© Springer International Publishing Switzerland 2017
Teresa K. Woodruff and Yasmin C. Gosiengfiao (eds.)Pediatric and Adolescent Oncofertility10.1007/978-3-319-32973-4_1212. Fertility Preservation in Patients with Gender Dysphoria
(1)
Department of Women and Infant Services, Department of Surgery, MedStar Washington Hospital Center, Children’s National Medical Center, 110 Irving St NW, Washington, DC, 20010, USA
(2)
Division of Urology Chicago, Department of Urology and Center for Healthcare Studies, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, Feinberg School of Medicine, 225 E. Chicago Ave, Chicago, IL 60616, USA
Keywords
TransGender dysphoriaCross-sex hormonesCisNatalAbbreviations
BPA
Bisphenol A
DES
Diethylstilbestrol
DHEA
Didehydroepiandrosterone
GD
Gender dysphoria
GnRH
Gonadotropin-releasing hormone
PCBs
Polychlorinated biphenyls
PCOS
Polycystic ovarian syndrome
PESA
Percutaneous sperm aspiration
TESA
Testicular sperm aspiration
TESE
Testicular sperm extraction
WPATH
World Professional Association for Transgender Health
Introduction
Recent events have demonstrated increasing media attention to the issue of transgender individuals. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) changed the nomenclature for transgender individuals from gender identity disorder to gender dysphoria in 2013. Gender dysphoria refers to the psychological distress encountered in persons whose gender at birth is contrary to the one they identify with. The psychiatric focus is on the distress experienced due to the incongruence between assigned and affirmed gender, and current evidence supports that gender affirming therapy greatly improves outcomes [1]. The American Psychiatric Association further states that such individuals should be able to obtain care without fear of discrimination and that treatment options for this condition include counseling, cross-sex hormones, gender reassignment surgery, and social and legal transition to the desired sex [1]. In 2009, the Endocrine Society along with the Pediatric Endocrine Society, World Professional Association for Transgender Health (WPATH), European Society of Endocrinology, and the European Society for Pediatric Endocrinology published the “Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline” [2]. These groups and the guidelines support the use of “cross-sex” hormones to further the gender affirming process and recommend counseling regarding fertility and options for fertility preservation, as cross-sex hormone therapy may impair future fertility.
Nomenclature
Although this chapter is titled “Fertility Preservation in Patients with Gender Dysphoria,” the information and concepts presented herein apply to the spectrum of individuals who exhibit gender variance and desire medical interventions to facilitate transition to a gender other than the one assigned at birth. As mentioned above, these medical interventions include pubertal suppression, cross-gender hormone therapy, and gonadectomy, all of which have the potential to affect future fertility. For consistency in this chapter, the authors have chosen to use the terms “trans,” “trans-woman,” and “trans-man.” However, a much larger range of terminology is applicable and relevant to the mental and physical health of individuals with gender variance, many of whom may pursue medical interventions which have the potential to affect fertility in the future.
The authors recognize that terminology related to the transgender experience is in evolution, and aim to provide some basic information about relevant nomenclature. It is important to note that some of the terms used may be offensive to some individuals, while preferable to others. Additionally, there have been recent shifts in language use that may not be fully reflected in the terms defined in this chapter. However, assembling the non-exhaustive list below was thought to be important to provide clarity and context for the remainder of the chapter:
Sex vs. gender
Sex – Anatomy of a person’s reproductive system and secondary sex characteristics.
Gender – Social roles based on sex, typically culturally based.
Gender-related terms
Biological sex/natal sex – Sex assigned at birth, based on both anatomy and chromosomes.
Gender identity/affirmed gender – An individual’s internal sense of their1 own gender, may it be male, female, or another gender. May not be aligned with biological/natal sex.
Gender expression – Physical manifestation of an individual’s gender identity (e.g., clothing, mannerisms, pronouns, chosen name).
Gender role – Societal norms regarding how men and women should think, behave, speak, and dress.
Gender variance, gender nonconforming – Closely related terms describing behavior not conforming to socially defined male or female norms (e.g., dress, activities) based on sex.
Gender identity
Cisgender – Individuals for whom internal gender identity agrees with their anatomy and the gender they were assigned at birth.
Transgender, trans – A person whose gender identity does not match their anatomy and gender assigned at birth. Often also abbreviated as trans* to emphasize the range of individuals who do not identify as a traditional cisgender man or woman.
Transsexual – A person who has the strong desire to assume the physical characteristics and gender role of the opposite sex. This term has a more binary connotation than transgender and has been viewed somewhat negatively in recent years, and thus is being used less often than terms such as transgender, and trans.
Trans-woman, male-to-female (MTF) transgender – Individuals with a male natal gender, but female gender identity. For this chapter, the authors have chosen the term trans-woman, as it affirms the individual’s gender identity.
Trans-man, female-to-male (FTM) transgender – Individuals with a female natal gender, but male gender identity. For this chapter, the authors have chosen the term trans-man, as it affirms the individual’s gender identity.
Genderqueer – Individuals who identify with both male and female genders, or who identify with neither gender.
Gender fluid – A dynamic mix between male and female gender identities.
Other helpful terminology
Gender dysphoria– The DSM-V diagnosis used by medical and mental health professionals to describe psychological distress caused by discontent with one’s natal sex. Gender identity disorder (GID) was the terminology previously used by the DSM-IV and has largely been abandoned.
Transitioning – The process of physically and permanently changing external gender presentation to align with one’s internal gender identity. Genital surgery is not a requirement.
Sexual orientation – Pattern of romantic or sexual attraction; separate from gender identity and gender expression. For example, a trans-man is not necessarily romantically attracted only to women. Traditional categories include heterosexual, homosexual, and bisexual. Newer classifications include asexual, polysexual, and pansexual.
