Bioidentical hormones and replacement therapy, how safe are they? How much do we know about the benefits and risks? by Ray Sahelian, M.D.
August 1 2014

Compounded " bioidentical hormones " are plant-derived hormones that are prepared and packaged as a drug by a compounding pharmacist. Bioidentical hormones are supposed to be the exact molecular structure as the hormones made in the human body. I have not come across good evidence to back the claim that compounded hormones are biologically identical to the hormones produced by the body. See also hormone replacement therapy information.

FDA cracks down on bioidentical hormone sellers
2008 - FDA sent letters to pharmacies saying that bioidentical hormones are not safe and claims about "bioidentical hormone replacement therapy" products are not supported by medical evidence and that the pharmacy operations are breaking the law by making false and misleading claimss. Some pharmacies claim these bioidentical hormone products prevent or treat serious diseases, including Alzheimer's, stroke and some cancers. FDA does not review compounded, or custom-mixed, drugs for safety and effectiveness. A 2002 study found replacement hormones made by drug companies raised the risk of heart attacks, breast cancer and strokes. Since then, many women have turned to the natural estrogen, progesterone and testosterone products sold by compounding pharmacies. Apparently the drug company Wyeth complained to the FDA about the Internet sales of compounded products. L.D. King, executive director of the International Academy of Compounding Pharmacists, says the FDA's action will deny hundreds of thousands of women access to many commonly compounded bioidentical hormones, "substituting its judgment for that of doctors." Warning letters by the FDA went to Panorama Compounding Pharmacy of Lake Balboa, Calif.; Saint John's Medical Plaza Pharmacy of Santa Monica, Calif.; Murray Avenue Apothecary of Pittsburgh; Village Compounding Pharmacy of Houston; Pharmacy Compounding Specialties of Dallas; Reed's Compounding Pharmacy of Tucson, Ariz.; and Pacifica Pharmacy of Torrance, Calif.

Comparing bioidentical hormones to synthetic hormones
The American College of Obstetricians and Gynecologists (ACOG) says. "There is no evidence that so-called " bioidentical hormones " are safer than synthetic hormones for menopausal women and there is a risk that they may not meet quality standards. The formulations present the same risk as commercial drugs, but because they are unregulated, patients may not be informed of the risk."
   Dr. Sahelian comments: I am not sure I agree with the American College of Obstetricians and Gynecologists that bioidentical hormones pose the same risk as synthetic hormones or horse derived hormones. The chemical structure of bioidentical hormones is different than synthetic pharmaceutical hormones or equine derived hormones. We can't say that one form of hormone is safer or better than the other unless very long term studies spanning decades are completed. Bioidentical hormones might be safer than synthetic hormones, but so far there have been no long-term studies to find out. Hormones, where synthetic or natural, carry serious risks when misused.

Hormone replacement controversies - response to the January 2009 newsletter
We had an unprecedented number of email responses. Here is one example: "The January 2009 newsletter discusses the disastrous effects of conjugated equine estrogens and synthetic progestins uncovered by the Womenís Health Initiative study in terms of increasing breast cancer risk, but you seem not to make a major distinction with natural bio-identical hormones. My understanding is that the WHI did not study the use of bio-identical human estrogens and progesterone at all. Everything Iíve read indicates that they have a completely different effect on womenís bodies, and in fact progesterone (the real thing, not synthetic progestins) may be protective against breast cancer. I think you should distinguish between the two."
   Over the past few decades doctors have prescribed horse-derived estrogens and synthetic progestins to women in order to relieve menopausal symptoms and as a way to potentially reduce the risk for osteoporosis or heart disease. A few years ago doctors began suspecting that, in many or most women, the harm from this treatment in terms of increased breast cancer risk and heart disease outweighs the benefits. Many women stopped taking these medications, others turned to herbs and supplements, and still others turned to natural hormones such as bioidentical hormones. Many of you may not be familiar with this term. Bioidentical hormones differ from traditional hormone replacement therapy since they are chemically identical to hormones found within the body -- such as estradiol, estriol, and progesterone -- rather than molecules that are similar, but not identical to human hormones (such as Premarin, derived from the urine of pregnant horses) or synthetic progestins (such as medroxyprogesterone). Many women believe that these bioidentical natural hormones are safe, or safer. These bioidentical hormones are promoted by compounding pharmacists, some alternative medicine practitioners and even one celebrity, Suzanne Somers. Estradiol is also available in many FDA-approved pills, patches, creams and gels from traditional pharmaceutical companies. Is there evidence to support the safety or superiority of bioidentical hormones over standard hormone replacement approaches? I will focus most of this newsletter on this issue.
   Here are some of the emails we received and my responses.

