Is bioidentical hormone therapy safe?

“There are several different types of HRT available, and one type may be more suitable for you than another,” says Dr Newman. “You can choose from tablets, skin patches or gel in a variety of doses and combinations.”


How long is it safe to use HRT?

Dr Davison says there is “no correct time frame” for using HRT, as it depends on the woman’s individual circumstances and the hormone therapy involved. But for the majority of women, this will be a few years.

Dr Newman says women aged under 60 generally benefitted from using HRT. “We certainly know that under the age of 60, women on HRT, compared to women who do not take HRT, have both better morbidity and mortality outcomes; that is, they’re less likely to experience health problems,” says Dr Newman.

“Overall the scientific studies are positive regarding women with menopausal symptoms taking HRT. The same cannot be said for bioidentical hormones because they have not been widely or appropriately researched.”
Further information about menopause treatment options can be found here.

This is a Jean Hailes free health article which can be republished free of charge in your organisation’s website, blog, newsletter or magazine. There are some simple guidelines to follow when republishing Jean Hailes’ free health articles. Please read the guidelines before using the article in your organisation’s publications and learn more.

Read the guidelines
Download the article as a PDF
  • Share
  • Tweet
  • Email

Is Bio-Identical Hormone Therapy Safe?

Just what is bio-identical hormone therapy? Is it a “natural” and safe alternative to standard hormone replacement therapy for menopause symptoms — or is it a potentially risky menopause treatment?

Interest in bio-identical hormone therapy started to take off in 2002 when a large study called the Women’s Health Initiative (WHI) was halted after researchers discovered an increased risk of breast cancer, heart attack, stroke, and other problems in post-menopausal women taking hormone replacement therapy.

The hormone used in that trial was an FDA-approved combination of non-bio-identical estrogen and progesterone. Many women stopped taking hormone replacement therapy (HRT), and some went looking for alternatives.

Unlike conventional hormone therapy that uses synthetic hormones or animal-based hormones that are slightly different from a woman’s own hormones, bio-identical hormones are biochemically the same as those made by the ovaries during a woman’s reproductive years, explains Charla Blacker, MD, a reproductive endocrinologist at Henry Ford Hospital in Detroit.

“The three major hormones made by ovaries are estradiol, progesterone, and testosterone,” says Dr. Black. “There are others that can be included such as DHEA or pregnenolone; however, most physicians do not include them as part of a mixture to replace a woman’s reproductive hormones.”

Within the category of bio-identical hormones, there are two types: preparations pre-made and distributed by major pharmaceutical companies and those made up in a compounding pharmacy. Both kinds can be created in a number of forms, including pills, creams, patches, and gels as well as vaginal rings.

The Controversy Over Bio-Identical Hormone Therapy

While the individual ingredients likely used by compounding pharmacies are approved by the U.S. Food and Drug Administration (FDA), the actual finished product is not. Prescription pharmaceuticals (such as the conventional hormone preparations) are FDA-regulated and guaranteed to be the same strength each time; whereas, compounding pharmacy versions of bio-identical hormones can contain slightly different dosages from batch to batch.

Compounded bio-identical hormones are sometimes touted as “all natural” and safer than standard hormone replacement therapy. Some well-known celebrities swear by them, saying they feel decades younger. But according to the American Congress of Obstetricians and Gynecologists (ACOG), there have been no large long-term clinical trials that have studied their safety and effectiveness. ACOG believes that compounded bio-identical hormones should be considered to carry the same risks as FDA-approved drugs, such as those uncovered in the WHI study, and possibly even more.

Robert S. Wool, MD, an ob-gyn at Noble Hospital, Mercy Medical Center, and Baystate Medical Center and in private practice in Westfield and Springfield, Mass., has concerns as well. “In my honest opinion, I believe bio-identical hormones (filled at a compounding pharmacy) are a marketing ploy,” he says. “They are the same hormones, estrogen and progesterone, but are ‘custom made’ for each patient that requests them.”

The FDA Take on Bio-Identical Hormone Therapy

FDA makes the following points about compounded bio-identical hormone therapy:

  • Since compounded bio-identical hormones are not FDA-approved, the federal government does not put them through rigorous safety evaluations. While drug companies are required to include safety warnings on drug labels and report adverse side effects, compounding pharmacies are not required to do either.
  • Preparation methods can vary from one pharmacist to another and from one pharmacy to another, so women may not get consistent amounts of hormones. (However, the International Academy of Compounding Pharmacies says compounding pharmacies are regulated at the state level and there are national standards and guidelines for compounded drugs.)
  • Some compounded hormone preparations contain estriol, a very weak estrogen that is not FDA-approved for use in any drug.
  • A woman’s prescription is sometimes based on results of saliva hormone testing done at the compounding pharmacy. The FDA and other groups say the test should not be used to adjust hormone doses because hormone levels are unpredictable and can vary greatly, even in one day.
  • Despite some marketers’ claims, bio-identical hormones cannot cure Alzheimer’s disease, heart disease, or cancer.
  • The North American Menopause Society (NAMS) says that although custom-compounded hormones may relieve menopause symptoms, they should be used only by women who cannot tolerate FDA-approved drugs.

The Pros and Cons of HRT

More research needs to be done on the benefits and risks of bio-identical hormones as compared to traditional hormone therapy. However, here is what is known at this point in time.

“An increasing number of studies indicate that estrogen itself does not seem to increase the rate of breast cancer whether given as estradiol, Premarin, or another form of estrogen,” says Dr. Blacker. “However, the addition of synthetic progestins, such as medroxyprogesterone acetate, norethindrone acetate, and others, are associated with higher rates of breast cancer in women using combined hormonal therapy. There is some data that progesterone — the natural hormone — does not increase the rate of breast cancer, however.”

Other advantages include women possibly experiencing less bleeding and less puffiness when on natural progesterone instead of some synthetic progestins. It is also easy to measure blood serum levels in women who are not responding to the hormone in the way that they should.

On the other hand, just like conventional hormone therapy, bio-identical hormones do have risks and are not right for everyone. Women who have had breast cancer or endometrial cancer, strokes, or blood clots would not want to take bio-identical hormones.

