Transgender patients are those whose gender identity differs from the gender assigned at birth (1). Around 1.4 million people in the United States are estimated to identify as transgender according to the William Institute (2). Many transgender individuals are misgendered and their physical appearance adds to their gender dysphoria leading them to pursue exogenous hormonal therapy and subsequent gender affirming surgery (GAS) (3,4). While these therapies have been shown to increase self-esteem, alleviate depressive symptoms and decrease symptoms of gender dysphoria (5), it can affect their reproductive potential. Hormonal therapy can cause oligo/azoospermia and erectile problems in transgender women and low ovarian reserve in transgender men. These effects can be reversible; however, orchiectomy and oophorectomy causes a permanent loss of fertility (6).
In order to pursue hormonal therapy, transgender individuals are required to present with persistent gender nonconformity or gender dysphoria which has emerged or has aggravated with puberty. In addition, any medical, social, and psychosocial conditions that can interfere with the hormones should be addressed and an informed consent should be obtained. Transgenders pursuing gender affirming genital surgery are required to live in their desire sex for a minimum of one year before the surgery (7). Plastic surgeons are involved in the care of transgender patients during their gender affirmation procedures and therefore, they should be aware of the fertility preservation options for this population. According to the World Professional Association for Transgender Health (WPATH) guidelines, healthcare professionals should discuss fertility preservation options with transgender patients prior to initiating gender affirming therapies (8,9).
In the last decade, the incidence of transgender women seeking sperm cryopreservation has increased compared with cisgender men (10). In a survey of 121 transgender women performed by De Sutter et al. (11), 77% reported that they would very interested in sperm banking if it was offered, and agreed that fertility preservation should be discussed with their healthcare provider. However, more than 90% of the responders reported that the loss of fertility secondary to gender confirmation therapies would not hinder their desire for pursuing such procedures. Another survey conducted by Wierckx et al. (12) showed that 62% of transsexual men wanted to have children. Moreover, transgender men with children scored better on vitality and self-perceived mental health status. In fact, parenting has been shown as a protective factor for suicide in transgender individuals (13).
The age in which transgender patients present to the physician has been trending down (11). In addition, there have been reports of low fertility preservation methods used among the transgender youth (14). This imposes a problem, since many of them have not yet defined their fertility wish or desire to have biological children; therefore, the importance of addressing fertility preservation options becomes crucial. While fertility preservation options have been used for oncologic patients, there is not many data on the fertility preservation options available for transgender patients. These options include sperm cryopreservation, surgical sperm extraction and testicular tissue cryopreservation for transgender women, and oocyte cryopreservation, embryo cryopreservation, in vitro maturation and ovarian tissue cryopreservation for transgender men (15). This systematic review aims to examine the outcomes of fertility preservation techniques for transgender patients and offer a guide for plastic surgeons during counselling of these patients.
We present the following article in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting checklist (available at http://dx.doi.org/10.21037/atm-20-4523).
This study is a systematic review of aggregated published data so no institutional review board approval was required.
Population and outcomes
A systematic review of studies evaluating fertility preservation options among transgender patients was conducted. The population were transgender men and women.
A comprehensive review of the literature was performed in accordance to the PRISMA guidelines (16). A comprehensive search of several databases from January 1st, 2000 to December 23rd, 2019 was conducted. The databases included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Ovid PsycINFO, and Scopus.
The search strategy was designed and conducted by an experienced librarian with input from the study’s principle investigator. Controlled vocabulary supplemented with keywords was used to search for studies describing fertility preservation options in transgenders and was limited to English, Spanish, Chinese, French, Turkish, Portuguese, Arabic, and German languages. The actual strategy listing all search terms used and how they are combined is available in the Appendix 1.
Inclusion and exclusion criteria
Inclusion criteria were articles on medical fertility preservation options for transgender patients that reported outcomes of these procedures. All time peer-reviewed original articles, written in English, Spanish, Chinese, French and Turkish; and studies involving human subjects were included. Primary outcomes were semen and oocyte parameters. The secondary outcomes were pregnancy and live birth rates after using fertility preservation methods. Exclusion criteria were articles in the form of abstracts, clinical overviews, clinical reviews, systematic reviews, opinion pieces, editorial letters, media reports and theses/dissertations, and any studies with animal models.
