Hormone Replacement Therapy for Women. Primer Part 1: Estrogen
By Lael Luedtke, MD
As was discussed last month, hormone replacement therapy (HRT), treats more than hot flashes and night sweats, and it involves more than estrogen. However, estrogen is the foundational hormone to address the myriad manifestations of menopause and is available commercially in many forms, so we will start here. Individual goals and needs are the most important determinants of the “best” option for any woman.
Optimization must take into consideration all the consequences of perimenopause and menopause, and this includes both symptoms that are obvious and other changes that are harder to notice. Of course, the vasomotor symptoms (night sweats and hot flashes) impact quality of life immediately, and we want to address that. B but arguably, other aspects of menopause have less noticeable symptoms but an even greater impacts on women’s healthspan. For example, , such as bone density and fracture risk are key elements that we also need to worry aboutk even though they are less symptomatic in the moment. The best choice also depends on whether the patient is looking at systemic versus localized vaginal HRT.
Choosing the Right Form of Estrogen
The systemic form of HRT used is first determined by whether a woman still has a uterus. Using only eEstrogen use only in women with a uterus can lead to overgrowth of the uterine lining with a risk of cancer of that lining, so progesterone or progestin must be used. If a woman is in perimenopause, birth control must be kept in mind as well.
Many people are familiar with Premarin or Prempro, which are frankly old fashioned, last century, forms of hormone replacement and are not considered first line treatment. The hormones come from pregnant mare (horse) urine, which includes a variety of estrogens, some of which are not found in humans. Premarin was first approved by the Food and Drug Administration (FDA) in 1942 and somehow became the dominant form of HRT in the 20th century. A better, more modern, option is estradiol: the form of estrogen actually found in humans! Surprisingly, estradiol was identified and the first form synthesized in 1933, and additional forms became available in the 1960’s and 1970’s. Estradiol is one of several forms of estrogen in humans and is the form created in the ovaries. Premarin was first approved by the Food and Drug Administration (FDA) in 1942 and somehow became the dominant form of HRT in the 20th century.
Estrogen replacement has evolved not only in the specific compound used, but also in the method of delivery. Premarin/Prempro was almost exclusively available as an oral preparation, and that route of administration is responsible for some of the negative consequences of HRT. When estrogen is taken orally, the hormone is absorbed in the gut and passes immediately through the liver where it is converted into other compounds and stimulates the creation of blood clotting factors. Because so much of the estrogen is lost to conversion, larger doses are required for the desired effect. Further, the blood clotting can lead to clots in the legs and even stroke. These same impacts can be seen with oral estradiol as well.
Absorption of estradiol through skin or vaginally avoids the reactions within the liver and thus a lower dose can be used; and the clotting issues are also diminished. Transdermal estradiol comes in several different forms and dosing regimens. Estradiol patches are well tolerated and commonly available in either twice weekly or weekly versions. A gel formulation comes in either a pump or a packet that is applied to skin daily. Estradiol mist likewise is used every day on the forearm. Delestrogen and Depo-Esstradiol are injectable options used monthly.
Vaginal forms of estradiol are used in two different ways. A vaginal ring provides systemic blood levels of HRT, thereby addressing issues such as the brain fog, bone health, etc, not just local symptoms. This long-acting form is replaced every 3 months but also faces such hurdles as prior authorization for insurance coverage. For those individuals seeking relief from more localized phenomena such as genitourinary syndrome of menopause (GSM) or painful intercourse, tablets or creams can be used locally and applied daily. There is also a locally used compound using DHEA (a precursor to both estrogen and testosterone) that is highly effective in addressing GSM.
One treatment option that is non-hormonal but is widely advertised and bears mentioning is neurokinin based. One widely advertised non-hormonal treatment option worth highlighting is neurokinin-3 receptor antagonists, which are used to manage hot flashes in menopausal women and provide an important alternative for those who are unable to use hormone therapy. This category of drugs, such as elinzanetant (Lynkuet) or fezolinetant (Veozah), blocks the receptors that regulate temperature. These drugs can be effective in the vasomotor symptoms of perimenopause and menopause but do not have some of the other benefits accrued from HRT.
How to Choose the Right Option
Given the wide variety of options available for management of perimenopause and menopause, deciding on the best option for any one woman requires a thorough discussion with her health care provider. Understanding the data deeply will provide a more thoughtfully considered treatment plan than a simple knee jerk reaction to headlines, which unfortunately have persisted in discouraging women from getting much needed help. (See the discussion of the Women’s Health Initiative in last month’s article.) The FDA has finally removed the terrifying black box warning on estrogen products in November 2025 that was not supported by the data. The nearly universal safety profile, especially of the low dose vaginal products, has been recognized. In the announcement, the FDA even went so far as to describe the warnings as an “American tragedy.”
As mentioned last month, estrogen is not the only hormone impacted by menopause. Progesterone and testosterone also play important roles in women’s well-being. Indeed, progesterone is essential for women with a uterus who are using estrogen replacement. Options and indications for their use will be discussed next in our next postmonth.
Reference
Levy B, Simon JA. A contemporary view of menopausal hormone therapy. Obstet Gynecol. 2024;144(1):12-23. doi:10.1097/AOG.0000000000005553