Compounded bio-identical hormones are often not covered by insurance, notes Blacker, though that may be changing. Insurance companies will typically cover estradiol in oral or patch form and some gels and lotions, while progesterone is usually covered but often with a higher co-pay. As all insurance companies are different, be sure to check for your plan’s specific coverage.

Talk to your doctor about whether the risks of any kind of hormonal menopause treatment outweigh the benefits for you. If you have a history of breast cancer, cardiovascular disease, or some other serious conditions, you might not be a good candidate. Your doctor may be able to prescribe other treatments or suggest lifestyle changes that could help.

Unknown Manufacturing Conditions

According to an Endocrine Society Scientific Statement, patients need to be counseled about the risks of custom-compounded bioidentical hormones. The preferred treatments should have been vetted by the U.S. Food and Drug Administration, not Oprah.

Physicians may need to take time to explain to patients the potential risks of using “bioidentical hormone” formulations made by compounding pharmacies, say the authors of an Endocrine Society scientific statement.

Many practitioners and patients find the subject confusing because of misleading information from the Internet and endorsements for alternative menopausal replacement hormones from celebrities such as Oprah Winfrey and Suzanne Somers. The compounded formulations are touted as “natural” and tailored to an individual’s needs, but “bioidentical hormones” is better understood as a marketing term to sell products that are not approved by the Food and Drug Administration (FDA), according to Nanette Santoro, MD, chair of the task force that wrote the scientific statement.

Patients need to understand that FDA-approved hormones from pharmaceutical companies offer protections of purity, controlled manufacturing processes, and evidence from clinical trials that products from less-regulated compounding pharmacies do not. In addition, many of the newer FDA-approved formulations can be described as bioidentical because they are the same molecules as hormones found in the body.

Patients are attracted to that “natural” label, but they can’t know the conditions under which the formulations are produced. An extreme example of the danger of the less-regulated environment of compounding pharmacies occurred in 2012, when more than 60 people died from fungal meningitis after receiving injections of tainted steroids supplied by the New England Compounding Center. The head of that pharmacy was recently found guilty of racketeering charges.

“The message that we would like to get to women and to prescribers is that they should only consider a compounded hormone therapy if they can’t tolerate a government-approved therapy, or if they need a dose or formulation that is not commonly available in a government-approved therapy.” – JoAnn Pinkerton, MD, executive director, North American Menopause Society; professor, obstetrics and gynecology, University of Virginia Health System

But another worrisome problem is that compounding pharmacists can, for example, introduce excipients with unknown effects on absorption of the hormone.

“The conditions under which it is produced and the exact excipients that are put into that substance are going to affect its absorption, and may affect whether or not it causes you harm,” says Santoro, who chairs the department of obstetrics and gynecology at the University of Colorado Anschutz Medical Campus, Aurora. “No matter how carefully it is prepared, it is impossible to know the product’s pharmacokinetics. So, I don’t know if my patient is getting a peak at one hour, two hours, five hours, six hours, or never because the excipient is blocking absorption.”

Millions of Women?

The number of women using these products appears to be huge, according to a study by Santoro and JoAnn Pinkerton, MD, executive director of the North American Menopause Society and professor of obstetrics and gynecology at the University of Virginia Health System. The study estimated that 1 million to 2.5 million U.S. women aged 40 years or older are using compounded hormone therapy. “It seems to be a bigger part of the market than we thought before. A quarter to a third of the market for hormone therapy products is in the custom-compounded realm,” Santoro says.

The study also found that many women are not aware that the custom-compounded products have not been evaluated by the FDA. “These custom-compounded products require prescriptions,” Pinkerton says. “Many women believe that if they are given a prescription, it means that the product is government-approved. So, when asked in the survey, many women couldn’t tell whether or not what they were taking was a government-approved or nongovernment-approved therapy.”

The Myth of Saliva Testing

Another tactic used by compounded products marketers is the notion that through saliva testing, they can provide each individual a perfect match of hormone needs, another claim that the scientific statement seeks to knock down. “The custom compounders for menopause ‘everybody is a special snowflake, and you need your special recipe of hormones, and we can do that for you,’” Santoro says.

“The scientific statement makes the point that salivary testing unreliable,” Pinkerton says. “Patients pay significant costs to receive data that they believe is individualized to them, when in reality, dosing for hormone therapy is done based on symptoms, not based on blood levels or salivary testing,”

A patient whose hot flashes are gone is on the correct dose, Santoro agrees: “Only in rare cases, if they are outliers on the pharmacokinetic curve, do you need to measure blood levels. Saliva testing adds a level of complexity that doesn’t need to be there.”

Thyroid Hormones

In addition to the menopausal hormones, thyroid insufficiency is the other main condition for which bioidentical hormones are marketed. Santoro says that “somewhere between 1 in 10 to 1 in 20 people do not do well” on replacement of levothyroxine (T4), and some seem to do better with a combination of T4 and triiodothyronine (T3). She says that marketers in the bioidentical field seize on this to push “the belief that if you got it from a biological source it is better. That has led to people taking things like porcine thyroid” because it contains both T4 and T3.

Treatment guidelines from organizations like the American Thyroid Association recommend avoiding these “natural” extracts from pig thyroid glands because they raise safety concerns — in particular because of their ratio of T4 to T3, with T3 levels being much too high. And it should be noted that the standard drugs for replacing T4 and T3 are in fact bioidentical — the exact same molecules as the hormones.

Successful Communication

Santoro and Pinkerton regularly encounter patients who request compounded bioidentical hormones, often because they are afraid of traditional hormone therapy.

Part of their worry stems from the spin that the compounding marketers put on the preliminary release of results from the Women’s Health Initiative more than a decade ago about risks of menopausal hormone replacement therapy. One fallout from the WHI was that FDA-approved estrogen therapies must include boxed warnings about potential dangers. The less-regulated compounded therapies are not required to include these warnings, which can lead women to make the unwarranted assumption that they have no risks.

“A lot of these marketers build on a small truth and then make it much more broadly applicable in an inappropriate way,” Santoro says, such as claiming that women experienced problems because they were not using “natural products.”

