Fear, loathing, HRT and women’s health research.

YOUR BRAIN ON MENOPAUSE: In this seven-part series, I explore menopause from a brain health perspective with a particular focus on the neurobiology of hot flashes, sleep, mood and memory, the role of hormone therapies and their long-term effects on the brain. This is Part 6.

---

This is a long and detailed read. Click here to download the series as a PDF to read offline.

---

Hormone replacement therapy (HRT; also called menopausal hormone therapy, MHT) is a drug combination of oestrogen and progesterone, and sometimes testosterone. It is most commonly used to treat symptoms of perimenopause such as hot flashes.

Here’s the deal,

MHT is the most effective treatment we currently have for symptoms related to oestrogen withdrawal during menopause if started when women are symptomatic.

The choice to use any type of MHT is tricky because there are complicated risks and benefits to weigh up. There are confusing messages, newspaper reports, and even conflicting advice from medical professionals. So the decision really comes down to deciding: are the risks worth the benefits that MHT can deliver? 

Thanks to the work of women’s health advocates such as Dr Jen Gunter, Dr Louise Newson, and organisations such as that named after the late Dr Jean Hailes, calm clear information is accessible.

Before I discuss some of the risks and benefits, it’s worth understanding the rather provocative history of MHT.

A quick history of hormone therapy research

Hormone therapy for menopause has been around longer than you might suspect — since the late 1800s!

As early as the 1930s, menopausal women were routinely offered extracts of human placenta or oestrogen distilled from the urine of pregnant women. This was was described as “socialized estrogenicity” whereby the “estrogen-rich woman gives to the estrogen-poor.”

The drug ‘Premarin’, which is made from urine extracted from pregnant mares (don’t be too horrified, for years insulin for diabetes was extracted pig pancreas), was first marketed in the 1940s. Hormone doses in these early preparations were far in excess (in the order of ten times) of those prescribed today, and modern doses of MHT contain less synthetic hormones than found in the oral contraceptive pill.

By the mid-1970s, it became apparent MHT was not without its risks and studies showed links between oestrogen therapy and endometrial cancer. This led to the finding women also needed progesterone added to the mix to prevent endometrial cancer (women without a uterus because of hysterectomy don’t need added progesterone).

Treating the “galloping catastrophe”

In 1972, one of the more expressive women’s health academic articles ever written appeared in The Journal of the American Geriatric Society penned by New York gynaecologist Robert Wilson and his wife, a nurse, Thelma Wilson.

“The estrogen molecule is by far the most important hormonal molecule in the body. There is no intention to denigrate other steroids, but this statement is not difficult to prove.”

“Estrogen produces the beauty, the allure which attracts the male. This can no more be resisted then the moth can resist the flame. Instead of death there results life – that is why we are here.”

In the paper, the Wilsons describe menopause as “truly a galloping catastrophe” and a time of “slowly foundering sexuality” treatable by the simple transfer of natural estrogens from one mammal to another.

“The timely administration of natural estrogens plus an appropriate progestagen to middle-aged women will prevent the climacteric and menopause – a syndrome that seems unnecessary for most of the women in the civilized world.”

The Wilsons’ correctly identify many of MHT’s positive benefits.

“The estrogenic treatment of older women will inhibit osteoporosis and thus help to prevent fractures, as long as they continue healthful activities and appropriate diets. Breasts and genital organs will not shrivel.”

The final line surely reflects the era in which it was published,

“Such women will be much more pleasant to live with and will not become dull and unattractive.”

Embracing the “feminine forever” in the 60s and 70s

The 60s and 70s marked the beginning of the sexual revolution and at the same time, younger women were embracing the reproductive freedom engendered by the oral contraceptive pill.

The feminist movement in the 1960s changed women’s status and life expectancy, encouraging menopausal therapy, especially in European countries, with the concept of “feminine forever”.  Women embraced MHT as an elixir of youth, freeing them from hot flashes, sleepless nights, and mood swings (and presumably also becoming dull and unattractive).

During the 1990s, prescriptions for MHT skyrocketed, with US statistics citing 58 million women taking MHT in 1995, and up to 90 million in 1999!

Whilst millions of women around the world embraced MHT, others questioned whether naturally dwindling hormone stores should be viewed as a problem. Some resisted the notion that women of a certain age suffered from ‘oestrogen deficiency’ that needed restoration in order to function as feminine. They pointed towards our western obsession with youth and beauty as the problem, not their ageing ovaries.

