JBRA Assist. Reprod. 2020;24(4):513-516
CASE REPORT
doi: 10.5935/1518-0557.20200024
1 Dra Suely Resende - Centro de Reprodução Humana Assistida - Campo Grande, MS, Brazil
CONFLICT OF INTERESTABSTRACT
Transgender men are individuals who identify as men but were assigned female at
birth. Gender-affirming medications include testosterone hormone therapy, known
for its diverse effects throughout the body, which include endometrial atrophy
and the induction of amenorrhea by suppressing ovulation, without however
affecting the ovarian follicle pool. This paper reports the first case in Brazil
involving a transgender man and a cisgender woman attempting to form a family. A
34-year-old transgender man and a 28-year-old woman came to our assisted
reproduction service. He had been on testosterone for two years. At their
initial consultation, testosterone therapy was discontinued. Controlled ovarian
stimulation for the transgender man was achieved using a combination of
recombinant gonadotropins FSH and LH. Pituitary blockage was performed using a
GnRH antagonist protocol. Twenty follicles were aspirated and 16 oocytes were
retrieved, 12 of which mature. They were inseminated with donor semen. On the
fifth day of development, one high quality blastocyst was transferred to the
cisgender woman, resulting in an ongoing pregnancy. Five supernumerary embryos
were cryopreserved. Controlled ovarian stimulation with high quality oocytes,
high quality embryos, and clinical pregnancy are possible for transgender men,
even with a history of testosterone use.
Keywords: transgender men, fertility, pregnancy, assisted reproduction
INTRODUCTION
The term transgender describes a man or woman whose gender identity is incongruent
with their phenotypic sex assigned at birth (Armuand et al., 2017; Goldman et al., 2017; Hoffkling et al., 2017; Cheng et al., 2019). The true prevalence of
transgenderism cannot be easily determined, since some transgender people come to
terms with their gender identity later in life, while others do not openly identify
as transgender due to social pressure (Irwig,
2017). Nonetheless, there is an estimated 700,000-1,000,000 transgender
individuals in the United States, which account for about 0.3-0.5% of the American
population (Obedin-Maliver & Makadon,
2016; Hoffkling et al.,
2017; Cheng et al.,
2019). Although an estimated 750,000 transgender individuals live in
Brazil, no other nation murders more transgender individuals in the world (IBGE, 2018).
Some transgender individuals suffer from gender dysphoria, the distress caused by a
mismatch between a person's gender identity and sex assigned at birth. Treatment for
gender dysphoria may include emotional, social, hormonal therapy and surgery, which
may affect the gonads and potentially the gametic pool, resulting in loss of
fertility (Coleman et al.,
2012; T'Sjoen et al.,
2013; Condat et al.,
2018). Transgender men identify as men but were assigned female at birth.
Gender-affirming surgery for these individuals leads to irreversible infertility from
hysterectomy and oophorectomy. Hormonal therapy includes testosterone, which has
diverse effects throughout the body, affecting patients both physically and
psychologically. The list of effects includes endometrial atrophy, ovarian cortex
and stroma hyperplasia, and induction of amenorrhea by ovulation suppression.
Nevertheless, testosterone apparently does not affect the ovarian follicle pool
(Coleman et al., 2012; T'Sjoen et al., 2013; Armuand et al., 2017; Irwig, 2017; Maxwell et al., 2017; Adeleye et al., 2019; Cheng et al., 2019).
Several questions around childbearing by transgender men remain unanswered, such as
the optimal time to preserve reproductive potential prior to or during the
initiation of gender affirming treatments (Coleman et al., 2012; Goldman et al., 2017; Adeleye et al., 2019). Transgender individuals are free to
access assisted reproductive services to preserve gametes or reproductive tissue for
future use. They may also use assisted reproductive technologies (ART) if they
choose to attempt to have children. While there is some data on oocyte
cryopreservation for transgender men, data on ovarian stimulation and retrieval, in
vitro fertilization, and pregnancy are limited (James-Abra et al., 2015; Goldman et al., 2017; Maxwell et al., 2017; Adeleye et al., 2019).
