“Management of Endocrine Disease: Optimal Feminizing Hormone Treatment in Transgender People” (2021) by Dorte Glintborg, Guy T’Sjoen, Pernille Ravn, and Marianne Skovsager Anderson

In 2021, Dorte Glintborg, Guy T’Sjoen, Pernille Ravn, and Marianne Skovsager Anderson published “Management of Endocrine Disease: Optimal Feminizing Hormone Treatment in Transgender People,” hereafter “Optimal Feminizing HT,” in the European Journal of Endocrinology. Glintborg and her colleagues compiled information regarding the safe administration of feminizing gender-affirming hormone replacement therapy, or GAHT. Feminizing GAHT uses hormones and medications that alter the effects of hormones in the body to spur development of secondary female characteristics and may also include the suppression of secondary male characteristics. Proper administration of GAHT can greatly improve the quality of life for individuals experiencing gender dysphoria, which is defined as a sense of distress due to a person’s assigned gender not aligning with their gender identity. By providing an up-to-date overview of current and developing practices, “Optimal Feminizing HT” provides physicians with knowledge relevant to tailoring feminizing GAHT to individual patients. 

At the time of publication, Glintborg worked as a physician and professor at Odense University Hospital in Odense, Denmark. Her clinical research subjects included endocrine diseases, transgender care, and bariatric surgery. T’Sjoen worked as a physician and clinical researcher at the Department of Endocrinology and Center for Sexology and Gender at Ghent University Hospital in Ghent, Belgium, where he studied pituitary disease, transgender health and sexual health. Ravn was a physician and associate professor at the Department of Gynecology and Obstetrics at Odense University Hospital, where she practiced medicine relating to pregnancy, delivery, and female reproductive health. Her research subjects included contraception and pregnancy-related complications. Andersen was a clinical professor at Odense University Hospital, studying hormone-related disorders.

Gender-affirming care, including feminizing hormone therapy, has existed since the early 1900s. According to many historians, one of the most prominent practitioners of that work was Magnus Hirschfeld, a doctor working in Germany who dedicated much of his career to the study of gender and sexuality. In 1919, Hirschfeld founded the Institute for Sexual Research in Berlin, Germany. The Institute for Sexual Research functioned as a sexual health clinic and research center, collecting clinical data on transgender individuals and providing gender-affirming care. Hirschfeld performed one of the first gender-affirming surgeries, which was a procedure called an orchiectomy where one or both testicles are removed, in 1921. He also provided feminizing hormone therapy and education on contraception. The Institute for Sexual Research closed following a raid by the Nazi party in May 1933. The Nazis burned research material and caused Hirschfeld to flee the country.

Hirschfeld’s work in transgender healthcare was largely lost after the destruction of his research, but his idea of gender-affirming care persisted. In the United States, the Johns Hopkins Gender Clinic, which operated from 1966 to 1979 at the Johns Hopkins Hospital in Baltimore, Maryland, was amongst the first medical facilities in the country to provide comprehensive care for transgender individuals, including gender-affirming surgeries and hormone therapy. The clinic emphasized the importance of emotional support, such as psychological counseling, for transgender patients as they received treatment. However, historians note that starting in the late 1970s, the gender-affirming care industry faced barriers to widespread implementation due to conservative ideologies that portrayed transgender people as having mental illnesses. For example, in the early 1980s, the Department of Health and Human Services under then President Ronald Reagan did not cover gender-affirming care under federal insurance, and most private insurances also adopted that policy afterwards. However, the Affordable Care Act of 2010, a law to increase health insurance coverage and control healthcare costs, expanded protections for gender-affirming care, leading to more clinics that provide those services opening or expanding.