For example, the fourth hit from a Google search of the term, “bioidentical hormones,” turns up a website that makes the false statement: “There is an overwhelmingly large body of evidence that supports the claim that bioidentical hormone therapy is safer and more effective than synthetic hormone replacement.” There is in fact no such evidence, the scientific statement emphasizes.

“There are reasons to use compounding, but there is not a reason for a third of American women to be using it as a preferred form of hormone therapy. Maybe 1% of people will have a reaction to all forms of hormone therapy and might do better with compounding.” – Nanette Santoro, MD, chair, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora

Santoro and Pinkerton both explain to patients influenced by such claims that there are FDA-approved products that can be defined as “bioidentical.” “I know it is going to be another 10 minutes of education added to the visit,” Santoro says. “I have to explain that what they are getting is much more reliable if we use an FDA-approved compound, so I feel much more comfortable giving that to them. There are real safety issues and efficacy issues with using something that is compounded, so it would not be my first recommendation for them, it would be my last, if nothing else worked.”

“The message that we would like to get to women and to prescribers is that they should only consider a compounded hormone therapy if they can’t tolerate a government-approved therapy, or if they need a dose or formulation that is not commonly available in a government-approved therapy,” Pinkerton says. “The majority of women are very willing to try a government-approved bioidentical hormone therapy once they understand that it is available, and the difference in the safety between government-approved vs. compounded.”

“There are reasons to use compounding, but there is not a reason for a third of American women to be using it as a preferred form of hormone therapy,” Santoro says. “Maybe 1% of people will have a reaction to all forms of hormone therapy and might do better with compounding.”

A Consensus

In addition to the Endocrine Society’s statement, Pinkerton says that “the majority of the key medical societies, including the North American Menopause Society, American Congress of Obstetrics and Gynecology, and American Society for Reproductive Medicine, as well as several international societies, all recommend the use of government-approved hormone formulations that provide many options without the unique risks of compounded hormone therapy.”

“Compounded Bioidentical Hormones in Endocrinology Practice: An Endocrine Society Scientific Statement” was published in The Journal of Clinical Endocrinology & Metabolism in April 2016.

Seaborg is a freelance writer based in Charlottesville, Va. He wrote about the increase in hip fractures in the May issue.

  • Huge numbers of women are taking hormones from compounding pharmacies, so endocrinologists need to be prepared to deal with their requests for “bioidentical hormones.”
  • The term “bioidentical hormones” engenders considerable confusion because of the way it is used to market hormone preparations made by custom-compounding pharmacies that do not have to meet FDA requirements. But there are FDA-approved bioidentical hormones, as well.
  • Because custom-compounded hormone preparations are not required to meet the strict purity and efficacy requirements of FDA-approved pharmaceutical preparations, the Endocrine Society and other professional societies recommend FDA-approved formulations as first-line treatments.

Menopausal Hormone Therapy
and Cancer Risk

For decades, women have used hormone therapy to ease symptoms of menopause, such as hot flashes and sweating. This is called menopausal hormone therapy, and you may see it abbreviated as HT or MHT. You may also hear it described as hormone replacement therapy (HRT), postmenopausal hormone therapy (PHT), or postmenopausal hormones (PMH).

In the past, many doctors and their patients believed that MHT didn’t just help with hot flashes and other symptoms – it had important health benefits. But well-conducted studies have led many doctors to conclude that the risks of MHT often outweigh the benefits.

This document discusses only how MHT can affect a woman’s risk of getting certain cancers. It does not discuss other possible risks of MHT such as heart disease or stroke.

You can use this information when you talk to your doctor about whether MHT is right for you.

What is menopause?

Menopause is the time in a woman’s life when the ovaries stop working and she stops having menstrual periods for good. Menopause is sometimes called the change of life, or the change.

The ovaries stop releasing eggs and making the female hormones, estrogen and progesterone. In the months or years leading up to natural menopause, menstrual periods may become less frequent and irregular, and hormone levels may go up and down. This time is called perimenopause or the menopausal transition. Since periods can become less frequent during this time, it can be hard to know when they have actually stopped (and you have gone through menopause) until you look back at a later time.

Women who have their ovaries removed by surgery (oophorectomy) or whose ovaries stop working for other reasons go through menopause, too, but much more suddenly (without the menopausal transition).

Women who have had their uterus removed (hysterectomy) but still have their ovaries stop having periods, but they don’t really go through menopause until their ovaries stop working. This is often determined based on symptoms, but your doctor can tell for certain by testing your blood for levels of certain hormones. Hormones made by the pituitary gland called luteinizing hormone (LH) and follicle stimulating hormone (FSH) help regulate the ovaries before menopause. When levels of estrogen get lower during menopause, the levels of FSH and LH go up. High levels of FSH and LH, along with low levels of estrogen, can be used to diagnose menopause. Blood tests for these may be helpful in a woman who has had her uterus removed.

Some drugs can turn off the ovaries and cause menstrual periods to stop for a time. Although this is not the same as menopause, it can lead to many of the same symptoms.

Most of the symptoms of menopause are linked to lower estrogen levels. Some symptoms – hot flashes and night sweats, for instance – tend to fade away at some point, whether or not they are treated. Other problems that start after menopause, like dryness and thinning of vaginal tissues and bone thinning, tend to get worse over time.

Because many of the symptoms and problems of menopause are linked to low levels of estrogen, this hormone has often been used in the past to treat menopause.

What hormones are used to treat the symptoms of menopause?

The hormones most commonly used to treat symptoms of menopause are estrogen and progesterone. (Progesterone and drugs that act like it are called progestins). Often, these 2 hormones are used together, but some women are given estrogen alone. It’s important to know which hormones you are talking about when looking at the risks.

Common estrogen preparations used to treat menopausal symptoms include conjugated equine estrogens (CEE or Premarin®) and estradiol, but several forms or types of estrogen are available.

There are also many progestins available, but medroxyprogesterone acetate (MPA or Provera®), is often used with an estrogen to treat menopausal symptoms. Some preparations contain both an estrogen and a progestin.

Androgens (male hormones like testosterone) are also sometimes used to treat menopausal symptoms. This is not common, though, and because only a few studies have looked at this practice, it isn’t clear how safe it is in the long run.

