Menopausal Hormone Therapy & Quality of Life

Advice from the UK Medicines and Healthcare Devices Regulatory Authority (MHRA) and US Federal Drugs Agency (FDA) hasn’t changed in nearly 20 years. The risks of breast cancer and stroke are small, but not zero, and outweigh the benefits in reduced fracture risk.  Menopausal hormone therapy (MHT)¹ should be prescribed for symptoms alone, i.e. not for health promotion, and in the lowest dose and for the shortest time possible.

When someone I follow, Dr Mark Porter², tweeted the MHRA’s recent table of risks Table1, I commented.

“The elephant in the room is that women are supposed to weigh up these risks against the quality of life gain. But menopausal hormone therapy has minimal benefit on QoL either.” Link to WHI QoL trial in New Engl J Med. More on that later.

Dr Porter; “That’s not the impression I get in the consulting room.”

Me: “Me too. Presumably what we’re seeing is either a placebo effect, or a short term benefit to which tolerance develops.”

And then a thought popped into my head. An analogy with another drug that gives short term symptom relief but definitely does not improve quality of life. Heroin.

Me: “Estrogen is addictive & withdrawal is bad. Loose analogy, but if you doled out heroin you’d get patient feedback that it was great stuff. But RCT of H v placebo would likely not show much benefit on qoL!”.

“Loose analogy” doesn’t absolve me. It was ill-judged. I’m sorry. Here are the screenshots.

It soon went viral as an example of the worst sort of male chauvinism, an ignorant, “mansplaining” gynaecologist. Someone threatened to report me to the president of the RCOG. Someone did complain to my boss, the Dean of Nottingham Medical School. Twitter’s leading gynaecologist, @DrJenGunter weighed in.  I follow and admire Dr Gunter², but attempts to defend yourself on Twitter often backfire. So I did what I’d done after a similar episode in relation to home birth (click here), muted the thread and went off to dig my allotment.

But a week has passed, so let me try to explain.

Weighing the symptomatic benefit of menopausal hormone therapy is not straightforward. The symptoms relievable by estrogen fall into two main groups, vasomotor hot flushes, and the effects of local deficiency on the vagina and bladder. The latter are best treated by local estrogen cream or pessaries, with as far as we know, little or no systemic risk. Only the hot flushes require tablets, implants or patches, the forms of estrogen, which cause the harms summarised in the table above.

Hot flushes are a response to falling estrogens rather than a feature of stable low levels. They often recur when estrogen is stopped, which is one reason why some women end up taking long term estrogen. My tweet about quality of life should have made clear I was referring to the long term.

Many quality of life studies are short term, sponsored by pharma, or pretty poor quality. But there is one primary source of high quality unbiased data. The Women’s Health Initiative (WHI) studies. These two enormous trials funded by the US government showed in the early 2000s, that far from being protective of cardiovascular disease and stroke, menopausal hormone therapy increased both. Prior to WHI the observational data on cardiovascular disease had largely been favourable. Some small trials had shown harm but the sponsoring manufacturers had concealed adverse cardiovascular and stroke events (click here and here) and played down the breast cancer risks. When the WHI trials were published the MHRA and FDA changed their advice to “not for health promotion, and in the lowest dose and for the shortest time possible”. Prescriptions fell dramatically and soon, so did breast cancer (kumle2008).

The drug companies were not pleased and ever since have paid doctors to criticise the WHI trials or downplay the risks. But biology doesn’t change. The trials have not been superseded, and remain the highest quality ones in the various Cochrane reviews (e.g. click here). The WHI QoL study I cited (click here) concluded.

“Estrogen plus progestin did not have a clinically meaningful effect on health-related quality of life.”

“Among the subgroup of younger women age 50 to 54 years of age with moderate-to-severe vasomotor symptoms it did improve vasomotor symptoms and resulted in a small benefit in terms of sleep disturbance but no benefit in terms of the other quality-of-life outcomes.”

It was a placebo-controlled trial, but my tweet suggesting that women who take estrogen to relieve hot flushes are experiencing a placebo effect provoked an understandable backlash. The short term effect on hot flushes is not a placebo effect. That was wrong.

But all drugs have some placebo effect. It’s not denigrating the experience of women going through the menopause to say so. It’s simply a fact. Women who are considering taking a drug to control menopausal symptoms, need to know if the placebo-controlled trials show it overall improves quality of life. For women with moderate-to-severe vasomotor symptoms short term, it does. Overall and longer term it does not.

