HRT: The full story

Hot flashes, irritability, mood swings, night sweats, depression, low libido, insomnia, fatigue, brain fog, vaginal dryness . . . most women of any age know what those symptoms add up to: menopause. The Change of Life. But very few probably know what weight gain, nausea, headaches, bloating, joint pain, brain fog, fatigue, mood swings, digestive issues and tender breasts indicate. These are all common side effects of taking hormone replacement therapy (HRT).

Of course, the possible repercussions of HRT don’t stop there. For women taking HRT to mitigate menopause and perimenopause symptoms, over the years studies have shown an increased risk of breast, ovarian and uterine cancers; blood clots and stroke; pulmonary embolisms; and cardiovascular disease.

HRT has had an enormously checkered history. It all started in 1941 when the American pharmaceutical company Wyeth Ayerst (then known as Canadian firm Ayerst, McKenna & Harrison) came out with Premarin, an estrogen product made from pregnant mares’ urine specifically designed to treat hot flashes. It was approved by the US Food and Drug Administration and quickly turned out to be a highly successful product.

As research identified links between menopause, osteoporosis and heart disease in the 1960s, the potentials and popularity of the drug expanded. Told that HRT would prevent these conditions, doctors wrote ever more prescriptions for female patients “of a certain age”—patients who quickly came to see estrogen as the magic bullet that would protect them from a wide variety of late-life “female problems.”

Then came Brooklyn gynecologist Robert A. Wilson with his 1968 book Feminine Forever. In the book, he convincingly wrote about how estrogen therapy (sometimes referred to as ERT or MHT for menopause hormone therapy) would allow women to stay feminine for the rest of their lives and not have to endure the “living decay” of post-menopausal life. “HRT can cure menopause,” the book proclaimed. Unsurprisingly, Feminine Forever rapidly became a best-seller, and the number of women asking their doctors to prescribe Premarin shot through the roof.

Red flags rise

There was very little oversight and few clinical studies were conducted until the early 1970s, when it became all too apparent that the steady use of estrogen, in moderate to high doses and without accompanying progestin, was triggering something called endometrial hyperplasia—an abnormal increase in the size of the uterine lining accompanied by irregular bleeding.1

By the mid-1970s, studies had linked estrogen replacement therapy (ERT) to endometrial cancer, with women on ERT experiencing anywhere from 4.5 to 8 times the risk compared to women not on the therapy.2

Despite other red flags, it wasn’t until 1993 that the Women’s Health Initiative, sponsored by the US National Institutes of Health’s National Heart, Lung, and Blood Institute (NHLBI), designed a study called the Heart and Estrogen/Progestin Replacement Study (HERS). The researchers planned to follow 27,347 US women ages 50–79 for 8.5 years, testing the effects and possible preventative benefits of taking HRT.

Half of the women with an intact uterus received estrogen (conjugated equine estrogen, CEE) under the brand name Premarin plus progestin (medroxyprogesterone acetate) under the brand name Provera, which had to be added to protect against endometrial cancer. The other half received a placebo. Women without a uterus in the trial received either a placebo or CEE alone.

The estrogen-plus-progestin portion of the study was stopped early because of a higher rate of invasive breast cancer in the estrogen (Premarin) plus progestin (Provera) group that exceeded the bounds of any possible benefit. There was also an increase in coronary heart disease (CHD), stroke, and pulmonary embolism (PE).3 Women taking estrogen plus progestin experienced a 12 percent greater increase in major illnesses and death than the placebo group.

The estrogen-only portion of the study continued. The final results spanning a 13-year period showed that women in their 50s taking estrogen alone experienced a 16 percent reduced risk of overall illness and death as compared to the placebo group. However, women in their 70s experienced the exact opposite effect: a 17 percent increased risk of overall illness and death.4 Neither approach—estrogen only or combined estrogen and progestin—was found to affect all-cause mortality.5

Women and doctors around the world were shocked and dismayed by the findings. Basically, the Women’s Health Initiative study slammed the door on the whole idea that HRT could be prescribed as a perimenopausal or postmenopausal prevention program for heart disease or anything else.