Q. I think your information is great, but I strongly disagree regarding estrogen / progestin. First of all, both Premarin and progestins should be against the law, as we women are not horses and synthetic progestins are carcinogenic. However, bioidentical hormones are a different breed and I have been on them (low dose) for the last 5 years. I don't even think about cancer. I eat a very strict, clean, mostly organic diet and go to an MD who knows what he's doing. Yes, Western medicine is the problem---still giving women Premarin and progestins---it's a disgrace how mishandled most women are today at the hands of misinformed and arrogant doctors who don't want to learn what's new and better.
   A. All doctors, including me, are fallible and have the potential to make mistakes or give wrong advice. In the past few decades many doctors were just as assured and complacent of the safety of hormone replacement therapy with PremPro as many bioidentical hormone promoters are today. There are currently no long term studies with bioidentical hormones to prove their safety.

Other points to keep in mind regarding the risks, dosages and benefit of bio-identical hormones:
How are we to know for sure whether compounding pharmacies are preparing the correct bioidentical hormones since there is little or no oversight?
How do we know the right dosages for these bioidentical hormones in terms of long term use? How many years should one take them? When should one stop using them?
How do we know which form of estrogen is best: estriol, estradiol, estrone, and in what proportions? How do we know whether slow steady release / absorption of these hormones is better or worse that a quick absorption with a high peak and low valley?
How do we know which is better, oral or topical hormone use?
How do we know whether saliva testing is reliable? How is one to know the right hormone dosage to use based on saliva testing or blood testing? There is little evidence that a blood level or saliva level of a hormone can predict exactly the actual hormone amount a woman needs to take. The dosage of these hormones is most likely best managed through symptom relief of hot flashes, mood swings, sleep problems, and other symptoms rather than relying on blood or saliva levels.
Could natural progesterone have a protective effect on breast cancer but potentially cause other health issues such as an increased risk for heart rhythm disturbances?

My opinion as of 2014
Every woman has to decide for herself whether the benefits of hormone use, in terms of menopause symptom relief and potential reduction of osteoporosis or treating other medical issues, outweighs the potential risks for cancer, heart attack, stroke, or other serious conditions from HRT use. Does the use of hormone replacement increase or decrease mortality? The answers are not yet in.
   Keep in mind that there is a physiological reason why hormone levels drop with age. The human body was not meant to be exposed to high levels of certain hormones with aging. Therefore, any form of hormone replacement through pills, creams, or shots, and whether synthetic or bioidentical, is not something the human body is genetically adapted to. Humans have lived on this planet for a long, long time but it has been only in the last few decades that doctors started prescribing hormone replacement therapy to such a large number of women. If, a decade or two from now, research shows bioidentical hormone use to be safe, I will wholeheartedly promote their use. Until then, women who are using these hormones, particularly in high dosages and for prolonged periods, are taking a gamble. If natural hormone replacement is the only solution to reducing your menopausal symptoms or taking care of other health issues you have, use the least dosage that works and for the shortest period of time. Exercise, weight training, calcium and vitamin D are a few good options in reducing the risk for osteoporosis. The risk for heart disease, stroke, and mental decline can be reduced through diet, exercise, low stress, yoga, deep sleep, and by taking certain natural herbs and supplements.
   I want to emphasize that I am not in favor nor am I against the use of hormone replacement therapy. I just want women to be aware of all the benefits and risks and make an informed decision. The quality of life of many women has improved through HRT, whether synthetic or bioidentical, while other women have discovered the use of hormones has caused more problems than benefits. I support a woman's decision, no matter what, as long as she is informed and knows all the options, benefits and risks.

Safety of bioidentical hormones, risks, dangers
The U.S. Food and Drug Administration requires drugmakers of FDA-approved products that contain estrogen and progestogen to include a warning about increased risk of heart disease. Compounded products are not approved by the FDA and pharmacies offering these products are exempt from including the warnings. The ACOG also said most compounded products, including bioidentical hormones, have not undergone rigorous clinical testing and there are concerns regarding their quality.  In 2001, the FDA analyzed a variety of 29 product samples from 12 compounding pharmacies and found that 34 percent of them failed one or more standard quality tests. When a pharmacist compounds a drug, there is no way to know the concentration or to be sure that a patient is getting the same product every time.l hormones through the skin.
   Dr. Sahelian comments: For the time being I have to take the word of FDA that in some cases the quality of bioidentical hormones may be inadequate.