Millions of women in many studies

Since the 1970s, the risks and benefits of MHT have been explored in numerous women’s health studies.

• The Women’s Health Initiative (WHI) is a randomised controlled trial designed to examine the effects of hormone therapy on heart attacks, stroke, blood clots, bone fractures, breast, colon and uterine cancer, and overall causes of death. Over 27,000 healthy women ages 50 to 79 enrolled and were randomly assigned to receive MRT (oestrogen alone or oestrogen plus progestin) or placebo.

• In 1996 the Million Women Study began recruiting one million UK women aged 50 to 64 into a cohort study to how various reproductive and lifestyle factors, including MRT, affect women’s health.

• Other studies include the Nurses’ Health Study, which has followed health of several hundred thousand US nurses to see if there is a relationship between medical and lifestyle choices such as the oral contraceptive pill, alcohol use, exercise, cigarette smoking, obesity and, of course, MRT. Thanks to the nurses, we know that a Mediterranean-style diet reduces the risk of colon cancer and obesity increases risk of stroke.

• The Postmenopausal Estrogen/Progesterone Interventions (PEPI) randomised controlled trial ran from 1987 till 1990 and studied 800 women ages 45 to 64 to learn about the risks and benefits of various HRT regimens. Thanks to the PEPI study we know HRT increases breast density on a mammogram, which makes it harder to detect breast cancers if they do occur.

• The Study of Women’s Health across the Nation (SWAN) is an observational study that has followed over 3000 American women from premenopause through their transition. SWAN is significant because it has taken into account women’s ethnic background, and found that ethnicity plays a big part on the menopausal transition experience.

There are many other studies I could mention, but I don’t want to bore you. Instead, appreciate that MHT is actually a deeply scrutinised women’s health issue. We have very detailed information about the risks and benefits for a wide range of health outcomes!

So, why, despite the wealth of knowledge we have available, is there still so much fear and confusion around MHT?

It all comes down to the WHI and the dramatic events that unfolded in 2002 and 2003.

Or as Jen Gunter comments in her book The Menopause Manifesto, “The WHI, a WTF for MHT.”

The early 2000s and the WHI controversy

In 2002, I was working at a national breast cancer organisation when news filtered in that stunned us all. The WHI announced it had stopped the MHT trial early because of safety issues. It appeared that combined MRT caused a small increased risk of breast cancer, heart disease, stroke and blood clots, but fewer cases of hip fractures and colon cancer.

Whilst researchers and statisticians quickly pointed out the risks were greatly exaggerated, and there were errors in the original paper, media attention was extraordinary.

Women on the trial were sent letters telling them to stop, and doctors were inundated with calls from frantic patients. Many doctors were rightly confused and advised their patients to come off MHT. Globally, 50% to 80% of women stopped MHT.

The Million Women’s Study followed with a 2003 report in the Lancet claiming the use of MRT increased the incidence of breast cancer.

I remember the CEO of my organisation spending that time fielding calls and media interviews from what can only be described as her ‘MHT war room’. She tried to project some calm and common sense around the data. But like most communication around risk, fear prevailed.

In the 15 years since then, studies have continued to gather and analyse data. Now, understanding of the risks and benefits is far more nuanced and less fear-based. But as Jen Gunter points out in The Menopause Manifesto,

“It’s not possible to overstate the impact of the WHI on how we view MHT today, and I suspect its reverberations will likely be felt for decades more.

Not just because of the results, but how they were communicated by the investigators and the press, and how they have been interpreted and reinterpreted ad nauseam—and will likely continue to be reinterpreted.”

Jen Gunter

Others agree,

“The damage done was huge, basically leaving many symptomatic women without an effective treatment, even if the epidemiological data were not strong enough to document a clear harm to women’s health.”

Angelo Cagnacci and Martina Venier, 2019. The Controversial History of Hormone
Replacement Therapy

A beneficial window of opportunity for MHT

The major problem since identified with the WHI trial was that most women were too old to be safely starting MHT.

The average age of the women in the trial was 63 – some were enrolled up to two decades after they experience their last menstrual period. Only 10% of the women started on MHT were younger than 55. We now understand, for these older women, the risks of MHT outweigh the benefits.

The evidence now stands that MHT should be started as young as possible, as soon as symptoms start if necessary, and no later than one decade after a woman’s final period.

For these young women, the benefits of MHT far outweigh the risk.

“This idea that there was a window of safety for starting MHT—meaning starting hormones closer to the final menstrual period is different risk-wise from starting later—was born and is now supported by an increasing amount of data.”

