This past July, after convening a panel of experts to review the safety of estrogen products, the FDA announced that it is removing the black box warning on these products.
The warning was added to these products back in 2003 over concerns that they might increase the risk of certain conditions such as breast cancer, heart disease, blood clots, and potentially dementia.
The warning was issued based on a severely flawed study on menopausal hormone replacement called the Women’s Health Initiative (WHI). There were a number of glaring deficiencies in this study that were carelessly overlooked.
The hormones used in this study were derived from pregnant horses’ urine. Furthermore, they were all given orally. There was no evaluation of hormones administered transdermally or injected subcutaneously. The progesterone or progestins were administered daily with no breaks.
Furthermore, the population of women in the study were at least 10 years post-menopause or older, so that it was conceivable that the illnesses they developed may have already been developing at the time they started to take the hormones.
There was also a subgroup of women in the study that had hysterectomies. This subgroup was not given any progestins. They showed the same rate of developing breast cancer taking the oral estrogens without progesterone compared to the control group of women who did not take any hormones.
This finding, in the hysterectomy subgroup, was basically ignored by the researchers when they generated their conclusions. Probably because they failed to understand it, and it didn’t fit into the general conclusions.
What is a Black Box Warning?
Black box warnings are specific health concerns that manufacturers of medications are required by law to apply to labels of medications.
Removing the black box warning on estrogens is a huge step forward towards more general acceptance of menopausal hormone replacement therapy for women gaining mainstream medicine acceptance.
WHAT IS DIFFERENT ABOUT HORMONES TODAY?
As I mentioned, the hormones studied in the WHI were all oral, derived from pregnant horse urine. Today’s hormones are extracted from plant sources, thus termed bioidentical. They are chemically identical to the hormones made in the human body. In addition, they are not administered orally, which makes a big difference. Oral hormones undergo what is called First Pass through the liver. In other words, the hormones are absorbed from the stomach and GI tract and go directly to the liver via the portal vein. This produces a high concentration of hormone to the liver all at once. This surge of hormone to the liver can increase the liver’s stimulus to produce clotting factors, which can lead to blood clots.
Today’s hormones are administered through the skin or under the skin. Since they don’t enter the GI tract, they are absorbed directly into the bloodstream. By the time they reach the liver, they are very dilute. Therefore, they don’t increase the risk of blood clots.
Progesterone is the only female hormone that can be administered orally, safely, without the risk of increasing clotting factors. So, progesterone is often taken orally with no problems.
DOES TAKING ESTROGEN INCREASE THE RISK OF BREAST CANCER?
This question has been a raging controversy for decades. And, it is generally thought that it does. However, a review of the world literature on female hormone replacement, published in the LANCET in 2017 concluded that estrogen by itself did not increase the risk of women developing breast cancer. This conclusion was based on many studies of women who had hysterectomies, taking all sorts of different estrogen preparations. But, the big difference with these women’s hormone regimens was that they didn’t take any progesterone. These women, including those in the WHI, had the same rates of developing breast cancer as women who never took hormones. Women who never take hormones still get breast cancer. It was therefore surmised that it was the addition of progesterone (or progestins) to the hormone cocktail that actually increased the rate of breast cancer. This finding is quite surprising. But, it has been confirmed in many hormone studies with various estrogen preparations.
I assume that when the panel of experts reviewed the available data on women’s hormones, this was the reason they decided to remove the black box warning on estrogen products.
The women with the highest rate of developing breast cancer on hormones were those who took progesterone every day.
Women who took cyclical progesterone (two weeks on and two weeks off) had a slightly higher rate of breast cancer than women who took no progesterone, but significantly lower than women who took progesterone daily.
It is necessary for women on estrogen replacement therapy (ERT) with an intact uterus to take some progesterone, or they run the risk of having “unopposed estrogen” stimulation to the uterus, which can lead to uterine cancer. The progesterone serves to protect the uterus and is therefore required for women with a uterus taking estrogen.
The interesting conclusion to this observation is that it’s the progesterone schedule which seems to be the culprit in increasing the risk of breast cancer from menopausal hormones, and not the estrogen as is so commonly thought.
This makes perfect sense physiologically. The only time in a woman’s life that she has daily progesterone is during pregnancy. Pregnancy is a relatively short period of time. So to put women on daily progesterone for prolonged stretches of time is very unnatural. It then seems logical that an unnatural hormone pattern would cause problems. Additionally, progesterone is a pregnancy hormone. Its job is to prepare the mother for the birth of a child, which includes stimulating the breasts to produce milk. It therefore further stands to reason that a hormone stimulating the breasts for an indefinite period of time will cause problems. And it does.
THIS IS A HUGE STEP FORWARD IN WOMEN’S HEALTH
Needless to say, the FDA’s action of removing the black box will serve to significantly help advance the use of postmenopausal hormone replacement, as more doctors become comfortable prescribing it, and more women feel more comfortable taking them.
If you or someone you know is interested in using hormones, call or email the office to set up a time to discuss it.
Dr. Howard Liebowitz
Disclaimer: These statements have not been evaluated by the Food and Drug Administration. This article is not intended to diagnose, treat, cure or prevent any disease.