What can one do if he has taken too much biodidentical hormones (7-keto-DHEA, Pregnenolone, Progesterone) and experience heavy side effects now?- Is there anything else but waiting?- How long could it take to come down from such a high level?- Does it make sense to take supplements to boost Glutathione (detoxification)? Thank you for your answer since none of the doctors I could find, working with bioidentical hormones knows that.
   Waiting is the best option to allow them to clear from the body.

Bio identical hormone replacement therapy - Is Suzanne Somers a Quack?
Most women who receive hormone replacement therapy are prescribed drugs like Premarin or Prempro, which come from the urine of pregnant mares. Bioidentical hormones, which are also prescribed, are derived from soy, wild yam and other plant extracts. Advocates say their molecular structure is similar to that of the hormones they are replacing and can serve the same purpose. But hormone replacement therapy may cause more harm than benefit and most of this research was based on Premarin (estrogens from horse urine) or progestins whose molecular structure is not the same as progesterone made by the body. Little research has been done on the bioidentical hormone alternatives, and it is not even known how or if they work, nor whether they carry the same risks as the drugs, like for breast cancer.  There is no research comparing bioidentical hormones to estrogen derived from horse urine or artificial progestins. Suzanne Somers insists  women should be taking bioidentical hormones to prevent aging and as an alternative to traditional therapies. She may potentially be right in the fact that bioidentical hormones may be a good alternative to Premarin and Prempro, however just taking hormones could potentially increase the risk for cancer and other conditions, particularly when masses of women take these bioidentical hormones without fully knowing the appropriate dosages.
   Suzanne Somers promotes bioidentical estradiol and progesterone preparation in a topical cream that is ďdosed to mimic the natural hormones produced by your body when you were 20 years old.Ē However she has limited medical knowledge and may not realize that certain tissues in the body, for instance heart tissue, may not be able to handle these hormones at a high amount in old age.

Doctors in Los Angeles, CA
For a physician who treats patients using bioidentical hormone therapy in Los Angeles, visit Shera Raisen, MD.

Emails
Q. I am a post-menopausal women on bioidentical hormone replacement (a low level estrogen patch and plant derived progesterone). Would DIM Diindolylmethane supplement be helpful in balancing the estrogen effects and perhaps making them a more healthy component?
   A. It is difficult to say without research being available.

Q. Regarding female hormone replacement therapy. I think oral supplements are very hard on the liver, even worse for the mares producing Premarin. I have venous insufficiency and after one bout of thrombophlebitis following use of a low-dose birth control pill to regulate my periods (I am now post-menopausal) I swore I'd never take them again. I use bio-identical HRT creams made up by a compounding pharmacist. I've been very happy with this method; my personal blend contains testosterone which many women aren't aware should sometimes also be supplemented. Dr. Elizabeth Vliet has some wonderful books available outlining her extensive research.
   A. I am cautious with the use of hormones whether synthetic or bio-identical, and whether oral or through creams. Many people end up using too high dosages and long term consequences are not fully understood.
      Q. I wanted to respond to regarding bio-identical hormones. Anything one ingests, applies, inserts or otherwise manages to add to the system can be abused whether it be food, chemicals, alcohol, et al. It is up to the individual to understand and properly monitor health and well being. I should have added to my original comment that my doctor blood draws every six months to check my TSH, free T3, free T4, estrogen, estradiol and testosterone (I'm also hypothyroid and take Armour sublingually twice a day; I took Synthroid for 25 years and still had hypothyroid symptoms which have disappeared with the use of Armour. It is my - and every person's - responsibility to not only take proper cautions but to know what works best for their own individual metabolism and chemistry. My T levels were "within normal range" with Synthroid - but I still felt awful. My levels are only slightly higher now, but I feel disproportionately improved. The current standard of "normal ranges" for various hormones is much too limited and does not take into account individual reactions. Additionally we are strongly discouraged by most M.D.s from giving any input or requesting alterations to any prescribed medications. This is outrageous - a physician knows much about a great many subjects but s/he does NOT know MY particular oddities and needs. Major pharmaceutical companies have almost ruined our health care system, and even the doctors blindly follow along with anything said despite the fact that one can barely turn around without running into more proof that the pharmaceutical companies skew research results, hide dangerous side effects as long as possible and in all ways seek to maximize profits at the expense of our health. It's disgusting. Incidentally, the primary reason major pharmaceutical companies would love to remove public access to bio-identical hormones is nothing more noble than the fact that they cannot patent bio-identical hormones.