Tibolone is a synthetic hormone drug that can act like estrogen, progesterone, and testosterone in different tissues of the body. Because this drug isn’t available in the US, it’s not discussed here.

Taking estrogen with a progestin vs. estrogen alone

Estrogen-progestin therapy

Treating menopausal symptoms with estrogen and progestin together is known as estrogen-progestin therapy (EPT) or combined hormone therapy. Although estrogen alone improves the symptoms of menopause, it increases the risk of cancer of the uterus ( endometrial cancer). Adding a progestin to the estrogen lowers the risk of endometrial cancer back to normal. Because of this, EPT is given to women who still have a uterus (those who have not had a hysterectomy). EPT can be given 2 ways:

  • Continuous EPT means the same dose of estrogen and progestin is taken each day. Women often prefer continuous EPT because it rarely leads to menstrual-like bleeding.
  • Sequential (cyclical) EPT means different amounts of each hormone are taken on specific days. There are different ways to do this. For example, estrogen can be taken by itself for 14 days, then estrogen plus progestin for 11 days, then neither hormone for 3 to 5 days. Other schedules involve taking progestin only every few months. This lowers the amount of progestin that you are exposed to. Monthly regimens are also thought to result in hormone levels that are more like the natural menstrual cycle. Cyclical EPT can produce bleeding like a menstrual period, but it can occur less often than monthly.

Bio-identical hormones

The word “bio-identical” is sometimes used by sellers to describe hormone preparations that contain estrogens and progesterone with the same chemical structure as those found naturally in people. Sometimes, how much of the hormones the woman takes are adjusted based on blood tests of hormone levels. Marketers often describe bio-identical hormones as “natural,” and buyers often think that they’re safer than other forms of estrogen and progestin used to control menopause symptoms. But so far, there are no long-term studies of bio-identical hormones, and no studies have found that women taking bio-identical hormones have less serious side effects than women taking other forms of these hormones. For this reason, bio-identical hormones should be assumed to have the same health risks as any other type of hormone therapy.

Some herbal remedies and supplements are also described as natural ways to treat the symptoms of menopause. For more on this, see “Herbs and supplements” in the section called “What does it all mean?”

Estrogen therapy or ET

Treating menopausal symptoms with estrogen alone is known as estrogen therapy (ET). ET improves the symptoms of menopause, but it increases the risk of cancer of the uterus (endometrial cancer). Because of this, ET is only safe for women who don’t have a uterus (such as those who have had a hysterectomy).

How are estrogen and progestin given to treat the symptoms of menopause?

Systemic hormones

Hormones can be given so that they enter the bloodstream and circulate to reach all parts of the body. This is called systemic hormone therapy, and it’s often used to treat the symptoms of menopause. Systemic hormone therapy includes:

  • Pills that contain estrogen and a progestin together, as well as pills that contain each drug separately
  • Skin patches (the hormones are absorbed through the skin) that contain estrogen alone and some that contain estrogen plus a progestin
  • Injections (or shots) into a muscle or under the skin (this isn’t often used to treat the symptoms of menopause).
  • A vaginal ring that delivers a large dose of estrogen to the whole body (Vaginal rings more often deliver low doses and are considered topical therapy. See below.).

Systemic hormones can help with certain symptoms of menopause, such as hot flashes and night sweats, as well as problems linked to thinning of the lining of the vagina (such as dryness that can make sex painful). They can also help prevent and treat osteoporosis (severe bone thinning).

Topical hormones

Hormones, most often estrogen, can also be placed in or near the place that needs treatment. This is called topical hormone therapy. If small doses are used, little of the hormone is absorbed into the bloodstream, so it has little if any effect on the rest of the body.

For women in menopause, very small doses of estrogen can be placed inside the vagina as topical therapy to help treat dry or thinned vaginal tissues. This type of estrogen comes in the form of vaginal creams, rings, and tablets. Even though tiny amounts of hormone may enter the blood, most of it stays in the vaginal tissues. Because so little of the hormone gets into the blood, topical treatment doesn’t help with problems like hot flashes, night sweats, or osteoporosis. Generally, topical estrogen is not needed in women taking systemic hormones.

(As noted earlier, there’s a type of vaginal ring that delivers high doses of hormones to the whole body, which would be considered systemic treatment. If you’re unsure about the type of ring you have, check with your doctor.).

Hormone therapy and cancer risk

Types of studies used to look at the effects of hormone therapy

Different types of studies can be used to look at cancer risk from menopausal hormone therapy (MHT).

Randomized controlled trials: In this kind of study, a group of patients get the drug being studied (like MHT), and another (control) group gets a placebo (like a sugar pill). Results from this kind of study are powerful because which group a patient is in is based on chance. This helps assure that the groups are similar in all ways, such as risk for cancer, except for the drug that’s being studied. This is the best way to see the effects of a drug. These types of studies can also be double-blinded, which means neither the people in the study nor their doctors know which group they are in. This lowers the chance that thoughts or opinions about treatment could affect the study results. Unfortunately, these kinds of studies are costly, which limits the number of people in the study, how long the study can continue, and the number of studies done.

Observational studies: These kinds of studies collect information about a large group of people but don’t give them a certain treatment, such as a drug. In observational studies of MHT, the women and their doctors decide what hormone drugs, if any, the women take and for how long. These kinds of studies can also gather information about other factors that can influence cancer risk. Some observational studies gather data about what happened over previous years. Others follow (observe) people for years to look at how different factors (like MHT) affect cancer risk. Observational studies can be less costly than randomized clinical trials, so they’re more common and often enroll many more patients.

A major drawback of observational studies is that the people getting the treatment being studied may have different cancer risk factors than the people who aren’t. Plus, the treatment (like which drugs are used for MHT and how long they’re taken) can differ between the people being studied. This makes it less clear that the differences seen are only due to the drug being studied (like MHT) and not other factors.

When observational studies and randomized controlled trials have different results, most experts give more weight to the results of the randomized controlled trial.

Major studies

Several large studies have looked at possible links between systemic hormone therapy in menopausal women and different types of cancer.