Two independent investigators (MY, SSB), screened the titles, abstracts, and full texts of the articles identified. The investigators were blinded to each other and disagreement between the reviewers was resolved by discussion and consensus. The authors extracted data regarding study type, sample size, population type, mean age, study period, fertility preservation method, use of gender affirming hormonal therapy, treatment length, ovarian stimulation medication, evaluation parameters and study results.
The Newcastle-Ottawa Quality Assessment Tool was used to identify the risk of bias of all studies included in this systematic review. A score of 0 to 3 was considered to be as low quality, 4 to 6 was considered as intermediate quality; and 7 or more was considered as high quality.
Two data extraction spreadsheets were developed and agreed upon between the co-authors. The selected studies were comprehensively assessed; all relevant data were extracted and entered into the spreadsheets by MY and SSB. Information selected included author details, year of publication, country of study, study design, study period, sample size, population, fertility preservation method, gender affirming hormone therapy, sperm or ovarian stimulation treatment, outcome of interest and results. Disagreements were resolved by discussion and if needed by the senior author.
The majority of studies were single-center experiences; therefore, a quantitative analysis was performed. Due to the high heterogeneity the studies, a meta-analysis was not conducted.
A total of 844 articles were identified, of which 396 were duplicated and were removed. A total of 448 abstracts were screened and 409 were excluded based on title and abstract screening. In total, 39 full articles were analyzed for eligibility, of which 15 met inclusion criteria. Reasons for exclusion were not articles unrelated to transgender patients (n=361), articles not reporting outcomes of fertility preservation methods (n=17), reviews (n=5) and commentaries (n=2) (Figure 1).
Fertility preservation options for transgender women (
Tables 1,2 )
Li et al. (10) performed a retrospective review of 78 transgender sperm bankers and compared them with 141 cisgender sperm bankers from the same private cryobank. Transgender specimens showed lower sperm concentration, total motile sperm count and post-thaw sperm parameters, as well as higher incidence of oligozoospermia. Only healthy cisgender men and transgender women with no reported previous hormonal therapy were included in this study.
Marsh et al. (17) conducted a prospective case-control study with 22 transgender women without current hormonal therapy treatment, and 17 cisgender men who had fathered a child in the previous 24 months. Semen collection occurred after at least seven days of sexual abstinence. The results showed lower semen parameters including sperm concentration, total motile sperm, volume, total sperm per ejaculate and normal sperm morphology in the transgender group. In addition, they reported a negative correlation between anxiety and stress and sperm concentration according to the Depression, Anxiety and Stress Scale (DASS-21).
Adeleye et al. (3) reported lower sperm concentration, percent of sperm motility and total motile count in patients on hormone treatment versus nontreatment. A total of 28 patients were included, 18 patients did not have any hormonal treatment, seven were on previous hormonal treatment and three remained on their hormones prior to semen collection. The median time of discontinuation ranged from 3 to 6.5 months. Additionally, lower semen parameters were found in patients on current gender affirming hormone therapy (GAHT) treatment versus those who previously used GAHT.
Jones et al. (18) described a case series of nine transgender women who underwent sperm cryopreservation. Of them, six patients had been on hormonotherapy for a mean duration of 0.33 months. A median of two sperm samples were cryopreserved. One patient obtained a successful intrauterine pregnancy following transfer of a cryopreserved embryo after intracytoplasmic sperm injection (ICSI) cycle.
Alford et al. (19) described a case report of a transgender woman who underwent a successful sperm cryopreservation after discontinuing estrogen and spironolactone therapy 2 months prior to attempting fertility preservation. At 6 months after stopping hormonotherapy, the patient had normalized her testosterone levels and semen parameters.
A study by Brik et al. (20) reported nine successful sperm cryopreservation among 13 patients. Nine patients successfully cryopreserved their semen to be used for intrauterine insemination or intracytoplasmic sperm injection. Of the remaining patients, one could not ejaculate, one had azoospermia and another had severe oligozoospermia with low post-thaw sperm parameters and no sperm with testicular sperm extraction. Of note, one patient had an inguinal testis, which could have influenced the outcomes. The authors did not record the hormonal therapy use.
