Cryopreservation of ovarian tissue may be considered in young girls with galactosemia
- 96 Downloads
The aim was to describe the first experience with fertility preservation by cryopreservation of ovarian tissue (OTC) in pre-pubertal girls with galactosemia and further to characterize ovarian follicular morphology and expression of proteins important for ovarian function.
Retrospectively, follicle density was estimated in ovarian cortical tissues from 6 pre-pubertal girls below the age of 12 years diagnosed with galactosemia and from 31 girls below the age of 18 years who had one ovary removed for fertility preservation for other reasons prior to gonadotoxic treatment. Additionally, expression of 4 glycoproteins important for follicle development were analyzed with immunohistochemistry in two galactosemic ovaries (aged 0.9 and 1.7 years) and compared to normal age-matched controls. The proteins included were: anti-Müllerian hormone (AMH) pro-mature and C-terminal, growth differentiation factor-9 (GDF-9), bone morphogenetic protein 15 (BMP-15), and pregnancy-associated plasma protein A (PAPP-A).
Girls with galactosemia below the age of 5 years presented with morphological normal follicles and follicle densities within the 95% confidence interval (CI) of controls. No follicles were detected in the ovary from an 11.7-year-old girl with galactosemia. Expression of AMH, GDF-9, BMP-15, and PAPP-A appeared similar in follicles from girls with galactosemia and controls.
These findings suggest that young girls with galactosemia maintain follicles in early childhood and fertility cryopreservation may be considered an option in this patient group. The pathophysiology of galactosemia leading to an accelerated follicle loss is unknown and it is currently unknown to what extent transplanted ovarian tissue can sustain fertility in adult life.
KeywordsGalactosemia Premature ovarian failure Fertility preservation Ovarian function AMH PAPP-A GDF-9 BMP-15
We thank Marianne Sguazzino for the excellent technical assistance.
L.S.M. and C.Y.A. designed and drafted the study. L.S.M. was responsible for the IHC staining and estimating the follicle densities in ovaries from patients with galactosemia. T.W.K. designed the mathematics for follicle density estimation and developed the density prediction model. E.E. and K.T.M. did the initial fertility preservation counseling with the parents and was responsible for the collection of the tissue. A.M.L. is the physician in charge of the girls with galactosemia and obtained their genetic information. The final manuscript was approved by all authors.
The Novo Nordisk Foundation and the EU interregional project ReproUnion funded this study. They had no role in the study design, collection and analysis of data, and data interpretation or in writing the report.
Compliance with ethical standards
The study was approved by the Scientific Ethical Committee for the Capital Region (KF (01) 170/99).
Conflict of interest
The authors declare that they have no conflict of interest.
- 18.Jensen AK, Macklon KT, Fedder J, Ernst E, Humaidan P, Andersen CY. 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.CrossRefPubMedGoogle Scholar
- 19.Gellert SE, Pors SE, Kristensen SG, Bay-Bjørn AM, Ernst E, Yding Andersen C. Transplantation of frozen-thawed ovarian tissue: an update on worldwide activity published in peer-reviewed papers and on the Danish cohort. J Assist Reprod Genet. 2018;Epub ahead.Google Scholar
- 24.Rosendahl M, Timmermans Wielenga V, Nedergaard L, Kristensen SG, Ernst E, Rasmussen PE, et al. Cryopreservation of ovarian tissue for fertility preservation: no evidence of malignant cell contamination in ovarian tissue from patients with breast cancer. Fertil Steril. 2011;95:2158–61.CrossRefPubMedGoogle Scholar
- 35.Sidis Y, Fujiwara T, Leykin L, Isaacson K, Toth T, Schneyer AL. Characterization of inhibin/activin subunit, activin receptor, and follistatin messenger ribonucleic acid in human and mouse oocytes: evidence for activin’s paracrine signaling from granulosa cells to oocytes. Biol Reprod. 1998;59:807–12.CrossRefPubMedGoogle Scholar
- 40.Kedem A, Fisch B, Garor R, Ben-Zaken A, Gizunterman T, Felz C, et al. Growth differentiating factor 9 (GDF9) and bone morphogenetic protein 15 both activate development of human primordial follicles in vitro, with seemingly more beneficial effects of GDF9. J Clin Endocrinol Metab. 2011;96:E1246–54.CrossRefPubMedGoogle Scholar
- 42.Kristensen SG, Andersen K, Clement CA, Franks S, Hardy K, Andersen CY. Expression of TGF-beta superfamily growth factors, their receptors, the associated SMADs and antagonists in five isolated size-matched populations of pre-antral follicles from normal human ovaries. Mol Hum Reprod. 2014;20:293–308.CrossRefPubMedGoogle Scholar