The main randomized studies of MHT were part of the Women’s Health Initiative (WHI). The WHI included 2 randomized placebo-controlled clinical trials of MHT in healthy women:

  • One study looked at estrogen therapy (ET) in post-menopausal women who didn’t have a uterus. Over 5,000 women in the ET group took a daily dose of estrogen in the form of conjugated equine estrogen (CEE) for an average of about 6 years. The researchers then continued to follow them for several years to look for any further effects of the hormone. The women were compared to more than 5,000 in the placebo group.
  • The other study looked at estrogen-progestin therapy (EPT) in post-menopausal women who still had their uterus. Over 8,500 women in the EPT group took a daily dose of CEE plus a progestin called medroxyprogesterone acetate for an average of about 5 years. This group was compared to a group of more than 8,000 women in the placebo group.

The WHI also conducted some observational studies. However, when we mention a WHI study below, we’re referring to one of the randomized studies.

Many observational studies have looked at MHT and cancer risk. One example is the Million Women Study. It enrolled over a million women aged 50 to 64 in the UK, collected information about hormone use and other health and personal details, and followed the women for many years. Not all of the women in the Million Women Study took MHT. Some of the women taking MHT were on ET, some were on EPT, and some took another drug. Some of the women on ET still had their uterus.

Estrogen-progestin therapy (EPT) and cancer risk

Endometrial cancer

Studies show that EPT does not increase the risk of endometrial cancer (cancer in the lining of the uterus). It is linked to a higher risk of abnormal vaginal bleeding. Because vaginal bleeding after menopause can be a symptom of endometrial cancer, this often leads to further testing.

Breast cancer

Based on the WHI study, taking EPT is linked to a higher risk of breast cancer. The longer EPT is used, the higher the risk. The risk returns to that of a woman who never used EPT (the usual risk) within 3 years of stopping the hormones. Breast cancers in women taking EPT are more likely to be found when they are bigger and have spread beyond the breast.

To put the risk into numbers, if 10,000 women took EPT for a year, it would result in up to about 8 more cases of breast cancer per year than if they had not taken hormone therapy (HT).

Taking EPT is also linked to increased breast density (as seen on a mammogram). Increased breast density can make it harder to find breast cancer on a mammogram.

Ovarian cancer

Risk factors for ovarian cancer are harder to study because it is a less common cancer. Even when something increases the risk of developing ovarian cancer, the risk of actually getting this cancer is still likely to be low.

The WHI did not find a real difference in ovarian cancer risk with EPT. Although there were more cases of ovarian cancer in the women on EPT, this may have been due to chance because of the small number of women who were affected with this cancer.

However, a recent analysis combined the results of more than 50 studies, including randomized controlled trials and observational studies. This analysis found that women who took estrogen and progestin (progesterone) after menopause did have an increased risk of getting ovarian cancer. The risk was highest for women taking hormones, and decreased over time after the hormones were stopped.

To put the risk into numbers, if 1,000 women who were 50 years old took hormones for menopause for 5 years, one extra ovarian cancer would be expected to develop.

Colorectal cancer

In the WHI study of EPT, the results were mixed. Women who took EPT had a lower risk of getting colorectal cancer at all, but the cancers they got were more advanced (more likely to have spread to lymph nodes or distant sites) than the cancers in the women not taking hormones.

Some observational studies have found a lower risk of colorectal cancer in women taking EPT, but some did not. So far, though, observational studies have not linked EPT with a higher risk of colorectal cancer.

Lung cancer

EPT is not linked to a higher risk of getting lung cancer, but it is linked to a higher risk of dying from lung cancer.

Skin cancer

EPT is not linked to a higher risk of any type of skin cancer (including both melanoma and other types of skin cancer).

Estrogen therapy (ET) and cancer risk

In women who still have a uterus, using systemic ET has been shown to increase the risk of endometrial cancer (cancer of the lining of the uterus). The risk remains higher than average even after ET is no longer used. Although most studies that showed an increased risk were of women taking estrogen as a pill, women using a patch or high-dose vaginal ring can also expect to have an increased risk of endometrial cancer.

Because of this increased cancer risk, women who have gone through menopause and who still have a uterus are given a progestin along with estrogen. Studies have shown that EPT does not increase the risk for endometrial cancer.

Long-term use of vaginal creams, rings, or tablets containing topical estrogen doses may also increase the levels of estrogen in the body. It’s not clear if this leads to health risks, but the amounts of hormone are much smaller than systemic therapies.

ET is not linked to a higher risk of breast cancer. In fact, certain groups of women taking ET, such as women who had no family history of breast cancer and those who had no history of benign breast disease, had a slightly lower risk of breast cancer.

The WHI study of ET did not report any results about ovarian cancer.

However, a recent analysis combined the results of more than 50 studies, including randomized controlled trials and observational studies. This analysis found that women who took estrogen after menopause did have an increased risk of getting ovarian cancer. The risk was highest for women currently taking estrogen, and decreased over time after estrogen was stopped.

To put the risk into numbers, if 1,000 women who were 50 years old took estrogen for menopause for 5 years, one extra ovarian cancer would be expected to develop.

Observational studies have shown that women who take ET have a higher risk for ovarian cancer compared with women who take no hormones after menopause. The overall risk remains low, but it does increase the longer a woman uses ET. The risk of ovarian cancer goes down after a woman stops taking the hormone.

In the WHI study, ET did not seem to have any effect on the risk of colorectal cancer.

Observational studies have found a lower risk of colorectal cancer in women who have used ET for many years.

ET does not seem to have any effect on the risk of lung cancer.

ET is not linked to a higher risk of any type of skin cancer (including both melanoma and other types of skin cancer).

Deciding to use menopausal hormone therapy (MHT)

The decision to use estrogen, alone (ET) or with a progestin therapy (EPT), after menopause should be made by each woman and her doctor after weighing the possible risks and benefits. Things to think about include:

  • The woman’s baseline risk of breast, endometrial, ovarian, and other types of cancer, and how much this might be affected by hormone therapy
  • The risks of other serious conditions affected by hormone therapy that aren’t covered here, like heart disease, stroke, serious blood clots, and effects on the brain
  • What other medicines might be used to treat menopausal symptoms or osteoporosis instead

Other factors to consider include how bad the woman’s menopausal symptoms are and the type and dose of the hormones the doctor recommends.