Current Treatment Guidelines
Psychological Evaluation
It is essential that individuals with GD be evaluated and managed by a mental health provider with experience in order to assess whether they indeed qualify for the diagnosis as well as evaluate for confounding psychological factors. The mental health provider may also provide psychotherapy and evaluate for psychological readiness for medical interventions such as puberty blockers and/or cross-sex hormones. Persons with GD are at high risk of adverse mental health including anxiety, depression, self-harm and suicide, poor school performance, and drug and alcohol abuse [3]. Thus, ideally a mental health provider will continue to evaluate and support the individual during social and biological transition.
Puberty Suppression
Some children with GD experience increasing distress during puberty as their body begins to change. The Endocrine Society Guidelines supports the use of puberty blockers starting when the child reaches Tanner 2 stage (breast budding in natal girls and testicular volume of 4 cc in natal boys) [2]. The mental health provider needs to assess whether the patient meets medical eligibility and provides a letter of support for the pediatric endocrinologist or gynecologist to begin puberty blockers. Such treatment not only addresses the mental distress of the child but also prevents secondary sexual characteristics from developing which may later be difficult to alter, such as the Adam’s apple or large breasts. In general, puberty suppression is usually achieved with gonadotropin-releasing hormone (GnRH) agonists such as a histrelin rod or Depo-Lupron.
Cross-Sex Hormones
Regardless of whether puberty suppression was undertaken, the Endocrine Society Guidelines support initiation of cross-sex hormones around the age of 16 years. Individuals considering cross-sex hormones need to be counseled extensively regarding the expected results of feminizing/masculinizing medications and their possible adverse health effects. Such a discussion should include the effects on fertility and options for fertility preservation, as cross-sex hormone therapy may impair future fertility. In addition, prior to initiation of cross-sex hormone therapy, the WPATH recommends that a qualified mental health professional should provide documentation (such as a referral letter) of the patient’s personal and treatment history, eligibility, and need for cross-sex hormone.
Testosterone Treatment for Trans-boys and Trans-men
Testosterone is recommended to achieve the desired masculinization of a natal female with gender dysphoria. In cases where an adolescent has received puberty suppression, it is given in low doses and increased slowly (as done with induction of puberty). In both prepubertal and postpubertal individuals, testosterone is generally administered subcutaneously or intramuscularly every 1–2 weeks at the lowest dose needed to maintain the desired clinical result and levels within normal male physiologic levels (320–1000 ng/dl) [4]. This requires discussion prior to initiation not only of the risks of masculinizing hormone therapy but also of the timing of development of the desired effects, so the patient has reasonable expectations. Monitoring for adverse effects includes both clinical and laboratory evaluation specific to the risks of hormone therapy and the patient’s individual risks/comorbidities [5]. The most concerning morbidity noted in trans-men is polycythemia which can be treated with reduction of the testosterone and/or phlebotomy with blood donation.
Estrogen Treatment for Trans-girls and Trans-women
Hormone therapy for adolescents desiring feminizing therapy is more complex, with most clinical studies reporting the concurrent use of antiandrogens with estrogen therapy if the patient has not undergone puberty suppression [6]. Puberty induction, in suppressed individuals, may be undertaken with oral estrogen as well as transdermal (patch) and parenteral formulations. While the inherent risk of VTE within the adolescent population is less than in adults, transdermal preparations may offer an advantage by lowering these risks [3]. Following puberty induction, serum estradiol should be maintained at premenopausal levels (<200 pg/ml), and testosterone should be in the physiologic female range (<55 ng/dl). In individuals who have experienced puberty, this treatment may require high doses of estradiol (2–6 mg) as well as androgen blockers such as spironolactone. As with testosterone therapy, regular clinical and laboratory assessment should be performed to monitor for adverse effects.
Cross-Sex Hormones Effect on Fertility
Estrogen and Fertility in Trans-women
Although some estrogen is necessary for spermatogenesis, an overabundance of estrogen can be detrimental to fertility. Specific data regarding the effect of exogenous estrogen on sperm production in trans-women are lacking. However, data from animal studies, human epidemiologic studies, and studies related to the effect of obesity on human male reproductive function are relevant to trans-women who may desire biological children in the future.
Animal Data
There is a large body of literature demonstrating reduced fertility parameters and alterations in genital anatomy in male rodents exposed to estrogenic compounds in utero. Of more relevance to the trans-women who may begin estrogen supplementation during adolescence or adulthood, several studies of adult rodents have explored the impact of exogenous estrogens on multiple different measures of fertility potential. For example, increasing doses of exogenous estrogens have been associated with alteration in sperm counts and motility [7], testicular histology [8], and epididymal sperm content [9] in adult male rats. High doses of exogenous estrogens administered to adult male rats have also been associated with lower fertility rates, as measured by litter size [7–9]; one study even demonstrated a complete loss of potency at the highest dose of an estrogen receptor-α agonist [8]. Reversibility of the effects of estrogen on testicular histology has been demonstrated, suggesting that the effects of estrogen on fertility potential may not be permanent [9].
Evidence in Humans
Environmental Estrogens
In addition to the animal data, concern has existed for many years that environmental estrogens may be contributing impairments in male reproductive health and functioning, including an increase in male factor infertility [10]. To a great extent, concern regarding the effects of environmental estrogens on male fertility is a result of studies evaluating the link between in utero diethylstilbestrol (DES) exposure and adult male infertility. Although there have been several studies suggesting a link between fetal DES exposure and reduced adult semen parameters, the data are far from definitive [11]. Similarly, concern exists that exposure to endocrine disruptors with estrogenic properties such as phthalates, polychlorinated biphenyls (PCBs), and bisphenol A (BPA) may be associated with male infertility [12], although clear causality has not been established.
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