Hormone Replacement Therapy side effects: is HRT worth the risk?

What are the hormone replacement therapy side effects?

Samantha Jones: poster child for bioidentical hormones in the Sex and the City 2 movie.

Menopause is a normal physical process. Yet many in the medical community believe it should be medicalised and treated with hormone supplementation to ameliorate its undesirable symptoms.

Unfortunately the consequences of long-term hormone therapy (HRT) are still not well understood. Research indicates it increases the risk of heart attack, stroke, blood clots, breast cancer and dementia, while alleviating symptoms including hot flushes, low libido, vaginal dryness and insomnia.

I have weighed up the benefits and the risks of HRT, as well as investigated the alternatives to pharmaceutical treatment for improving both the health and quality of life for women undergoing and following menopause. 

What’s in HRT?

The hormones typically supplemented by HRT are oestrogen and progesterone.

Oestrogens are steroid hormones secreted by ovarian follicles and the adrenal glands. The hormone we mean when we speak of “oestrogen” is generally oestradiol (E2) – the one which causes the majority of biologic effects.

Oestrogens are responsible for the development and maintenance of female reproductive characteristics such as breasts, the uterine lining and the menstrual cycle, as well as regulating fluid balance, increasing osteoblastic activity and decreasing calcium loss from bones, and lowering blood cholesterol among other functions.  The reduction of oestrogen secretion typical to menopause can result in vaginal dryness, hot flashes and night sweats, vulvovaginal atrophy and cognitive decline.

Progesterone, which is secreted by the corpus luteum, prepares the uterus for the fertilised egg and maintains pregnancy, as well as supporting bone density and the building of bone tissue. But perhaps its main function in the body is to balance and even oppose the effects of oestrogen.

Whereas oestrogen stimulates growth of the uterine lining, progesterone maintains it. Oestrogen increases body fat, progesterone helps burn it. More importantly, oestrogen unopposed by progesterone is associated with a greatly-increased risk of developing endometrial cancer.

How the body changes during menopause

Menopause is the condition when a woman has not menstruated for 12 months, and is at the end of a her reproductive phase, usually between the ages of 45 and 55. The average age of menopause in western countries is 50-52 years.

As the number of active follicles declines, this results in a drop in the amounts of oestrogen and progesterone produced. A post-menopausal woman produces between 40% to 50% of the oestrogen she did before menopause, and almost no progesterone. As sex hormones are no longer required for reproduction, this oestrogen is designed to be just enough to nourish body tissues.

One of the important roles of oestrogen is to stimulate both osteoblast activity and synthesis of bone extracellular matrix. A hypo-oestrogenic state such as menopause leads to loss of bone density via activating the bone remodelling units with an excess of bone resorption relative to formation, causing women to lose 50% of their skeleton by the age of 70 years. The exact biochemical mechanisms are not fully understood, but it is believed that oestrogen deficiency makes osteoclasts more sensitive to parathyroid hormone – which increases osteoclast activity in order to increase blood calcium levels. The ovarian steroid hormones play an essential role in skeletal homeostasis and are as critical to bone health as calcium.

Not all women suffer from undesirable symptoms of menopause such as an increased chance of osteoporosis, vasomotor symptoms of hot flushes and night sweats, vaginal atrophy, diminished libido and insomnia, although symptoms affect around 75% of Australian women.

What is Hormonal Replacement Therapy (HRT)?

Conventional medical practice views menopause as “a condition of oestrogen deficiency” which is treated with hormonal supplementation. Since the 1930s, doctors have recommended HRT to counter menopausal symptoms such as hot flashes, insomnia and vaginal dryness, and until recently to help prevent osteoporosis and possibly reduce the risk of heart attacks, strokes and dementia.

HRT consists of either synthetic oestrogen (conjugated from horse’s urine) and progestin (a synthetic hormone designed to mimic the effect of progesterone), or oestrogen alone. Oestrogen combined with progestin is more typically prescribed to women with an intact uterus, due to “unequivocal evidence” demonstrating an increased risk of developing endometrial cancer with oestrogen-only treatment.

Progestin, like progesterone, balances the unwanted effects of oestrogen.