Two years later, a follow-up study (HERS II) also found no reduced risk of CHD in postmenopausal women. Instead, it highlighted the increased chance of CHD in the first year of HRT use and the lessened degree of risk in years three to five, but found the reduction did not persist after HRT was stopped. The HERS II study ultimately concluded that HRT was not effective in protecting postmenopausal women from heart disease and should not be prescribed for this purpose.6

In 2003, the Million Women study verified that HRT, particularly estrogen-progestin combinations, was associated with an increased risk of breast cancer and of dying from breast cancer.7

In 2010 the results of the initial Women’s Health Initiative findings were again confirmed in another follow-up study that flat-out stated that the use of combined estrogen-progestin therapy more than doubled the risk of heart disease in healthy postmenopausal women in the first two years.8

Then the counter-studies, mostly funded by the pharmaceutical companies, started showing up. For example, a study published in the prestigious medical journal The Lancet announced that estrogen-only HRT was indeed effective for reducing the risk of breast cancer by as much as 23 percent for women who had taken the therapy for anywhere from five to nine years.9

Although in 2012 clinical trials showed that estrogen, both by itself and with a progestogen, increased the possibility of stroke,10 in 2017, an 18-year follow-up study was conducted with the women who had been enrolled in the trials between 1993 and 1998. The published report stated that there was no increased overall risk of all-cause deaths or deaths from cancer or heart disease in women who had used menopausal hormone therapy for five to seven years.11

In 2019, the Collaborative Group on Hormonal Factors in Breast Cancer countered the 2017 “no worries” claim by collecting worldwide evidence showing that menopausal hormone therapy of all types except vaginally applied estrogen-only therapy was associated with “a significant excess incidence of breast cancer,” and that overall women who had used MHT had a higher risk of breast cancer than women who had never touched the therapy.12 

A $600 billion business opportunity

In 2020, a venture capital firm identified the menopause industry as capable of harvesting an average $2,000 per year for medical visits, prescriptions and various other products designed to mitigate menopause symptoms from each and every one of the over one billion women who will officially be in perimenopause and menopause by 2025.13

Despite the dubious and just plain dangerous use of HRT to prevent such things as breast cancer and heart disease in menopausal women, doctors and researchers continued to hope that HRT would finally prove capable of definitively preventing something. And that something, they believed, turned out to be Alzheimer’s disease (AD).

As early as 1998, studies had begun to suggest that estrogen therapy could reduce the generation of what was called Alzheimer β-amyloid peptides in the neurons of the brain that aggregate, creating amyloid plaques.14 Amyloid plaques are neurofibrillary tangles—the abnormal aggregation of a protein inside neurons in the brain—believed to be a primary cause of AD.

By 2002, the buildup of evidence showing that HRT enhanced cognition in women suffering from Alzheimer’s as well as preventative abilities created quite a stir, stimulating further research.15 The effectiveness of estrogen therapy to alleviate the symptoms of menopause plus the fact that the majority of AD sufferers are women stimulated the theory that Alzheimer’s disease itself was caused by reduced estrogen in the brain during perimenopause and menopause.

According to the Alzheimer’s Association, AD remains the fifth-leading cause of death among people aged 65 and above, and almost two-thirds of Americans in that age group with AD are women (12 percent of women and 9 percent of men).16

With this new and potentially lucrative preventative avenue for HRT, pharmaceutical companies funded more and more studies on HRT for AD . . . with mixed results. For example, a four-year study completed in 2016 of women using synthetic estrogen (CEE) or estradiol and an intermittent regimen of progesterone to prevent AD showed that while the CEE regimen increased the capacity of ventricles in the brains of younger menopausal women, it did nothing to improve cognitive function (ventricles produce, transport and remove cerebrospinal fluid).17 This as opposed to a study completed in 2019 claiming that estrogen plays “a significant role” in cognitive function.18

Because of the conflicting evidence and continued negative overall results of HRT studies, for decades doctors have been reluctant to prescribe any sort of hormone replacement therapy. However, a perfect storm of social factors—such as millions of women suffering from menopausal symptoms, fear of AD, profitability, a shortage of HRT in the UK and documentaries like Davina McCall’s 2021 Sex, Mind and the Menopause—is currently driving an enormous public push from women to make HRT more available.

