Hormone Replacement Therapy for Menopausal Symptoms

Hormone replacement therapy, or HRT, is a form of medication often used to treat the symptoms of menopause. According to the National Institute on Aging, menopause is the point in a female’s life twelve months after she has had her last period. The time leading up to menopause, often called perimenopause, is a transition stage when levels of sex hormones, namely estrogen and progesterone, begin to fall. For approximately eighty-five percent of menopausal females, that decline results in symptoms such as vaginal dryness, shifting moods, and hot flashes, or an abrupt feeling of warmth typically in the upper body. HRT replenishes a person’s sex hormones, and though there are many methods of HRT, people most commonly take a pill that contains either estrogen only or both estrogen and progesterone. HRT has evolved scientifically but has at times resulted in controversy over potential side effects. Despite historical controversy, as of 2024, researchers recognize that with careful consideration of an individual's health conditions and history, HRT can be an effective treatment for menopausal symptoms.

1. The Primary Female Sex Hormones
2. Early Hormone Therapies
3. Growing Use and Side Effects of Hormone Replacement Therapy
4. Hormone Replacement Therapy in 2024

The Primary Female Sex Hormones

HRT aims to replicate the important roles that estrogen and progesterone play in maintaining female body systems, such as the female reproductive system. Ovaries, which are organs in the female reproductive system, secrete the sex hormones estrogen and progesterone. Both estrogen and progesterone help maintain the function and development of the female reproductive system. Estrogen hormones also assist in the development of secondary sex characteristics, which are characteristics that correlate with a person’s sex but are not directly involved in reproduction, such as the growth of breasts, facial hair, or pubic hair. Both progesterone and estrogen maintain the menstrual cycle and work to create an optimal environment for the fertilization of an egg cell in the uterus, another organ in the female reproductive system. Furthermore, both hormones assist in various parts of the process of pregnancy, such as the growth of the uterus as the fetus develops. Additionally, estrogen hormones help maintain more than the reproductive system and assist in the functioning of the skeletal, cardiovascular, and central nervous system. Since both hormones help support multiple body systems, their depletion results in various symptoms during menopause such as vaginal dryness, hot flashes, and osteoporosis, or brittle bones. In the late nineteenth century, as researchers began to better understand the role of hormones in menopausal symptoms, they aimed to find ways to replace those lost hormones, which eventually led to HRT.

Early Hormone Therapies

In the late 1800s, researchers created some of the earliest forms of treatment for menopausal symptoms using forms of ovarian tissue. In 1896, Ferdinand Mainzer, a medical student from Berlin, Germany, and Richard Mond, from the University of Kiel in Kiel, Germany, independently conducted two studies investigating how to treat female patients who either had their ovaries removed, or who were suffering from menopausal symptoms. Most of their patients were experiencing sexual dysfunction, which includes a variety of issues that result in one not being able to experience sexual satisfaction from sexual activity. Both Mainzer and Mond used bovine ovarian tissue to treat their patients, and the patients experienced major reductions in sexual dysfunction.

While some researchers were exploring early forms of treatment for menopausal symptoms around the same time, others began investigating hormones released by the ovaries. In 1898, Gustav Jacob Born, a researcher who studied cells and embryology, and another researcher, Louis August Prenant, independently proposed that the corpus luteum, a cyst found within the ovary that appears during every menstrual cycle, released a hormone that helped implant a fertilized egg in the uterus. Future researchers realized that the secretion was a hormone, and they called it progesterone. Then in 1889, Charles-Édouard Brown-Séquard, a physician who researched neurology and physiology, injected himself with testosterone extracts from guinea pig and dog testicles and stated that it rejuvenated him at seventy-two years old. Testosterone is a hormone that is primarily involved in male sexual development and in developing male sex characteristics, such as a deeper voice, and it is produced by the testes, an organ involved in male reproduction. According to Thom Rooke, an author and physician in Rochester, Minnesota, all the research surrounding sex hormones was propelling a new era of pharmacology, or the study of drug development and how they interact with the body or other biological systems.

In the 1890s, a pharmaceutical company based in the US created and sold the product Ovariin, a drug made from cow ovaries, in the forms of flavored powder and pills. According to Grace Kohn and colleagues, a group of US-based researchers studying the history of estrogen, the product effectively treated symptoms of menopause, and Rooke also explains that the treatment was an instant success. Furthermore, Kohn and colleagues explain that researchers at the time understood that hormones in the ovarian tissue treatments were easing the menopausal symptoms, yet they did not know the specifics of the hormones until the twentieth century.

In the early twentieth century, researchers began studying hormones in more depth, and in the 1920s they started trying to extract and isolate estrogen. In 1917, according to Kohn and colleagues George Papanicolaou, a physician and researcher studying the female reproductive system and cancer, became one of the first to accurately describe the function of estrogen, or what researchers initially called the primary ovarian hormone, in guinea pigs. In 1923, researchers Edgar Allen and Edward Doisy from St. Louis, Missouri, were among the first to find that the ovaries produce and contain the primary ovarian hormone. Allen and Doisy were also some of the first to extract and partially isolate estrogen. Chemists typically use extraction to remove a specific compound, for example, a hormone, from a mixture, while isolation is the process of purifying the resulting impure extract. Isolating hormones and other compounds or chemicals help ensure that medications do not contain undesired products, since those undesired products could cause harmful side effects.

