TurnerFertility trial: PROTOCOL for an observational cohort study to describe the efficacy of ovarian tissue cryopreservation for fertility preservation in females with Turner syndrome

Myra Schleedoorn, Janielle van der Velden, Didi Braat, Ina Beerendonk, Ron van Golde, Ron Peek, Kathrin Fleischer, Myra Schleedoorn, Janielle van der Velden, Didi Braat, Ina Beerendonk, Ron van Golde, Ron Peek, Kathrin Fleischer

Abstract

Objective: To investigate the occurrence of live birth in women with Turner syndrome (TS) after ovarian tissue cryopreservation in childhood followed by auto transplantation in adulthood and to find reliable prognostic markers for estimating the ovarian reserve in girls with TS in the future.

Setting: An observational cohort study with long-term follow-up in a tertiary fertility clinic in the Netherlands. Patients recruitment between January 2018 and December 2021.

Participants: 100 females aged 2 through 18 years with classical Turner (ie, 45,X0) or Turner variants (ie, 45,X mosaicism or structural anomalies). Girls with Y chromosomal content, minor X deletions with marginal impact on fertility, active HIV, hepatitis B or hepatitis C infection, and/or an absolute contra indication for surgery, anaesthesia or future pregnancy will be excluded.

Interventions: Ovarian cortical tissue will be harvested by performing a unilateral oophorectomy via laparoscopic approach. Ovarian cortex fragments will be prepared and cryopreserved. One fragment per patient will be used to determine follicular density by conventional histology, and to perform fluorescence in situ hybridisation analysis of ovarian cells. Routine chromosome analysis will be performed on both lymphocytes and buccal cells. A blood sample will be taken for hormonal analysis and all subjects will undergo a transabdominal ultrasound to determine the uterine and ovarian size. Patient characteristics, pregnancy rates and pregnancy outcomes will be collected from the patient's medical record.

Ethics and dissemination: The study protocol has been approved by the Central Committee on Research Involving Human Subjects in November 2017 (CCMO NL57738.000.16).

Trial registration number: NCT03381300.

Keywords: cryopreservation; fertility preservation; live birth; ovarian reserve; turner syndrome.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Flowchart of study. AMH, anti Müllerian hormone; FSH, follicle stimulating hormone; i(X), isochromosome X; LBR, live birth rate; r(X), ring chromosome X; TS, Turner syndrome; X del, X deletions; 45,X, 45,X Monosomy.