Within six months after McCall’s highly publicized film was released, the global pharmaceutical company Theramax reported a 130 percent increase in demand for HRT products. Unfortunately, what is not made clear in the vast majority of mainstream media covering the film, the topic of HRT and the hugely increased public demand for HRT is the dismissal of known risks of exogenous hormones or any distinction in risk between the two different types of hormone replacement therapy available to women: synthetic hormone replacements such as CEE, and bioidentical hormone replacement therapies (BHRT) made from plants. The latter supposedly have an identical molecular structure to the hormones that women produce in their own bodies.

Synthetic vs. Bioidentical Hormones

Natural sex hormones are made by the gonads (the reproductive glands, ovaries and testicles) as well as by other sex steroids found in tissues such as the liver or fat. Synthetic hormones are made in the laboratory from chemicals structurally similar to endogenous hormones but not identical. Natural hormones work over short periods of time because they are produced in the body at specific times for specific reasons. Synthetic hormones linger in the body because they are artificially introduced rather than endogenously produced and thus have no appropriate “time sense.”

Bioidentical hormones are FDA approved and many pharmaceutical companies make them. They are standardized to ensure they deliver just the right dosage of the hormone needed. Bioidentical hormones made from plant sources have some distinct, sometimes even opposite effects compared to other synthetics because they have different chemical structures.1

One of the major differences of BHRT is that, depending on the individual’s unique biochemistry and sometimes rapidly changing hormonal needs, compounding pharmacies can make specialized bioidentical hormone preparations on the order of licensed practitioners. So, if a patient needs more estriol to balance estradiol or more progesterone or more or less testosterone, prescriptions can be “custom made” for a more finely tuned hormone therapy regime. However, harm from compounding has occurred. The lack of standardization and quality control has led to occasional overdosing or underdosing, and contaminants can find their way into the final products.2

Another risk specific to custom-compounding bioidenticals is the possibility of estrogen-progesterone imbalance resulting in endometrial cancer.3 Because these preparations are individual, they cannot be and are not required to be approved by the FDA.

Bioidentical alternatives

“Using synthetic hormones like Premarin are only acceptable if you’re a pregnant horse,” states Sharon Stills, NMD, a specialist in perimenopausal and menopausal health with a large practice in Scottsdale, Arizona. “For women, synthetic hormones are a huge detriment to health. It’s going to drive uterine cancer and breast cancer and God knows what other kinds of cancers. It’s going to mess with your neurotransmitters triggering emotional issues, depression, anxiety and weight gain. Frankly, I tell any woman that if they only had a choice between nothing or synthetic, I would advise nothing. Synthetics are just plain dangerous.”

According to Stills, two major issues with synthetic hormones are the molecular shape of the hormones themselves and the lack of dosage flexibility and subtlety. Synthetic hormones are not the same shape as endogenous ones, and the human estrogen receptors formed by specific proteins inside a woman’s reproductive organ and breast cells (and in liver, brain, bone, colon and even skin tissues) can’t adequately receive them.

“When you get the synthetic hormone the body does not recognize it. Basically, it’s like it’s blocking what the body needs. And because you’re not getting the balancing and protective benefits you’re more apt to have mental changes—definitely mood swings—dementia and higher cholesterol levels. I’ve seen women on synthetics come in with breast tenderness, headaches, and digestive issues. They’re bleeding even though they’re postmenopausal and at the same time they’re experiencing things like teenage acne. They’re just totally out of balance.”

Bioidentical hormones, asserts Stills, have been deliberately manipulated in the laboratory to pair with human hormone receptors, meaning the body absorbs them more quickly and fully than traditional synthetic hormones like Premarin (lab-manipulated horse urine) and Provera (a synthetic derivative of progesterone).

