“Mortality and Morbidity in Transsexual Patients with Cross-Gender Hormone Treatment” (1989), by Henk Asscheman, Louis J. G. Gooren, and P. L. E. Eklund

In 1989, physicians Henk Asscheman, Louis J. G. Gooren, and P.L.E. Eklund published the article “Mortality and Morbidity in Transsexual Patients with Cross-Gender Hormone Treatment,” hereafter “Mortality and Morbidity,” in the journal Metabolism. The authors presented clinical data regarding patients with gender dysphoria who were actively undergoing gender-affirming hormone replacement therapy. The data highlighted frequencies of various side effects of the treatment, including high blood pressure, blood clots, mood changes, as well as varying risk percentages of osteoporosis and cardiovascular disease, as those side effects are typically common in conventional hormone replacement therapy. According to “Mortality and Morbidity,” few scientists were studying the long-term effects of estrogen and androgen treatment for transgender people at the time of publication. The retrospective study was one of the first to research the long-term effects of hormone treatments on transgender individuals and found health concerns, such as more frequent blood clots and weight gain, in those undergoing gender-affirming hormone treatment.

Background and Context

The authors of “Mortality and Morbidity” researched the long-term effects of hormone treatment, as a means of gender affirmation, because physicians and researchers lacked data on those long-term effects. One common form of hormone treatment is sex steroid replacement, which is the addition or substitution of specific sex steroids in the body. Scientists have conventionally used sex steroid replacement for many hormonal-related treatments, such as oral contraceptives, estrogen substitution to alleviate symptoms of menopause in women, and androgen replacement in men. People who choose to go through gender-affirming hormone therapy may identify as transgender, which is a term used to describe people whose own gender identity differs from the gender they were assigned at birth. Individuals may undergo hormone replacement therapy as a means of gender affirmation to align their sex to their gender identity. A person could seek out one or multiple gender affirming medical procedures in order to feel more comfortable and confident in their body and gender identity. Through hormone replacement therapy, individuals can diminish as well as emphasize physical characteristics of one sex or the other, as viewed by society. Gender-affirming treatments through hormone replacement can alleviate gender dysphoria long-term. The terms “transsexual” and “cross-gender” were terms used at the time of publication. However, as of 2026, the term “transgender” is more commonly used.

Asscheman and his coauthors primarily focus on the effects of hormones such as estrogen and androgens, which scientists commonly use in hormone replacement therapy. Testosterone, a type of androgen, is a steroid hormone that plays a key role in the male reproductive system and allows for the testes and the prostate to develop in a fetus. It is also responsible for promoting and maintaining secondary male characteristics during and after puberty, such as body hair, increased muscle mass, increased bone density, and voice deepening. Testosterone is produced in both males and females, as a small amount is produced in the ovaries and adrenal glands. Estrogen is another steroid hormone that promotes the development of the female reproductive system and allows for the maintenance of secondary female characteristics during and after puberty. Secondary sex characteristics for females include enlarged breasts, wide hips, egg cell maturation, and fat increase.

The authors collected data from Vrije Universiteit Amsterdam’s VU University Medical Center in Amsterdam, The Netherlands. Physicians Gooren, Asscheman, and Eklund specialize in endocrinology, the study of the hormonal system, and andrology, the study of the male reproductive system at the Free University Hospital in Amsterdam. Gooren has treated over 2,200 patients and was one of the first researchers to treat transgender youth. At Vrije Universiteit, he was appointed full professor of endocrinology in 1988, and served as the head of Andrology.

