Outcomes in Adolescent and Young Adult Feminizing Transgender Patients Emily P. Barnard, DO,a Cherie Priya Dhar, MD,b Stephanie S. Rothenberg, MD,a Marie N. Menke, MD,a Selma F. Witchel, MD,b Gerald T. Montano, DO,b Kyle E. Orwig, PhD,c Hanna Valli-Pulaski, PhDc

BACKGROUND: Fertility preservation enables patients undergoing gonadotoxic therapies to retain abstract the potential for biological children and now has broader implications in the care of transgender individuals. Multiple medical societies recommend counseling on fertility preservation before initiating therapy for gender dysphoria; however, outcome data pre- and posttreatment are limited in feminizing transgender adolescents and young adults. METHODS: The University of Pittsburgh Institutional Research Board approved this study. Data were collected retrospectively on transgender patients seeking fertility preservation between 2015 and 2018, including age at initial consultation and semen analysis parameters. RESULTS: Eleven feminizing transgender patients accepted a referral for fertility preservation during this time; consultation occurred at median age 19 (range 16–24 years). Ten patients attempted and completed at least 1 . Eight patients cryopreserved semen before initiating treatment. Of those patients, all exhibited low morphology with otherwise normal median semen analysis parameters. In 1 patient who discontinued leuprolide acetate to attempt fertility preservation, transient azoospermia of 5 months’ duration was demonstrated with subsequent recovery of spermatogenesis. In a patient who had previously been treated with spironolactone and estradiol, semen analysis revealed persistent azoospermia for the 4 months leading up to orchiectomy after discontinuation of both medications. CONCLUSIONS: Semen is a viable method of fertility preservation in adolescent and young adult transgender individuals and can be considered in patients who have already initiated therapy for gender dysphoria. Further research is needed to determine the optimal length of time these therapies should be discontinued to facilitate successful semen cryopreservation.

WHAT’S KNOWN ON THIS SUBJECT: Most adult feminizing transgender aUPMC Magee-Womens Hospital, Pittsburgh, Pennsylvania; bUPMC Children’s Hospital of Pittsburgh, Pittsburgh, individuals on gender-affirming therapy have abnormal semen Pennsylvania; and cMagee-Womens Research Institute and Foundation, Pittsburgh, Pennsylvania parameters; however, studies show that parameters months after Dr Barnard collected the data, conducted the initial analysis, and drafted the initial manuscript; Dr discontinuing treatment were similar to those of individuals not on Rothenberg assisted in data analysis and reviewed the manuscript for important intellectual therapy. Literature is sparse on this topic, particularly in adolescents. content; Drs Dhar, Menke, Witchel, and Montano were instrumental in acquiring the data and WHAT THIS STUDY ADDS: This study features adolescents and young selecting patients for inclusion as well as critically reviewing and revising the manuscript; Dr Orwig adults not previously studied in this context. Consecutive semen conceptualized the study and reviewed and revised the manuscript; Dr Valli-Pulaski conceptualized analyses were collected from 2 patients after discontinuing therapy and designed the study and reviewed and revised the manuscript; and all authors approved the for gender dysphoria to determine how cessation may change sperm final manuscript as submitted and agree to be accountable for all aspects of the work. quantity and quality. DOI: https://doi.org/10.1542/peds.2018-3943 To cite: Barnard EP, Dhar CP, Rothenberg SS, et al. Accepted for publication Apr 30, 2019 Fertility Preservation Outcomes in Adolescent and Young Adult Feminizing Transgender Patients. Pediatrics. 2019; 144(2):e20183943