The American Cancer Society has no position or guidelines regarding menopausal hormone therapy.

Reducing the cancer risks of hormone therapy

If you and your doctor decide that MHT is the best way to treat symptoms or problems caused by menopause, keep in mind that it is medicine and like any other medicine it’s best to use it at the lowest dose needed for as short a time as possible. And just as you would if you were taking another type of medicine, you need to see your doctor regularly. Your doctor can see how well the treatment is working, monitor you for side effects, and let you know what other treatments are available for your symptoms.

All women should report any vaginal bleeding that happens after menopause to their doctors right away – it may be a symptom of endometrial cancer. A woman who takes EPT does not have a higher risk of endometrial cancer, but she can still get it.

Women using vaginal cream, rings, or tablets containing only estrogen should talk to their doctors about follow-up and the possible need for progestin treatment.

For women who have had a hysterectomy (surgery to remove the uterus), a progestin does not need to be a part of hormone therapy because there’s no risk of endometrial cancer. Adding a progestin does raise the risk of breast cancer, so ET is a better option for women without a uterus.

Women should follow the American Cancer Society guidelines for cancer early detection, especially those for breast cancer. These guidelines can be found in Breast Cancer Early Detection.

Herbs and supplements during menopause

Many over-the-counter “natural” (herbal) products are promoted in stores and online as helpful with menopausal symptoms. These include vitamins and soy-based and herbal products (like black cohosh and red clover). There are also endless arrays of special blends of herbs and vitamins that claim to reduce the discomforts of menopause.

These products are considered dietary supplements (not drugs). They have not been evaluated by the Food and Drug Administration (FDA) to be sure that they work or even that they are safe. Some supplements have been tested in small clinical trials, but often the studies only looked at taking the substance for a short time (months), so it isn’t clear how safe it would be if taken for a long time. Another concern has been applying the results of a study of a particular version and dose of a supplement to others that weren’t tested.

Most of the plain herbs that are touted for menopausal symptoms carry a low risk of harm for most women, but some can interact with other drugs and/or cause unexpected problems. You should discuss herbs or supplements with your doctor before taking them.

Well-controlled scientific studies are needed to help find out if these products work and if they are any safer than the hormone therapy drugs now in use.

Beware of products with “secret formulas” or hormone-like ingredients that may cause harm. In the past, some “natural herbal supplements” made in other countries have been found to contain actual drugs, some of which have been banned from the United States because they are dangerous. It’s your right to know exactly what you’re taking and what side effects and drug interactions it may have.

You can learn more in Dietary Supplements: What Is Safe?

Bioidentical Hormones

What are bioidentical hormones?

Hormones are special chemicals made by parts of the body called glands. They are messengers that tell other parts of the body how and when to work. Hormones control almost all tasks in the body. These include sex and brain function, growth and the breakdown of food. When hormones are out of balance, symptoms can occur.

Bioidentical hormones are defined as man-made hormones that are very similar to the hormones produced by the human body. Common hormones that are matched are estrogen, progesterone and testosterone. These are then used as treatment for men and women whose own hormones are low or out of balance. Some prescription forms of bioidentical hormones are pre-made by a drug company. Other forms are custom-made by a pharmacist based on a doctor’s order. This is called compounding. The US Food and Drug Administration (FDA) has approved a number of preparations of bioidentical estradiol and progesterone, which are molecularly identical to the structure of the hormones generated by the human body. They have been through testing for safety and purity and to be sure each dose has the same amount of hormones. The compounded forms have not been tested and approved by the FDA. Though it is often advertised that products that are made from plants like soybeans and yams are “natural” choices, they are altered greatly in a lab so are no longer natural when done with processing. Both the FDA-approved and compounded hormones come in a variety of doses and routes of delivery (pills, creams, gels, sprays, and vaginal inserts).

Customized bioidentical hormones are often advertised as being a safer, more effective, natural, and an individualized alternative to conventional hormone therapy. However, these claims remain unsupported by any large-scale, well designed studies. Also, the lack of FDA oversight for compounded hormones generates additional risks regarding the purity and safety of custom compounded bioidentical hormones. Although custom hormone combinations often include blends of the same ingredients found in FDA-approved bioidentical hormones (i.e., plant-derived 17β-estradiol or micronized progesterone), some custom compounded preparations include additional hormone varieties (i.e., estriol, pregnenolone, and DHEA). These additional hormones have not undergone adequate testing and are therefore not included in any FDA-approved products.

Why are bioidentical hormones used?

As men and women age, the levels of some key hormones in the body go down. These include estrogen, progesterone and testosterone. This can lead to certain symptoms. Some are very common to women who are past the age of having periods (menopause). Some common effects of low hormones include:

  • Hot flashes
  • Night sweats
  • Vaginal dryness
  • Loss of interest in sex
  • Pain during sex
  • Problems sleeping
  • Loss of energy
  • Fatigue
  • Loss of muscle mass
  • Weight gain
  • Foggy thinking
  • Mood changes
  • Memory loss

The treatment is to replace the hormones that have been lost with the hormone therapy. As a result, hormone levels will increase and symptoms will improve. Currently, national societies and expert recommendations state that the risks and benefits of conventional and bioidentical hormones should be considered equal. Your doctor can discuss with you the variety of options available, and guide therapy based on your preferences.

How common are bioidentical hormones?

The use of the compounded type is very common in the U.S. in women in menopause. The North American Menopause Society (NAMS) reports that about 1.4 million women are using this treatment. NAMS notes that that is 40% of all prescriptions for hormone therapy in women who are in menopause. The number of men using this treatment is not noted.

How are bioidentical hormones given?

There are many ways to get bioidentical hormones. These include pills, patches, creams, gels, shots and implanted pellets. Your doctor will decide which method is best for you. You may try more than one way before you find one that works well for you.

How does my doctor select my dose?

People on hormone treatment are watched very closely by their doctors. Most often, doses are adjusted according to a patient’s symptoms and needs, with the goal of keeping the dose to the minimum required to achieve your goals. Depending on your doctor, you might have routine blood, urine or saliva tests to check your hormone levels. Your doctor may adjust your dose based on your changing hormone needs. It should be noted that the FDA recommends against using hormone levels to guide the dosing of hormone therapy in women, as normal levels fluctuate day to day, and vary between patients. In particular, salivary hormone levels are known to fluctuate widely, and have not been shown to be related to menopausal symptoms.

