By the time we reach menopause, our ovaries have pretty much quit producing the two major types of female hormones – estrogen and progesterone. There is still a small amount of these hormones circulating in our systems, but at levels far lower than during our reproductive years. The loss of estrogen leads to a number of symptoms (primarily hot flashes and vaginal dryness), as well as a host of medical issues, which will be discussed in future posts. It is still a little unclear about how the loss of progesterone affects us long term – and so, right now, it plays only one major role in hormone replacement therapy (to be discussed shortly).
Because the loss of hormones affects women in many ways, it would seem logical that replacing them would be a good idea. However, this has turned out to be a hugely controversial issue over the last 75 years. Many of my future posts will be addressing this complicated subject, but the theme of this article is to discuss which kinds of hormones are the best if you are considering taking them.
The two main estrogens circulating in our bloodstream are estradiol and estrone. A third type, estriol, is primarily present during pregnancy and is a very weak estrogen. Most products prescribed for HRT contain estradiol, and this is labeled as 17-beta-estradiol. Most of the products containing estradiol or estrone are created by chemically converting estrogen-like compounds found in plants, such as yams and soy. Estradiol is available in generic forms and comes in pills as well as a variety of preparations designed to be applied to the skin (in creams, gels, sprays, and patches). Estrone is also available in a pill form. You probably have heard of Premarin, which was the first estrogen preparation approved for HRT treatment back in the 1950s. It is obtained through the purification of pregnant horses’ urine (thus the name derives from pregnant mare’s urine). Half of Premarin is estrone and the other half is a mixture of estrogens unique to horses. Since the body converts estrone to estradiol, all of these preparations essentially can provide similar levels of estradiol in the bloodstream, which is the main active form of estrogen. When we give menopausal women hormone replacement treatment, the goal is to provide enough estradiol that would make the level in their bloodstream at the low end of where it was during their reproductive years.
I will go into more detail in future posts about these various estrogens, but for the purpose of this discussion there are two principle take-home points to be aware of:
- The distinction between taking horse-derived estrogens and pure estradiol
- The distinction between taking estrogens orally in pill form vs. estrogen applied directly onto the skin (topically)
We used to think that all forms of estrogen behaved the same way in the body. Now we realize that horse-derived estrogens do act a little differently. This is because, although the estrone component is converted to estradiol, the estrogens unique to horses have some different effects than our natural estrogens. In future blogs, I will be going into the details of what we know, but for the most part, there is not a huge overall difference in the way the different oral estrogens affect our heart, bones, and clotting system. Interestingly, women taking Premarin may actually have a decreased risk of breast cancer.
The bigger issue becoming apparent is that estrogen behaves differently depending on how it enters our system. When a pill is taken by mouth it goes into the stomach and then travels directly into the liver. This flood of estrogen causes the liver to manufacture various proteins that can have other consequences in the body – some positive and some negative. Oral estrogens trigger a lowering of bad cholesterol, which can help decrease the risk of heart attacks. On the other hand, they can increase the risk of gallstones, as well as blood clots.
Estrogen applied onto the skin seeps into the bloodstream slowly and doesn’t travel immediately to the liver – thus, it does not trigger the same effects as oral estrogen. To put it simplistically, the way this form of estradiol is delivered most closely resembles the way the ovary releases estrogen, and so perhaps is the most “natural.” One major benefit is that these transdermal estrogens do not appear to increase the risk of blood clots.
Let’s move on to progesterone. During our reproductive years, the natural progesterone in our body plays a major role in our menstrual cycles and pregnancies. After menopause, it was generally believed that progesterone no longer had much use and so for many years menopausal women were treated only with estrogen – until it was discovered that this increased the risk of uterine cancer. Around 1970, it was conclusively shown that adding a progesterone-like drug would prevent this. So now, it is the standard of care that women always take a progesterone-like drug in addition to estrogen if they have a uterus. Women who have had a hysterectomy don’t need to worry about this risk so they continue to be treated only with an estrogen.
Until recently, the natural progesterone our body makes was not available as a pill because it was difficult to produce in a form that could be easily absorbed. So, a number of progesterone-like drugs were formulated. We refer to these as synthetic progestins. These products are structurally very different than our natural progesterone. Most of the studies examining the benefits and risks of HRT have been conducted using synthetic versions. For years, we assumed these products behaved similarly to natural progesterone in the body, but we now know they can have some adverse effects, and in fact, they may be partly responsible for some of the negative consequences of HRT, such as an increased risk in breast cancer and heart disease. I will be discussing much more about these important issues in future posts.
