Gender Affirming Hormone Replacement for the Adolescent and Young Adult Cancer Survivor with Hypogonadism

Case Presentation

A16 year old, assigned male at birth, was treated for stage IV diffuse central nervous system Primitive Neuroectodermal Tumor with chemotherapy, radiation, and autologous stem cell transplant. Therapy was completed 9 years prior. The chemotherapy regimen included vincristine, cyclophosphamide 10,000 mg/m², and cisplatin 150 mg/m². A total of 41.4 Gy photon beam craniospinal radiation was given. Off-therapy neurocognitive evaluations found that the patient tested in the age appropriate to superior range. The patient developed no hearing deficit.

However, at 1 year off therapy (age eight), the patient was referred to endocrinology for evaluation of hypopituitarism and was shortly thereafter diagnosed with growth hormone deficiency, central adrenal insufficiency, and hypothyroidism. Pubertal status was tracked with serial physical exams and laboratory measurement of gonadotropins and testosterone. At 14 years old, they were diagnosed with hypogonadotropic hypogonadism based on lack of pubertal development and persistently low gonadotropin and testosterone levels. Testosterone cypionate 50 mg intramuscular every 4 weeks was started.

At 15 years old, a referral was made to the Seattle Children's Gender Clinic to discuss medical management of gender dysphoria after identifying themselves as gender flux and experiencing symptoms of depression and anxiety. The clinic's psychologist addressed symptoms of dysphoria and assisted the patient in identity formation and management of complex social relationships. The patient disclosed that they were gay at age five and was currently sexually attracted to individuals with whom they had an emotional connection.

The family and clinic's endocrinologist decided to continue testosterone and to add spironolactone to counter the virilizing effects of the male hormone. The patient was interested in an androgynous appearance and wanted to specifically avoid developing facial hair and an Adam's apple. The patient's history of severe migraines made estrogen a suboptimal choice. The patient has been on this regimen for 10 months and continues to receive comprehensive services through the gender clinic. The patient continues to do well in school and is engaging more in peer and community groups.

Late Effects of Cancer Treatment

In 2014, nearly 14.5 million survivors of cancer were alive in the United States and this number is expected to rise to 19 million by the year 2024.^1,2 Approximately 675,000 of these survivors are adolescents and young adults (AYA) ages 15–39. ³ Late effects of cancer treatment are evaluated in survivorship clinics using history and physical examination, diagnostic screening tests, and education/counseling. The Children's Oncology Group's Long Term Follow Up Guidelines provides risk-based and exposure-based recommendations for screening and management of late effects. ⁴

Hypogonadism is one known late effect of cancer treatment. ⁵ Testicular and ovarian hormonal dysfunction has been associated with the following chemotherapy: busulfan, carmustine, chlorambucil, cyclophosphamide, ifosfamide, lomustine, mechlorethamine, melphalan, procarbazine, thiotepa, carboplatin, cisplatin, dacarbazine, and temozolomide. ⁴ Additionally, gonadotropin and sex hormone deficiency is a potential late effect of head/brain, testicular, ovarian, pelvis, sacral spine, and total body irradiation. ⁴ Patients who have undergone oophorectomy or orchiectomy are also at risk (Tables 1 and 2). ⁴

Hormonal deficiencies are evaluated through history, physical exam, and laboratory testing. ⁴ Screening with an early morning testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) and/or endocrinology referral is recommended for patients assigned male at birth without signs of puberty by age 14, failure of pubertal progression, poor growth, and sexual dysfunction. Screening with FSH, LH, Anti-Mullerian hormone, and estradiol and/or endocrine/gynecology referral is recommended for patients assigned female at birth without signs of puberty by age 13, failure of pubertal progression, and abnormal menstrual patterns or menopausal symptoms. Clinicians are encouraged to refer a patient with hypogonadism or a patient who received ≥30 Gy of head/brain radiation directly to an endocrinologist for further evaluation and management.

Endocrine Treatment of Hypogonadism

The treatment of hypogonadism requires the replacement of sex-steroid hormones with the dosing and goal of therapy determined by the patient's pubertal state at the time of therapy initiation. For children who have not yet completed puberty but who are of a pubertal age, the goals of treatment include the development of secondary sexual characteristics, augmentation of growth through puberty, improvement of bone mineralization, and the alleviation of symptoms related to hypogonadism. Benefits of sex steroid replacement extend into adulthood after puberty has completed, and include cardiovascular risk improvement, muscle mass development, and continued accrual of bone mass. ⁶

For patients with primary hypogonadism due to injury or abnormality at the level of the testicle or ovary, the initiation of hormone replacement can be considered when the patient reaches a pubertal age (between 8–13 years of age in girls and 9–14 years of age in boys) and the gonadotropin values begin to rise, typically coinciding with a skeletal maturity near 10–12 years of age as judged by a bone age radiograph. ⁷ For patients with secondary hypogonadism due to injury of the pituitary or hypothalamus, the appropriate timing of sex steroid initiation can be more complex, as there is no spontaneous rise in FSH and LH to signal a physiologic start of puberty.

