A.M. Clark, PhD Philadelphia Trans Health Conference 2012

1. Preservation of Fertility for Pre- & Post-Pubertal Trans People:Current Reproductive Options & Research In-Progress A.M. Clark, PhD Philadelphia Trans Health Conference 2012

2. Goal of this presentation • Provide information about the current and potential future options for trans people to have genetically-related (biological) offspring (Will not be discussing adoption.)

3. Talking about trans people • Descriptions of people in this presentation will be based the reproductive organs they have, except in cases from the literature where certain labels have been used.

4. Sources of Information • Dr. Samuel Pang & Reproductive Science Center of New England • American Society of Reproductive Medicine (ASRM) • Society for Assisted Reproductive Technologies (SART) • International Society for Fertility Preservation (ISFP) • Sperm Bank Directory.com • American Association of Tissue Banks (AATB)

5. References • De Sutter, P. 2007. Reproduction and fertility issues for transpeople. In: Principals of Transgender Medicine and Surgery, R Ettner, S. Monstrey, A.E. Eyler, eds, pp. 209-221 • De Sutter, P, 2009. Reproductive options for transpeople: Recommendations for revision of WPATH’s Standards of Care, Intl J Transgenderism 11: 183-185. • Rainbow Health Ontario Fact Sheet: Reproductive Options for Trans People (and references therein). • Standards of Care for Health of Transsexual, Transgender, and Gender Nonconforming People, WPATH, 7th Version (and references therein).

6. Reproductive Needs and Rights of Trans People • Health Care Needs of Transgendered Patients, Lawrence et al., 1996, J Am Med Assoc 276:874 • ASRM Ethics Committee Report (2009), “Access to fertility treatment by gays, lesbians, and unmarried persons.” • Assisted Human Reproductive Act in Canada (2004) non-discrimination clause includes sexual orientation and marital status.

7. Reproductive Needs and Rights of Trans People Reproductive wish in transsexual men. Wierckx et al., 2012, Hum Reprod 27:483-487 Survey of 50 transsexual men (Belgium) 64% had partners 54% wanted children 38% had considered freezing oocytes 16% had children with female partner inseminated with donor sperm 6% had given birth to children prior to medical transition The desire to have children and the preservation of fertility in transsexual women: A survey. De Sutter et al., 2002, Intl J Transgenderism 6(3) Survey of 121 transsexual women in Western Europe 43% had partners 40% had biological children 77% answered that sperm freezing should be offered to all trans women prior to hormonal treatment, but 45% would have refused because of the emotional link to their “male” past

8. Post-PubertalAdults PRESERVATION OF FERTILITY

9. Preservation of Fertility in Adults • Cryopreservation of sperm • Method has been used since the 1950s • Semen analysis should be performed prior to banking to determine sperm quality and quantity • Some sperm banks will perform initial freeze-thaw test • Recommendation is to store samples from at least 3 ejaculates with minimum of 2-days between ejaculates • With poor sperm quality or quantity, current reproductive technologies can still result in successful pregnancy • Sperm can be frozen indefinitely – successful pregnancies known from sperm frozen for more than 10 years

10. Preservation of Fertility in Adults • Cryopreservation of sperm • Verify bank has accreditation from American Association of Tissue Banks • Semen sample can be collected at clinic or at home – some sperm banks require sample collection on-site • Sample collection methods • Masturbation (most common) • Special (nontoxic) condom via intercourse • Electroejaculation • Minor surgery to remove sperm from epididymis or testis • No known detrimental effects of freezing on sperm DNA

11. Preservation of Fertility in Adults • Cryopreservation of oocytes (eggs) • Method not systematically used until the 1990s • Initially, outcomes were poor – now >900 live births recorded from frozen oocytes with no apparent increase in abnormalities • Still considered “experimental” by ASRM but expected to be a more “standard” method in the near future

12. Preservation of Fertility in Adults • Cryopreservation of oocytes (eggs) • Egg bank clinics may first evaluate ovarian reserves by ultrasound and check blood hormone levels • Ovarian stimulation & egg retrieval • May begin with GnRH analogue to suppress endogenous pituitary hormones • Self-injection of (pituitary) hormones to stimulate ovarian follicles to develop ~12 days, possibly with ultrasound monitoring every 3-4 days • Retrieval under anesthesia using vaginal ultrasound-guided needle aspiration of oocytes from ovarian follicles

13. Preservation of Fertility in Adults • Cryopreservation of oocytes (eggs) • Two methods with goal of avoiding formation of ice crystals either within the oocytes or in the surrounding liquid • Controlled-rate freezing • Oocyte is dehydrated in cryoprotectants and temperature is reduced slowly at a controlled rate • Vitrification • High concentration of cryoprotectants + ultra-rapid freezing rate, forming a glass-like (vitrified) state