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 144, number 2, September 2019:e20183943 ARTICLE In the pediatric population, fertility building, including adoption and METHODS preservation techniques were having biological children.8 Study Population initially used to enable patients However, other surveys have noted undergoing gonadotoxic cancer lower rates of interest in biological AYA transgender patients at our therapies to retain the option to children in youth who identify as institution are seen predominantly by have biological children after transgender, but notably, adolescent medicine or pediatric treatment. Fertility preservation approximately half of them also endocrinology providers. Each patient techniques have now expanded questioned whether their feelings receives counseling on fertility their application to the preservation on having genetic children may preservation options before initiation of fertility for transgender and change in the future.7 Interestingly, of GnRH agonist and/or gender- gender-nonconforming individuals in companion surveys of the parents affirming hormone therapy. All undergoing therapy for gender of transgender youth and young feminizing transgender AYA patients dysphoria. As early as Tanner Stage adults, only 1 in 5 wished their who expressed interest were referred II, pubertal suppression with children would have biological for fertility preservation. Those -releasing hormone offspring; these numbers are lower referred between January 1, 2015, (GnRH) agonists can be used to halt when compared with the pediatric and September 30, 2018, were further development of secondary cancer population.7 included in the study. Institutional sex characteristics.1 The effects of review board approval was obtained GnRH agonist therapy are Limiteddataareavailableonthe from the University of Pittsburgh reversible, allowing for the return of use of fertility preservation services (PRO17060610). spermatogenesis after in the transgender AYA population. discontinuation.2 Other androgen- Surveys show that counseling on Outcome Measures lowering medication commonly reproductive options and fertility Chart abstraction included patient employed in this population preservation is variable depending age at fertility preservation includes spironolactone.1 For natal on the patient population surveyed, consultation, age at semen – males, gender-affirming therapy ranging from 20.5% to 98%.8 10 In cryopreservation, and semen analysis primarily consists of estradiol. 1 study focusing on referral parameters. Any history of GnRH Although there is a lack of high- patterns, only ∼13% of transgender agonist and/or gender-affirming quality longitudinal data, there is AYAs were ultimately referred for therapy was obtained as well as concern that estradiol could induce fertility preservation, with whether these therapies were irreversible damage to germ cells in a disproportionate number of discontinued before semen analysis. the testes.3 For this reason, the referrals going to those of male Semen parameters collected included World Professional Association for natal sex.10 With respect to use, volume of ejaculate, sperm Transgender Health, the Endocrine a study of 105 transgender AYAs concentration, motility, and Society, and the American Society showed that only 13 opted for morphology (modified Kruger for Reproductive Medicine consultation on fertility criteria). Statistical analysis was recommend counseling regarding preservation options, with 4 performed by using Stata version fertility preservation before completing semen cryopreservation 15.1 (Stata Corp, College Station, TX). initiating a GnRH agonist or gender- and 1 completing oocyte affirming therapy.4–6 cryopreservation.4 In regard to RESULTS semen cryopreservation outcomes Although limited, recent studies in the transgender AYA population, Patient Characteristics have shed light on the reproductive reports are limited to a single case All patients participating in fertility insight and desires of transgender series that describes the outcome of preservation were of non-Hispanic, adolescents and young adults semen cryopreservation in 2 AYA white race. The median age at which (AYAs) considering GnRH agonist transgender females.9 No studies in patients first experienced gender and gender-affirming therapy. Most the AYA population address semen dysphoria was 12 (range 6–14), with youth use online sources for cryopreservation after initiation of initial presentation for evaluation of information regarding the effects of GnRH agonist and/or gender- gender dysphoria at age 17 (range these therapies on fertility, although affirming therapy. We aimed to 15–24; Table 1). 56% of the youth in 1 study also report fertility preservation reported hearing about these issues outcomes in the AYA population of Eleven feminizing transgender from a physician.7 An online survey feminizing transgender patients patients accepted a fertility revealed that transgender youth are undergoing semen cryopreservation preservation referral from adolescent interested in many types of family at our institution. medicine or pediatric endocrinology

Downloaded from www.aappublications.org/news by guest on October 2, 2021 2 BARNARD et al TABLE 1 Demographics for AYA Feminizing Transgender Patients Previous Therapy, n Age of Initial Gender Dysphoria Age at Initial Gender Dysphoria Age at Fertility Consultation Preservation Consultation No previous therapy 1 7 17 17 2141516 3132021 4122020 5122424 6 6 15 16 7 Unknown Unknown 23 Previous therapy 1131718 2 Unknown 18 19 for semen cryopreservation. Referrals 6.0% normal forms (modified Kruger (5 months after the last leuprolide from these providers resulted in criteria, normal range .13.0%). After acetate dose), semen telephone fertility preservation semen cryopreservation, all patients cryopreservation was again consultation with a member of the in the study proceeded with initiation attempted and revealed semen fertility preservation team at median of GnRH agonist therapy, and 4 analysis parameters that were within age 19.5 (range 16–24). One patient patients concurrently started normal limits, with the exception of accepted a referral due to strong estradiol therapy. One patient opted low morphology (9%). parental preference but ultimately to discard their collection for declined to proceed with fertility personal reasons ∼4 months after The second patient had previously preservation. A total of 10 (90.9%) collection. been on a regimen of spironolactone patients completed at least 1 collection. and estradiol for 26 months. Before The median interval from referral to Patients With Previous History of fertility preservation, she was using fi collectionwas17days(range1–30 GnRH Agonist or Gender-Af rming 100 mg of spironolactone daily and days). Results of the semen analysis Therapy a weekly transdermal estradiol patch m were discussed via telephone with Two patients had previously initiated delivering 75 g per day. Although areproductiveendocrinologyand treatment of gender dysphoria on the patient was able to collect provider. presentation for semen a specimen on all attempts, semen cryopreservation (Table 3). The first analysis revealed persistent Patients With No Previous GnRH patient had been treated with azoospermia 2, 3, and 4 months after fi Agonist or Gender-Af rming Therapy leuprolide acetate (15 mg discontinuation of both medications. Eight of the 10 patients who intramuscular injection every 28 The patient ultimately was participated in fertility preservation days) for 6 months before semen unsuccessful in fertility preservation (80.0%) had no previous history of collection. At the recommendation of efforts before completing scheduled fi GnRH agonist and/or gender- the pediatric endocrinologist, this gender-con rmation surgery with affirming therapy. All patients were medication was stopped before orchiectomy. able to complete a collection attempting semen cryopreservation. (Table 2). Semen analysis parameters Three months after the last dose, were overall within normal limits semen analysis was attempted and DISCUSSION with the exception of abnormal showed 12 total sperm, with only 2 Semen cryopreservation is a feasible morphology; median morphology was being motile. Two months later method of fertility preservation in

