Replicative and biochemical ageing mechanisms among females with Turner syndromes

BACKGROUND: 2025 is going to be the 100th anniversary of the first historical description of Turner syndrome — complex of  genomic abnormalities, congenital gonadal disruption and hypergonadotropic hypogonadism. Total estrogenic deficiency triggers development of age-related comorbidities. There is no doubt that personalized search for replicative markers of cellular aging among females with Turner syndrome is needed.

AIM: To evaluate features of replicative (telomere length) and biochemical (lipid profile, calcium-phosphate album, thyroid hormones, markers cytolysis and cholestasis, carbohydrate metabolism, nitrogenic metabolism, electrolytes, FSH) markers among females with Turner syndrome.

MATERIALS AND METHODS. Research has been provided in collaboration between Endocrinology Research Centre of the Russian Ministry of Health and Lomonosov Moscow State University Medical Research and Educational Centre in the period since 10.01.2021 until 01.08.2022. Females with non-iatrogenic hypergonadotropic hypogonadism caused by Turner syndrome (45,X0; 45,X/46,XX; 45,X/46,X,r(X); 13–40 y.o.; n=26) and primary ovarian insufficiency (18–39 нyears=26); healthy females of reproductive age (15–49 y.o.; n=24). Patients have undergone laboratory genetic (leucocyte telomere length), biochemical (fasting glycaemia, urea, creatinine, common/conjugated bilirubin, ALT, AST, gamma-glutamyl transferase, triglycerides, HDL-P, LDL-P, common cholesterol, common/ionized calcium, phosphate, vitamin D, sodium/potassium/chlorides, FSH, HbA1c) analyses. Body measurements — body mass, body height. DNA extraction — provided with Qiagen DNA blood mini kit (Germany). Leukocyte telomere length — with real-time polymerase chain reaction PCR (Flow-fish). Soft program IBM SPSS Statistics (version 26,0 for Windows).

RESULTS. 1. Females with Turner syndrome have significantly lower mean telomere length (8,22 kB [6,63–9,30]) than with primary ovarian insufficiency (10, 34 кБ [8,41–13,08], p<0,001) and healthy reproductive age females (10,77 kB [9,95–13,16], р>0,05).

2. Telomere length correlates directly and significantly with longevity of menopausal hormonal therapy among females with primary ovarian insufficiency (ρ = 505; p<0,001).

3. Patients with Turner syndrome are inclined to vitamin D deficiency (р<0,001), dyslipidemia (р=0,01); increase of levels of aminotransferases, cholestasis markers, phosphate and FSH (р<0,001).

CONCLUSION. Turner syndrome is serious genetic disease that leads not only to infertility but to significant decrease of quality/life longevity out of “healthy aging” conception.

1. Dedov II, Peterkova VA, Volevodz NN. Sindrom Shereshevskogo–Ternera (patogenez, klinika, diagnostika, lechenie). Metodicheskoe posobie dlia vrachei. Moscow; 2009. (In Russ.).

2. Turner HH. A syndrome of infantilism, congenital webbed neck, and cubitus valgus. Endocrinology. 1938;23(5):566-574. doi: https://doi.org/10.1210/endo-23-5-566

3. Ford CE, jones KW, Polani PE, et al. A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner’s syndrome). Lancet. 1959;273(7075):711-713. doi: https://doi.org/10.1016/s0140-6736(59)91893-8

4. 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(3):G1-G70. doi: https://doi.org/10.1210/endo-23-5-566.10.1530/EJE-17-0430

5. Keefe DL, Marquard K, Liu L. The telomere theory of reproductive senescence in women. Curr Opin Obstet Gynecol. 2006;18(3):280-285. doi: https://doi.org/10.1210/endo-23-5-566.10.1097/01.gco.0000193019.05686.49

6. Liu B, He Y, Wang Y, et al. Structure of active human telomerase with telomere shelterin protein TPP1. Nature. 2022;604(7906):578-583. doi: https://doi.org/10.1038/s41586-022-04582-8

7. Roake CM, Artandi SE. Regulation of human telomerase in homeostasis and disease. Nat Rev Mol Cell Biol. 2020;21(7):384-397. doi: https://doi.org/10.1038/s41580-020-0234-z

8. Turner KJ, Vasu V, Griffin DK. Telomere biology and human phenotype. Cells. 2019;8(1):73. doi: https://doi.org/10.1210/endo-23-5-566.10.3390/cells8010073.

9. Gaydosh L, Mitchell C, Notterman D, et al. Demographic and developmental patterns in telomere length across adolescence. Biodemography Soc Biol. 2020;66(3-4):208-219. doi: https://doi.org/10.1080/19485565.2021.1983758

10. Ishizuka B. Current understanding of the etiology, symptomatology, and treatment options in Premature Ovarian Insufficiency (POI). Front Endocrinol (Lausanne). 2021;12(3-4):208-219. doi: https://doi.org/10.3389/fendo.2021.626924

11. 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(3):G1-G70. doi: https://doi.org/10.1530/EJE-17-0430

12. Klein KO, Rosenfield RL, Santen RJ, et al. Estrogen replacement in turner syndrome: literature review and practical considerations. J Clin Endocrinol Metab. 2018;103(5):1790-1803. doi: https://doi.org/10.1210/jc.2017-02183

13. Donadille B, Christin-Maitre S. Heart and Turner syndrome. Ann Endocrinol (Paris). 2021;82(3-4):135-140. doi: https://doi.org/10.1016/j.ando.2020.12.004

14. Shankar Kikkeri N, Nagalli S. Turner Syndrome. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022.

15. Fuchs MM, Jost CHA, Said SM, et al. Cardiovascular surgery in Turner syndrome - early outcome and longterm follow-up. World J Cardiol. 2020;12(3):97-106. doi: https://doi.org/10.4330/wjc.v12.i3.97

16. Davis SM, Geffner ME. Cardiometabolic health in Turner syndrome. Am J Med Genet C Semin Med Genet. 2019;181(1):52-58. doi: https://doi.org/10.1002/ajmg.c.31678

17. Kveiborg M, Gravholt CH, Kassem M. Evidence of a normal mean telomere fragment length in patients with UllrichTurner syndrome. Eur J Hum Genet. 2001;9(11):877-879. doi: https://doi.org/10.1038/sj.ejhg.5200722