Gender dysphoria refers to distress that is caused by a sense of incongruity between an individual’s self-identified gender and natal sex. Diagnosis is made in accordance with the Diagnostic and Statistical Manual of Mental Disorders and treatment first involves psychiatric therapy, which can help determine a patient’s true goals in regards to achieving gender identity. Patients who wish to transition to the opposite sex must undergo a supervised real-life test and often are treated with hormonal therapy to develop physical characteristics consistent with their gender identity. Sex reassignment surgery is an option for patients who wish to transition completely. Transpatients face many barriers when it comes to basic health needs including education, housing, and health care. This is a result of long-standing marginalization and discrimination against this community. Because of these barriers, many patients do not receive the proper health care that they need. Additionally, because of certain high-risk behaviors as well as long-term hormonal therapy, transpatients have different routine health care needs that should be addressed in the primary care setting. Gynecologists play an important role in caring for transgender patients and should be knowledgeable about the general principles of transgender health.
Gender identity is the sense one has of being male or female. Transgender individuals are people who feel an incongruity between their self-identified gender and their birth gender. Manifestation of transgenderism exists on a spectrum. Patients may simply live their lives as members of the opposite sex, they may choose to undergo partial transition with hormonal therapy and/or some minor physical changes, or complete the transition with genital reassignment surgery.
About two-thirds of transgender individuals have early onset of identification with the opposite sex in early childhood, while a third of patients discover their identity later in life. Understanding proper terminology is an important part of the diagnostic stage, as historically, there has been muddling of certain terms. Psychiatric diagnoses in the Diagnostic and Statistical Manual of Mental Disorders ( DSM ) for conditions that relate to gender identity and sex behaviors have always been very controversial. It was not until the 1940s that a distinction was made among the terms “transgenderism,” “transsexualism,” and “homosexuality.” “Transgenderism” was used to describe individuals who identified with the opposite sex and desired to live their lives in that role; while “transsexualism” was specific to individuals desiring complete transition through sex reassignment. However, “transsexualism” did not appear as a formal diagnosis in the DSM until 1980, 7 years after “gender dysphoria” was introduced as a standard psychiatric term. In 1994, “transsexualism” was removed from the DSM and replaced with “gender identity disorder,” a term used to diagnose patients who experience significant gender dysphoria and wish to live their lives as the opposite sex. The DSM-V , published in May 2013, revised their diagnostic criteria for patients experiencing gender incongruence. In an attempt to depathologize gender identity and to eliminate some of the social stigma attached to it, “gender identity disorder” was removed from the DSM as a formal psychiatric diagnosis, and it was replaced with “gender dysphoria,” which refers to the distress that is caused by a discrepancy between a person’s gender identity and natal sex. This new diagnosis attempts to avoid classifying patients who may vary in their gender identity or expression with an actual psychiatric condition, and it provides guidelines for diagnosis that will assist providers with treatment to reduce the distress that these patients experience. “Transsexualism” is still used to describe those individuals who wish to or have completed transition with reassignment surgery. “Gender nonconformity” refers to behavior and is the extent to which an individual’s expression of gender identity differs from cultural norms for that particular gender. The most important thing to realize is that while there are subtle distinctions among “gender nonconformity,” “transgenderism,” and “transsexualism,” any of these conditions or forms of expression can be associated with gender dysphoria, which implies distress in an individual’s life, and can be treated with a combination of psychotherapy, hormonal therapy, and surgery. Figure 1 lists the different terms and their definitions commonly used to describe gender identity and sex behaviors.
Large epidemiologic studies on the incidence and prevalence of transgenderism have not been conducted, as this population has proven to be very difficult to study. The only data available are on the prevalence of individuals who present for sex reassignment or gender-related care in Europe. A study from The Netherlands reported a prevalence rate of 1:11,900 and 1:30,400 in men and women, respectively. In Europe, this 1:3 ratio of women to men is common, perhaps because it is easier for women to assume masculine roles in these societies without having to seek sex reassignment, whereas assuming a feminine role for men is less accepted. However, in other parts of the world, small studies have revealed that there are as many, if not more, women than men who are transgender. Therefore, no definitive conclusions can be drawn regarding the actual prevalence between the 2 sexes.
