ISSN 0300-9092 (Print)
ISSN 2412-5679 (Online)

Association of clinical, laboratory, and morphological characteristics of the ovaries in girls with Turner syndrome and spontaneous puberty

Turchinets A.I., Badlaeva A.S., Uvarova E.V., Asaturova A.V., Kamaletdinov N.S., Kiseleva I.A., Kumykova Z.Kh., Gavisova A.A.

1) Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, Moscow, Russia; 2) I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University), Moscow, Russia

Objective: To present the characteristics of the ovarian reserve in girls with Turner syndrome based on morphological, clinical, laboratory, and instrumental parameters.
Materials and methods: A comparative morphological, morphometric, and immunohistochemical study of the ovarian cortex fragments was conducted in 20 girls. This group included 10 patients with Turner syndrome and spontaneous puberty, who exhibited no clinical or laboratory signs of premature ovarian insufficiency, and 10 girls with paraovarian cysts. The study examined the relationship between the morphological characteristics of the obtained samples and the stage of sexual development according to Tanner, ultrasound parameters of the ovaries, results of cytogenetic studies of blood lymphocytes, and hormonal status of girls with Turner syndrome.
Results: All girls with paraovarian cysts and 9 of 10 patients with Turner syndrome had follicles in the ovarian cortex, and abnormal morphology was observed in all girls with Turner syndrome and 80% in the control group. All follicles from patients with Turner syndrome expressed the oocyte-specific immunohistochemical markers ZP2, GDF9, BMP15, and CD117. Follicle density in Turner syndrome was 6.8 times lower than that in the control group and did not correlate with age, stage of puberty according to the Tanner scale, serum levels of FSH, LH, estradiol, AMH, inhibin B, testosterone, antral follicle count, or ovarian volume. However, this was associated with the presence of a 46,XX, or 47,XXX cell clone in the karyotype. Healthy follicles in the ovarian cortex were not detected in girls with Turner syndrome who had FSH and AMH levels > 15 IU/l and < 0.307 ng/ml, respectively. Among patients with X-chromosome mosaicism without structural anomalies, a positive correlation was found between follicle density and inhibin B level in the blood.
Conclusion: The prospects for performing the ovarian cortex cryopreservation procedure in girls with Turner syndrome may be determined by the combined presence of X-chromosome mosaicism without structural abnormalities, normal serum FSH levels for the corresponding age, inhibin B levels appropriate for the stage of sexual development according to Tanner, and detectable AMH levels.

Authors' contributions: Uvarova E.V., Asaturova A.V. – conception and design of the study; Badlaeva A.S., Turchinets A.I., Kamaletdinov N.S., Kiseleva I.A., Gavisova A.A. – collection and processing of material; Turchinets A.I., Badlaeva A.S. – data analysis; Badlaeva A.S., Turchinets A.I. – drafting of the manuscript; Uvarova E.V., Asaturova A.V., Kumykova Z.Kh. – editing 
of the manuscript.
Conflicts of interest: The authors have no conflicts of interest to declare.
Funding: There was no funding for this study.
Ethical Approval: The study was reviewed and approved by the Research Ethics Committee of the V.I. Kulakov 
NMRC for OG&P on October 22, 2022.
Patient Consent for Publication: The parents (legal representatives) of patients provided informed consent for the publication 
of data and associated images.
Authors' Data Sharing Statement: The data supporting the findings of this study are available upon request from the corresponding author after approval from the principal investigator.
For citation: Turchinets A.I., Badlaeva A.S., Uvarova E.V., Asaturova A.V., Kamaletdinov N.S., Kiseleva I.A., 
Kumykova Z.Kh., Gavisova A.A.  Association of clinical, laboratory, and morphological characteristics of 
the ovaries in girls with Turner syndrome and spontaneous puberty.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2025; (5): 97-109 (in Russian)
https://dx.doi.org/10.18565/aig.2025.42

Keywords

Turner syndrome
adolescent girls
ovarian reserve
follicular density
premature ovarian insufficiency
immunohistochemical study

