated.

New Zealand Guidelines Group HRT pamphlet, April 2004 (still current): Previous studies have shown oestrogen only is associated with an increased risk of breast cancer that increases the longer it is taken - though it may be less than combined HRT. WHI study evidence has so far not confirmed this finding.

NZGG website, February 2006: According to the results of the major trial, there was no increased risk of breast cancer. But international drug regulatory agencies have nevertheless considered that long-term treatment with oestrogen alone might also increase the risk of breast cancer.

Dr Fenton's guide to alternative HRT

What works

Remifen, a quality-controlled, FDA-approved German product which raises serotonin levels in the brain. It has been available for 60 years, and six proper randomised, placebo-controlled, clinical trials show a response of between 60-80 per cent.

What doesn't

Soy: None of the 30 clinic trials with soy and soy products has consistently shown any benefits above placebo. Says Fenton: "Data about soy and breast cancer is rather mixed. Data from the last two-five years shows exposing breast tissue to soy products actually increases the activity of breast cancer cells grown in a lab. So rather than being a safe thing they may be not as safe as we thought. If you start taking it when older it may actually do harm."

Red clover: Studies show it doesn't work.

Don Quai: Data shows no better than placebo.

Wild yam cream: Meant to convert it to natural hormones if you rub on your skin. "Unfortunately the body does not have an enzyme to activate the cream."

Progesterone cream: Data is inconsistent.

Synthetic progesterone: "We're becoming really concerned. Data we have [linking progesterone with breast cancer and coronary artery disease] means it's not something we're advocating people should take in large amounts."