Testimonial
I appreciate your objective approach to hormone replacement therapy. My wife has been using bio identical progesterone for a number of years and has seen a great reduction of PMS and peri-menstrual acne. I recognize that her results are subjective and anecdotal. Unfortunately I don't foresee a U.S. peer reviewed study of bio identical hormones in the future because American pharmaceutical companies dictate where the research will be directed and non- prescription approaches to medical treatment is simply not profitable enough for them. Perhaps the Europeans, with their different philosophical approach to health care, will fund a study in this much needed area.

Dr. John Lee
You do not mention all the research done by the late Dr. John Lee. Do you recognize that he was one doctor who did a lot of research on bio identical hormones and that his books are worth reading by millions of women. It seems to me that since the research by Dr. John Lee has definitely proved the safety of bio-identical hormones, doctors should have no trouble endorsing natural bio identical hormones as safe. especially his research on the natural progesterone cream used in correct dose and applied to the skin, namely 15 to 20 mg (which is the size of a small pea). applied morning and evening.
    I am not aware of Dr. John Lee conducting double blind, placebo controlled studies for a minimum of ten years to determine the safety of these bio identical hormones.

Claims and studies
Are you familiar with the French study on the use of bio identical hormones? It was published in a journal called Maturitas. It says tens of thousands of French women were studied who used bio identical hormones. The study claims that women who used the Bio identicals, had no elevated risks of cancer. I am on bioidentical hormones and I am researching any studies that show the safety of these hormones. I wondered what you thought of this French study. "Could transdermal estradiol plus progesterone be a safer postmenopausal HRT? A review." Marc LíHermitea, Tommaso Simoncinib, Sarah Fullera, Andrea Riccardo Genazzanib. Published online 22 August 2008. It says, "Hormone replacement therapy (HRT) in young postmenopausal women is a safe and effective tool to counteract climacteric symptoms and to prevent long-term degenerative diseases, such as osteoporotic fractures, cardiovascular disease, diabetes mellitus and possibly cognitive impairment. The different types of HRT offer to many extent comparable efficacies on symptoms control; however, the expert selection of specific compounds, doses or routes of administration can provide significant clinical advantages. This paper reviews the role of the non-oral route of administration of sex steroids in the clinical management of postmenopausal women. Non-orally administered estrogens, minimizing the hepatic induction of clotting factors and others proteins associated with the first-pass effect, are associated with potential advantages on the cardiovascular system. In particular, the risk of developing deep vein thrombosis or pulmonary thromboembolism is negligible in comparison to that associated with oral estrogens. In addition, recent indications suggest potential advantages for blood pressure control with non-oral estrogens. To the same extent, a growing literature suggests that the progestins used in association with estrogens may not be equivalent. Recent evidence indeed shows that natural progesterone displays a favorable action on the vessels and on the brain, while this might not be true for some synthetic progestins. Compelling indications also exist that differences might also be present for the risk of developing breast cancer, with recent trials indicating that the association of natural progesterone with estrogens confers less or even no risk of breast cancer as opposed to the use of other synthetic progestins. In conclusion, while all types of hormone replacement therapies are safe and effective and confer significant benefits in the long-term when initiated in young postmenopausal women, in specific clinical settings the choice of the transdermal route of administration of estrogens and the use of natural progesterone might offer significant benefits and added safety. Keywords: Micronized progesterone, Transdermal estrogens, MPA, Postmenopause-hormonal replacement therapy, Cardiovascular risk, Hypertension, Breast cancer, Venous thromboembolism."
    The first sentence of this review makes me suspect that the individuals who wrote this review do not have a balanced position. They say, "Hormone replacement therapy (HRT) in young postmenopausal women is a safe and effective tool...." Most scientists are not as cavalier as these doctors. It would take at least several 10 to 15 year long studies with bioidentical hormones, in oral and transdermal forms, in various dosages, in various combinations of estrogen and progesterone, and by independent, non-pharmaceutical company funded honest researchers, to have a better understanding of their long term benefits and side effects. To my knowledge, these types of studies for these time periods have not yet been done as of 2009. When Premarin and progestins first became available decades ago for hormone replacement therapy, many doctors were assuring their patients that they were safe. It took several decades to find out that serious problems could occur. I do not know Marc LíHermitea, Tommaso Simoncinib, Sarah Fullera, Andrea Riccardo Genazzanib and do not know if they have any affiliations with pharmaceutical companies that sell these hormones.

