Hormone replacement therapy is not usually my first recommendation, but it does have its time and place. Let’s review a great paper detailing the pros and cons of bioidentical versus synthetic hormones.
Dr. Michael Ruscio: Bioidentical versus synthetic hormones—what’s better for your health?
Hi, this is Dr. Ruscio, and just the other day I had a patient walk into the office who is a nurse anesthesiologist, and she was on a synthetic estrogen replacement patch. I went into my normal spiel about the pros and cons and some of the dangers associated with synthetic hormones, and she seemed receptive but a little bit unsure because she hadn’t heard any of this information before. So I said, “I’ll tell you what. I’ll send you a paper on the issue. Give it a read, and then let me know what you think.” Well, she came back in two days later, and she said, “I’m totally convinced. I want to switch to bioidentical.” So I thought I’d review this research paper Trusted SourcePubMedGo to source, which is one of my favorite research papers on the topic, to help give you a synopsis of the same thing.
The paper I’ll be discussing today is by Kent Holtorf, and he is a medical doctor who did a great review paper on the risks and benefits associated with synthetic versus bioidentical hormones. To jump right in, we’ll start with his conclusion. “Physiological data and clinical outcomes demonstrate that bioidentical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animal-derived counterparts.” He continues, “Until evidence is found to the contrary, bioidentical hormones remain the preferred method of hormone replacement therapy.” There’s his conclusion.
Let’s first define what bioidentical hormones are and what synthetic hormones are.
Bioidentical hormones are exact copies of estrogen or progesterone, and they are typically synthesized from plants. Synthetics are not exact copies, and this is likely why they have undesirable side effects. They’re often synthesized or derived from animals.
So how did Dr. Holtorf arrive at his conclusion? Well, he reviewed three topics: clinical effectiveness, physiological actions on breast tissue, and the risk of breast cancer and cardiovascular disease. Let’s examine some of the evidence supporting his conclusion.
Regarding the clinical effectiveness, let’s look at synthetic versus bioidentical progestins or progesterone. “Progestins” is the nomenclature used for synthetic progesterone, and “progesterone” is the nomenclature used for bioidentical progesterone. He reviewed four studies, and in these four studies, after switching from synthetic to bioidentical hormones, all four groups of women in all four of these studies reported greater satisfaction, fewer side effects, and improved quality of life. Now, again, this was when women switched from synthetic to bioidenticals. All the women in each of these four studies concluded what I’m listing here, and here are the specifics. A 30 percent reduction in sleep problems, a 50 percent reduction in anxiety, a 25 percent reduction in menstrual bleeding, a 30 percent improvement in sexual function, a 60 percent decrease in depression, a 30 percent decrease in body pain, and a 40 percent reduction in difficulty thinking. Overall, 65 percent of the women said they preferred or they felt better when making the switch from synthetic to bioidentical, so there’s some pretty compelling evidence there.
Now, an important note is that synthetic and bioidentical progesterone don’t seem to have much difference on endometrial tissue, but they do on breast tissue. More data is showing negative effects in regards to breast cancer and breast-related disorders than on endometrial tissue in reference to synthetic or bioidentical progestins or progesterone.
Continuing on, looking at the physiological action on breast tissue, looking at synthetic versus bioidentical: Synthetic progestins may increase cancer risk. They may decrease apoptosis, which is an anticancer process. Essentially apoptosis is a process in which a cell recognizes it has now turned into a cancerous cell and then self-destructs, so you want to have good apoptotic function.
Bioidentical progesterone, on the other hand, may decrease cancer risk and may be protective from cancer, as it can induce apoptosis, which again is that cellular recognition of being cancerous, which prompts destruction of the cell. Continuing on, synthetic progestins may increase estrogen-stimulated cell growth that’s associated with cancer, whereas bioidentical decreases estrogen stimulation on breast cells, and specifically this is in the breast epithelium.
Now, synthetics may also convert estrogens into a more dangerous form, and they may increase the formation of cancer-causing metabolites, and specifically, this is the 16-hydroxyestrone. The 16-OH is just a way of showing what estrogens are broken down into. For example, estrone will get broken down into methoxy and then hydroxy estrogen as the body is trying to detoxify and push it out of the body. As this is happening, you can form byproducts that are actually dangerous, and the 16-hydroxy breakdown product has actually been correlated with cancer. Synthetics may increase this dangerous fraction of estrogen known as 16-hydroxy.
Now, switching back to the other side here with the bioidenticals, bioidenticals may downregulate estrogen receptor 1, which is associated with breast cancer, and may also have antiestrogenic effects in breast tissue and decrease breast cell growth and division. What this really means is that estrogen has a stimulatory effect on breast cells, and if breast cells are overstimulated, you may run into cancer. Progesterone has the ability to dampen this division activity that is stimulated by estrogen, so progesterone has a pretty important effect to regulate some of the cancer-promoting effects of excessive estrogen stimulation.