Article Roadmap

The authors divide the five-page medical article “Mortality and Morbidity” into four sections. In the untitled introduction, the authors discuss the types of hormonal treatments they performed, along with the specific medications the patients took. Continuing in the introduction, Asscheman and colleagues discuss the lack of knowledge about long-term gender affirming hormone treatment and list a series of complications that they observed in patients. In the second section, “Materials and Methods,” the team lays out the characteristics of the examined group like age and duration of hormonal treatment, and how often they came back in for checkups. The scientists also recorded the physical symptoms of patients at each visit. In the third section, “Results,” the authors utilize graphs and some statistical analysis of mortality rates, and other health complications mentioned in earlier paragraphs, comparing them to groups of patients who did not undergo hormone therapy. Finally, in the last section, “Discussion,” the researchers describe that while the study did have minor drawbacks in terms of not having a definitive control group, there were slightly higher but treatable risk factors in the observed group than in the general population. While the authors explain that their data cannot give definitive conclusions about the risks of gender-affirming hormone treatment, Asscheman and colleagues give suggestions about what might be an effective method of reducing risks depending on the patient.

The untitled introduction section explains that the main reason for the study was to understand the side effects of hormonal therapy in transsexual individuals. The team explains that, for transsexual individuals, hormonal treatment suppresses certain sexual characteristics associated with their original sex and amplifies those of the opposite sex. The authors note that there is extensive research explaining the effects of hormone therapy in standard cases, such as estrogen replacement for menopause, or androgen in males. However, they report that not many studies have been done on the effects of hormonal treatment for transsexual patients. Prior to publication, scientists reported effects such as changes in cholesterol levels, breast cancer in estrogen-treated male-to-female, or MTF, individuals and heart attacks in androgen-treated female-to-male, or FTM, individuals.

In the “Materials and Methods” section, the authors describe that 558 patients had been diagnosed with gender dysphoria and were observed from 1972 to 1986 and they include 425 patients in the study. The authors excluded patients who did not undergo hormonal treatment, who used only androgen treatment, who failed to comply with follow up check-ins, or who had insufficient treatment duration. In the 303-person MTF group, the standard hormone treatment consisted of 100 mg of cyproterone acetate, which blocks the action of androgens and reduces androgen production, along with 100 g of ethinylestradiol, which increases the production of estrogen. Those hormones reduce the appearance of typically male traits and accentuate typically female traits. Patients took those supplements once daily in the form of a pill. Forty-five of the patients taking supplements insisted on injectable estrogen treatment along with clinical treatment, which they procured outside of the clinic and administered themselves. For the 122-person FTM group, the standard hormonal treatment consisted of two different options that worked to reduce the appearance of typically female traits and increase the appearance of typically male ones. The first option consisted of an injection of 250 mg of long-lasting testosterone esters every two weeks, which increases the solubility of testosterone in fats, and results in a slow release of testosterone for an extended period of time. The other option was 120 to 160 mg of testosterone undecanoate, which helps the body maintain secondary male sex characteristics. The researchers prescribed both treatments to some patients, but they did not take the treatments simultaneously. If the menstrual cycle did not stop after three months of androgen treatment, the scientists would prescribe the patient five mg of oral progestin, which researchers commonly use to prevent ovulation.

Continuing in the “Materials and Methods” section, the authors explain that the ages of the MTF group ranged from sixteen to sixty-seven years with a median age of thirty-two, and the FTM group ranged from sixteen to fifty-four with a median age of twenty-five. The duration of hormone therapy ranged from six months to thirteen years. The median duration of hormone therapy was 4.4 years for MTF patients and 3.6 years for FTM patients. The authors explain that, for the first two years of hormone treatment, patients saw the researchers every three months, and then every six months after the two-year mark. During visits, researchers put physical changes and complaints on their records along with occasional blood tests to examine liver enzyme percentage in the blood, and they performed x-rays of the veins to check for blood clotting. Twelve individuals from the study died during the follow-up process.