Observational studies report that a majority (65%-75%) of women cease HRT after two years once symptoms have abated, although many women were until recently long-term users in the hope it would reduce the risk of heart disease and osteoporosis.

In 2001, there were over three million prescriptions issued for the “opposed” HRT regimen of oestrogen and progestin among concession card holders in Australia. This fell 40% to 1,854,060 prescriptions in 2003.

Benefits of HRT

There are definite benefits to using HRT to treat vasomotor symptoms, the most common complaint in postmenopausal women. Treatment with either the Australian-approved opposed regimen or oestrogen-only are equally effective.

The National Health and Medical Research Council of Australia (NHMRC) literature review found HRT “appears to have a beneficial effect” on urogenital symptoms (vaginal atrophy and dryness) and sexual dysfunction associated with menopause, while the Women’s Health Initiative study concluded HRT was associated with a reduced risk of colorectal cancer.

Osteoporosis-related fracture prevention also appears to be a benefit. The NHMRC’s literature review found good evidence to suggest HRT offers a protective effect against fractures during use, taking into account research by the Women’s Health Initiative which concluded that oestrogen plus progestin “reduces the risk of fracture in healthy postmenopausal women”.

When it comes to benefits to the cardiovascular and central nervous systems, the evidence becomes less clear.  Many medical bodies still claim HRT has a beneficial effect on both. The NHMRC found however that on balance, the evidence suggests HRT does not provide protection against either cardiovascular disease or coronary artery disease.

Furthermore, they found that evidence from systematic reviews “fails to show a consistent benefit” of HRT upon cognition/dementia.

Risks associated with HRT, or hormone replacement therapy side effects

The 40% drop in HRT prescriptions among concession card holders in Australia from 3,070,299 in 2001 to 1,854,060 prescriptions in 2003 was due to the 2002 release of the most comprehensive medical research into the risks and benefits of HRT.

The double-blind, placebo-controlled study conducted by the Women’s Health Initiative, under the auspices of the US National Institutes of Health, followed 16,608 postmenopausal women to gauge the effects of animal-derived oestrogen and synthetic progestin on their health. This large-scale study was scheduled to continue into 2005 but was cancelled prematurely when investigators reported that the overall risks of oestrogen plus progestin “outweighed the benefits”.

Women taking part in the study were found to have significantly increased risks of breast cancer, heart attacks, blood clots and strokes, and a director of the study, Dr Jacques Rossouw, said the increased breast cancer risk “exceeded the predefined boundary for safety”.

Breast cancer
Subsequently to the release of the WHI findings, another study — the UK ‘Million Women Study’ — also showed an increased risk of breast cancer in HRT users. The NHMRC’s literature review confirms an increased risk of breast cancer with hormone therapy, although there was no apparent increased risk to women exposed to shorter durations of HRT use.

In 2003 the New England Journal of Medicine found the risk of breast cancer drops close to normal within a year of ending HRT, whereas the NHMRC states “it is not possible to precisely determine the duration of therapy after which risk is elevated, but greater than 2–5 years appears to be associated with significantly increased risk”.

A study published in the Medical Journal of Australia in 2008 found that the substantial reduction in HRT prescriptions in Australia after the release of the WHI findings “was accompanied by a statistically significant fall in breast cancer incidence” in women at or above 50 years, leading to the conclusion that the cessation of HRT had a positive affect on breast cancer rates. In 2009 the New England Journal of Medicine also reported a “marked decline” in breast cancer risk after discontinuing HRT.

A defence of HRT published in 2009 in the Medical Journal of Australia concedes “the short interval between stopping HRT and an alteration in the number of cancers being reported suggests that hormones were promoters, not initiators, of breast cancer”. But wouldn’t even the promotion of breast cancer be undesirable?

A follow-up WHI study in October 2010 concluded that “breast cancer mortality also appears to be increased” in subjects using HRT.

Stroke, heart attack, blood clots
Evidence from the NHMRC’s systematic review and the WHI study indicates a “substantial” increased risk of stroke with HRT. Even supporters of hormone therapy within the medical community agree there is a “statistically significant increase” in stroke, venous thromboembolism and myocardial infarction.