So, in summary, what is best? More research needs to be done to know with certainty, but at this point, most experts are leaning toward recommending a topical estradiol – in the form of a patch or cream – and natural oral progesterone as the best choices. These forms appear to have the least risk of adverse effects. It is important to realize, however, that even if it turns out that other types and forms of HRT have more risks, the absolute risk of an adverse event is quite low.
Another great post!
Valuable information! Thank you.
Thanks for the clarifying article! I have been taking hormones since I was 46, in the firm of a transdermal patch and oral progesterone derived from yams. I am the daughter of a nurse and also a science teacher, so I did my homework on the study. I DID have trouble obtaining hormones at first, but went to the U of M and found my Dr. that would help me along with some great nurses. I was not sleeping due to hot flashes. It was ruining my life, and by that, I mean, I was exhausted, emotional from no sleep and had to stare down classrooms of 35 students and do hours of prep. I was a wreck. I could not exercise because I was so tired. That lasted two weeks. Once I was able to get the hormones, I slept like a baby, was happy, exercising, liking my job and kids and working on my old house. By comparison, my friends who were afraid to take hormones because of the study and their doctor’s refusal ended up taking anti-depressants, gained considerable weight, still did not sleep and had limited exercise due to fatigue. I am quite happy to be taking them now, at 62. I am part of CARDIA, a heart study I have been in since I was 35. They do know I take hormones but I will ask them if anyone is researching any of the women that are on hormones to see if this has affected outcomes on heart disease. At any rate, I am happy, healthy, sleeping and exercising. I have a wonderful doctor who understands hormones and supports me. I would encourage all women to read your column and book.
Hi Cynthia, thank you for your comment. When a medical treatment is controversial, such as HRT, women really need to evaluate the benefits and risks. So kudos to you for taking charge of your health and doing the research into hormone therapy. I love that you are a science teacher and were able to use your intelligence and instincts to come to your decision. Too many women simply put up with hot flashes thinking the “cure” is worse than the cause, when in realty for most women the benefits of HRT substantially outweigh the potential risks.
With respect to heart disease we know that women going through early menopause (especially women who had to have their ovaries removed) have higher risks of heart disease. It is reasonable to suspect that it is the loss of estrogen that causes this and a number of large observational studies have found that women who take HRT have lower risks of heart attacks. However, we don’t have a definitive clinical trial that “proves” that taking HRT at the time of menopause decreases the future risk of heart attacks. I am confident a study enrolling newly menopausal women would uphold the results of the observational studies. (The younger group of women on HRT in the WHI did not have an increased risk of heart disease, and in fact the women on estrogen showed a decrease in risk.) What I find frustrating is that we are in a “catch-22” regarding doing such a study of HRT in younger women. There is not much financial incentive, and the current guidelines do not advise HRT for preventative therapy. So the best thing we can do is educate women. Please reach out and recommend my book to anyone who you think may benefit from it.
Thank you for the article Dr. Rice. Can you comment on the name of the natural oral progesterone I should ask my doctor for? I’m currently on a low dose estradiol patch and an oral progesterone that is generic for a “progestin” and I’m concerned about taking a progestin. Thank you,
Hello Kathy, your question brings up an excellent point, and that is there is a lot of confusion about all the terms we use to describe progesterone. The term progestin and the term progestogen are terms that apply to any type of drug that has progesterone-like actions in the body. So your progesterone pills are considered to be a progestin. The original brand name for oral progesterone is Prometrium, but now there are a number of generic progesterone pills and they come in 100 mg and 200 mg sizes. We call these products “natural” progesterone because they are made from plant sources and formulated to be the exact same molecule as the progesterone made by the ovary. The other progestins, such as such as medroxyprogesterone, levonorgestrel, drospirenone, and many others have chemical formulas that are different than natural progesterone. A lot of times we simply call these types of drugs “synthetic progestins.” These behave differently in the body than natural progesterone and so intuitively it seems like the best progestin to use for HRT is natural progesterone and that would be the drug to request, which it sounds like you have. I am guilty in using the term synthetic progestin to refer to anything that isn’t natural progesterone, so I’m sorry if I caused confusion.