“Optimal Feminizing HT” is comprised of seven sections. In the “Introduction,” the authors define the term transgender, why transgender individuals seek hormonal feminization, and what physicians and patients aim to do with GAHT. In “Methods,” they explain their goal to provide a narrative review of GAHT specifically in adult transgender women, and they explain their methods for compiling their data. The section titled “Gender Affirming Hormone Therapy (GAHT)” explains the desired effects of GAHT for transgender women, as well as various estrogen and anti-androgen treatments available. The section titled “Feminizing Effects of GAHT” describes the physical effects of feminizing hormone therapy. The section titled “Other Treatment Effects of GAHT” discusses the potential negative side effects of GAHT, including mental and physical health risks. The section titled “Monitoring GAHT in Transgender Care” details the methods that physicians use when tracking the progress of GAHT, as well as a description of the long-term risks associated with hormone therapy. The final section, “Conclusion,” asserts that, while feminization treatment is safe, physicians should specifically tailor GAHT to each patient.

In “Introduction,” the authors discuss that the term transgender refers to people whose assigned gender at birth differs from their gender identity. They also give statistics on the frequency of gender dysphoria in Europe, which is about 0.7 to 0.1 percent of the population. The authors also report that, as of 2020, one in three transgender people identifies as gender non-binary, which serves as an umbrella term for individuals who do not identify as strictly male or female. The authors report that, even if someone identifies as gender non-binary, they may still want to undergo feminizing GAHT. The authors explain that feminizing GAHT reduces male hormones like testosterone and suppresses secondary masculine characteristics such as facial hair, while also developing and maintaining secondary feminine characteristics including breast growth and fat redistribution to the hips and buttocks.

The “Methods” section describes the approaches for the inclusion of studies within the narrative review framework. The authors included clinical and placebo-controlled trials in study cohorts of transgender women at least eighteen years old. They compiled a wide range of published studies and experiments by searching keywords that related to hormones used in feminizing GAHT. The authors excluded studies about lifestyle interventions, surgical procedures or transgender patients under the age of eighteen, as pediatric patients typically receive puberty blockers, which are a different type of gender-affirming medication. The authors included studies that discussed the effects of hormones in cisgender study populations to account for limitations in the existing literature on transgender study populations.

In the section titled “Gender-Affirming Hormonal Treatment (GAHT),” the authors describe different types of feminizing GAHTs and their chemical mechanisms. The subsection titled “Estrogen Treatment” details the types of estrogen used in modern feminizing GAHT and includes three different forms of estrogen: E1, E2, and E3. E2 is the most highly concentrated form of estrogen in the body and the most commonly prescribed form of GAHT. It can be administered through oral contraceptives, trans-dermally through a patch stuck on the skin, or through injections. The authors found that transdermal methods of E2 administration resulted in less fluctuations of E2 levels in the blood, and maintained a continuous distribution of E2, reducing the risk of weight gain, obesity, and high blood pressure. The authors do not recommend clinical usage of E2 injections, as they cause the highest E2 levels in the blood and can cause blood clotting.

In the next subsection “Anti-androgen Treatment,” the authors explain that anti-androgen treatment is a necessary component of a feminization treatment plan in addition to other GAHTs, as E2 administration is not enough to fully suppress the testosterone in a patient’s system. Therefore, patients often receive feminizing GAHT in combination with various methods of anti-androgen treatment. The authors discuss two main methods of anti-androgen treatment for adult transgender women, with the most common being cyproterone acetate, or CPA, and spironolactone. The authors explain that CPA is a pill that inhibits testosterone receptors and acts as synthetic progesterone, which can cause more rapid breast development and lasts within the body for about three days depending on the dosage. Spironolactone is a pill that blocks the action of dihydrotestosterone, a more active form of testosterone. The authors reference studies showing that, while spironolactone is less effective than CPA at lowering testosterone levels, it has less severe blood clotting and metabolic risks like increased blood pressure and abnormal cholesterol.

The authors discuss less common anti-androgen treatments in the subsections “GnRH-a,” “5α-reductase inhibitors,” and “Flutamide.” The authors state that doctors typically use GnRH-a with transgender adolescents, as it can suppress sexual maturation. Physicians commonly use 5α-reductase inhibitors to treat prostate tissue overgrowth in cisgender men. Transgender women undergoing GAHT may request 5α-reductase inhibitors to improve the effects of anti-androgen treatments. However, in the presence of CPA and spironolactone treatment, the benefits of 5α-reductase inhibitors are negligible, and the authors relay that physicians do not recommend it for GAHT. Flutamide blocks the effects of androgens by binding to their receptors. Physicians do not recommend its usage for GAHT.