[Start of Video Part Two]
Now looking at the risk of breast cancer, synthetic progestins versus progesterone: I’m quoting Dr. Holtorf here, “Synthetic progestins have been clearly associated with an increased risk of breast cancer,” and probably the best reference for this is the Women’s Health Initiative study. They may increase the incidence of breast cancer, depending on the study that you read, anywhere between 5 and 67 percent.
Now, for bioidentical progesterone, we have no randomized controlled trials doing a direct comparison of synthetic to bioidentical, but we do have randomized, placebo-controlled and observational studies. To quote Dr. Holtorf here again, “Studies have consistently shown a decreased risk for breast cancer when using bioidentical progesterone.” He also cites that population-wide studies show an inverse relationship between progesterone and levels of breast cancer.
So let’s look a little more deeply here at estrogens and their receptors. It’s a fact that there are three types of estrogen: E1, E2, and E3, or estrone, estradiol, and estriol. These are depicted here in this graph. You see E1, E2, and E3. Now, there are also two kinds of estrogen receptors. There is alpha receptor, which promotes cancer, and there’s beta receptor, which actually can be cancer protective. As we see here, estrone, or E1, preferentially binds to the alpha, or cancer-causing, estrogen receptor, where on the other end of the spectrum, estriol preferentially binds to the beta receptor, and the larger arrows are showing more of a binding affinity.
To give you the breakdown again here, E1, or estrone, has a 5:1 relationship to the alpha receptor, so it’s five times more likely to go to the alpha receptor, a 5:1 affinity favoring the alpha receptor. E2, which is estradiol, has an equal affinity for either, and then E3, or estriol, has a 3:1 relationship preferentially binding to the anticancer beta receptor compared to the procancer alpha receptor.
Hopefully that makes some sense. I know it is a little bit of a complicated concept, but it dovetails right into this next slide , which is that we know from observational studies that pregnancy is associated with a decreased risk of breast cancer. Part of the reason for this is because estriol, which preferentially binds to that protective beta receptor, increases by a thousand fold during pregnancy, whereas progesterone also increases by 15 percent.
A quick note on what’s called unopposed estrogen: Unopposed estrogen is when a woman is being given estrogen replacement therapy and nothing else. She’s not being given progesterone along with it. We really should always have these two given together. While there is not much data on this, it is suggested that estrogen should never be given alone because progesterone has a balancing effect on estrogen.
Now, Dr. Janet Lang, I think, is the one who articulated this most eloquently. She said that estrogen causes cells to grow; progesterone causes cells to grow up. Another way you can think of this is that estrogen stimulates cell growth, but eventually cells have to not only grow, but they have to differentiate into the specialized types of cells that they will become. Estrogen provides the growth signal; progesterone provides the differentiation signal. You really want to have both of them so that we can steer cells to grow and the mature into the kind of cells that they are destined to become. If you don’t have controlled cell growth, you have a higher potential for coming down with some kind of hormone-mediated, estrogen-progesterone-mediated cancer.
Risk of heart disease: synthetic versus bioidentical progesterone. To quote Dr. Holtorf again, “The Women’s Health Initiative study demonstrated that the addition of medroxyprogesterone acetate,” which is a synthetic progestin, “to Premarin,” which is a synthetic form of estrogen, “resulted in a substantial increase in the risk of heart attack and stroke.” He continues, “Synthetic progestins produce negative cardiovascular effects and negate the cardioprotective effects of estrogen,” while bioidenticals seem to have the opposite effect.
Really what this means—and this is probably one of the things that you’ve heard of if you’ve looked into hormone replacement therapy—is that the Women’s Health Initiative study, part of this trial was stopped early because of the increased risk of death, and part of that was because of how the synthetic hormones were affecting these women.
Now, synthetics may be damaging because they decrease HDL, may increase coronary artery spasms, may promote plaque formation or atherosclerosis, and may increase insulin resistance. On the other hand, bioidenticals appear to be cardioprotective. They may increase HDL, or your good cholesterol, protect from spasms, decrease plaque formation, and protect from coagulation. So we see here again, not only with breast issues, but also some evidence that from a cardiovascular perspective bioidentical progesterone is better than synthetic progestins.
In summary here again, Dr. Holtorf states, “Until evidence is found to the contrary, bioidentical hormones remain the preferred method of HRT.”
Hopefully, this has given you some food for thought. There is a lot of misinformation out there about hormones, and it is my personal belief, as well as what you can see here from the medical literature, that bioidentical hormones should really be what are used when one is undergoing hormone replacement therapy, and synthetics should be used sparingly, if at all.
This is Dr. Ruscio. I hope this has been helpful. If you have any questions, please feel free to reach out. Remember, synthetic hormones, if you’re on them or thinking about going on them, are something that you should really be careful with, and it’s a much better idea to opt for bioidentical.
I care about answering your questions and sharing my knowledge with you. Leave a comment or connect with me on social media asking any health question you may have and I just might incorporate it into our next listener questions podcast episode just for you!
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