The etiology of transgenderism is not known. A biological theory supports the concept of sexual differentiation in the brain and relies on the notion that the human brain is dimorphic in nature and in utero develops into either the female or male brain. Cadaver studies examining male-to-female transsexual brains have shown a female-specific pattern of development and size specifically in the bed nucleus of the stria terminalis, which is responsible for sex behavior. Interestingly, the size of this bed nucleus was shown to be independent of sexual orientation and only correlated with biologic sex. These limited data imply that there may be an inherent biologic component to gender identity, but this theory requires further research.
While there were once strong beliefs that transgenderism was purely psychiatric in nature, there is no evidence currently that this is the case. Additionally, theories exist regarding the role of the environment and child rearing, but there are not enough data to conclude that this plays a major role in the disorder either. As previously mentioned, there have been efforts recently to “depsychopathologize” conditions related to gender nonconformity and identity. In 2010, the World Professional Association for Transgender Health (WPATH) released a statement addressing this, stating the following: “the expression of gender characteristics, including identities that are not stereotypically associated with one’s assigned sex at birth is a common and culturally diverse human phenomenon [that] should not be judged as inherently pathological or negative.” The organization emphasizes that gender nonconformity is simply a matter of diversity while gender dysphoria may require treatment as the individual’s feelings of discrepancy between natal sex and gender identity may cause significant distress. Only some individuals with gender nonconformity experience gender dysphoria and it is crucial to understand that while this is mislabeled as a psychiatric disorder, the actual etiology is multifactorial, and should simply be considered a variant of what society may consider to be normal.
Diagnosis and initial management
The standards of care and treatment for patients with gender dysphoria have been established by 2 important organizations: the WPATH (formerly the Harry Benjamin International Gender Dysphoria Association) and the Endocrine Society. The first Standards of Care for Gender Dysphoric Persons was drafted in 1978 with the most recent version (7th edition) published in 2011. While these standards are flexible to meet the needs of all transgender individuals, they offer a framework for providers to care for these patients.
An important goal of WPATH has been “lasting personal comfort with the gendered self to maximize overall psychological wellbeing and self-fulfillment.” Individuals who experience gender dysphoria must be properly evaluated before this goal can be achieved, and this evaluation takes place in 2 parts. First, the criteria put forth by the DSM must be met ( Figure 2 ). This is determined by a trained mental health professional who is competent in the care of transgender patients and understands his or her role in the care of these patients, as outlined by the WPATH standards of care. Once patients are determined to meet criteria for gender dysphoria, a period of up to 12 months is sometimes necessary to assess the severity of the gender dysphoria and to determine if the patient will benefit from a variety of transition processes, including sex reassignment surgery. Additionally, in this stage, patients are assessed for psychiatric comorbidities and treated accordingly. Because of the stigma that is attached to gender nonconformity, prejudice and discrimination often ensues toward this population, which can result in a phenomenon termed “minority stress.” This type of social impact and stress can lead individuals to experience debilitating stress and anxiety, and therefore, psychiatric therapy is sometimes necessary to treat any comorbid psychiatric conditions such as depression, anxiety, and posttraumatic stress disorder. During this diagnostic phase, patients are encouraged to participate in the real-life test, which involves an extended period of time (at least 12 months) where the patient lives full time as a person of the desired sex. This experience is imperative for individuals as they learn to interact in the community as their desired sex, and helps them to affirm their decision to move forward with hormonal therapy and surgical reassignment if desired.
As outlined by the 2011 WPATH standards of care, the above-mentioned initial management strategies are important for patients before they proceed with further treatment. The most basic requirement is that patients undergo assessment by a mental health professional, and have well-documented gender dysphoria. To proceed with hormonal therapy, a referral from a mental health provider is important and at least 3 months of the real-life experience is recommended. Most surgical procedures require this referral as well, if not 2 separate referrals, while some procedures require 12 months of continuous hormonal therapy as well as the completion of the real-life experience. Providers managing hormonal therapies and/or performing gender-related surgeries are responsible for ensuring that these requirements have been met. While some providers believe it is important for patients to undergo formal psychotherapy for gender dysphoria, it is not an absolute requirement for hormonal or surgical management.