In the “Results” section, the researchers relay that there were twelve deaths in the study group, which was about 2.5 to nine times the expected number of deaths compared to the average rate of the general population not undergoing hormone replacement. However, six deaths occurred due to suicide or miscellaneous causes of death, and three deaths occurred due to unknown reasons. Nineteen MTF patients developed blood clotting in the legs, which was most common in the first year of treatment. However, only one patient from the group was expected to develop those symptoms according to the proportion of individuals with blood clotting in the legs in the general population. The experimental frequency was higher than expected. The authors also found strong association with age in patients that developed blood clotting, with most of the blood clotting cases being above the age of forty. The authors explain that ten patients developed high blood pressure, but since previous studies show that estrogen can increase blood pressure, the number was close to their expectation. Physicians kept the symptoms of patients experiencing increased blood pressure under control through the use of other medication without discontinuing the hormone treatment. Physicians also observed an increase of depressive mood changes in about eight percent of the studied population. However, patients received information about the potential risk of mood changes prior to the start of treatment.

The authors also found that forty-six MTF patients had high levels of prolactin, a hormone responsible for breast enlargement and milk production. In 46 patients, the team observed elevated prolactin levels. The researchers reduced estrogen doses, which helped prolactin levels to decrease, yet five patients, out of a group of 15 who had elevated prolactin levels, had developed an enlarged pituitary gland, which is in the brain and is responsible for hormone secretion. The FTM population experienced fewer morbid effects, with only three patients developing high blood pressure, and fifteen developing severe acne. Doctors treated the maladies with appropriate medication. FTM patients also experienced a large increase in body hair after just one year of treatment, with some growing full beards by the end of the year. Patients also experienced voice deepening, severe acne, and patients that were previously obese experienced about a ten-percent body weight increase. MTF and FTM patients both encountered slight weight gain.

In the “Discussion” section, the authors conclude that the hormone therapies observed in the study are associated with increased risks such as blood clots. Since the study was retrospective, the researchers cannot draw definitive conclusions describing the risks of hormone therapies. The authors explain that the study was limited by the fact that there was no available control group to contrast the hormone group from, and the only comparable data consisted of individuals from the general population. The authors also concluded that the use of hormone replacement therapy cannot be guaranteed to absolve any pre-existing mental health issues such as depression due to gender dysphoria. The authors describe concerns that they found definitive evidence of increased blood clotting in the legs and lungs, depressive mood changes, and gradual elevation of liver enzymes for MTF patients. FTM patients had a lower frequency of health complications, as only acne and weight gain were associated with androgen use. MTF patients experienced temporary mood changes that the authors attribute to adjusting to a new gender role in society.

Also in the “Discussion” section, the authors also relay possible solutions of side effects caused by hormone therapy. Authors suggest battling blood clotting from estrogen treatment by either lowering the dosage of estrogen in use or using the lowest possible effective dosage, similarly to how physicians treat the same issues in oral contraceptive users. They also suggest possibly using estrogen injections with less long-term issues rather than oral pills. The researchers write that the hormonal changes during estrogen treatment could decrease the risk of coronary heart disease. The discussion ended by concluding that high blood pressure levels increased slightly less than expected but could be due to the general population in the Netherlands having an existing high blood pressure to begin with.

Impacts

“Mortality and Morbidity” has been cited over 250 times by researchers focusing on transgender medicine and quality of life before and after treatment. Multiple other research studies have cited the article to expand upon the effects of hormone replacement therapy that Asscheman and colleagues mention in the article. Hormone replacement therapy for gender-affirming purposes can improve the quality of life for transgender patients. Researchers from The Trevor Project, a nonprofit organization based on LGBTQ+ suicide prevention, suggest that gender-affirming hormone replacement therapy may reduce the risk of depression in young people under eighteen by almost forty percent. “Mortality and Morbidity” focuses on the slight risk factors of hormone replacement therapy for gender affirmation, and what preventative methods scientists can utilize to lessen negative effects. The use and access to gender-affirming care for transgender individuals serves as a tool to improve the emotional and behavioral wellbeing in individuals who choose to undergo the process, and can benefit transgender individuals in various aspects of daily life.

Sources

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