Jen Gunter

In July 2017, the North American Menopause Society (NAMS) released a position statement that came about after society members reviewed decades of data amassed from millions of women to see the effect of MRT when started at the appropriate age. The extraordinary list of women’s health issues explored included:

• heart disease and diabetes
• breast, endometrial, lung, colon and ovarian cancers
• osteoporosis and fracture prevention
• mood and cognition
• hot flashes
• quality-of-life
• liver and gallbladder
• musculoskeletal and joints
• special senses (skin, eyes, ears)
• and, vaginal dryness.

NAMS concluded that the benefits of MHT outweigh the risks for healthy women with menopausal symptoms.

“The evidence suggests that, for menopausal women aged younger than 60 years or within 10 years of menopause onset, without contraindications, systemic hormone therapy benefits outweigh risks for relief of menopause hot flashes and sleep disturbances and for prevention of bone loss for those at elevated risk.

“We’ve now learned there is a critical window for starting HRT and it should not be started years after the menopause is complete — this is when the risks start to outweigh the benefits.”

In other words, timing is everything!

No ‘one-size-fits-all’ approach to MHT

Decisions about the type, dose, formulation, route of administration, and duration of use of MHT should be based on the unique health risks of each woman, her age or time from menopause, and her goals for therapy.

Various additional risks and benefits must be weighed up for each woman, for example,

• a history of breast cancer
• gene mutations predisposing them to breast cancer
• early menopause or surgical menopause
• cardiovascular disease risk,
• symptoms.

There are also plenty of complexities around the combinations of hormones (oestrogen and/or progesterone and/or testosterone), and how you deliver the treatment (pill, gel, patch, vaginal pessary, lozenge, and so on).

Such considerations are well outside the scope of this blog. But as the saying goes, please consult a good women’s health doctor.

Here in Australia, the Jean Hailes Foundation is my go-to resource for up-to-date, evidence-based (not fear-based), simple information. They state,

I and many others hope the most recent information will allow conversations between women and their health care providers about initiating, continuing, changing or stopping MHT to be evidence-based, and not fear-based.

Weighing up the risks and benefits of MHT

A generation of women has missed out on MHT because of fear of developing breast cancer, blood clots, or heart disease. Of course, no therapy is without risk, but for perspective, let’s put your risk of developing breast cancer into context. According to Jean Hailes,

• if you ARE taking MHT, you have a 4 in 1000 chance of breast cancer, within a given year.
• if you are NOT taking MHT, you have a 3 in 1000 chance of breast cancer, within a given year.

The amounts to an absolute increased risk of one woman per 1000, within a given year.

And for perspective, the following factors have been identified to put you at a higher risk of developing breast cancer than taking MHT:

• Having more than two standard alcoholic drinks per day
• Being overweight or obese
• Having your first child over the age of 35
• Going into menopause at a later age

I’m not here to minimise the horror of breast cancer. But you might also find it comforting to know we’re getting very good at detecting and treating breast cancer if it does occur. And here in Australia, over 90% of women diagnosed with breast cancer are alive five years later (and if the cancer is limited to the breast, 96% will be alive five years after diagnosis).

The risk of having a heart attack related to the use of hormone therapy appears to depend on your age. There is no increased risk of heart attacks related to hormone therapy in women who:

• Start taking MHT less than 10 years after their last period, or
• Started taking MHT when they were 50 to 59 years.

What about the benefits of HRT?

• Hot flashes. MRT is, hands down, the best evidence-based treatment. And if hot flashes generate other symptoms, all the better.  
• Insomnia. If your sleep disturbances are due to night sweats and/or hot flashes, MRT improves sleep.
• Mood disorders. If anxiety and depression are tied up with disrupted sleep patterns due to hot flashes, then HRT is likely to help. If anxiety or depression are the dominant symptoms without hot flashes, then doctors typically suggest a range of treatments. These include talking therapy, anti-depressants, exercise, diet and social connection.
• Brain Fog. Once again, if hot flashes wake you up at night, then brain fog may clear with MRT. Some trials of MRT and verbal memory show a benefit, others show no benefit. However, it is very clear HRT does not cause dementia or AD.

YOUR BRAIN ON MENOPAUSE: In this seven-part series, I explore menopause from a brain health perspective with a particular focus on the neurobiology of hot flashes, sleep, mood and memory, the role of hormone therapies and their long-term effects on the brain. This is Part 6.

---

This is a long and detailed read. Click here to download the series as a PDF to read offline.

---