References

  1. Dowlut-McElroy T., Shankar R.K. The care of adolescents and young adults with Turner syndrome: a pediatric and adolescent gynecology perspective. J. Pediatr. Adolesc. Gynecol. 2022; 35(4): 429-34. https://dx.doi.org/10.1016/j.jpag.2022.02.002
  2. Webber L., Davies M., Anderson R., Bartlett J., Braat D., Cartwright B. et al.; European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum. Reprod. 2016; 31(5): 926-37. https://dx.doi.org/10.1093/humrep/dew027
  3. Lunding S.A., Aksglaede L., Anderson R.A., Main K.M., Juul A., Hagen C.P. et al. AMH as predictor of premature ovarian insufficiency: a longitudinal study of 120 Turner syndrome patients. J. Clin. Endocrinol. Metab. 2015; 100(7): E1030-8. https://dx.doi.org/10.1210/jc.2015-1621
  4. Fitz V.W., Law J.R., Peavey M. Characterizing ovarian function by karyotype in a cohort of women with Turner’s syndrome. Fertil. Steril. 2019; 111(4): e27-e28. https://dx.doi.org/10.1016/j.fertnstert.2019.02.074
  5. Reynaud K., Cortvrindt R., Verlinde F., De Schepper J., Bourgain C., Smitz J. Number of ovarian follicles in human fetuses with the 45,X karyotype. Fertil. Steril. 2004; 81(4): 1112-9. https://dx.doi.org/10.1016/j.fertnstert.2003.12.011
  6. Hook E.B., Warburton D. Turner syndrome revisited: review of new data supports the hypothesis that all viable 45,X cases are cryptic mosaics with a rescue cell line, implying an origin by mitotic loss. Hum. Genet. 2014; 133(4): 417-24. https://dx.doi.org/10.1007/s00439-014-1420-x
  7. Burgoyne P.S., Baker T.G. Perinatal oocyte loss in XO mice and its implications for the aetiology of gonadal dysgenesis in XO women. J. Reprod. Fertil. 1985; 75(2): 633-45. https://dx.doi.org/10.1530/jrf.0.0750633
  8. Modi D.N., Sane S., Bhartiya D. Accelerated germ cell apoptosis in sex chromosome aneuploid fetal human gonads. Mol. Hum. Reprod. 2003; 9(4): 219-25. https://dx.doi.org/10.1093/molehr/gag031
  9. Mercer C.L., Lachlan K., Karcanias A., Affara N., Huang S., Jacobs P.A. et al. Detailed clinical and molecular study of 20 females with Xq deletions with special reference to menstruation and fertility. Eur. J. Med. Genet. 2013; 56(1): 1-6. https://dx.doi.org/10.1016/j.ejmg.2012.08.012
  10. Persani L., Rossetti R., Cacciatore C., Bonomi M. Primary ovarian insufficiency: X chromosome defects and autoimmunity. J. Autoimmun. 2009; 33(1): 35-41. https://dx.doi.org/10.1016/j.jaut.2009.03.004
  11. Fukami M. Ovarian dysfunction in women with Turner syndrome. Front. Endocrinol. (Lausanne). 2023; 14: 1160258. https://dx.doi.org/10.3389/fendo.2023.1160258
  12. Persani L., Rossetti R., Di Pasquale E., Cacciatore C., Fabre S. The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders. Hum. Reprod. Update. 2014; 20(6): 869-83. https://dx.doi.org/10.1093/humupd/dmu036
  13. San Roman A.K., Page D.C. A strategic research alliance: Turner syndrome and sex differences. Am. J. Med. Genet. C Semin. Med. Genet. 2019; 181(1): 59-67. https://dx.doi.org/10.1002/ajmg.c.31677
  14. Nadesapillai S., van der Velden J., Smeets D., van de Zande G., Braat D., Fleischer K. et al. Why are some patients with 45,X Turner syndrome fertile? A young girl with classical 45,X Turner syndrome and a cryptic mosaicism in the ovary. Fertil. Steril. 2021; 115(5): 1280-7. https://dx.doi.org/10.1016/j.fertnstert.2020.11.006
  15. Hreinsson J.G., Otala M., Fridström M., Borgström B., Rasmussen C., Lundqvist M. et al. Follicles are found in the ovaries of adolescent girls with Turner syndrome. J. Clin. Endocrinol. Metab. 2002; 87(8): 3618-23. https://dx.doi.org/10.1210/jcem.87.8.8753
  16. Mamsen L.S., Charkiewicz K., Anderson R.A., Telfer E.E., McLaughlin M., Kelsey T.W. et al. Characterization of follicles in girls and young women with Turner syndrome who underwent ovarian tissue cryopreservation. Fertil. Steril. 2019; 111(6): 1217-1225.e3. https://dx.doi.org/10.1016/j.fertnstert.2019.02.003
  17. Bernard V., Donadille B., Zenaty D., Courtillot C., Salenave S., Brac de la Perrière A. et al. CMERC Center for Rare Disease. Spontaneous fertility and pregnancy outcomes amongst 480 women with Turner syndrome. Hum. Reprod. 2016; 31(4): 782-8. https://dx.doi.org/10.1093/humrep/dew012
  18. Gravholt C.H., Andersen N.H., Christin-Maitre S., Davis S.M., Duijnhouwer A., Gawlik A. et al.; International Turner Syndrome Consensus Group; Backeljauw P.F. Clinical practice guidelines for the care of girls and women with Turner syndrome. Eur. J. Endocrinol. 2024; 190(6): G53-G151. https://dx.doi.org/10.1093/ejendo/lvae050
  19. Schmidt K.L., Byskov A.G., Nyboe Andersen A., Müller J., Yding Andersen C. Density and distribution of primordial follicles in single pieces of cortex from 21 patients and in individual pieces of cortex from three entire human ovaries. Hum. Reprod. 2003; 18(6): 1158-64. https://dx.doi.org/10.1093/humrep/deg246