Further analysis published five years after the first WHI findings concluded that women who began hormone therapy closer to menopause had a reduced risk of cardiovascular disease compared to those who initiated therapy later, but the risk of stroke “was elevated regardless of years since menopause”.

Dementia
In 2003, findings from the NIH study indicated that women taking hormone therapy for an average of more than four years had twice the risk of dementia, including Alzheimer’s disease.

Reactions

In the USA, lawsuits were filed against Wyeth Pharmaceuticals, manufacturer of the most popular HRT drug, Prempro, who began recommending that hormone therapy be used only to treat undesirable symptoms of menopause at the lowest dose for the shortest duration. In February 2011 Wyeth’s new owner, Pfizer, agreed to pay about $330 million to settle more than 2,200 lawsuits in the first large-scale settlements in eight years of litigation.

The NSW Cancer Council’s present position on HRT is that it should only be used to treat menopausal symptoms, and only for up to two years, due to the increased risk of stroke, heart disease, blood clots and breast cancer.

Oestrogen-only therapy, without the addition of progestin, also shows risks. The WHI’s oestrogen-only study by the WHI was halted in February 2004 when researchers concluded that oestrogen alone increased the risk of stroke and blood clots.

Although no increased risk of breast cancer was evident, one observational study following 44,241 women for 20 years concluded that women following oestrogen-only therapy were twice as likely to develop ovarian cancer.

The Women’s Health Initiative study furthermore found an increased risk of stroke and blood clots with oestrogen-only therapy, as well as the risk of gallbladder disease.

Yet there are still doctors in Australia championing oestrogen-only therapy for postmenopausal women when begun within five years of menopause, saying that it “results in far greater benefits than adverse outcomes“.

Current medical protocol

The Australian medical community no longer recommends HRT for cardioprotection or dementia but many still recommend it to reduce bone fracture risk and to alleviate vasomotor symptoms.

Medical bodies also continue to recommend HRT on the basis that some of the risks (e.g.: myocardial infarction) are decreased for women initiating treatment at the time of menopause – that this represents a “window of opportunity” for the safe use of hormone therapy to relieve menopausal symptoms. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists reviewed the research on HRT and their findings, published in 2004, concluded the short-term benefits “are likely to outweigh the risks for otherwise healthy women with moderate to severe menopause symptoms” .

Use of HRT for the sole purpose of preventing osteoporosis-related fractures is generally not recommended “as a first-line option” these days, due to the increased risk of cardiovascular complications in women over 60.

Many practitioners still consider HRT the most effective therapy to reduce the “distressing” symptoms of menopause and restore a women’s wellbeing and sexual enjoyment. Women are encouraged to use HRT for short periods, in lower doses, and even to discontinue it throughout treatment to assess its ongoing need.

Critics of the WHI study point out that two-thirds of participants were over 60 years old at recruitment, that 69% were overweight or obese, 50% were current smokers and 36% were being treated for hypertension. “It is now generally accepted”, states one editorial, “that these problems primarily arose due to an older generation of women being given a relative overdose of HRT”.

While it is probably correct that this age group is not typical of women seeking hormonal therapy, the other factors are likely a fair representation of the US population at the time of recruitment.

Alternatives to HRT

‘Natural’ or bioidentical hormones have received a lot of interest since concerns over the adverse effects of synthetic hormones led to demand for other options. They are molecular duplicates of oestradiol and progesterone synthesised in laboratories, often derived from yams and/or soy.

In theory the body recognises them as their own and can readily use them, which is probably why women tend to tolerate them better than the synthetic ones – although none of the claims made have yet been clinically proven.

Although marketed as a “natural” alternative to HRT, they are heavily refined in order to isolate the active ingredients. Binders, additives and further processing transforms them into pills or creams. As highly manipulated products they lack “nature’s balancing touch” to regulate their effects on the human body.

The data we have on bioidentical hormones is only anecdotal, because they can’t be patented and therefore no drug companies will foot the prohibitive expense required to run studies. Therefore we can’t be certain they don’t increase the same health risks observed with HRT, and it’s not apparent they offer any advantage over HRT for menopausal symptom relief.