Hormone therapy
Many transgender patients choose to initiate hormone therapy to help make their physical appearance concordant with their gender identity. The diagnostic phase must be complete prior to initiating hormones and many patients also remain in therapy during this time period. Some patients choose to overlap the real-life experience with hormone therapy, which is encouraged. The main objectives of hormonal therapy are to suppress the sex characteristics associated with the patient’s natal sex, and to induce the characteristics of the desired sex. Figure 3 describes the options for hormonal therapy for both male-to-female and female-to-male patients and Figure 4 outlines the standards for monitoring hormonal therapy once it is initiated. Guidelines for initiation and maintenance of hormonal therapy for transgender patients are outlined by the Endocrine Society. The most important step in the initiation of hormonal therapy is to ensure that patients do not have comorbid conditions that could be exacerbated by hormonal treatments. Per the society’s guidelines, estrogen therapy should be used with caution, if used at all, in male-to-female patients with history of thromboembolic disease, prolactinoma, significant liver disease, breast cancer, coronary artery disease, and migraine headaches with aura. Similarly, female-to-male patients are at risk for exacerbation of breast or endometrial cancer and significant liver disease while on testosterone therapy.
In male-to-female patients, androgen effects are suppressed with progestational agents such as progesterone or medroxyprogesterone acetate. In Europe, the most commonly used progestational agent is cyproterone acetate, which is currently not available for use in the United States. Nonsteroidal antiandrogens such as spironolactone and finasteride can be used, as well as the gonadotropin-releasing-hormone analogue leuprolide and gonadotropin-releasing-hormone agonists such as the histrelin implant, commonly used to treat prostate cancer. Feminine characteristics such as breast formation, female pattern of fat distribution with reduction of overall lean body mass, and a reduction in male-pattern hair growth are induced with the use of estrogens. The most commonly used form of estrogen is estradiol, which can be administered orally, intramuscularly, or transdermally. In the past, oral ethinyl estradiol was commonly used, however the doses required to achieve sex reassignment were associated with a high risk of venous thrombotic events, and use of this medication is now avoided. The transdermal route of estrogen administration is highly recommended, as therapeutic effects are achieved at lower peak doses since first-pass hepatic metabolism is avoided, plasma hormone levels remain constant, and the sustained drug delivery reduces the need for frequent self-administration, which improves patient compliance.
The primary objective of hormonal therapy for female-to-male patients is to induce virilization. This is achieved with testosterone therapy. The 2 most commonly used formulations include testosterone enanthate and testosterone undecanoate. Androgen therapy results in increased muscle mass, decreased fat mass, increased facial hair and acne, male pattern baldness, and increased libido. Frequently, testosterone therapy will lead to the suppression of menses, especially if it is administered intramuscularly. If this is not achieved, especially in the case of transdermal testosterone administration, progesterone therapy can be used concomitantly to stop menstrual flow.
Patients who have initiated hormonal therapy report good satisfaction from this treatment. A metaanalysis of 28 observational studies looked at 1833 patients who received hormonal therapies. In all, 80% (69-89%) of patients reported significant improvement in gender dysphoria, 78% (56-94%) reported significant improvement in psychological symptoms, 80% (72-88%) had improvement in quality of life, and 72% (60-81%) stated they had improvement in sexual function. While there are formulations of hormonal therapy that are commonly used to reach the above goals, it is important to note that there are no comparative or randomized studies to test the efficacy and safety of these drugs. Current recommendations for management are based on expert opinion and experience. Continued medical supervision by a trained physician is required during hormone therapy. This is paramount as the prevalence of unsupervised hormone use has been reported to be as high as 58% in male-to-female transgender patients. The Endocrine Society recommends monitoring patients every 3 months during the first year of therapy then once or twice yearly thereafter. At these visits, patients are monitored for metabolic alterations resulting from therapy as well as changes in their quality of life. Documented side effects from these formulations include depression and increased risk of suicidal thoughts, mood swings, hyperprolactinemia, elevated liver enzymes, migraines, and decreased insulin sensitivity. All of these changes are important to monitor as they can significantly impair the health of these patients.