  20. Hassan J., Knuus K., Lahtinen A., Rooda I., Otala M., Tuuri T. et al. Reference standards for follicular density in ovarian cortex from birth to sexual maturity. Reprod. Biomed. Online. 2023; 47(4): 103287. https://dx.doi.org/10.1016/j.rbmo.2023.103287
  21. Gougeon A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr. Rev. 1996; 17(2): 121-55. https://dx.doi.org/10.1210/edrv-17-2-121
  22. Pangas S.A., Choi Y., Ballow D.J., Zhao Y., Westphal H., Matzuk M.M. et al. Oogenesis requires germ cell-specific transcriptional regulators Sohlh1 and Lhx8. Proc. Natl. Acad. Sci. U. S. A. 2006; 103(21): 8090-5. https://dx.doi.org/10.1073/pnas.0601083103
  23. Gook D.A., Edgar D.H., Borg J., Martic M. Detection of zona pellucida proteins during human folliculogenesis. Hum. Reprod. 2008; 23(2): 394-402. https://dx.doi.org/10.1093/humrep/dem373
  24. Rankin T.L., O'Brien M., Lee E., Wigglesworth K., Eppig J., Dean J. Defective zonae pellucidae in Zp2-null mice disrupt folliculogenesis, fertility and development. Development. 2001; 128(7): 1119-26. https://dx.doi.org/10.1242/dev.128.7.1119
  25. Park M.J., Ahn J.W., Kim K.H., Bang J., Kim S.C., Jeong J.Y. et al. Prediction of ovarian aging using ovarian expression of BMP15, GDF9, and C-KIT. Exp. Biol. Med. (Maywood). 2020; 245(8): 711-9. https://dx.doi.org/10.1177/1535370220915826
  26. Belli M., Shimasaki S. Molecular aspects and clinical relevance of GDF9 and BMP15 in ovarian function. Vitam. Horm. 2018; 107: 317-48. https://dx.doi.org/10.1016/bs.vh.2017.12.003
  27. Driancourt M.A., Reynaud K., Cortvrindt R., Smitz J. Roles of KIT and KIT LIGAND in ovarian function. Rev. Reprod. 2000; 5(3): 143-52. https://dx.doi.org/10.1530/ror.0.0050143
  28. Remmele W., Stegner H.E. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987; 8: 138-40.
  29. Dolmans M.M., Donnez J., Camboni A., Demylle D., Amorim C., Van Langendonckt A. et al. IVF outcome in patients with orthotopically transplanted ovarian tissue. Hum Reprod. 2009; 24(11): 2778-87. https://dx.doi.org/10.1093/humrep/dep289
  30. Schleedoorn M.J., Fleischer K., Braat D., Oerlemans A., van der Velden A., Peek R. Why Turner patients with 45, X monosomy should not be excluded from fertility preservation services. Reprod. Biol. Endocrinol. 2022; 20(1): 143. https://dx.doi.org/10.1186/s12958-022-01015-z
  31. Nadesapillai S., van der Velden J., van der Coelen S., Schleedoorn M., Sedney A., Spath M. et al. TurnerFertility trial: fertility preservation in young girls with Turner syndrome by freezing ovarian cortex tissue-a prospective intervention study. Fertil. Steril. 2023; 120(5): 1048-60. https://dx.doi.org/10.1016/j.fertnstert.2023.08.004
  32. Jeve Y.B., Gelbaya T., Fatum M. Time to consider ovarian tissue cryopreservation for girls with Turner's syndrome: an opinion paper. Hum. Reprod. Open. 2019; 2019(3): hoz016. https://dx.doi.org/10.1093/hropen/hoz016
  33. Bayne R.A., Kinnell H.L., Coutts S.M., He J., Childs A.J., Anderson R.A. GDF9 is transiently expressed in oocytes before follicle formation in the human fetal ovary and is regulated by a novel NOBOX transcript. PLoS One. 2015; 10(3): e0119819. https://dx.doi.org/10.1371/journal.pone.0119819
  34. Gilchrist R.B., Lane M., Thompson J.G. Oocyte-secreted factors: regulators of cumulus cell function and oocyte quality. Hum. Reprod. Update. 2008; 14(2): 159-77. https://dx.doi.org/10.1093/humupd/dmm040
  35. Wei L.N., Huang R., Li L.L., Fang C., Li Y., Liang X.Y. Reduced and delayed expression of GDF9 and BMP15 in ovarian tissues from women with polycystic ovary syndrome. J. Assist. Reprod. Genet. 2014; 31(11): 1483-90. https://dx.doi.org/10.1007/s10815-014-0319-8
  36. Sehested A., Juul A.A., Andersson A.M., Petersen J.H., Jensen T.K., Müller J. et al. Serum inhibin A and inhibin B in healthy prepubertal, pubertal, and adolescent girls and adult women: relation to age, stage of puberty, menstrual cycle, follicle-stimulating hormone, luteinizing hormone, and estradiol levels. J. Clin. Endocrinol. Metab. 2000; 85(4): 1634-40. https://dx.doi.org/10.1210/jcem.85.4.6512
  37. Wen J., Huang K., Du X., Zhang H., Ding T., Zhang C. et al. Can inhibin B reflect ovarian reserve of healthy reproductive age women effectively? Front. Endocrinol. (Lausanne). 2021; 12: 626534. https://dx.doi.org/10.3389/fendo.2021.626534
  38. Borelli-Kjær A., Aksglaede L., Jensen R.B., Hagen C.P., Ljubicic M.L., Busch A.S. et al. Serum concentrations of inhibin B in healthy females and males throughout life. J. Clin. Endocrinol. Metab. 2024; 110(1): 70-7. https://dx.doi.org/10.1210/clinem/dgae439