This paper describes the case of a Brazilian couple made up by a transgender man and
a cisgender woman who underwent ART at our service.
CASE DESCRIPTION
Couple information and medical history
A 34-year-old transgender man and a 28-year-old woman sought our private assisted
reproduction service with the desire to build a family. He wanted to undergo
ovarian stimulation for in vitro fertilization (IVF) and then have his eggs
inseminated with donor sperm, so that the resulting embryos were transferred to
his partner. He had been on 250 mg of injectable testosterone (Durateston, Aspen
Pharma, Brazil) for two years and had undergone a bilateral mastectomy three
months prior. He was advised to discontinue testosterone therapy at the first
consultation and was prescribed folic acid supplementation. The patient was
advised to wait for his menstrual cycles to return. After obtaining a general
medical history from both patients, the two were ordered to undergo a thorough
assessment of general health. The main findings for the cisgender woman were
hypothyroidism and hyperprolactinemia.
Controlled ovarian stimulation (COS) and egg retrieval
COS for the transgender man was achieved using a combination of recombinant-hFSH
150 IU plus recombinant-hLH 75 IU (follitropin-α and lutropin-α in a 2:1 ratio;
Pergoveris; EMD Serono, São Paulo, Brazil) with recombinant-hFSH 75 IU
(follitropin-α; GONAL-f; EMD Serono, São Paulo, Brazil) for the first two days.
On the third day, the daily dose of recombinant-hFSH (follitropin-α; GONAL-f;
EMD Serono, São Paulo, Brazil) was adjusted to 150 IU plus a fixed dose of
highly purified menotropin 75 IU (human menopausal gonadotropin; hMG; Menopur,
Ferring, São Paulo, Brazil). On the last two days of COS, the dose of
recombinant-hFSH (follitropin-α; GONAL-f; EMD Serono, São Paulo, Brazil) was
adjusted to 225 IU, with the aforementioned hMG dose. Gonadotropin
administration was continued up to and including the day of human chorionic
gonadotropin (hCG) administration.
Pituitary blockage was performed using a daily dose of 1.5 mg of GnRH antagonist
(Cetrotide; Asta Medica, Frankfurt, Germany), beginning when at least one
follicle ≥14 mm was visualized, on the 8th day of COS.
Follicular growth was monitored using transvaginal ultrasound, beginning on the
first day of gonadotropin administration. When three or more follicles attained
a mean diameter of 17 mm, and serum estradiol levels were noticed (2,375 pg/mL),
recombinant hCG (rhCG; Ovidrel; Merck Serono, São Paulo, Brazil) was
administered to trigger final follicular maturation. The oocytes were collected
35 hours after hCG administration through transvaginal ultrasound ovum pick-up,
12 days after ovarian stimulation.
Twenty follicles were aspirated and 16 oocytes were retrieved, of which 12 were
metaphase II (MII), two were metaphase I, and two were prophase I. Fertilization
of 12 MII oocytes took place by intracytoplasmic sperm injection (ICSI) with
donor sperm. The fertilized oocytes were cultured and resulted in eight
two-pronuclear (2PN) zygotes, one 1PN zygote, and three non-fertilized (NF)
oocytes.
Embryo transfer (ET) and luteal phase support
The embryos were cultured until day 5 (D5), when one high quality blastocyst was
transferred to the cisgender woman. Five supernumerary embryos were
cryopreserved.
The cisgender partner had undergone cycle synchronization using 6mg/day of oral
estradiol valerate (Primogyna, Schering, São Paulo, Brazil) for eight days,
until an endometrial thickness of 5.9 mm was reached. The dose of estradiol was
then adjusted to 8mg/day and transdermal estradiol 100 Mcg (Estradot; Novartis,
São Paulo, Brazil) each 72 hours was added. Thirteen days later, on the day of
ovum pick-up, her endometrial thickness was 7.6 mm. Luteal phase support was
then conducted with micronized vaginal progesterone 400mg (Utrogestan -
Farmoquimica, São Paulo, Brazil), with a dose adjustment to 800mg on the
14th day until ET, with five days of progesterone.