In the section titled “Feminizing Effects of GAHT,” the authors discuss various aspects of feminization that physicians expect to occur during GAHT. Breast development occurs in the presence of E2 treatment in conjunction with anti-androgen treatment, and patients on average saw modest breast development within the first six months to one year of treatment. The method of E2 administration had no significant effects on breast development in female transgender patients in conjunction with anti-androgen treatment. Physicians also observed changes in body composition to obtain a societally recognized feminine body shape, with fat being redistributed to the face, hips, and buttocks. Studies examined in the article also relayed a decrease in external hair growth, along with decreased sebum production, which is a natural skin lubricant.

In the section titled “Other Treatment Effects of GAHT,” the authors discuss the possibility of mental and physical effects during hormone treatments in six different subsections. In the first subsection “Patient-Reported Outcomes, Depression and Aggression,” the authors emphasize how the frequency of depression and self-reported low quality of life is high in the transgender population regardless of hormonal treatment. Depression in transgender women is twice as prevalent as in cisgender men, and the authors explain how estrogen is associated with depression in cisgender populations during puberty, postpartum, and menopause. The authors explain that research comparing specific hormone treatments is limited, suggesting that it is unclear whether certain treatments produce better psychological outcomes.

In the subsection “Sexual Health,” the authors discuss a questionnaire-based cross-study of 214 transgender women that found that sixty-four percent had experienced a decrease in sexual desire after feminizing treatment, and seventy-three percent rarely experienced responsive sexual desire. The authors assert that the results indicate a negative association between feminizing GAHT and sexual desire.

In the subsection “Arterial Cardiovascular Disease (CVD),” the authors explain that some studies indicate that transgender women may have an increased risk of heart attack and stroke during feminizing treatment, but there is not enough long-term data to definitively calculate risk. Cisgender men also are at higher risk of stroke or heart attack that increases with age, and the timing of feminizing hormone treatment is important regarding the risk factors of estrogen and blood clotting. In the subsection titled “Venous thrombosis (VTE),” the authors define VTE as blood clotting in the veins and assert that, in transgender women, the likelihood of VTE is higher due to the blood clotting effects associated with estrogen. In the subsection titled “Bone health,” the authors discuss that, while testosterone levels decreasing during feminizing GAHT, adequate E2 treatment maintains bone health in transgender women. They reference studies which show that bone density at the spine increases significantly after one to two years of treatment. In the subsection titled “Cancer risk,” the authors state that GAHT may affect the risk of hormone-sensitive cancer types like breast cancer and prostate cancer. They also assert that breast cancer screening guidelines for cisgender women are sufficient for transgender women undergoing feminizing treatment. Risk levels for cancer vary for every patient because of factors like age, obesity, smoking, and healthcare access barriers. 

In the section titled “Monitoring GAHT in Transgender Care,” the authors describe the assessments that physicians typically perform when tracking feminizing GAHT in transgender women. The authors explain that one of the most common monitoring methods is the measurement of E2 in the bloodstream. The goal of GAHT is to match the E2 and testosterone levels in transgender women to cisgender women of similar ages. In order to assess the average hormone level, blood sampling should occur halfway between hormone doses, as that avoids an artificially high reading shortly after a dose. In the subsection titled “Contraindication and reservations for E2 treatment in transgender women,” the authors list various risk factors for GAHT. Those include modifiable risk factors like smoking status and blood pressure and non-modifiable risk factors like age. In the section titled “Conclusion,” the authors reiterate the necessity of customized treatment for each patient undergoing feminizing GAHT, as physicians should prescribe hormone therapy after consideration of risk factors and potential side effects. Although GAHT is safe, the authors emphasize that it is crucial to modify hormonal treatments if health risk factors develop over time.

“Optimizing Feminizing HT” provides a review of various feminizing GAHT approaches and a discussion of compiled knowledge of the effects of different GAHT treatment techniques in transgender women. It suggests ways that physicians can tailor feminizing GAHT to individual patients in order to improve the quality of life for individuals experiencing gender dysphoria. According to Google Scholar, “Optimizing Feminizing HT” has been cited eighty-nine times as of 2026.

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