Stills espouses the view of many in integrative medicine: that bioidentical hormones are the far safer alternative. Because they are considered a better “fit” for hormone receptors in the human body, bioidenticals are commonly referred to as “natural,” and the word bioidentical itself leads many people to believe they are the same as human hormones. But they are not.

Yams, sisal root and soybeans do not produce human hormones. Wild yams, for example, produce something called diosgenin, a plant steroid similar to estrogen that scientists tinker with in the lab until they get the molecular parameters just right. Which means bioidenticals are every bit as “synthetic” as traditional HRT.

Some clinical studies suggest that bioidentical hormones offer a lower risk of breast cancer and cardiovascular disease and are actually more effective than their synthetic counterparts.19 Studies indicate that in rats, stimulating estrogen receptor β can reduce amyloid-β deposits typical of AD without the use of a strong synthetic hormone like estradiol.20 And proponents say that BHRT can do exactly that using estriol, a weaker estrogen that binds more tightly to estrogen receptor β than to receptor α. Unlike synthetic HRT, it can also be used by women with breast cancer with no worries about exacerbating the cancer, improving their quality of life, proponents say.21

But while this early research suggests that the use of bioidentical hormones is associated with lower risks than synthetic hormone therapy, “lower risk” does not mean no risk.19 Because BHRT is a relative newcomer on the menopause treatment scene, no long-term studies have been done to determine whether long-term use of bioidenticals is any less harmful than long-term use of regular HRT.

In fact, worrying studies are beginning to emerge showing that taking bioidenticals long-term also exposes women to the risk of cancer and more. Despite so much tinkering with types and amounts of synthetic hormones, it’s well known that taking extra estrogen, whether as a synthetic or bioidentical hormone, increases the risk of endometrial cancer. It’s always been assumed that adding a progesterone or progestogen will counteract that risk.

But with bioidentical hormones, there is the issue of whether women are receiving the right dosage of progesterone to adequately protect themselves—or too high a dose. Some studies demonstrate that the amount of bioidentical progesterone delivered in patches or cream can’t really be properly assessed since only about 10 percent of a topical dose can be detected in blood serum. However, the amount recorded in capillary blood vessels is some 100-fold greater.22

This suggests, claims a French review of available studies, “that tissue exposure might be greater than currently admitted, possibly through lymphatic delivery.”23 And if it is too much, that lays a woman open to all the risks of too much progesterone, including breast cancer.

As for its other cancer-protective effects, at least two studies claim there is no evidence that topical progesterone provides endometrial protection.24

Many doctors like to create their own compounds with a local pharmacy and are extremely experienced at creating customized hormone levels for individual patients. However, custom compounding does not undergo quality control, and there have been cases of contamination in the lab causing fatalities, albeit rarely.

But perhaps the greatest issue is whether a woman is receiving the right dosage—not too little and not too much. Too much estrogen and too little progesterone, and a woman faces the possibility of venous thromboembolism and endometrial cancer.

Some studies have shown a higher rate of endometrial cancer with custom-compounded bioidentical estrogen, as well as an increased rate of vaginal bleeding.23

Too much progesterone, and the woman faces breast cancer risk.

Doctors and scientists have assumed that the risk of endometrial cancer is lowered when women are given progestogens, sequentially or at the same time. Although most studies of conventional HRT do show some endometrial protection when progestogen is added, because progestogens increase the risk of breast cancer, a review of all available studies in 2005 showed an overall increased risk of cancer in women taking the two hormones together.25

In fact, a 2017 study concluded that women using bioidentical hormones (including vaginal progesterone) for up to five years face little risk of breast cancer, but thereafter that risk increases with oral progesterone.26 Use after six years or more is associated with a “slight but significant increase in breast cancer risk.”

As the researchers warned, “Counseling on combined MHT should cover breast cancer risk—regardless of the progestogen chosen.”

BHRT can come with other troublesome side effects, especially during periods when bioidenticals are being adjusted to maintain optimum hormone levels—which is frequently.