Hamanda et al. (21) performed a retrospective review of 29 transgender women and reported altered semen parameters with high rates of oligozoospermia, asthenozoospermia, and teratozoospermia; in addition to low sperm motility in the majority of specimens. This study did not provide information on previous hormonal therapy use, and lacked a cisgender control group.
Barnard et al. (22) conducted a retrospective analysis of ten transgender women. Two of them had been on hormonal therapy before attempting semen cryopreservation and the remaining eight had not yet started hormonal therapy. Of the two patients who received hormonal therapy, one of them received treatment with leuprolide acetate (15 mg intramuscular injection every 28 days) for 6 months prior to specimen collection. The sperm parameters were assessed both at 3 and 6 months after stopping the hormonal therapy. At 3 months, the semen analysis showed only 12 total sperm with two of them being motile. At 6 months, only low morphology was reported with the remaining semen parameters within normal limits. The second patient who received hormonal therapy was treated with spironolactone (100 mg daily) and estradiol (75 mg daily, transdermal patch) for 26 months prior to sperm collection. The results showed persistent azoospermia at 2, 3, and 4 months after discontinuation of both medications, and the semen cryopreservation was unsuccessful.
Broughton and Omurtag (23) described the outcomes of three patients who underwent semen preservation. One of them was a transgender woman who cryopreserved four semen specimens with normal parameters and attempted three intrauterine inseminations (two natural cycles and one with clomiphene treatment); and one in vitro fertilization with one blastocyst; however, none of these attempts were were successful.
A surgical sperm extraction consists of a percutaneous aspiration of sperm from the epididymis or testis. The specimen can be used for intracytoplasmic sperm injection or in vitro fertilization.
Another method is the immature testicular tissue cryopreservation that consists of a biopsy of testicular tissue from pre-pubertal patients. It remains an investigational method and it is the only option available for pre-pubertal males at the moment. There were no articles reporting outcomes of these techniques in our literature search.
Fertility preservation options for transgender men
Oocyte and embryo cryopreservation
Chen et al. (24) reported five cases of transgender men adolescents that successfully achieved oocyte cryopreservation before starting hormonal therapy. The mean number of oocytes retrieved were 18.22 (11 to 28), of which 14.2 (8 to 25) were mature and were cryopreserved.
Wallace et al. (25) described a case of a 17-year-old transgender man who successfully cryopreserved 35 mature oocytes prior to initiating hormonal therapy.
Maxwell et al. (4) described a case series of one adolescent and two adult transgender patients who underwent oocyte cryopreservation before initiating hormonal therapy. The number of cryopreserved mature oocytes collected ranged between 13 and 45. After 5–8 years, two patients used their specimens and both achieved successful twin pregnancies.
Broughton and Omurtag (23) reported a case series with two transgender men successful pregnancies. One patient achieved a successful pregnancy after transferring two blastocysts to his wife’s uterus. This couple attempted in vitro fertilization using the patient’s oocytes followed by embryo transfer into his wife’s uterus. A total of 16 oocytes were obtained, of which 13 were matured oocytes. At the end, seven were fertilized using ICSI. Prior to pursuing fertility preservation, he had been on intramuscular depot testosterone therapy for 26 months and discontinued it 3 months before attempting fertilization. At that time, his hormonal levels (antimullerian hormone, follicle-stimulating hormone, and estradiol) were equivalent to a premenopausal cisgender female. The second patient identified as non-binary, and both the patient and the cisgender partner underwent in vitro fertilization with donor sperm. After gonadotropin stimulation, the patient had 16 oocytes retrieved, of which nine were fertilized with sperm. The cisgender partner did not conceive after uterine implantation of her own blastocyst; however, she did achieve intrauterine twin pregnancy after implantation of two blastocysts from the patient.
Adeleye et al. (4) conducted a retrospective study of 13 transgender men and 13 cisgender women. Seven transgender patients discontinued testosterone prior to fertility preservation, and six patients had not yet started hormone therapy. Median testosterone use was 46 months and the median discontinuation was 6 months (1 to 13) prior to fertility preservation. The median number of oocytes collected in transgender men with testosterone use prior to oocyte collection [12 (4 to 26)] was significantly lower than that of transgender men without prior testosterone treatment [25.5 (18 to 28)], P=0.038).