Some medical practitioners are also concerned over their consistency and safety, because these compounded products aren’t subject to the same level of regulation as pharmaceuticals. Australasian doctors heard at a menopause congress in 2009 that patients could present high levels of plasma testosterone after consuming compounded bioidentical hormones and concern was expressed that they often contain DHEA and melatonin, which are banned substances in Australia.

Drugless approaches to HRT

Preventative health strategies such as stress management, lifestyle changes (including yoga!), appropriate diet and supplementation of vitamin D3 and calcium may well be the best approach to the relief of menopausal symptoms.

Chronic stress compromises the body’s ability to manufacture sex hormones such as oestrogen, because the body prioritises stress response over reproductive function. Therefore progesterone is diverted to create cortisol rather than oestrogen. In this way, managing one’s stress response has a positive effect on hormonal balance, which helps prevent oestrogen deficiency and alleviate menopausal symptoms. Furthermore, a decrease in cortisol production has a positive effect on bone tissue deposition.

Between 25% and 30% of postmenopausal women are estimated to have osteoporosis and maintaining bone density is one of the most critical concerns for menopausal women as oestrogen levels drop. While HRT does appear to slow osteoporosis, it neither prevents nor reverses it so it’s helpful to consider preventative strategies for maintaining bone density.

Adequate intake of calcium and vitamin D3 is recommended, via supplementation if necessary, as is weight-bearing exercise (yoga!) which exerts a “statistically significant” effect on bone density. Exercise also improves muscle tone, thus reducing the likelihood of falls, and improves both circulation and quality of life.

A diet high in calcium-rich foods such as leafy vegetables and some phytoestrogens is also recommended, as studies suggest high soy consumption may inhibit bone resorption and stimulate bone formation. Good-quality soy consumption may also explain why Australian women reported experiencing significantly more vasomotor menopausal symptoms than Japanese women in one study.

Reduced consumption of meat and of refined carbohydrates may also benefit, with several studies indicating low-acid/vegetarian diets are associated with a lower risk of osteoporosis. Reduced consumption of alcohol and coffee are also important, and ceasing smoking is strongly advised; these are all known to accelerate bone loss because they create a negative blood calcium balance.

Maintaining an ideal weight also benefits bone health and has a positive effect on  preventing cardiovascular disease, which accounts for about 40% of female deaths after the age of 50.

Although it was thought for many years that the menopausal drop in oestrogen accounted for many of these cases, the WHI study indicated women who took an oestrogen-progestin supplement actually had a 26 percent higher risk of heart disease. Gentle exercise such as walking and frequent naps help protect against heart attack, counter chronic stress and benefit bone health – minimising the need for HRT to treat menopausal symptoms.

Is HRT worth the risk?

Many conventional medical practitioners still consider HRT the “gold-standard treatment” for vasomotor symptoms and effective for bone density. Natural therapists instead ask: do the benefits outweigh the risks?

Synthetic hormone therapy, in the form of oestrogen plus progestin, appears to result in an increased risk of heart attack, stroke, blood clots, breast cancer and dementia. For many women, this price is too high for an easing of vasomotor symptoms, vulvovaginal atrophy and bone fracture prevention.

Many bodies such as the NSW Cancer Council recommend HRT should only be used to treat menopausal symptoms, and only for up to two years, due to the serious risks associated with it. If quality of life could be increased by other means, and given that osteoporosis won’t be prevented in only two years of hormone supplementation, it stands to reason that alternatives be considered.

Numerous studies suggest vasomotor symptoms are particularly responsive to acupuncture and herbal medicines. Mood symptoms, quality of life and sleep disturbance can also be treated with natural therapies as well as exercise, appropriate diet and lifestyle maintenance. Bone density can also be treated with preventative strategies such as diet and weight-bearing exercise.

A recent study of menopausal women below 55 years reported they believed they have greater control and feel “empowered” by complementary medicines and what their practitioners taught them about the changes in their body.

There is much to be said for a supportive and instructional treatment process – one taking into account a woman’s unique set of symptoms and helping reduce the emotional effects – rather than prescribing hormone therapy.

Menopause is not a pathological condition but a natural phase of life. It should be treated with intelligence, respect, and an emphasis on health.

Remember: Health and wellness topics on this website are for general information only. Please discuss your situation with your own healthcare professionals for advice tailored to you.