Are bioidentical hormones safe?

The bioidentical hormones that have been approved by the FDA have been tested for safety. They have passed the FDA’s very strict standards and have been shown to be safe for people to use. The compounded hormones have not gone through the FDA’s testing. As yet, little research has been done on them. They have not been proven to be safe or unsafe. Many major medical groups do not support using them because not enough is known about their safety and long-term side effects.

Are compounded bioidentical hormones bad?

There are risks to taking the compounded hormones. But in some cases, they might be the better choice. They might be needed to get the right source (gel, cream, pill, etc.), dose or mix of hormones for a patient. Also, a patient might have a bad reaction to the pre-made form. Your doctor will know which type is better for you.

What are the risks of bioidentical hormones?

It has been shown in research studies that there are risks for women who take hormones, called hormone therapy (HT). It can increase the risk of blood clots, stroke, and gallbladder disease. In women who are older, and who use hormone therapy for an extended period, the risk of heart disease and breast cancer may also increase. Many doctors who use bioidentical hormones claim they are safer than regular HRT. But there have been no large research studies of bioidentical hormones. It has not been shown that they really reduce the risk of these problems.

What are the side effects of bioidentical hormones?

When the FDA approves a drug, the drug company must report on any side effects they are told about, including prominently noting it in the paperwork when picked up at the pharmacy. Pharmacies that compound hormones do not have to report drug side effects to the FDA, or provide such paperwork. This contributes to the myth that compounded hormones are safer, when in fact doctors don’t know all of the possible side effects of these hormones.

Side effects can occur when a dose is first given. The body is not used to the new level of hormones. The dose may need to be changed. Some side effects can be linked to a certain hormone in the mixture. Many side effects get better as the body adjusts to the new level of hormones. Some common side effects include:

  • Weight gain
  • Blurred vision
  • Tiredness
  • Acne
  • Increased facial hair (women)
  • Headaches
  • Breast tenderness
  • Spotting
  • Cramping
  • Bloating
  • Mood swings
  • Indigestion

You may itch or get red around the area where you get a shot or where you apply your hormones if you use a patch, cream or gel.

When should I call my healthcare provider?

Call your healthcare provider if you have a bad side effect after getting a dose of hormones. If you have a side effect that you cannot manage or does not go away in a short time, your hormone level might be too high.

Share Facebook Twitter LinkedIn Email Get useful, helpful and relevant health + wellness information enews

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

Bioidentical Hormones

Bioidentical hormones are defined as “compounds that have exactly the same chemical and molecular structure as hormones that are produced in the human body,” whether they are synthesized or derived from plants. However, there is no recognized standard definition, so variation in the formula and manufacturing is common.

Where are bioidentical hormones found?

Bioidentical hormones are available through a doctor or at a drugstore with a prescription. They are offered in various forms including pills, creams, and patches.

What evidence links bioidentical hormones to breast cancer?

The research on bioidentical hormones varies, and there are no conclusive findings on the impact of bioidentical hormones on the development of breast cancer. Estradiol and progesterone often have opposing effects on the development of cancer and other health outcomes, which are reflected in the studies on bioidentical hormones as well.

  • Post-menopausal primates administered a naturally occurring estradiol showeding increased breast cell growth compared to primates given a synthetic estradiol.
  • A study found that women taking bioidentical progesterone had a lower risk of developing invasive breast cancer than women taking a synthetic progesterone.

Who is most likely to be exposed to bioidentical hormones?

Women experiencing negative menopausal symptoms may be prescribed bioidentical hormones.

Who is most vulnerable to the health effects?

Anyone taking bioidentical hormones may be vulnerable to the health effects.

What are the top tips to avoid exposure?

The best way to avoid exposure is to avoid hormone replacement therapies or to use them for the shortest time period possible.

Reviewed 2019

HRT Has an Uncertainty Problem. Does Compounding Make It Worse?

JoAnn Pinkerton, MD, a gynecologist whose medical practice focuses on women’s midlife issues, worries about the millions of women who have sought out hormone therapy for their menopause symptoms from alternative practitioners because of fear of, disdain for, or distrust of Big Pharma and traditional hormone replacement therapy. Pinkerton tells of a 65-year-old patient whose naturopath put her on an estrogen product and an alternative anti-aging protocol for years. What the naturopath apparently didn’t factor in was the patient’s breast cancer history, which had been a large, node-positive, estrogen-positive cancer. Pinkerton checked the woman’s blood and found very high levels of estrogen. “If she had any cells that escaped she could be feeding them,” Pinkerton says.

Menopausal women struggling with symptoms from the ebbing of estrogen have seen the medical establishment’s advice on what to do swing wildly back and forth. Starting in the 1960s, they could get estrogen HRT and later, estrogen with progesterone, added to protect against uterine cancer. When, in 2002, the results of the NIH-sponsored Women’s Health Initiative study on postmenopausal health suggested that HRT could raise cardiovascular and breast cancer risks, many women either gave up on HRT altogether or turned to alternative options.

In the intervening years, new interpretations of the WHI data and follow-up research have produced a more nuanced picture of the risks and benefits. As a result, the advice is complex, evolving, and still percolating down to providers. Clinicians who see women at midlife may offer widely varying advice about HRT.

The uncertainty has created an opening for alternative practitioners (and their celebrity promoters) for so-called bioidentical hormones—versions of estrogen and progesterone derived from Mexican yam and soy that are closer to those a woman’s body produces than the conjugated estrogen derived from mares’ urine (Premarin). Bioidentical versions of estrogen and progesterone are produced by both pharmaceutical companies and compounding pharmacists working with alternative providers.

The difference is that compounding pharmacists are free to include varying dosages of estrogen and progesterone. Their recipes may also include testosterone and DHEA (a hormone produced by the adrenal glands). Some use blood tests to track the amount of resulting estrogen and labs that they say can track subtle changes in hormone levels through saliva tests. All of this makes many doctors nervous.