One possible reason is that people given estrogen experience pleasant effects but gradually become tolerant. When estrogen was given by implants some women came back for repeat implants at ever decreasing intervals, with estrogen levels far above even the pre-menopausal range. This also occurs with patches, but not with oral tablets. When treatment was stopped in the WHI trials more than half the women in the active treatment group experienced withdrawal symptoms (click here).  See also bewley1992.

Summary one

The risks of MHT are not very great, and it is reasonable for women to take it for symptoms. However, local symptoms are better treated with safer local therapy. Only hot flushes need tablets or patches. But women should surely be told that these may simply defer the symptoms till the course is finished, withdrawal may not be easy, and long term treatment does not overall improve quality of life compared with placebo. The explanation for this is not completely clear but may be related to the fact that people become tolerant to the beneficial effects of estrogen.

But why keep mansplaining?

Because big pharma pays medical societies, and opinion leaders, to mislead women. Some doctors write dozens of partisan papers (click here). Other doctors get taken on conference trips to the Caribbean to be told how the WHI trials were flawed. For just one example (click here). Conflicted doctors advise on, and appear in, films about women missing out on life saving menopausal hormone therapy (click here).

It’s still going on. Conflicted doctors influenced the current NICE guidelines (click here), while real experts were ignored (click here). The largest, best quality, and most up to date review of the risks of breast cancer in the Lancet earlier this year (click here) suggested that the risks were about twice as high as NICE had estimated. Within days the British Menopause Society (BMS) was downplaying the risks (click here). The Guardian covered the story rather well (click here) but didn’t report how many conflicted doctors remain BMS trustees or on their advisory council. You have to dig deep (click here) to learn that the BMS still takes money from hormone manufacturers.

At one point in the Twitter thread someone advised me to read an article by Professor Susan Davis of Monash university. No, no, no! Professor Davis is one of ten high profile doctors called out by Andrea Fugh-Berman and her colleagues from Georgetown university (click here) for taking money from pharma to write biased opinion pieces in favour of menopausal hormone therapy.

Someone else pointed out that the debate about my tweet had reached the magazine and discussion board Menopause Matters, edited by Dr Heather Currie. Read about her conflicts and links with manufacturers here.

Women need to know who’s pushing this stuff.

My story

Much of the Twitter criticism came from women saying that their personal experience trumped any evidence I could come up with. I get that. Stories are important. But they cut both ways. At the risk of weakening the rest of this post, here’s mine.

About 35 years ago my mother asked me – then a young OBGYN – whether she should take hormone replacement therapy, as it was then known, to prevent fractures. My answer:

“Yes. It’s good for your bones. There may be a small breast cancer risk, but that’s far outweighed by the benefits to your arteries in terms of reduced heart attacks and strokes”.

Orthodox advice then. My mother, who still had her uterus, took combined HRT, and suffered a fatal stroke in 2001. She died three months before the WHI trial of combined HRT was suspended by its data monitoring committee because, far from preventing strokes, it caused them. Wyeth’s share price fell off a cliff. The MHRA and FDA changed their advice to “… never for health promotion”. And I learned why randomised trials matter.

I’m not seeking sympathy. My mother was a good age. You’ve got to die of something, and I’m told there is only about a one in four chance that her stroke was caused by the HRT that I had recommended.  But…, stories are important.

Summary two

There are two narratives around menopausal hormone therapy.

One is simple and easy to understand. It is a highly effective, safe and underused treatment that some misogynistic male doctors, who never have and never will experience a hot flush, are reluctant to prescribe.

The other is a bit more complicated. Drug companies and some doctors are making money from medicalising a natural, variably unpleasant, but self-limiting transition. For years they misled women by hiding and downplaying the risks. When neutral researchers finally did good trials, they paid doctors to undermine the results.  And they’re still pushing conflicted doctors onto the NICE committee. Hiding the evidence that although estrogen relieves hot flushes while you’re on it, you might find it difficult to stop. And long term it won’t make you feel better and has rare but serious side effects.

I’m sorry for my ill-judged tweet. Perhaps it’s fortunate that women don’t need to listen to me.

Better to listen to the genuine independent advice that comes out of the MHRA and FDA, and the independently assessed evidence collected by Cochrane.

Jim Thornton

Notes

1. This term is preferred to Hormone Replacement Therapy (HRT) for hormones given after a natural menopause. The latter should be reserved for women who have undergone a premature menopause due to surgery or disease.
2. I’ve named names in this and other blogs. But, so far as I’m aware, neither Dr Porter nor Dr Gunter have ever received money from the manufacturers of menopausal hormone therapy and their writings on this topic seem completely fair and unbiased. They are not in my sights.