Study of hormonal status and bone metabolism in underage female athletes with primary amenorrhea

Introduction. Fractures, particularly low-energy ones, are more common in female athletes with oligo/amenorrhea compared to their peers without menstrual disorders. This problem is associated with various hormonal changes and impaired bone remodeling processes.

Objective. Assessment of bone metabolism and serum hormonal parameters in highly qualified under-18 female athletes both with primary amenorrhea and without menstrual cycle disorders.

Materials and methods. A single-center single-stage study involved 111 young female athletes aged 15–18 years (median age 15.9 [14.9; 16.6] years), who were members of Russian national teams in five sports. All the participants underwent comprehensive medical examination at the Federal Scientific and Clinical Center for Children and Adolescents of FMBA of Russia between March 2021 and July 2023. The athletes were divided into two groups based on the presence of primary amenorrhea. The group with primary amenorrhea included 23 athletes (median age 15.8 [15.1; 16.3] years); the comparison group consisted of 88 athletes (median age 15.9 [14.9; 16.6] years) with a regular menstrual cycle. Serum levels of osteocalcin, C-terminal telopeptide (β-CrossLaps), type 1 procollagen (P1NP), parathyroid hormone (PTH), vitamin D (25(OH)D3), and alkaline phosphatase (ALP) activity were measured. To assess hormonal status, levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and leptin were evaluated. Sexual maturity was assessed according to the Tanner rating, and body composition was evaluated using bioelectrical impedance analysis. Statistical data processing was performed using the Statistica v. 10.0 software package (StatSoft Inc., USA).

Results. Athletes with primary amenorrhea were characterized by lower body weight (p < 0.0001) and body fat percentage (p < 0.0001) compared to their peers without menstrual disorders. The analysis of LH (p = 0.328) and FSH (p = 0.069) levels did not reveal statistically significant differences between the study groups; however, the adolescent athletes with primary amenorrhea had lower levels of estradiol 182.0 [123.0; 227.0] and 244.0 [143.5; 518.5] (p = 0.002) and leptin 2.1 [1.2; 4.1] and 9.1 [5.1; 14.9] (p < 0.0001) compared those without menstrual cycle disorders. The athletes with primary amenorrhea showed an increase in both bone formation markers (P1NP, osteocalcin) and bone resorption markers (β-CrossLaps and ALP) compared to their peers without menstrual disorders.

Conclusions. Minors with primary amenorrhea are characterized by disharmonious physical development due to underweight, accompanied by reduced body fat content, decreased levels of leptin and estradiol, preserved gonadostat function, and increased markers of bone metabolism. The identified hormonal and metabolic features may represent a significant risk for impaired bone remodeling in this group of athletes.

1. Mountjoy M, Ackerman KE, Bailey DM, Burke LM, Constantini N, Hackney AC, et al. 2023 International Olympic Committee’s (IOC) consensus statement on Relative Energy Deficiency in Sport (REDs). British Journal of Sports Medicine. 2023;57(17):1073–97. https://doi.org/10.1136/bjsports-2023-106994

2. Hackney AC, Constantini NW. Endocrinology of Physical Activity and Sport. 3rd ed. Cham: Humana press; 2020. https://doi.org/10.1007/978-3-030-33376-8

3. Khosla S. Update on estrogens and the skeleton. The Journal of Clinical Endocrinology and Metabolism. 2010;95(8):3569–77. https://doi.org/10.1210/jc.2010-0856

4. de Assis GG, Murawska-Ciałowicz E. Exercise and weight management: the role of leptin — a systematic review and update of clinical data from 2000–2022. Journal of Clinical Medicine. 2023;12(12):4490. https://doi.org/10.3390/jcm12134490

5. Christo K, Prabhakaran R, Lamparello B, Cord J, Miller KK, Goldstein MA, et al. Bone metabolism in adolescent athletes with amenorrhea, athletes with eumenorrhea, and control subjects. Pediatrics. 2008;121(6):1127–36. https://doi.org/10.1542/peds.2007-2392