Serum β-hCG reached 355.05mIU/L 11 days after ET, and an ongoing pregnancy was
detected.
Ethical approval
The couple gave informed consent to having their case published.
DISCUSSION
To our knowledge, this is the first Brazilian report of a transgender man in a couple
to undergo COS for ART. Moreover, this case report contributes to the literature on
family building involving transgender men previously on testosterone who had their
oocytes retrieved and submitted to ICSI to produce a successful pregnancy.
Studies have shown that approximately half of transgender individuals wish to have
biological children, as also do cisgender individuals (Condat et al., 2018). The World Professional
Association for Transgender Health (WPATH) Standards of Care recommends that
fertility preservation options be discussed with transgender individuals with an
interest in having genetically related children prior to the start of
gender-affirming treatments (Coleman et
al ., 2012; Condat et
al. , 2018). Typically, transgender men take progestins or
GnRH agonists for a short period of time in early hormonal therapy, and then move to
testosterone for the rest of their lives (Irwig,
2017; Condat et al.,
2018). Testosterone therapy is generally regarded as safe in the short
term, but little is known about its long-term effects. In most cases, testosterone
leads produces reversible amenorrhea by suppressing ovulation, but follicles are not
depleted from the ovaries. On the other hand, increased androgen levels may
adversely affect follicle growth. Mature follicles are particularly affected due to
their androgen-sensitive granulosa cell layer. In some circumstances, a polycystic
ovarian morphology and ovarian hyperplasia have been described, (De Roo et
al ., 2016; Irwig, 2017; Cheng et al., 2019).
Transgender men are required to discontinue testosterone therapy if they wish to
undergo COS. Individuals dealing with the effects of testosterone cessation go
through physical and mental challenges, including changes in odor and voice,
fatigue, and resumption of menstruation, which may be perceived as a typically
female characteristic. Bleeding was described as psychologically stressful and as a
trigger to anxiety, exacerbated gender dysphoria, and self-harming behavior relapse
(Armuand et al., 2017; Cheng et al., 2019).
ART and gamete cryopreservation have shaken conservative family arrangement patterns.
Medical advances have extended parenting options of transgender individuals beyond
adoption. Furthermore, the fight for equality and non-discrimination has led to
wider recognition of Lesbian-Gay-Bisexual-TransIntersex-Questioning (LGBTIQ) rights,
including in family law (Condat et
al ., 2018). While society in general has come to accept gay
and lesbian couples as potential parents, transgender individuals have long faced
prejudice, including from health professionals (Goldman et al., 2017; Hoffkling et al., 2017). Nevertheless, transgender
individuals have increasingly sought access to ART, and about 12% of transgender men
who experienced pregnancy used reproductive technologies. However, transgender
individuals and their partners have predominantly negative interactions with
assisted reproduction when they access or attempt to procure the services of
fertility clinics (James-Abra et
al., 2015; Adeleye et
al., 2019).
Our data show that an antagonist-based protocol is suitable for ovarian stimulation
in this case. In our case, a transgender man had taken testosterone for two years
prior to COS, with discontinuation occurring only at the initial consultation.
Although lower in transgender men with a history of testosterone use, peak estradiol
in this case was high (2,375pg/mL). From 20 follicles aspirated, 16 oocytes were
retrieved, 12 of which mature (75%). On D5, six embryos were in culture and five
were cryopreserved, with one high quality blastocyst being transferred. This may
suggest that the follicular development and oocyte quality was not significantly
impacted by prior testosterone therapy.
Recent studies described cases of transgender men undergoing COS for oocyte
cryopreservation (Maxwell et al.,
2017; Leung et al., 2018; Adeleye et al., 2019). Maxwell et al. (2017) reported the cases of three
transgender men who underwent oocyte cryopreservation before starting
gender-affirming hormone therapy. Two patients returned for ovum pick up and had COS
performed with a low-dose leuprolide acetate protocol; both had twin pregnancies
carried by their partners.
