There is no question that hormone replacement therapy in menopausal women has been a subject of significant confusion and controversy among medical providers and patients alike. The general public has also been subjected to a plethora of misinformation and direct-to-consumer marketing of various products of unproven safety and efficacy.
Fortunately, we now have a significant body of evidence that allows us to support women through this phase of their lives and beyond. Unfortunately, there has been a rather slow uptake and adoption of the new evidence on the part of the medical community. In order to understand where we are today, we need a little bit of history behind this topic. About 25 years ago, the National Institute of Health conducted a large randomized controlled trial called Women’s Health Initiative (WHI) to study the impact of hormone therapy on heart disease risk. In July 2022, NIH terminated the study prematurely when the initial results indicated an increased risk of heart disease in women using the hormone replacement therapy involving conjugated equine estrogen (Premarin) and medroxyprogesterone acetate (Provera). As a result of this announcement, most patients on hormone therapy discontinued their treatment. Following this, most professional organizations and government agencies recommended the use of hormone replacement therapy only for those women having severe symptoms around the time of menopausal transition for a limited period of time. In the intervening years, the use of non-FDA approved compounded hormones in the form of creams, drops, and injectable pellets, etc. proliferated as it was marketed as bioidentical hormone replacement therapy (BHRT) implying that these were safer and more effective alternatives to traditional hormone therapy. The truth is that these compounded hormones have never been demonstrated to be safe or effective. They have not been subjected to any scientific studies. The basic ingredients of the compounded hormones are imported from other countries and simply compounded in this country. They are not “natural” hormones as they are all synthesized in chemical laboratories. There is no data to show the purity, safety or efficacy of these compounded hormone products. This is why the American College of Obstetricians and Gynecologists does not recommend the use of these products. They are often very expensive, and the prescriptions are not covered by insurance companies because they are not approved by the FDA. But many women are happy to pay out-of-pocket for these hormones believing that they must be worth the cost.
It is now a well-established fact that 17 beta-estradiol (estrogen hormone produced in the human ovary) effectively relieves most symptoms associated with menopause while preventing the development of osteoporosis. Osteoporosis-related fracture has become a major public health challenge in older women. This frequently leads to surgery, prolonged immobilization, significant pain, and premature death. There is also credible evidence that estradiol decreases the risk of breast cancer and heart disease. It should be noted that the WHI study mentioned above used conjugated equine estrogen and medroxyprogesterone acetate (progestin hormone) which are no longer used in the current hormone replacement therapy. Even then, these hormones were not associated with increased risk of breast cancer and were found to be effective in decreasing the incidence of osteoporosis and colon cancer. In addition, the average age of women participating in the WHI study was 64 which turned out to be a crucial factor that led to a misleading conclusion.
To be clear, it is important to understand the differences between the hormones used in the WHI study and those in common use today. The estrogen used in the study was conjugated equine estrogen (CEE, Premarin) which was extracted from pregnant mares’ urine. There are two estrogen receptors called alpha and beta. CEE binds predominantly to the beta receptors whereas 17 beta-estradiol binds equally to both receptors. CEE is far more active in increasing certain inflammatory markers. The early increase in heart disease seen in the study is most likely due to the atherosclerotic plaque destabilization and rupture in the artery supplying the heart muscle. Medroxyprogesterone acetate (MPA) is the progestin used in the study that is potentially associated with increased breast cancer risk and adverse effects in lipid metabolism. However, long-term follow up of the original WHI study patients using both CEE and MPA showed no increase in breast cancer risk whereas CEE alone (used in women after hysterectomy) users had a significantly decreased risk of breast cancer. Oral estrogen of any type and synthetic progestin MPA appear to be associated with an increased risk of blood clot formation.
17 beta-estradiol and micronized progesterone (both natural hormones produced by the human ovary) do NOT carry the same risks as the hormones that were used in the WHI study and are safer for patients. Many studies have shown that estrogen (17 beta-estradiol) may protect against the heart disease, especially when therapy is initiated within the first 10 years after the menopause. It is likely that women in the WHI study experienced early increase in the risk of heart disease due to the fact that average age was 64 and significant atherosclerotic plaques were already formed. When estrogen is started, it can cause destabilization of the plaque and rupture leading to cardiovascular events like a heart attack.
Considering all of the above evidence, my current recommendation for hormone therapy is as follows:
- Estrogen patch (17 beta-estradiol)- It is continuously absorbed through the skin and maintains steady hormone levels. It does not go through the liver (as does oral administration) and does not increase the risk of blood clots. It is changed once or twice a week.
- Oral micronized progesterone- because it is not absorbed well through the skin. Synthetic progestin is available in a patch form, but I do not generally recommend it due to potential adverse effects. Progesterone is not needed in women after hysterectomy as the sole function of progesterone is to decrease the risk of uterine cancer.
- Vaginal estrogen (estradiol) therapy is used in women who experience vaginal dryness and painful intercourse but cannot use the estrogen patch for any reason. The newer low dose formulation (Vagifem or Imvexxy) is preferred instead of cream which can be messy and . Vaginal estrogen therapy is not effective in reducing hot flushes. Furthermore, it is not effective in preventing osteoporosis or heart disease. Nonhormonal alternatives include Osphena (pill) and Imtrarosa (vaginal inserts).
- Testosterone therapy is not approved by FDA for use in women. However, it may be beneficial for postmenopausal women with hypoactive sexual desire disorder (decreased libido). It is available in cream.
- Nonhormonal treatment options for menopausal symptoms include oral paroxetine, venlafaxine, and gabapentin. These are not as effective as hormone replacement. They also do not have a positive impact on bone density or heart disease.
PAUL H EUN, MD, FACOG Dr. Eun is a board-certified obstetrician and gynecologist at Dedicated Women's Health Specialists. Dr. Eun has many areas of special interest and expertise which include minimally invasive surgery, pelvic prolapse, and incontinence. In addition, he is a principal investigator for many clinical research projects in women's health.