Side effects, safety
I went onto bioidentical HRT years back because of severe sleep problems, low level depression, and found that supplementation did help but increased fibroid size and caused blood pressure fluctuations that tended to be extreme at night. The other effect was obliteration of sex drive even though testosterone was included at low levels. Most of this was eventually withdrawn because it only led to constant acne and hair loss, neither of these sexually enhancing from the standpoint of desireability. Are there any libido boosters that do not cause skin outbreaks and hair loss for women? Does the Passion Rx formula do this? The levels of primarily estrogen balanced by progesterone, although bioidentical have caused bloating and fat gain around the middle and also lead to breast cellular hyperplasia. I do take fish oils, multivitamins and minerals, extra vitamin D and selenium, crucifierous vegetables, get some moderate exercise most days and have tried maca herb but without observing any effect. Currently my levels of sex hormones are all low as when I try to bring them up into desired ranges as determined by my physician, I also get side effects. Since I have slightly low thyroid I am on supplements for this of natural thyroid plus take a tyrosine containing product and kelp for extra support as called for by my physician. I have mulltiple awakenings at night but if I remain in bed for rest and sleep long enough I function now with fairly normal energy afternoons, otherwise I do not have a normal day or night. Have tried many sleep enhancing formulas and find that melatonin works slightly but does not stop the awakenings. Is the Passion Rx formula something that could enhance breast precancer or cancer in terms of stimulating natural internal levels of estrogen? Have any women complained about increased hot flashes or sleep disturbance or does this even out? Is skin outbreak or hair loss a problem for the women who are trying Passion Rx? Many thanks for your research and work in formulating herbal and supplement solutions that bring relief to so many.
    We have not had any reports of skin outbreaks and we have no reason to suspect this natural herbal sexual formula increases the risk for cancer. However, on higher dosages, it can lead to shallow sleep. One option is to go slow and take half a capsule daily or every other day. Once the sexual benefits begin, the dosage and frequency of use can be decreased. Taking a long walk in daylight, especially in the early part of the day, can improve sleep patterns.

I am a 37 year old female who has started taking bioidentical progesterone cream for about 2 months now due to low saliva levels . Progesterone / estrogen ratio was 19. 1 ml starting on day 5 through 15 of my cycle and 3 ml on day 16 through 26 and nothing on the rest of the days. I am now experiencing terrible joint pain in hands arms and shoulders and feet. Could this be from the progesterone cream as I have never had joint issues before? So many things that I read is that it should help joint pain. The rest of my symptoms are improving so much and above all my quality of life is sooo much better, but I hurt now. Is it possible that if I stay on it that my body will adjust and get used to it and the pain will subside.
   It is possible that the treatment is causing joint pain. One way to find out for sure is to stop it for a few days to see if the pains go away and then to resume. Sometimes a lesser dose works well, too.

Opinions and feedback
I was just reading your article on bio-identical hormones and seem to want to see double-blind studies and doubt that will ever happen since there is not enough money in bio-identical hormones for any drug company to pay for it. I honestly donít think they are the only way to determine safety. There are doctors that have been using bio-identical hormones for 20 years or more and their patients have low rates of cancer and greatly improved lives. I donít agree with extremely high doses either and do believe one needs to be monitored, in balance and such by someone that knows what they are doing. For myself my life has been greatly improved and after several years I have very clear, cool breast thermography and the fibroids I had have never gotten larger either. I was miserable Ė sickening hot flashes, migraines every week and no libido along with vaginal atrophy. No way do I want to live like that!

Congratulations, Dr Sahelian, on your note of caution regarding the new bio-identical hormones. You may be fighting an uphill battle because it's pretty hard to beat a popular showbiz personality promoting her books and ideas on the Oprah show, claiming to feel better now at 60 than she has ever felt. And I don't blame the women for wanting relief from the symptoms that so many of them are plagued with...God love them. I hope that large studies from recognized schools will prove these hormones to be of value. In the mean time you are wise to promote caution.