A related study from Leung et al.
(2018) described a cohort of 22 transgender men who underwent 25 COS
cycles. The authors compared their outcomes to the results attained in 75 COS cycles
performed with cisgender women. The mean number of oocytes retrieved and the number
of MII oocytes in the transgender group (19.7 and 14.6, respectively) were
significantly higher than the numbers found in the control group (13.2 and 10.6).
Peak estradiol levels and mean total gonadotropin doses used in stimulation were
similar in the two groups. The mean number of fertilized oocytes of the 11
transgender men who proceeded to oocyte fertilization was not significantly
different from the number seen in the control group. Recently, Leung et al. (2019) published more results
regarding this cohort. A total of 12 embryo transfers were performed in seven
patient couples, five of which were fresh embryo transfers and seven were
frozen-thawed embryo transfers. The pregnancy rate was 83.3% and the live birth rate
was 58.3%.
Adeleye et al. (2019) reported the cases of 13 transgender men who underwent COS. Seven had been on
testosterone for a median length of 46 months, and had COS only six months after the
discontinuation of testosterone therapy. Interestingly, a comparison between
transgender men with and without a history of testosterone use found no differences
in baseline follicle count, cycle length, or FSH and hMG use. Transgender men with a
history of testosterone use had lower peak estradiol levels and fewer oocytes
retrieved compared to transgender men without a history of testosterone use. There
were no differences in estradiol levels per oocyte, MII oocyte yield, or maturity
rates between the two groups. A comparison between transgender men on testosterone
and cisgender women found that peak estradiol levels were lower in transgender men.
This is possibly due to the latter's lower follicle counts, although there was no
statistical difference in the number of oocytes and remaining cycle characteristics.
However, estradiol levels per oocyte were similar between the two groups, suggesting
that granulosa cell function was maintained.
Similarly to our case, three successful pregnancies were developed using the oocytes
of transgender men with a history of testosterone use, although one ended in a
miscarriage. Leung et al.
(2019) reported similar peak estradiol levels between transgender men
with a history of testosterone use and cisgender women, but higher gonadotropin
doses were administered to the transgender men group. Retrieved and mature oocytes
were also similar between the two groups, suggesting that even long periods of
gender-affirming androgen therapy do not appear to have negative effects on ovarian
stimulation outcomes.
CONCLUSION
Controlled ovarian stimulation with high quality oocytes and high quality embryos
leading to clinical pregnancy is a possibility for transgender men, even with a
history of testosterone use. This paper describes the first Brazilian report of a
couple featuring a transgender man with a history of testosterone therapy who
underwent controlled ovarian stimulation, with resulting eggs submitted to
intracytoplasmic sperm injection, followed by an embryo transfer that ultimately
resulted in his cisgender partner having an ongoing pregnancy.
REFERENCES
Adeleye AJ, Cedars MI, Smith J, Mok-Lin E. Ovarian stimulation for
fertility preservation or family building in a cohort of transgender men. J
Assist Reprod Genet. 2019;36:2155-61. PMID: 31435820 DOI:
10.1007/s10815-019-01558-y
Medline Crossref
Armuand G, Dhejne C, Olofsson JI, Rodriguez-Wallberg KA. Transgender
men's experiences of fertility preservation: a qualitative study. Hum Reprod.