14. Preservation of Fertility in Adults • Cryopreservation of oocytes (eggs) • Potential risks of ovarian stimulation • Ovarian cysts – may cause pelvic pain • Mild/moderate ovarian enlargement with possible abdominal distention/pain in ~20% of patients • Ovarian hyperstimulation syndrome (OHSS) • Risk can be up to 6% depending on doses of hormones • Ovaries enlarge and leak fluid into abdomen • Possible pleural effusion, blood clots, abnormal kidney function • Can be life-threatening and may require hospitalization

15. Preservation of Fertility in Adults • Cryopreservation of embryos • Better success rates than with cryopreservation of oocytes • For individuals with ovaries, “Embryo freezing is the most efficient technique for fertility preservation.” (ISFP) • Considerations: • Requires ovarian stimulation and retrieval of oocytes • Individual might not have sperm donor/partner at time of fertility preservation

16. Preservation of Fertility in Adults • Because hormone therapy inhibits folliculogenesis and spermatogenesis, the desire to procreate after medical transition would require individuals to stop hormone therapy for months or even years in order to produce germ cells • Spermatogenic cycle = 74 days + ~15 days maturation in the epididymis • Development of a primordial follicle to a preovulatory dominant follicle = almost one year (although secondary and tertiary follicles might be present and reinitiate development once hormone therapy is stopped) • Hormones would render ovaries unresponsive to stimulation for oocyte retrieval • Recovery of gamete development might not occur depending on the age of the individual and the length of time they have been on hormone therapy

17. Preservation of Fertility in Adults • Questions: • How long can sperm be retrieved from individuals once they have started hormones? • Are some sperm produced in testes of individuals who have been on hormone therapy mid-to-long term? • (My) Answer: The risk of epigenetic effects from hormone treatment that could potentially be passed onto offspring should not be ignored • Clear sperm-related effects for nutrition, alcohol consumption, toxins smoking, drug use • Reviewed in: Epigenetics and the origins of paternal effects. Curley et al., Hormones and Behavior 2011 59:306-314

18. Preservation of Fertility in Adults • Cryopreservation of gametes (sperm and oocytes) should be performed before individuals begin transition-related hormone therapy • However, this may not be possible due to cost, lack of information/counseling, unacceptable potential delay of transition, unacceptable link to “gender-based” function, unacceptable clinical procedures (e.g. ovarian stimulation and egg retrieval)

19. Preservation of Fertility in Adults - Future • Cryopreservation of ovarian or testicular fragments • Currently experimental • Would avoid difficulties of cryopreservation of oocytes, sperm or embryos

20. Preservation of Fertility in Adults - Future • Cryopreservation of ovarian or testicular fragments June 28, 2005

21. Preservation of Fertility in Adults - Future • Cryopreservation of ovarian or testicular fragments • The female-to-male transsexual patient: a source of human ovarian cortical tissue for experimental use. Van Den Broecke et al., 2001 Hum Reprod 16:145-147 • Ovarian tissue donated by 21-year-old FTM treated with testosterone undecanoate for 12 months • 2mm x 1mm ovarian cortex frozen-thawed fragments transplanted subcutaneously into 17 female immunocompromised mice (3 fragments/mouse) • 10-weeks post-grafting, mice injected with FSH for 14-days • 86% of grafts recovered, all ~50% reduced in size • Non-grafted ovarian biopsy = 98.6% primordial and 1.4% primary follicles • Engrafted ovarian fragments = 79.4% primordial and 20.6% later staged follicles, including 2.1% secondary and 1.4% pre-antral follicles

22. Post-PubertalAdults REPRODUCTIVE OPTIONS

23. Reproductive Options for Adults • Needs influenced by availability of gametes (sperm, eggs) from both members of a couple and whether one member of the couple will carry the child • Sperm/egg donors – known or anonymous, may involve sperm/egg bank and/or egg donor agency • Gestational carrier / surrogate – often involves surrogacy agency

24. Reproductive Options for Adults • One member of the couple has ovaries (oocytes) and uterus, will be inseminated and will carry the child • Example: Fenway Health Clinic, Boston • Couple attends orientation at the clinic • Couple charts menstrual cycles for 3 months by monitoring basal body temperature (BBT), note changes in cervical mucus and cervix and practice using ovulation prediction kit • Enrollment Visit for reviewing BBT charts, lab results • Preconception Counseling Visit for discussing current state of health and medical history, information discussion, mandatory medical tests • Clearance for procedure based on medical assessment and medical test results • Order sperm from bank if necessary • Sperm deposition timed with ovulation -- intra-vaginal (can be done at home using a kit), intra-cervical or by intrauterine insemination (IUI)