Systemic bioidentical hormone therapy
BHT approved by the FDA Compounded BHT
Estradiol oral tablets (0.5, 1.0, or 2.0 mg) Estradiol
Estradiol transdermal patches (14, 25, 37.5, 50, 75, 100 μg) Estriolb
Estradiol transdermal gels, emulsions, spray (doses range) Biestrogen (20% estradiol, 80% estriol)
Estradiol vaginal ring (provides 90-day systemic levels) Triestrogen (10% estrone, 10% estradiol, 80% estriol)
Micronized progesterone oral capsules (100, 200 mg) Progesteronea
Combination therapiesc
Estradiol with progesterone
Estriol with progesterone
Biestrogen with progesterone
Triestrogen with progesterone
BHT=bioidentical hormone therapy, FDA=U.S. Food and Drug Administration, HRT=hormone-replacement therapy.
aCompounded products (estradiol, estriol, biestrogen, triestrogen, progesterone, testosterone) are available as oral capsules, creams, or gels.
bEstriol is an endogenous estrogen that is prominent during pregnancy. There is no FDA-approved preparation of estriol. Compounding of this product has been permitted because estriol has a United States Pharmacopeia monograph. The FDA has urged compounders to file an investigational New Drug Application for this product.
cCombination therapies are available as capsules or creams; no FDA-approved estradiol and progesterone combination therapy is currently available.
dTestosterone is not available in FDA-approved formulations specifically dosed for women.
Source: Adapted from Stuenkel CA and Manson JE, JAMA Internal Medicine, December 2017

But that hasn’t stopped millions of women from seeking out compounded hormones; a 2015 survey estimated 26 million to 33 million such prescriptions are filled each year, with sales over $1 billion. There are plenty of conventional providers willing to take their patients on this alternative path; a survey of Kansas physicians published in 2018 found 66% had prescribed compounded bioidentical HRT. More than half of the primary care doctors in that survey disagreed with the statement that conventional HRT is more appropriate than compounded preparations.

This is all despite a clear message from mainstream endocrinologists that getting your hormones from a compounding pharmacy is unsafe. Their main arguments include the absence of FDA approval and uncertainty about whether they are delivering the promised level of hormone. Moreover, as in the case of Pinkerton’s patient, some of the practitioners who prescribe bespoke HRT may have a blind spot about the possible risks because tailored and natural may seem safe.

In mid-2018, the California Medical Board came down hard on so-called “doctor to the stars” Prudence Hall, MD; her “mindful” medical approach was featured on Oprah’s television network and drew testimonials from Suzanne Somers and Cindy Crawford. When one of her patients developed an aggressive ovarian cancer after being given compounded hormones and other supplements, the board placed Hall on probation for four years and faulted her for being unaware of the health risks of plant-based hormones.

False dichotomy

While some doctors still hew to the anti-HRT line resulting from the WHI study and recommend their patients steer clear altogether, others are following the latest practice guidelines that say hormone replacement is just fine if it is initiated within a few years after a woman’s periods end and doesn’t continue for more than 10 years.

Women also need an individualized risk assessment; someone with breast cancer risk, for instance, would not be a candidate for any form of HRT.

The problem is that many providers (and insurers) haven’t kept up with choosing the right product for a woman’s specific problem, says JoAnn Pinkerton, MD.

Pinkerton, executive director of the North American Menopause Society and a professor of obstetrics and gynecology at the University of Virginia Health System, likes to bust one myth right up front: Women aren’t facing a binary choice between old-fashioned, mainstream Big Pharma HRT and a “natural” approach offered by an alternative provider. She points out that there are plenty of FDA-approved, mainstream products made from bioidentical hormones, and they come in a wide variety of forms (pills, patches, gels, sprays, creams, rings) to suit a woman’s specific needs. For instance, if a woman’s main problem is vaginal dryness, she can be prescribed a bioidentical hormone cream that treats the local area and has minimal systemic effects.

The problem is that many providers (and insurers) haven’t kept up with choosing the right product for a woman’s specific problem or risk factors, Pinkerton says. “In the past five years we’ve made tremendous strides in understanding who are the best candidates for hormone therapy and all the different options available.”

For many symptomatic menopausal women under age 60 or within 10 years of menopause, the benefits of hormone therapy will outweigh the risks, says Pinkerton (and that is what the North American Menopause Society guidelines say). “But for women who use hormones later, we need to minimize risks, often with lower dose, transdermal products,” she says.

Many providers and insurers don’t know what products to choose for a specific problem, says JoAnn Pinkerton, MD, of the North American Menopause Society.

Pinkerton is frustrated by the narrow set of options most insurers will cover, mostly focused on pills or a weekly patch. “Insurance companies don’t really understand the differences between systemic and vaginal therapies and the different risks women have, particulary as they age, while on oral therapies,” she says. Her older patients do better on newer low-dose transdermal hormone therapy options but may have trouble getting them covered. “I wish managed care could understand that in 16 years we’ve come a long way in understanding for whom hormone therapy is safe and that we need to use our knowledge to pick the safest therapy for women as they age.”

The HRT landscape is constantly shifting and will again in spring 2019 when the newly FDA approved Bijuva, the first oral combination of bioidentical estrogen and progesterone, comes on the market. One analyst said that Bijuva, made by TherapeuticsMD, a company in Boca Raton, Fla., that specializes in products for women, could be a blockbuster. Pinkerton says the new medication may be attractive to many women who want to take oral combined bioidentical hormones but are more comfortable with an FDA-approved version. However, she worries about how long it may take to get on to insurers’ formularies.

There are a growing number of FDA-approved bioidentifical hormones. However, as Pinkerton points out, they are estrogen alone. For women with a uterus, bioidentical progesterone has needed to be given separately.

Overall, women and their physicians have an increasing number of HRT products to choose from, although for women with insurance, formulary tiers and cost may hem in the range of affordable picks. Pinkerton points to the increasing number of low-dose synthetic combinations on the market and the range of options for women with vaginal atrophy or who suffer from painful intercourse, which include both bioidentical vaginal estradiol creams and rings, low-dose suppositories, and Osphena (ospemifene), a selective estrogen receptor modulator.

About the author

Leave a Reply

Your email address will not be published. Required fields are marked *