TABLE 2 Semen Analysis Parameters for Patients With No Previous GnRH Agonist or Gender-Affirming Therapy (n =8) Semen Analysis Parameters Median Range Normal Reference Volume, mL 3.0 0.75–6.1 .1.4 Density, million 21.0 2–80 .14.9 Motility, % 54.0 16.6–74 .39 Morphology,a % 6.0 3–10 .13 No. vials cryopreserved 10 4–25 N/A No. collections 2 1–3 N/A N/A, not applicable. a Modified Kruger criteria.

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 144, number 2, September 2019 3 AYA feminizing transgender patients. normal semen analysis parameters an For those individuals with no average of 4.7 months after previous treatment of gender discontinuation of gender-affirming 0 0 0 12 dysphoria, the process can be therapy.12 To date, no prospective No. Sperm

Cryopreserved completed quickly, with collections studies have been published occurring every 2 to 3 days to describing the time course of preserve several samples before resumption of spermatogenesis after % initiating GnRH agonist or gender- discontinuation of GnRH agonist or affirming therapy. We found that gender-affirming therapy in patients patients with previous use of a GnRH who are azoospermic while on agonist may require discontinuation treatment. for several months to allow for Motility, % Morphology, Semen Parameters resumption of spermatogenesis. For many transgender patients, the Further studies are needed to potential need to discontinue GnRH determine the length of time required agonist or gender-affirming therapy for spermatogenesis to resume (if at to allow for resumption of mL), Sperm Density (per all) after exposure to estradiol and/or spermatogenesis may be a significant spironolactone. The 1 individual barrier to pursuing fertility 21.5 73 million1.7 0 56 0 N/A 9 N/A N/A 146 million N/A 1 12 16.6 N/A 2.5 0 N/A N/A mL taking these medications before preservation because cessation of Volume, collection in our study was therapy may result in exacerbation of azoospermic up to 4 months after gender dysphoria and progression of discontinuation and opted to proceed undesired male secondary sex 9 5 3 4 3 2 with a scheduled orchiectomy. This characteristics. For individuals for information is critical to address as whom this risk is not acceptable or if part of a multidisciplinary fertility azoospermia is noted on semen Duration of Therapy Discontinuation, mo discussion with youth and their analysis, there are several alternate guardians so that an informed options, including electroejaculation, 6

26 decision can be made regarding testicular sperm extraction, and fertility preservation use. testicular tissue cryopreservation. For Duration of Therapy, mo feminizing youth who are Limited studies in the adult uncomfortable with or unable to population evaluating feminizing masturbate, electroejaculation with Age of

Initiation, y transgender patients pursuing semen a transrectal probe can produce cryopreservation for fertility semen for cryopreservation.13 g m preservation also reveal abnormal Testicular sperm extraction is 75 18 N/A 17.5 semen analysis parameters. In 1 a surgical procedure that can be used per d rming Therapy report of 7 adult patients who for AYA feminizing transgender Estradiol, completed semen cryopreservation individuals with azoospermia, similar while on gender-affirming therapy, 3 to its use in the infertility population fi Gender-Af (42.9%) were azoospermic.11 These or in patients with cancer for fertility 14 N/A 100 individuals were taking estradiol and preservation. The option of per d spironolactone, and 2 of the 3 were testicular tissue cryopreservation, also on the 5-a-reductase inhibitor either as a fertility preservation finasteride.11 However, the other 4 procedure or in conjunction with adults who continued on gender- gender-confirming surgery, offers an affirming therapy with estradiol and alternative experimental method.15,16 spironolactone during semen This therapy is currently offered cryopreservation were able to under research protocols for 15 N/A successfully cryopreserve sperm, prepubertal boys undergoing other with 1 having completely normal forms of gonadotoxic therapy, and its semen analysis parameters.11 In low-risk safety profile makes it an