The most common side effects with compounded BHRT are weight gain and bloating, breast tenderness.27 Other side effects include fatigue, headache, cramps, spotting and an increased production of facial hair, although nearly all of these are more severe with traditional HRT.

Bottom line, hormone replacement therapy is a tricky business. Not only do hormone levels constantly fluctuate in a woman’s body, necessitating constant monitoring, but there are genetic differences in how each individual processes hormones.

Although many researchers attacking BIH therapy are conventional doctors, some with ties to drug companies, a great deal of fear and ignorance remains about what menopause is and how to approach it.

The greatest question of all has to do with our feelings about women’s aging. Once reproductive potential is finished, should women just be gently downshifting to new hormone levels, with some safe assistance from tried and tested alternatives? Or should they be experimenting with powerful hormones the body no longer produces itself without the full understanding of their effects in the long term?

Because at the end of the day, that’s what hormone replacement of every variety is: one giant experiment.

Natural Alternatives to Hormone Replacement Therapy

If you decide to eschew hormone therapy of any variety, Dr Sharon Stills’ go-tos are maca root (aka Peruvian ginseng, though it’s not in the ginseng family), dong quai (aka Angelica sinensis or female ginseng) and Leonurus (aka Leonurus japonicus, used in Chinese herbal medicine). 

“If you don’t have enough estrogen and your estrogen levels are taking a roller coaster ride, one sign will be heart palpitations. During perimenopause, for imbalanced estrogen levels, Leonurus is great for that. Estrogen also produces serotonin, so if someone’s depressed and needs support, you want to think about 5-HTP, a supplement made from the seeds of the plant Griffonia simplicifolia,” she says.

Diet

Depending on what kind of hormone supplementation you need, consider designing your diet around different hormone-promoting foods.

To promote estrogen eat foods that contain phytoestrogens like legumes, pinto beans, alfalfa, chickpeas and red clover; isoflavone-rich foods like soybeans and other soy products; and lignan-rich foods like cruciferous vegetables (particularly broccoli), fruits (bananas, kiwi, grapes) and white potatoes.

To promote progesterone go for fish like salmon and mackerel, poultry (chicken and turkey), foods high in vitamin B6, avocados, cruciferous veggies and citrus fruits.

To promote testosterone eat magnesium-rich foods like spinach and kale, pumpkin seeds, and black beans. Don’t skimp on egg yolks or oysters, and definitely include strawberries and raw cacao.

Exercise

Get plenty of aerobic exercise several times a week along with strength training.

Relaxation

Ditch the caffeine and alcohol and try meditation, puzzles, crosswords—any pastime you enjoy that gives you the opportunity to relax. 

Alzheimer’s: What No One Is Considering

With all the focus on the theory that estrogen deficiency is the culprit behind the prevalence of AD in women, and with the drug industry chomping at the bit to profitably promote synthetic HRT as a preventative, no one seems to be looking at other causative factors behind AD’s sex bias.

Many lifestyle differences between women and men could account for the predominance of women with AD, such as the use of antidepressants (SSRIs like Prozac). Far more women use and are prescribed them than men,1 and the use of antidepressants has been linked to the development of dementias, including AD.2

For almost 70 years, the diet soda and artificial sweeteners market has directly targeted women, far and away their main consumers. Ingestion of these substances has been linked to a higher incidence of stroke and dementia, including AD.3

Women who carry the novel MGMT gene, which in addition to the APOE ε4 gene has been linked to the onset of AD, are more highly susceptible to the disease than men who carry the same gene.4 

Interestingly enough, exposure to cadmium, a natural element, triggers the APOE ε4 gene in mice,5 increasing the risk of developing and dying of AD.6 And what products containing cadmium are almost exclusively purchased and used by women? Lipstick and makeup.

These other factors should be explored before blaming high rates of AD among women exclusively on declining levels of estrogen after menopause.

Main article

Synthetic vs. Bioidentical Hormones

Alzheimer’s: What No One Is Considering

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