25. Reproductive Options for Adults • Intrauterine Insemination (IUI) • Sperm cells first washed and concentrated • Sperm cells then placed directly into uterus • Improves contraception rates, especially in cases where • Individual has ovulatory disorder that responds to co-administered fertility medication • Individual has mild endometriosis, does not ovulate, has structural problem of the uterus or oviduct • Sperm quality and/or concentration is low • Some (low) risks: infection, uterine cramping, side effects and/or multiple pregnancy if fertility medications are administered, STI from sperm

26. Reproductive Options for Adults • In Vitro Fertilization (IVF) / Assisted Reproductive Technologies (ART) may be employed when: • Cryopreserved eggs are used • Donated eggs are used • Sperm cells are poor quality and/or incapable of fertilizing the egg (can use Intracytoplasmic Sperm Injection – ICSI) • Individual with ovaries who will carry the child has fertility issues or structural problems of the reproductive tract • A gestational surrogate will carry the child

27. Reproductive Options for Adults • In Vitro Fertilization (IVF) / Assisted Reproductive Technologies (ART) • The cycle preceding ART: • Oral contraceptives may be used to synchronize irregular cycles and help prevent ovarian cysts from GnRH analog • GnRH analog may be administered to suppress endogenous pituitary hormones • Baseline pelvic ultrasound –checks for ovarian cysts • ART Cycle: Same steps as given for ovarian stimulation and egg retrieval for oocyte cryopreservation

28. Reproductive Options for Adults • In Vitro Fertilization (IVF) / Assisted Reproductive Technologies (ART) • Sperm is collected fresh if frozen sperm are not being used, is washed to remove semen • Sperm and eggs are cultured together under special conditions for fertilization - or - ICSI is performed

29. Reproductive Options for Adults • In Vitro Fertilization (IVF) / Assisted Reproductive Technologies (ART) • Fertilized eggs/embryos allowed to develop “in the dish” • Embryos may develop at different rates • Can help distinguish which are “good” embryos • Next day (Day 1): Single cell with 2 nuclei • Day 2: 4-cell embryo • Day 3: 8-cell embryo • Day 5: blastocyst (>80 cells, fluid-filled cavity, inner cell mass)

30. Reproductive Options for Adults • In Vitro Fertilization (IVF) / Assisted Reproductive Technologies (ART) • Embryo transfer: • Best embryos selected for transfer based on recipient’s age, appearance of embryos • Embryos placed in recipient’s uterus • Menstrual cycle of gestational surrogate, if used, must be synchronized to accept embryo(s) at the proper time so uterine lining can support implantation • If fresh eggs from an egg donor are used, the cycles of both the egg donor and the embryo recipient must be synchronized

31. Reproductive Options for Adults • In Vitro Fertilization (IVF) / Assisted Reproductive Technologies (ART) • Also with embryo transfer: • Some clinics will perform assisted hatching • Hormonal support for uterine lining – progesterone supplementation by vaginal, oral and/or injectable route, usually administered the day of or after oocyte retrieval • Progesterone support administered daily until pregnancy test • Pregnancy test performed 9-12 days after embryo transfer and repeated 2-days later if positive • Close evaluation of pregnancy to identify miscarriages or ectopic pregnancies and counsel for multiple pregnancy • Patient released to obstetrician 8-10 weeks of gestation

32. Reproductive Options for Adults • Gamete Intrafallopian Transfer (GIFT) / Assisted Reproductive Technologies (ART) • Unfertilized sperm and eggs are placed together in the fallopian tubes where fertilization takes place • May be used in place of IVF by individuals with less severe infertility issues • Does not result in issue of unused, stored frozen embryos • Requires laparoscopy under general anesthesia • Could result in multiple pregnancy • Rarely performed - Only ART not excluded by the Catholic church

33. Reproductive Options for Adults • Breastfeeding/lactation • For individuals whose breast development was a result of transition hormone treatments, lactation may be stimulated with methods used by mothers who adopt, although no data available for trans people using this method • Wittig & Spatz, 2008 Am J Maternal Child Nursing 33:76 • For individuals who have had chest masculinization surgery and who gestate and give birth, remaining breast tissue may grow with pregnancy and might even lactate and/or become inflamed (mastitis) • Might require revision post-pregnancy, as tissue may not completely regress • Drugs are available to stop lactation

34. Post-PubertalAdults Costs and legal considerations

35. Reproductive Options for Adults – Costs of Procedures “Costs of different procedures vary from clinic to clinic and from state to state, with costs at RSC New England being on the low side of the range. Costs of surrogacy also vary and could be up to twice the amount given here.” www.GayIVF.com www.RSCNewEngland.com