In the late 1920s, researchers began to extract and isolate progesterone, and they also finished isolating the pure form of estrogen. In 1928, at the University of Rochester in Rochester, New York, Willard Allen, who was a medical student at the time, and George Corner, an anatomy professor under whom Allen worked, published works confirming that secretions from the corpus luteum, later called progesterone, were pivotal to the implantation of an embryo into the walls of the uterus. Future researchers called the secretion from the corpus luteum progesterone. They also created some of the first impure extracts of progesterone. In 1929, two researchers independently determined how to isolate the pure form of estrogen. While researchers were still in the process of purifying progesterone, they knew more about estrogen, so pharmaceutical companies began producing and distributing estrogen-based treatments. They did so by extracting and isolating the hormone itself instead of using crushed animal products, such as the ovaries that they used previously.

In the early 1930s, researchers started using the urine of pregnant women to extract estrogen and produce forms of hormone therapy, and researchers also determined how to create consistently pure forms of progesterone. Around that time, James Bertram Collip, a researcher studying biochemistry, isolated and created what he referred to as Emmenin, a drug that used estrogen from pregnant women’s urine to treat menopausal symptoms. He worked with Ayerst, McKenna and Harrison, a pharmaceutical company later purchased by Pfizer, to commercialize Emmenin, and in 1933, the company started selling the drug in the US. Around the same time, in 1934, researchers from all over the world, including Allen and Corner, finally figured out how to isolate and synthesize progesterone. Then in 1935, the Second International Conference on the Standardization of Sex Hormones, in London, England, gave progesterone its name. Maintaining the production of estrogen from the urine of pregnant women was expensive, leading companies to investigate other sources of estrogen.

Starting in the 1930s and 1940s researchers began to explore different sources of estrogen. To avoid the high costs of using human urine, companies started using hormones from the urine of pregnant horses to create estrogen therapies, and they began marketing the therapies to menopausal women. Then in 1938, Edward Charles Dodds and Robert Robinson, researchers studying biochemistry in Oxford, England, created one of the first synthetic forms of estrogen called diethylstilbestrol, or DES. However, the FDA did not approve DES for that purpose until 1941. Later that same year, Ayerst started producing Premarin, which consisted of isolated natural estrogens from pregnant mares. Soon after, in 1942, the FDA approved Premarin as a treatment for hot flashes only, and Ayerst was able to market it as a way to orally replace estrogen and ease struggles with menopause.

Growing Use and Side Effects of Hormone Replacement Therapy

Throughout the 1940s and 1950s, companies continued making new forms of HRT, and the general approval of it as a treatment for menopause grew as both physicians and popular media praised it for its efficacy. In 1947, a group of physicians referred to as the Physicians’ Desk Reference staff, or PDR staff, published the first edition of the Physicians’ Desk Reference, which was a collection of various drugs, their manufacturers, and recommendations for their use, and it contained over fifty formulations of medications used to treat symptoms associated with menopause. Furthermore, authors and physicians published many articles and books on the effectiveness of HRT in treating menopausal symptoms, which propelled its use into the 1960s. For example, in 1966, author and physician Robert A. Wilson published a book titled Feminine Forever. In it, Wilson drove the point that estrogen-based treatments were a cure-all for any ailments related to menopause, as menopause was just what he called a deficiency disease. Wilson also stated that estrogen treatments would decrease signs of aging and would make women easier to live with, ultimately making them “feminine forever.” Due to all the supposed benefits of estrogen-based treatments, the use of HRT doubled and tripled into the mid-1970s.

Sales for specific brands of HRT, such as Premarin, remained high until the mid-1970s when many women stopped using it because of a newfound association between estrogen-based treatments and an increased risk of endometrial cancer, or cancer in the lining of the uterus. In 1975, estrogen was the fifth most prescribed drug in the US. However, researchers were exploring the effects of estrogen on the body, and in the same year, Harry K. Ziel and William D. Finkle, researchers from Los Angeles, California, claimed that the use of estrogen, or more specifically a mix of estrogens, by itself resulted in an increased risk of developing endometrial cancer. According to Angela Cagnacci and Martina Venier, researchers and physicians in female health, HRT’s reputation declined after the announcement of its possible risks. Researchers began exploring ways to decrease the risks of endometrial cancer associated with estrogen.

