ESPE Yearbook of Paediatric Endocrinology

Brief summary: This prospective observational cohort study determined leukocyte telomere length (LTL) in 76 patients with genetically confirmed CAH (83% classic CAH). LTL was shorter in patients with classic vs nonclassic CAH, in overtreated than in optimally treated patients, and patients receiving prednisolone compared with hydrocortisone.

Telomeres are tandem repeats of a noncoding hexameric nucleotide sequence (5′-TTAGGG-3′) located at the ends of human chromosomes (1). In somatic cells, telomerase activity is very low, almost undetectable, so telomeres shorten progressively with cell division, ultimately leading to loss of telomere protection and a DNA damage response that induces senescence or cell death (2). A frequently used assay involves the measurement of telomere length in leukocytes (leukocyte telomere length, LTL), while the shortening of LTL is a robust marker of biological aging and contributes to the rise in mortality rates found in chronic conditions, such as increased body weight, cardiovascular disease and chronic stress (3). LTL is influenced by changes in the activity of telomerase (telomere terminal transfer-ase), as well as by the alternative lengthening of telomeres pathway (2). Studies have also shown that an individual’s exposure to hypercortisolism (e.g. in Cushing’s syndrome) is associated with decreased LTL (1). Individual risk factors analysis has shown that telomere length variability may be partially explained by lifestyle practices, with healthy lifestyle being associated with longer LTL (4).

Interestingly an increase in LTL has been reported when beneficial interventions have been studied, such as the increase in LTL following 12 months of a multidisciplinary, personalized, lifestyle intervention program in children and adolescents with overweight and obesity, indicating the potential of LTL to assess both current health status and also the benefits of an intervention (3). This phenomenon has been attributed to increased circulation of younger leukocytes, suggesting that telomere attrition is likely a modifiable factor as there is substantial variability in the rate of telomere shortening probably independent of chronological age (5).

In this prospective observational cohort study, conducted at 4 academic pediatric endocrinology outpatient clinics, 76 patients (median age: 12 years, IQR: 6.3–15,1) with genetically confirmed CAH were assessed at 2 follow-up visits (mean 4.1±0.7 months apart). At each visit, LTL was determined by quantitative real-time PCR. LTL was shorter in patients with classic vs nonclassic CAH (−0.29, P=0.012), in overtreated than in optimally treated patients (−0.07, P=0.002), and in patients receiving prednisolone compared with hydrocortisone (−0.34, P < 0.001). LTL was not associated with undertreatment or daily hydrocortisone-equivalent dose (P > 0.05).

The decreased LTL in these patients may be attributed to chronic exposure to supraphysiologic glucocorticoid concentrations, as has been previously described in Cushing’s (6). This is supported by the fact that patients with Cushing syndrome have shorter LTL compared with healthy controls, which increases following successful treatment (6). Furthermore, the lack of association in this study between undertreatment and reduced LTL, may indicate that chronically elevated androgen concentrations per se might not be associated with accelerated shortening of telomeres. Indeed, this is also shown in other conditions associated with increased androgen concentrations, such as PCOS, where androgens were not associated with shorter LTL (7). A potential mechanism comes from in vitro and epidemiologic studies showing that androgens might upregulate telomerase expression and/or activity and enhance telomere length through aromatization to estradiol (8). This is an interesting thought and can incite further research studies aiming to elucidate the relation between the chronic androgen burden in CAH due to 21-OHD and changes in LTL. It is worth noting that the greatest effect on LTL shortening was observed in patients treated with the more potent, longer-acting prednisolone compared with hydrocortisone. This finding reinforces the need to avoid prolonged use of prednisolone in children with CAH, as suggested in the current international guidelines, given the less favorable metabolic profile and growth outcomes (9).

These data indicate that LTL might have a use as a biomarker for monitoring glucocorticoid treatment, particularly the adverse effects of supraphysiologic dosing or long-acting prednisolone. This is of particular clinical significance given the recognized increased cardiometabolic morbidity even from an early age in overtreated subjects (10).

References: 1. Lina J, Epel E. Stress and telomere shortening: Insights from cellular mechanisms. Ageing Res Rev. 2022 January; 73: 101507. 2. Zhao Z, Pan X, Liu L, Liu N. Telomere length maintenance, shortening, and lengthening. J. Cell Physiol. 2014, 229, 1323–1329. 3. Paltoglou G, Raftopoulou C, Nicolaides NC, et al. A comprehensive, multidisciplinary, personalized, lifestyle intervention program is associated with increased leukocyte telomere length in children and adolescents with overweight and obesity. Nutrients. 2021;13(8):2682. 4. Sun Q, Shi L, Prescott J, Chiuve SE, Hu FB, De Vivo I, Stampfer MJ, Franks PW, Manson JE, Rexrode KM. Healthy lifestyle and leukocyte telomere length in U.S. women. PLoS ONE. 2012, 7, e38374. 5. Aviv A, Chen W, Gardner JP, Kimura M, Brimacombe M Cao X, Srinivasan SR, Berenson GS. Leukocyte telomere dynamics: Longitudinal findings among young adults in the Bogalusa Heart Study. Am. J. Epidemiol. 2009, 169, 323–329. 6. Aulinas A, Ramírez MJ, Barahona MJ, et al. Telomere length analysis in Cushing’s Syndrome. Eur J Endocrinol. 2014;171(1):21–29. 7. Tajada M, Dieste-Pérez P, Sanz-Arenal A, et al. Leukocyte telomere length in women with and without polycystic ovary syndrome: a systematic review and meta-analysis. Gynecol Endocrinol. 2022;38(5):391–397. 8. Cheung AS, Yeap BB, Hoermann R, et al. Effects of androgen deprivation therapy on telomere length. Clin Endocrinol (Oxf). 2017;87(4):381–385. 9. Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(11):4043–4088. 10. Torky A, Sinaii N, Jha S, et al. Cardiovascular disease risk factors and metabolic morbidity in a longitudinal study of congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2021;106(12): e5247–e5257.