36. Reproductive Options for Adults – Costs of Procedures • IUI (Intrauterine Insemination) • $300-$500/attempt (cycle), $300 ultrasound, $100-$1000 fertility drugs, $1000/cycle donor sperm • IVF (In Vitro Ferilization) • ~$15,000 per treatment cycle, including meds • Egg donor • $10,000 - $15,000 – covers compensation to egg donor, agency and legal fees, donor expenses (such as travel, etc.) • Surrogate • $40,000 - $60,000 – covers compensation to surrogate, agency and legal fees, surrogate expenses

37. Reproductive Options for Adults – Legal Considerations “I am not a lawyer so cannot provide legal counsel. These are simply issues which I raise to heighten the awareness of the audience that they need to have legal counsel with an attorney who is familiar with this highly specialized area of law.” www.GayIVF.com www.RSCNewEngland.com

38. Reproductive Options for Adults – Legal Considerations • Donors: sperm and eggs • Known donor – need to agree on involvement, parental and visitation rights, etc.; need to document expectations of both parties in a legal contract • Anonymous donor – laws vary from state to state regarding anonymity, disclosure, etc. • Prenatal & perinatal care • Laws vary from state to state whether the (non-pregnant) partner (if not married) can participate in prenatal visits and birth. • Living wills are needed to determine fate of frozen embryos if one partner becomes incapacitated • Second parent adoption • May be necessary if intended parents are not married to each other – affects custody, hospital visitation, travel, taxes, etc.

39. Reproductive Options for Adults – Legal Considerations • Surrogacy • Banned in several states (e.g. New York) • Need to ensure that surrogate lives in and delivers baby in a state that is “surrogacy-friendly” or court may rule in favor of surrogate if she wants to keep the baby. • Massachusetts is one of the most surrogacy-friendly states – having a “pre-birth order” from the court allows the names of the intended parents to go directly on the birth certificate at the time of birth. Otherwise, the surrogate needs to “give the baby up for adoption” and the intended parents need to “adopt” their own baby, which adds the complications of adoption laws.

40. Reproductive Options for Adults – Legal Considerations www.GLAD.org

41. Reproductive Options for Adults – Legal Considerations • Chapter 3: Relationship Recognition and Protections • Chapter 4: Protecting Parental Rights • Chapter 6: Parental Rights After Relationship Dissolution www.GLAD.org

42. PRE-PubertalCHILDREN PRESERVATION OF FERTILITYEXPERIMENTAL methods

43. Preservation of Fertility in ChildrenExperimental Techniques • Children on hormone blockers will not go through puberty. Will not have mature gametes to preserve. • Teenage trans children with ovaries might respond to ovarian stimulation for collection and cryopreservation of eggs, even if they have been on hormone blockers. May need to go off the blockers for several months – “uncharted territory.”

44. Preservation of Fertility in ChildrenExperimental Techniques • An ethical consideration Children are not necessarily thinking about having their own children, so parents may end up making decisions to preserve their children’s reproductive cells or tissues that their children will then have control of when they become adults.

45. Preservation of Fertility in ChildrenExperimental Techniques • Methods are currently being developed for children and adults who have cancer and who will be rendered sterile by chemotherapy and radiation treatments. • International Society for Fertility Preservation (ISFP)

46. Preservation of Fertility in ChildrenExperimental Techniques • Cryopreservation of ovarian tissue (pieces) • Children have abundant follicles throughout the ovarian cortex • Puberty blockers would keep follicles in primordial stage • Ovaries could be removed upon medical transition, sectioned into small pieces and slow-frozen in cryoprotectant • Pieces could be stored until needed for generating embryos • Would require culture and in vitro maturation of follicles/oocytes and possibly ICSI to generate embryos • Live young (mice, kittens) have been born from this procedure • Studies published where human follicles were matured in vitro

47. Preservation of Fertility in ChildrenExperimental Techniques • Cryopreservation of sperm • Sperm have been successfully collected from children as young as 11 years of age • Number of sperm low, so may require two or three ejaculates • Would need to be done prior to use of puberty blockers • May be difficult for children who are uncomfortable with their birth sex • Sperm may not be mature for fertilization, so may require ICSI

48. Preservation of Fertility in ChildrenExperimental Techniques • Cryopreservation of testicular tissue • Puberty blockers would stop development of spermatogonia • Testes could be removed upon medical transition, sectioned into small pieces or dissociated into cell suspensions and slow-frozen in cryoprotectant • Pieces/suspensions could be stored until needed for generating sperm • Would require culture and in vitro expansion and maturation of spermatogonia to spermatid stage • Up to 60% post-thaw viability reported with human testicular cell suspensions. • Some development of germ cells in cultured human testicular tissue and cell suspentions. • Recent development of mouse sperm from testis cell suspensions in a 3-D soft agar culture system

49. What will the more distant future hold?

50. Recent Headlines January 18, 2012