References

    1. Elsheikh M, Dunger DB, Conway GS, et al. . Turner's syndrome in adulthood. Endocr Rev 2002;23:120–40. 10.1210/edrv.23.1.0457
    1. Karnis MF. Fertility, pregnancy, and medical management of Turner syndrome in the reproductive years. Fertil Steril 2012;98:787–91. 10.1016/j.fertnstert.2012.08.022
    1. Stochholm K, Juul S, Juel K, et al. . Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006;91:3897–902. 10.1210/jc.2006-0558
    1. Noordman I, Duijnhouwer A, Kapusta L, et al. . Phenotype in girls and women with Turner syndrome: association between dysmorphic features, karyotype and cardio-aortic malformations. Eur J Med Genet 2018;61:301–6. 10.1016/j.ejmg.2018.01.004
    1. Weiss L. Additional evidence of gradual loss of germ cells in the pathogenesis of streak ovaries in Turner's syndrome. J Med Genet 1971;8:540–4. 10.1136/jmg.8.4.540
    1. Reynaud K, Cortvrindt R, Verlinde F, et al. . Number of ovarian follicles in human fetuses with the 45,X karyotype. Fertil Steril 2004;81:1112–9. 10.1016/j.fertnstert.2003.12.011
    1. Hreinsson JG, Otala M, Fridström M, et al. . Follicles are found in the ovaries of adolescent girls with Turner's syndrome. J Clin Endocrinol Metab 2002;87:3618–23. 10.1210/jcem.87.8.8753
    1. Pasquino AM, Passeri F, Pucarelli I, et al. . Spontaneous pubertal development in Turner's syndrome. Italian Study Group for Turner's syndrome. J Clin Endocrinol Metab 1997;82:1810–3. 10.1210/jcem.82.6.3970
    1. Tanaka T, Igarashi Y, Ozono K, et al. . Frequencies of spontaneous breast development and spontaneous menarche in Turner syndrome in Japan. Clin Pediatr Endocrinol 2015;24:167–73. 10.1297/cpe.24.167
    1. da Silva Negreiros LP, Bolina ER, Guimarães MM. Pubertal development profile in patients with Turner syndrome. J Pediatr Endocrinol Metab 2014;845 10.1515/jpem-2013-0256
    1. Hadnott TN, Gould HN, Gharib AM, et al. . Outcomes of spontaneous and assisted pregnancies in Turner syndrome: the U.S. National Institutes of health experience. Fertil Steril 2011;95:2251–6. 10.1016/j.fertnstert.2011.03.085
    1. Bryman I, Sylvén L, Berntorp K, et al. . Pregnancy rate and outcome in Swedish women with Turner syndrome. Fertil Steril 2011;95:2507–10. 10.1016/j.fertnstert.2010.12.039
    1. Bernard V, Donadille B, Zenaty D, et al. . Spontaneous fertility and pregnancy outcomes amongst 480 women with Turner syndrome. Hum Reprod 2016;31:782–8. 10.1093/humrep/dew012
    1. Birkebaek NH, Crüger D, Hansen J, et al. . Fertility and pregnancy outcome in Danish women with Turner syndrome. Clin Genet 2002;61:35–9. 10.1034/j.1399-0004.2002.610107.x
    1. Hovatta O. Pregnancies in women with Turner's syndrome. Ann Med 1999;31:106–10. 10.3109/07853899908998785
    1. Sutton EJ, McInerney-Leo A, Bondy CA, et al. . Turner syndrome: four challenges across the lifespan. Am J Med Genet A 2005;139A:57–66. 10.1002/ajmg.a.30911
    1. Sylvén L, Magnusson C, Hagenfeldt K, et al. . Life with Turner's syndrome--a psychosocial report from 22 middle-aged women. Acta Endocrinol 1993;129:188–94. 10.1530/acta.0.1290188
    1. Oktay K, Bedoschi G, Berkowitz K, et al. . Fertility preservation in women with Turner syndrome: a comprehensive review and practical guidelines. J Pediatr Adolesc Gynecol 2016;29:409–16. 10.1016/j.jpag.2015.10.011
    1. Borgström B, Birgit B, Hreinsson J, et al. . Fertility preservation in girls with Turner syndrome: prognostic signs of the presence of ovarian follicles. J Clin Endocrinol Metab 2009;94:74–80. 10.1210/jc.2008-0708
    1. Jensen AK, Kristensen SG, Macklon KT, et al. . Outcomes of transplantations of cryopreserved ovarian tissue to 41 women in Denmark. Human Reproduction 2015;30:2838–45. 10.1093/humrep/dev230
    1. Van der Ven H, Liebenthron J, Beckmann M, et al. . Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates. Hum Reprod 2016;31:2031–41. 10.1093/humrep/dew165