2017;32:383-90. PMID: 27999119 DOI: 10.1093/humrep/dew323
Medline Crossref
Cheng PJ, Pastuszak AW, Myers JB, Goodwin IA, Hotaling JM. Fertility
concerns of the transgender patient. Transl Androl Urol. 2019;8:209-18. PMID:
31380227 DOI: 10.21037/tau.2019.05.09
Medline Crossref
Coleman E, Bockting W, Botzer M, Cohen-Kettenis P, DeCuypere G,
Feldman J, Fraser L, Green J, Knudson G, Meyer W, Monstrey S, Adler RK, Brown
GR, Devor AH, Ehrbar R, Ettner R, Eyler E, Garofalo R, Karasic DH, Lev AI, Mayer
G, Meyer-Bahlburg H, Hall BP, Pfaefflin F, Rachlin K, Robinson B, Schechter LS,
Tangpricha V, van Trotsenburg M, Vitale A, Winter S, Whittle S, Wylie KR, Zucker
K. Standards of Care for the Health of Transsexual, Transgender, and
Gender-Nonconforming People, Version 7. Int J Transgend. 2012;13:165-232. DOI:
10.1080/15532739.2011.700873
Medline
Condat A, Mendes N, Drouineaud V, Grundler N, Lagrange C, Chiland C,
Wolf JP, Ansermet F, Cohen D. Biotechnologies that empower transgender persons
to self-actualize as individuals, partners, spouses, and parents are defining
new ways to conceive a child: psychological considerations and ethical issues.
Philos Ethics Humanit Med. 2018;13:1. PMID: 29343272 DOI:
10.1186/s13010-018-0054-3
Medline Crossref
De Roo C, Tilleman K, T'Sjoen G, De Sutter P. Fertility options in
transgender people. Int Rev Psychiatry. 2016;28:112-9. PMID: 26835612 DOI:
10.3109/09540261.2015.1084275
Medline Crossref
Goldman RH, Kaser DJ, Missmer SA, Farland LV, Scout, Ashby RK,
Ginsburg ES. Fertility treatment for the transgender community: a public opinion
study. J Assist Reprod Genet. 2017;34:1457-67. PMID: 28900753 DOI:
10.1007/s10815-017-1035-y
Medline Crossref
Hoffkling A, Obedin-Maliver J, Sevelius J. From erasure to
opportunity: a qualitative study of the experiences of transgender men around
pregnancy and recommendations for providers. BMC Pregnancy Childbirth.
2017;17:332. PMID: 29143629 DOI: 10.1186/s12884-017-1491-5
Medline Crossref
Irwig MS. Testosterone therapy for transgender men. Lancet Diabetes
Endocrinol. 2017;5:301-11. PMID: 27084565 DOI:
10.1016/S2213-8587(16)00036-X
Medline Crossref
James-Abra S, Tarasoff LA, Green D, Epstein R, Anderson S, Marvel S,
Steele LS, Ross LE. Trans people's experiences with assisted reproduction
services: a qualitative study. Hum Reprod. 2015;30:1365-74. PMID: 25908658 DOI:
10.1093/humrep/dev087
Medline Crossref
Leung A, Sakkas D, Pang S, Thornton K, Resetkova N. Female to male
transgender patients have good egg yields with controlled ovarian
hyperstimulation. Fertil Steril. 2018;110:e21-2. DOI:
10.1016/j.fertnstert.2018.07.077
Crossref
Leung A, Sakkas D, Pang S, Thornton K, Resetkova N. Assisted
reproductive technology outcomes in female-to-male transgender patients compared
with cisgender patients: a new frontier in reproductive medicine. Fertil Steril.
2019;112:858-65. PMID: 31594633 DOI:
10.1016/j.fertnstert.2019.07.014
Medline Crossref
Maxwell S, Noyes N, Keefe D, Berkeley AS, Goldman KN. Pregnancy
Outcomes After Fertility Preservation in Transgender Men. Obstet Gynecol.
2017;129:1031-4. PMID: 28486372 DOI:
10.1097/AOG.0000000000002036
Medline Crossref
Obedin-Maliver J, Makadon HJ. Transgender men and pregnancy. Obstet
Med. 2016;9:4-8. DOI: 10.1177/1753495X15612658
Crossref
T'Sjoen G, Van Caenegem E, Wierckx K. Transgenderism and
reproduction. Curr Opin Endocrinol Diabetes Obes. 2013;20:575-9. PMID: 24468761
DOI: 10.1097/01.med.0000436184.42554.b7
Medline Crossref