There is some variation in practice with some providers waiting to initiate sex steroid replacement until age 13 for patients assigned female at birth or 14 for patients assigned male at birth if there is no biochemical and physical evidence for the start of puberty. ⁷

Another option is to perform earlier gonadotropin releasing hormone stimulation testing to make a diagnosis of hypogonadotropic hypogonadism and initiate replacement at that time. ⁷ Once started in a pre-pubertal patient, sex hormone replacement with estrogen or testosterone is increased gradually over a period of 3–4 years to simulate the physiologic increase seen with normal pubertal development.^7,8 The development of secondary sexual characteristics is followed, side effects are assessed, and when appropriate, hormone levels are measured and doses adjusted accordingly.

Gender Diverse AYAs

Before starting hormonal therapy it is important to discuss an individual's gender identity. Gender identity is a person's internal sense of their gender (i.e., feeling male, female, or non-binary). An individual who is gender nonconforming is one who has a gender identity different than that of the gender assigned to them at birth based on their genitalia and may not follow the gender role or expression set as a norm by social or cultural standards. Gender dysphoria occurs when there is significant distress due to discordance between gender identity and the gender assigned at birth. ⁹

Gender diverse youth are at risk of anxiety, depression, victimization, substance abuse and homelessness, which may be mitigated with gender affirming care.^10,11 Gender affirming care includes both knowledge and acceptance of an individual's gender identity within the clinical environment as well as availability of medical treatment for gender dysphoria. ¹²

A gender nonconforming individual should receive hormone treatment to match their gender identity to prevent worsening dysphoria. Treatment is best facilitated through a medical care team practicing gender affirming care. This team should include medical professionals to provide appropriate hormone treatment and monitoring as well as mental health providers to follow the individual through transition. If available, a multidisciplinary gender clinic can provide coordinated gender care. ¹⁰

Both the Endocrine Society and World Professional Association for Transgender Health offer care guidelines for gender affirming care.^9,13 Age of initiation of estrogen or testosterone treatment (cross-sex hormone) which matches gender identity is debated. Some past guidelines suggest initiating cross sex hormone at 16, however many adolescents prefer to have peer-congruent pubertal development. Current guidelines recommend a case-by-case approach. Therefore, some centers will start treatment earlier to match peer congruent pubertal development with the assent/consent from child and parent/guardian if they meet the same standards of psychological readiness posed to older adolescents. ¹⁰

When and How to Discuss Gender

Many providers think of gender identity as a conversation for older teens and adults; this misconception can prevent crucial conversations with pediatric cancer survivors. While every child's gender development is unique, gender diverse children recognize their own identities on average at age 8.5, and may wait an average of 10 years to disclose gender identity to others. ¹⁴ The American Academy of Pediatrics asserts that pediatric providers are key players in addressing gender identity in all patients to promote positive health outcomes.

In treating all patients with hypogonadism, conversations about gender should start concurrently with discussions of future puberty. Providers should ask open-ended questions that acknowledge all possible outcomes, and elicit how the patient is feeling currently. “Most people born with ovaries identify as female and will want to take estrogen in puberty to develop breasts and have a period. Some others may not feel like a girl and will want to take testosterone in puberty to have a lower voice and facial hair. How are you feeling about gender and puberty? What changes are you excited or worried about?” Patients exploring gender may benefit from prompt referral to a multidisciplinary gender clinic, including supportive mental health services. The survivorship clinician needs to explore gender identity when caring for the whole patient to ensure comprehensive care is provided.

Gender Diverse AYA Cancer Survivors with Hypogonadism

Once it has been established that a child or adolescent is gender nonconforming, referral to a multi-disciplinary gender clinic is advisable. If such a clinic is not available, then referral to a mental health provider with gender experience as well as a provider knowledgeable about gender affirming hormone care should be made.

This team can provide guidance regarding hormone therapy that will be gender affirming as well as accomplish the medical goals previously discussed. When appropriate, hormone treatment meeting the gender identity of the patient should be started using the same guidelines used for hypogonadal and gender nonconforming children and adolescents. Specifically, getting consent/assent for treatment, starting peer-congruent treatment, and meeting treatment goals of providing gender affirming medical treatment that optimizes growth, bone health, body composition, cardiovascular health, and development of desired secondary sexual characteristics.

Conclusion

Our case is an example of a long-term childhood cancer survivor with subsequent hypogonadism who is gender nonconforming. This case is not unique in the AYA population and presents an opportunity to bring awareness of gender diversity to the greater medical community. The lesbian, gay, bisexual, transgender, and queer population is associated with less involvement in cancer screening, higher rates of psychological stress post-therapy, lower insurance rates, and higher rates of perceived discrimination in the health care setting. ¹⁵ Additionally,cancer and its treatment during childhood can negatively affect social and emotional development due to psychological distress and physical diabilities. ¹⁶ Itis important for all medical providers to recognize the significance of open discussion regarding gender identity as it can impact health outcomes and treatment plan. Treatment should be individualized to meet medical goals as well as affirm gender identity.