Leuprolide Acetate, mg per 28 d Spironolactone, mg a retrospective study of patients attractive option despite the Semen Analysis Parameters After Discontinuation of Therapy for Gender Dysphoria discontinuing gender-affirming limitations regarding future tissue therapy to pursue fertility use.17 Although data on efficacy are 1 Patient 2

TABLE 3 N/A, not applicable. preservation, all individuals had lacking in the transgender population,

Downloaded from www.aappublications.org/news by guest on October 2, 2021 4 BARNARD et al accessing the myriad fertility transgender adults, although it is important to explore other options, preservation options available to the unclear if these behaviors contribute such as electroejaculation, testicular infertility and cancer populations to altered semen parameters.23 sperm extraction, or testicular affords health care providers the Because counseling for semen tissue cryopreservation, for these ability to individualize treatment and cryopreservation does address sperm patients to preserve fertility if they minimize gender dysphoria in use in future fertility treatments, desire. transgender AYA patients undergoing those with low morphology or other fertility preservation. abnormal semen analysis parameters CONCLUSIONS For the patients in our study who had should have a particular focus on the Semen cryopreservation can be used no previous therapy, isolated low potential need for advanced as a method of fertility preservation sperm morphology was noted in all reproductive technologies, such as in the transgender AYA population. It samples. Morphologic assessment of in vitro fertilization, to achieve future would be optimal to have normative sperm is the most subjective aspect of pregnancy. data with which to guide AYA the semen analysis, even within Strengths of our study include the 18 transgender patients to avoid a high-volume . first published data on outcomes, collection attempts resulting in Additionally, there are no established including semen analysis azoospermia. Our experience semen analysis parameters for the parameters, in the transgender AYA suggests that further research is AYA population. Comparison of the population. Our study is unique in needed to determine the length of semen analysis parameters of youth that it includes both individuals time needed for spermatogenesis to (age #20) with malignancy to adults who are naïve to GnRH agonist and/ resume after discontinuation of GnRH (age .20) with malignancy did not or gender-affirming therapy as well agonist treatment. Further study is report any significant difference in as 2 individuals who were already 19 also needed to ascertain the long- values. Other studies looking at on treatment for gender dysphoria. term effects of gender-affirming semen analysis results in the We are limited by a small sample therapy and prognosis for the return population of young patients with size and the retrospective nature of of spermatogenesis in transgender cancer do not include morphology as this study. Lifestyle factors, 20,21 AYAs who present with azoospermia. a parameter studied. A small including medication or illicit drug Finally, additional studies are needed study of adult transgender women use and behaviors such as tucking, to assess if some AYA patients may be referred for semen cryopreservation were unable to be accounted for able to cryopreserve sperm without before starting gender-affirming unless noted in the medical record. discontinuation of gender-affirming therapy also noted sperm We also did not have any patients therapy. abnormalities with low morphology present for semen cryopreservation (7.98%) and total motile sperm whowereunabletoejaculateto concentration (8.7 3 106/mL).22 produce a specimen. It is possible Studies have also shown greater use that patients who are unable or ABBREVIATIONS of tight undergarments and tucking, uncomfortable with masturbation AYA: adolescent and young adult whereby the penis and testicles are are self-selecting out of fertility GnRH: gonadotropin-releasing maintained in an inguinal position preservation discussions once they hormone close to the body, in feminizing understand the process, and it is

Address correspondence to Hanna Valli-Pulaski, PhD, Magee-Womens Research Institute, 204 Craft Ave, Pittsburgh, PA 15213. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2019 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose. COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-2000.

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Downloaded from www.aappublications.org/news by guest on October 2, 2021 Fertility Preservation Outcomes in Adolescent and Young Adult Feminizing Transgender Patients Emily P. Barnard, Cherie Priya Dhar, Stephanie S. Rothenberg, Marie N. Menke, Selma F. Witchel, Gerald T. Montano, Kyle E. Orwig and Hanna Valli-Pulaski Pediatrics 2019;144; DOI: 10.1542/peds.2018-3943 originally published online August 5, 2019;

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