6. Kaga M, Takahashi K, Ishihara T, Suzuki H, Tanaka H, Seino Y, et al. Bone assessment of female long-distance runners. Journal of Bone and Mineral Metabolism. 2004;22(5):509–13. https://doi.org/10.1007/s00774-004-0515-1

7. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Archives of Disease in Childhood. 1976;51(3):170. https://doi.org/10.1136/adc.51.3.170

8. Ackerman KE, Cano Sokoloff N, de Nardo Maffazioli G, Clarke HM, Lee H, Misra M. Fractures in relation to menstrual status and bone parameters in young athletes. Medicine and Science in Sports and Exercise. 2015;47(8):1577–86. https://doi.org/10.1249/mss.0000000000000574

9. Kiseleva NG, Taranushenko TE, Golubenko NK. Diagnosis of osteoporosis at an early age. Medical Counsil. 2020;1:179–86 (In Russ.). https://doi.org/10.21518/2079-701X-2020-1-186-193

10. Riggs BL, Khosla S, Melton LJ. Sex steroids and the construction and conservation of the adult skeleton. Endocrine Reviews. 2002;23(3):279–302. https://doi.org/10.1210/edrv.23.3.0465

11. Duncan CS, Blimkie CJ, Cowell CT, Burke ST, Briody JN, Howman-Giles R. Bone mineral density in adolescent female athletes: relationship to exercise type and muscle strength. Medicine and Science in Sports and Exercise. 2002;34(2):286–94. https://doi.org/10.1097/00005768-200202000-00017

12. Markou KB, Mylonas P, Theodoropoulou A, Kontogiannis A, Leglise M, Vagenakis A, et al. The influence of intensive physical exercise on bone acquisition in adolescent elite female and male artistic gymnasts. The Journal of Clinical Endocrinology and Metabolism. 2004;89(9):4383–7. https://doi.org/10.1210/jc.2003-031865

13. Bezuglov EN, Lazarev AM, Khaitin VYu, Barskova EM, Koloda YuA. The impact of professional sports on menstrual function. Russian Journal of Human Reproduction. 2020;26(4):37–47 (In Russ.). https://doi.org/10.17116/repro20202604137

14. Evdokimova NV, Bodrova MV, Solovyova AS, Salikova PD, Moskvina AR. Features of physical development, menstrual function and body composition in children engaged in professional sports (rhythmic gymnastics). Medicine: Theory and Practice. 2024;9(2):32–9 (In Russ.). https://doi.org/10.56871/MTP.2024.58.20.004

15. Odle AK, Akhter N, Syed MM, Allensworth-James ML, Beneš H, Melgar Castillo AI, et al. Leptin regulation of gonadotrope gonadotropin-releasing hormone receptors as a metabolic checkpoint and gateway to reproductive competence. Frontiers in Endocrinology. 2018;8:367. https://doi.org/10.3389/fendo.2017.00367

16. Mathew H, Castracane VD, Mantzoros C. Adipose tissue and reproductive health. Metabolism: Clinical and Experimental. 2018;86:18–32. https://doi.org/10.1016/j.metabol.2017.11.006

17. Chubb SAP, Vasikaran SD, Gillett MJ. Reference intervals for plasma β-CTX and P1NP in children: A systematic review and pooled estimates. Clinical Biochemistry. 2023;118:110582. https://doi.org/10.1016/j.clinbiochem.2023.05.001

18. Bayer M. Reference values of osteocalcin and procollagen type I N-propeptide plasma levels in a healthy Central European population aged 0–18 years. Osteoporosis International. 2014;25(2):729–36. https://doi.org/10.1007/s00198-013-2485-4

19. Crofton PM, Evans N, Taylor MR, Holland CV. Serum CrossLaps: pediatric reference intervals from birth to 19 years of age. Clinical Chemistry. 2002;48(4):671–3.