Hormone therapy
Many transgender patients choose to initiate hormone therapy to help make their physical appearance concordant with their gender identity. The diagnostic phase must be complete prior to initiating hormones and many patients also remain in therapy during this time period. Some patients choose to overlap the real-life experience with hormone therapy, which is encouraged. The main objectives of hormonal therapy are to suppress the sex characteristics associated with the patient’s natal sex, and to induce the characteristics of the desired sex. Figure 3 describes the options for hormonal therapy for both male-to-female and female-to-male patients and Figure 4 outlines the standards for monitoring hormonal therapy once it is initiated. Guidelines for initiation and maintenance of hormonal therapy for transgender patients are outlined by the Endocrine Society. The most important step in the initiation of hormonal therapy is to ensure that patients do not have comorbid conditions that could be exacerbated by hormonal treatments. Per the society’s guidelines, estrogen therapy should be used with caution, if used at all, in male-to-female patients with history of thromboembolic disease, prolactinoma, significant liver disease, breast cancer, coronary artery disease, and migraine headaches with aura. Similarly, female-to-male patients are at risk for exacerbation of breast or endometrial cancer and significant liver disease while on testosterone therapy.
In male-to-female patients, androgen effects are suppressed with progestational agents such as progesterone or medroxyprogesterone acetate. In Europe, the most commonly used progestational agent is cyproterone acetate, which is currently not available for use in the United States. Nonsteroidal antiandrogens such as spironolactone and finasteride can be used, as well as the gonadotropin-releasing-hormone analogue leuprolide and gonadotropin-releasing-hormone agonists such as the histrelin implant, commonly used to treat prostate cancer. Feminine characteristics such as breast formation, female pattern of fat distribution with reduction of overall lean body mass, and a reduction in male-pattern hair growth are induced with the use of estrogens. The most commonly used form of estrogen is estradiol, which can be administered orally, intramuscularly, or transdermally. In the past, oral ethinyl estradiol was commonly used, however the doses required to achieve sex reassignment were associated with a high risk of venous thrombotic events, and use of this medication is now avoided. The transdermal route of estrogen administration is highly recommended, as therapeutic effects are achieved at lower peak doses since first-pass hepatic metabolism is avoided, plasma hormone levels remain constant, and the sustained drug delivery reduces the need for frequent self-administration, which improves patient compliance.
The primary objective of hormonal therapy for female-to-male patients is to induce virilization. This is achieved with testosterone therapy. The 2 most commonly used formulations include testosterone enanthate and testosterone undecanoate. Androgen therapy results in increased muscle mass, decreased fat mass, increased facial hair and acne, male pattern baldness, and increased libido. Frequently, testosterone therapy will lead to the suppression of menses, especially if it is administered intramuscularly. If this is not achieved, especially in the case of transdermal testosterone administration, progesterone therapy can be used concomitantly to stop menstrual flow.
Patients who have initiated hormonal therapy report good satisfaction from this treatment. A metaanalysis of 28 observational studies looked at 1833 patients who received hormonal therapies. In all, 80% (69-89%) of patients reported significant improvement in gender dysphoria, 78% (56-94%) reported significant improvement in psychological symptoms, 80% (72-88%) had improvement in quality of life, and 72% (60-81%) stated they had improvement in sexual function. While there are formulations of hormonal therapy that are commonly used to reach the above goals, it is important to note that there are no comparative or randomized studies to test the efficacy and safety of these drugs. Current recommendations for management are based on expert opinion and experience. Continued medical supervision by a trained physician is required during hormone therapy. This is paramount as the prevalence of unsupervised hormone use has been reported to be as high as 58% in male-to-female transgender patients. The Endocrine Society recommends monitoring patients every 3 months during the first year of therapy then once or twice yearly thereafter. At these visits, patients are monitored for metabolic alterations resulting from therapy as well as changes in their quality of life. Documented side effects from these formulations include depression and increased risk of suicidal thoughts, mood swings, hyperprolactinemia, elevated liver enzymes, migraines, and decreased insulin sensitivity. All of these changes are important to monitor as they can significantly impair the health of these patients.
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