In vitro maturation
Lierman et al. (26) conducted a prospective cohort study with 13 transgender men. All of them had received testosterone therapy at the time of fertility preservation for 53.6±21 weeks. The procedure consisted of collecting cumulus-oocyte-complexes (COC) at the time of GAS. A total of 680 COC were obtained which were then subjected to in vitro maturation, and the median number of COC collected per transgender men was 42.5 (5 to 174), which was higher in patients 20 years of age or younger. In total, 38.1% of COC reached metaphase II stage, of them, 133 oocytes underwent cryopreservation through vitrification and fixation for spindle staining; and 126 oocytes were immediately fixed for spindle staining. The results reported normal spindle structure and chromosomes alignment (92.2% vs. 85.7%; P=0.27) in both groups. The study included only patients 18 years or older. Since more COC were obtained in the younger group of patients, future studies that provide insight on the COC collected from young adolescents could provide more information about the fertility options in this population.
The prospective cohort study by De Roo et al. (27) included 40 transgender men and studied the hormone serum levels, ovarian histology and COC at the time of GAS. All patients had been previously treated with testosterone for 58.18±26.57 weeks. A total of 1,313 COC were retrieved, of which 34.30% reached metaphase II. Of them, 87.1% showed normal spindle structure.
Ovarian tissue cryopreservation
It consists of cryopreserving ovarian tissue during GAS. The ovarian tissue can later be transplanted onto the ovaries or grafted heterotopically for maturation of the oocytes. No studies were found in this review.
Even though the number of transgender patients pursuing fertility preservation has been increasing, it remains an underutilized resource (16). This could be due to barriers to access to healthcare, such as high costs, low awareness, late referral when patients have advanced reproductive age, psychosocial reasons and family values (28,29). Plastic surgeons are involved in a critical part of the gender affirming journey. Gender affirming genital surgery may have an irreversible impact on fertility; thus, plastic surgeons should be aware of the options for fertility preservation in transgender patients, and offer counselling to these patients before undergoing any gender affirming procedures. If the patient has not undergone genital surgery, hormone therapy may be discontinued to allow for potential recovery of reproductive function. Many patients who present to the plastic surgeon have been utilizing hormones for a period of months, thus their reproductive potential may have been altered. A multidisciplinary approach with other specialists such as psychologists and endocrinologists is essential to ensure proper counselling about their fertility preservation options.
Current fertility preservation options for transgender women include sperm cryopreservation and testicular sperm extraction. Semen cryopreservation is the current most simple and reliable technique (30). It can be achieved with masturbation or vibratory stimulation without the need for invasive procedures, and is available at many fertility clinics. If the sperm quality is low, multiple samples can be collected and additional methods such as intrauterine insemination (IUI) and in vitro fertilization (IVF) can be used to increase the chances of pregnancy. A testicular sperm extraction consists of a percutaneous aspiration of sperm from the epididymis or testis. It is an option for patients who are unable to ejaculate or for those with severe oligospermia or obstructive azoospermia. It requires only local anesthesia and can be used for IVF or ICSI (31).
For patients on hormonal therapy, spermatogenesis may be altered and the results are often unsuccessful. A study assessing spermatogenesis in fifty transgender women on hormonal therapy showed spermatogenesis in 20% of specimens and maturation arrest at the level of spermatogonia in 80% of the samples (32). For these patients, testicular sperm harvesting at the time of GAS can be contemplated. Immature testicular tissue cryopreservation is another experimental method for fertility preservation used in transgender patients. It involves biopsy of testicular tissue from pre-pubertal and adolescent patients, which then undergoes vitrification and is subsequently xenografted to induce spermatogenesis (33). It remains an investigational method that has shown successful results in animal studies, and it is the only option available for pre-pubertal males at the moment.