In the 1980s and 1990s, HRT became more accepted again by women and physicians as researchers continued exploring its benefits and finding safer dosages and hormone combinations. Researchers noted that decreasing the dosage of estrogen and adding progesterone to the treatment decreased the risk of endometrial cancer. Thus, they posed that the combined HRT was better suited for females with a uterus. HRT continued to gain approval for its uses, especially when, in 1988, the FDA approved it for the treatment of osteoporosis along with hot flashes. Furthermore, many observational studies suggested that HRT could prevent chronic diseases. For example, researchers at the time linked estrogen therapy to decreased rates of heart disease. The American College of Physicians created guidelines for the use of HRT as a preventative method for chronic diseases, like heart disease. However, researchers at the time worried that too much progesterone would counteract the protective effects that estrogen had against heart disease. Therefore, the FDA demanded additional tests to examine the supposed cardiovascular benefits that HRT had, and those tests began in the 1990s and continued into the 2000s.

Initiated in 1992, the Women’s Health Initiative, one of the first long-term studies that aimed to research and improve the health conditions associated with postmenopausal females in the US, examined HRT’s ability to prevent cardiovascular disease. The WHI study found that HRT did not prevent cardiovascular disease, leading to a significant decline of its use. The WHI tested the use of both estrogen-only hormone therapy a combined hormone therapy, which contained estrogen and progestin, a synthetic form of progesterone. In 2002, the WHI stopped the combined hormone therapy portion of the trial earlier than the organization initially planned since the researchers of the study observed too many risks. The researchers noted that females who took the combined hormone treatment were at a higher risk of coronary heart disease, stroke, and pulmonary embolism, which is when a blood clot gets stuck in the arteries of the lung, as well as a small increased risk of breast cancer. Eighteen months later, the WHI also stopped the estrogen-only trial because they observed that the estrogen-only treatment presented the same risks as the combined hormone trial, other than a decrease in the risk of breast cancer.

Hormone Replacement Therapy in 2024

Although HRT decreased in use in the early 2000s due to the WHI’s findings, as of 2024, researchers have critiqued the WHI for focusing on females who were older and well past experiencing menopausal symptoms. Researchers have noted that because the subjects in the WHI study were sixty years or older, they had a higher risk of developing many of the health conditions the WHI noted, such as strokes or heart attacks, regardless of whether they were using HRT. Thus, researchers, such as Sarah McKay, an author who studies neurology, argue that there might be a window of time, around when they are in their fifties, where females taking HRT would acquire most of its benefits instead of its possible side effects. 

Though the WHI findings caused setbacks in HRT use, as of 2024, many researchers and physicians are raising awareness that the understanding of HRT has changed. As early as 2004, a study published by Shelly R. Salpeter and colleagues, a group of researchers and physicians from the US, describes that females younger than sixty on HRT have a thirty-nine percent lower mortality risk than those who are not on any HRT, highlighting a major benefit to the treatment. However, some physicians still relied on the WHI’s conclusion and, thus, were hesitant to prescribe HRT to their patients. According to JoAnn Manson, one of the chief investigators of the WHI study, it has been hard to get information out about the newer studies of HRT on the treatment’s benefits in the decades since the WHI study. She has also emphasized that women who are appropriate candidates for HRT are unsure about treatment for their menopausal symptoms, due to the confusion surrounding HRT. Thus, researchers such as Avrum Bluming, an oncologist, and Carol Tavris, a researcher who studies social psychology, published a book in 2018 called Estrogen Matters to promote a better understanding of HRT and clear up the misconceptions surrounding it. As of 2024, other physicians, researchers, and authors continue to create various works, such as news articles, to promote new knowledge surrounding HRT. 

In 2024, physicians still prescribe HRT to supplement the low levels of hormones in menopausal women. The treatment contains forms of either estrogen or estrogen and progesterone to help ease symptoms of menopause. Physicians primarily give a form of estrogen-only treatment to those who no longer have a uterus, while they typically give combined HRT with a form of progesterone and estrogen to individuals who still have a uterus to avoid increasing their risks of endometrial cancer. HRT still primarily treats symptoms such as hot flashes and bone loss, but physicians also prescribe it to reduce forms of vaginal discomfort, such as dryness or itchiness, and mood changes. Women can take HRT either orally or through the skin in the forms of pills, patches, creams, gels, vaginal inserts, or sprays. The method that a person takes primarily depends on the symptoms they are experiencing, along with a physician’s recommendations. For example, if a person is experiencing only vaginal symptoms such as vaginal dryness, a low-dose vaginal cream might be the better option than a pill or patch.

There are alternatives for people who cannot take HRT to treat menopausal symptoms. For example, physicians avoid prescribing HRT to menopausal females with cancer, as the hormones could worsen their conditions. In those cases, physicians can prescribe medications that they would typically prescribe to treat other health conditions related to the symptoms a person is experiencing. For instance, physicians may prescribe antidepressants to treat symptoms such as hot flashes and depression itself.

Physicians’ willingness to prescribe HRT has fluctuated from the late 1800s to the 2000s due to the supposed side effects that researchers proposed could result from HRT. In the early 2000s, the public shift in attitude toward HRT was negative, but then, in the 2010s, researchers found that HRT risks are often rare compared to its benefits. Around eighty-five percent of females have experienced a menopausal symptom, and HRT may be a possible treatment for many of them. Researchers continue to study HRT, but with careful consideration of an individual's health background and age, HRT may be a beneficial option for many females experiencing menopausal symptoms.