Received 20.02.2025

Accepted 30.04.2025

About the Authors

Anna I. Turchinets, PhD student, Physician at the Department of Pediatric and Adolescent Gynecology, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia,
117997, Russia, Moscow, Ac. Oparin str., 4, +7(926)522-87-39, Ponomarevaanna28@gmail.com, https://orcid.org/0000-0002-4478-9133
Alina S. Badlaeva, PhD, Senior Researcher at the 1st Pathology Department, Physician at the 1st Pathology Department, V.I. Kulakov NMRC for OG&P, Ministry of Health
of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, alinamagnaeva03@gmail.com, https://orcid.org/0000-0001-5223-9767
Elena V. Uvarovа, Corresponding Member of the Russian Academy of Sciences, Dr. Med. Sci., Professor at the Department of Obstetrics, Gynecology and Perinatology,
I.M. Sechenov First MSMU, Ministry of Health of Russia (Sechenov University); Head of the Department of Pediatric and Adolescent Gynecology, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, elena-uvarova@yandex.ru, https://orcid.org/0000-0002-3105-5640
Aleksandra V. Asaturova, Dr. Med. Sci., Head of the 1st Pathology Department, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia, 117997, Russia, Moscow,
Ac. Oparin str., 4, a_asaturova@oparina4.ru, https://orcid.org/0000-0001-8739-5209
Nail S. Kamaletdinov, Embryologist at the 1st Gynecological Department, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia, 117997, Russia, Moscow,
Ac. Oparin str., 4, sunsh86@mail.ru
Irina A. Kiseleva, PhD, Clinical Care Supervisor at the Department of Pediatric and Adolescent Gynecology, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, kiseleva_i@oparina4.ru
Zaira Kh. Kumykova, PhD, Senior Researcher at the Department of Pediatric and Adolescent Gynecology, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, zai-kumykova@yandex.ru, https://orcid.org/0000-0001-7511-1432
Alla A. Gavisova, Dr. Med. Sci., Head of the 1st Gynecological Department, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia, 117997, Russia, Moscow,
Ac. Oparin str., 4, gavialla@yandex.ru
Corresponding author: Anna I. Turchinets, Ponomarevaanna28@gmail.com

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