Several studies have shown that semen parameters including sperm concentration, total motile sperm count and post-thaw motility are lower in transgender women when compared to cisgender men (3,10,17,18,22). The etiology of these findings is unknown; however, some of the reasons could be wearing tight underwear, self-induced high scrotal positioning of the testes, psychological stress, genetic factors and gender affirming hormone therapy (21,34). Other factors such as obesity (35), smoking (36) and psychosocial stress (37) could influence semen parameters. It is well known that hormonal therapy negatively affects sperm parameters (28). Ideally, the best time for attempting fertility preservation is before any hormonal therapy to avoid adverse effects on fertility including testicular atrophy or testicular function disorders (38). Studies analyzing semen parameters of transgender women before starting hormonal therapy have reported them to be within normal limits (10,17,23). A study of four patients with prostate cancer who used gonadotropin agonist for at least 1 year, showed an inhibition of spermatogenesis on testicular histology after orchiectomy (39). Payer et al. (40) described partially arrested spermatogenesis and changes on Leydig cell morphology on testicular biopsies of six transgender women who had been on hormone therapy with estrogen for one to 8.5 years. Discontinuing the hormonal therapy may restore reproductive function; however, it may take up 3 to 24 months after stopping the medication. During this time, previous gender characteristics that were suppressed may return along with feeling of gender dysphoria. Alford et al. (19) reported a case of a transgender woman who showed recovery of testosterone levels and semen parameters 6 weeks after stopping hormonal therapy.
For transgender women who are seeking fertility preservation, semen cryopreservation is usually the first option offered. If the patient is taking gender affirming hormonal therapy, it should be stopped before semen collection. If the sperm quality remains low, other methods such as testicular sperm extraction or testicular sperm harvesting at the time of GAS can be attempted. Due to the many factor influencing semen parameters, as well as differences of semen quality between samples, it is difficult to accurately predict which transgender patient will have active spermatogenesis. Therefore, it is crucial that fertility preservation options be discussed before initiating exogenous hormonal therapy.
Transgender men have more challenges when attempting fertility preservation. Age plays a bigger role in transgender men than transgender women, since the rates of successful oocyte collection declines with increased age (41). In addition, the process is more expensive and less effective than sperm banking. It requires invasive procedures such as transvaginal ultrasounds and transvaginal aspiration of oocytes, which can be perceived as a physically and psychologically challenging experience, and can worsen gender dysphoria (42). In 2014, Wallace et al. (25) described the first case of oocyte cryopreservation before initiating hormone therapy in a transgender man. Since then, many other studies have also reported successful oocyte or embryo cryopreservation in transgender men (4,24).
Advances in technology have increased the options and outcomes of fertility preservation in transgender men. In some cases, pregnancy rates fertility preservation methods have been reported to be similar to IVF cycles (43-46). The most common method for fertility preservation in transgender men is oocyte cryopreservation. It requires ovarian hyperstimulation with hormones, followed by transvaginal ultrasound—guided oocyte retrieval with oocyte cryopreservation. Embryo banking is another option, however, it requires a sperm donor. Maxwell et al. reported successful pregnancies in transgender couples after oocyte cryopreservation (47). Immature oocyte aspiration at the time of GAS with in vitro maturation and oocyte cryopreservation is another method. There are two studies in transgender men who have attempted this technique and obtained normal spindle structure of the oocytes, which is necessary for subsequent fertilization (15,26). These studies were performed in patients 18 years old or older, and showed that most of the COC were obtained from the younger group of patients. Future studies on COC collected from young adolescents could provide more information about fertility options in this population.
Hormonal therapy has shown to have negative effects on ovarian tissue reserve and ovarian stimulation response to gonadotropin, with arrest of follicle maturation (6,8,9,27). Two studies (15,26) in this review reported successful results after stopping testosterone therapy; however the duration of testosterone therapy was relatively short, between 53 to 58 weeks; therefore, data on long-term testosterone use is still needed. Early oocyte retrieval before any gender affirming hormone treatment could prevent patients on having to temporarily stop their hormonal therapy if they decide to undergo fertility preservation in the future. Discontinuing testosterone may impose a regression in their gender affirming journey and could worsen gender dysphoria (42).
Limitations of this study are that several studies did not provide the dose of the hormone therapy or sperm/ovarian stimulation medication. In addition, only original peer reviewed articles were included, obviating other studies.
Improving physician and patient awareness on fertility preservation options in the transgender population is important. Several fertility preservation methods have shown to be effective in the transgender population. Our review shows that fertility preservation should be discussed early during gender transition and if possible, before any exogenous hormonal therapy is started, as the timeline for these interventions is important in order to preserve their reproductive potential as much as possible.
Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine, for the series “Transgender Surgery”. The article has undergone external peer review.
Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-4523
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-4523). The series “Transgender Surgery” was commissioned by the editorial office without any funding or sponsorship. OJM served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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