    1. Jensen AK, Macklon KT, Fedder J, et al. . 86 successful births and 9 ongoing pregnancies worldwide in women transplanted with frozen-thawed ovarian tissue: focus on birth and perinatal outcome in 40 of these children. J Assist Reprod Genet 2017;34:325–36. 10.1007/s10815-016-0843-9
    1. Donnez J, Dolmans M-M, Pellicer A, et al. . Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue: a review of 60 cases of reimplantation. Fertil Steril 2013;99:1503–13. 10.1016/j.fertnstert.2013.03.030
    1. Van der Ven H, Liebenthron J, Beckmann M, et al. . Ninety-Five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates. Hum Reprod 2016;31:2031–41. 10.1093/humrep/dew165
    1. Jadoul P, Guilmain A, Squifflet J, et al. . Efficacy of ovarian tissue cryopreservation for fertility preservation: lessons learned from 545 cases. Hum Reprod 2017;32:1046–54. 10.1093/humrep/dex040
    1. Silber S, Pineda J, Lenahan K, et al. . Fresh and cryopreserved ovary transplantation and resting follicle recruitment. Reprod Biomed Online 2015;30:643–50. 10.1016/j.rbmo.2015.02.010
    1. Dittrich R, Hackl J, Lotz L, et al. . Pregnancies and live births after 20 transplantations of cryopreserved ovarian tissue in a single center. Fertil Steril 2015;103:462–8. 10.1016/j.fertnstert.2014.10.045
    1. Meirow D, Ra'anani H, Shapira M, et al. . Transplantations of frozen-thawed ovarian tissue demonstrate high reproductive performance and the need to revise restrictive criteria. Fertil Steril 2016;106:467–74. 10.1016/j.fertnstert.2016.04.031
    1. Loren AW, Mangu PB, Beck LN, et al. . Fertility preservation for patients with cancer: American Society of clinical oncology clinical practice guideline update. J Clin Oncol 2013;31:2500–10. 10.1200/JCO.2013.49.2678
    1. Practice Committee of American Society for Reproductive Medicine Ovarian tissue cryopreservation: a Committee opinion. Fertil Steril 2014;101:1237–43. 10.1016/j.fertnstert.2014.02.052
    1. Coccia PF, Pappo AS, Altman J, et al. . Adolescent and young adult oncology, version 2.2014. J Natl Compr Canc Netw 2014;12:21–32. quiz 32 10.6004/jnccn.2014.0004
    1. von Wolff M, Montag M, Dittrich R, et al. . Fertility preservation in women--a practical guide to preservation techniques and therapeutic strategies in breast cancer, Hodgkin's lymphoma and borderline ovarian tumours by the fertility preservation network FertiPROTEKT. Arch Gynecol Obstet 2011;284:427–35. 10.1007/s00404-011-1874-1
    1. Fallat ME, Hutter J, American Academy of Pediatrics Committee on Bioethics, et al. . Preservation of fertility in pediatric and adolescent patients with cancer. Pediatrics 2008;121:e1461–9. 10.1542/peds.2008-0593
    1. Lambertini M, Del Mastro L, Pescio MC, et al. . Cancer and fertility preservation: international recommendations from an expert meeting. BMC Med 2016;14:1 10.1186/s12916-015-0545-7
    1. Rodriguez-Wallberg KA, Oktay K. Fertility preservation during cancer treatment: clinical guidelines. Cancer Manag Res 2014;6:105–17. 10.2147/CMAR.S32380
    1. Heineman MJ, Beerendonk CCM, Kaandorp CJE. [National guideline 'Cryopreservation of ovarian tissue']. Ned Tijdschr Geneeskd 2008;152:2452–5.
    1. Font-Gonzalez A, Mulder RL, Loeffen EAH, et al. . Fertility preservation in children, adolescents, and young adults with cancer: quality of clinical practice guidelines and variations in recommendations. Cancer 2016;122:2216–23. 10.1002/cncr.30047
    1. Jakes AD, Marec-Berard P, Phillips RS, et al. . Critical review of clinical practice guidelines for fertility preservation in teenagers and young adults with cancer. J Adolesc Young Adult Oncol 2014;3:144–52. 10.1089/jayao.2014.0032
    1. The Oncofertility Consortium Learning about cancer and fertility. A guide for parents of young girls.
    1. Quinn GP, Vadaparampil ST, Sehovic I. Patient and family tools to aid in education and decision-making about oncofertility : Woodruff KT, Clayman LM, Waimey EK, Oncofertility communication: sharing information and building relationships across disciplines. Springer: New York, 2014: 35–47.
    1. Snyder KA, Tate A, Infertility C-R. Cancer-related infertility and young women: strategies for discussing fertility preservation : Woodruff KT, Clayman LM, Waimey EK, Oncofertility communication: sharing information and building relationships across disciplines. Springer: New York, 2014: 49–60.
    1. Wartella E, Lauricella AR, Hurwitz LB. Communicating oncofertility to children: a developmental perspective for teaching health messages : Woodruff KT, Clayman LM, Waimey EK, Oncofertility communication: sharing information and building relationships across disciplines. Springer: New York, 2014: 99–109.
    1. Murphy D, Sawczyn KK, Quinn GP. Using a patient-centered approach to develop a fertility preservation brochure for pediatric oncology patients: a pilot study. J Pediatr Adolesc Gynecol 2012;25:114–21. 10.1016/j.jpag.2011.10.007
    1. Clayman ML, Galvin KM, Arntson P. Shared decision making: fertility and pediatric cancers : Woodruff KT, Snyder KA, Oncofertility fertility preservation for cancer survivors. Springer US: Boston, MA, 2007: 149–60.
    1. Huang JYJ, Tulandi T, Holzer H, et al. . Cryopreservation of ovarian tissue and in vitro matured oocytes in a female with mosaic Turner syndrome: case report. Hum Reprod 2008;23:336–9. 10.1093/humrep/dem307
    1. Balen AH, Harris SE, Chambers EL, et al. . Conservation of fertility and oocyte genetics in a young woman with mosaic Turner syndrome. BJOG 2010;117:238–42. 10.1111/j.1471-0528.2009.02423.x
    1. von Wolff M, Dittrich R, Liebenthron J, et al. . Fertility-preservation counselling and treatment for medical reasons: data from a multinational network of over 5000 women. Reprod Biomed Online 2015;31:605–12. 10.1016/j.rbmo.2015.07.013
    1. Grynberg M, Bidet M, Benard J, et al. . Fertility preservation in Turner syndrome. Fertil Steril 2016;105:13–19. 10.1016/j.fertnstert.2015.11.042
    1. Mamsen LS, Charkiewicz K, Anderson RA, et al. . Characterization of follicles in girls and young women with Turner syndrome who underwent ovarian tissue cryopreservation. Fertil Steril 2019;111:1217–25. 10.1016/j.fertnstert.2019.02.003
    1. Huang L, Mo Y, Wang W, et al. . Cryopreservation of human ovarian tissue by solid-surface vitrification. Eur J Obstet Gynecol Reprod Biol 2008;139:193–8. 10.1016/j.ejogrb.2008.03.002
    1. Gravholt CH, Andersen NH, Conway GS, et al. . Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati international Turner syndrome meeting. Eur J Endocrinol 2017;177:G1–70. 10.1530/EJE-17-0430
    1. Gravholt CH, Conway GS, Dekkers OM, et al. . Clinical practice guidelines for the care of girls and women with Turner syndrome. Eur J Endocrinology 2017;177:G1–70.
    1. Peek R, Schleedoorn M, Smeets D, et al. . Ovarian follicles of young patients with Turner's syndrome contain normal oocytes but monosomic 45,X granulosa cells. Hum Reprod 2019;34:1686–96. 10.1093/humrep/dez135
    1. Demeestere I, Simon P, Dedeken L, et al. . Live birth after autograft of ovarian tissue cryopreserved during childhood. Hum Reprod 2015;30:2107–9. 10.1093/humrep/dev128
    1. Donnez J, Dolmans MM, Demylle D, et al. . Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. The Lancet 2004;364:1405–10. 10.1016/S0140-6736(04)17222-X
    1. Jensen AK, Kristensen SG, Macklon KT, et al. . Outcomes of transplantations of cryopreserved ovarian tissue to 41 women in Denmark. Hum Reprod 2015;30:2838–45. 10.1093/humrep/dev230
    1. Hulley SB CS, Browner WS, Grady D, et al. . Designing clinical research : an epidemiologic approach. Philadelphia: Lippincott Williams & Wilkins., 2013.
    1. Bouchlariotou S, Tsikouras P, Dimitraki M, et al. . Turner's syndrome and pregnancy: has the 45,X/47,XXX mosaicism a different prognosis? Own clinical experience and literature review. J Matern Fetal Neonatal Med 2011;24:668–72. 10.3109/14767058.2010.520769

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever