Using LC–MS Hormone Profiling to Better Understand XY DSD in Elite Athletes

Separating athletes into male and female categories helps protect women’s sports from the physical advantages that can develop during male puberty. However, some people with XY differences in sex development (DSD) do not fit neatly into this classification. In particular, the hormone-related characteristics of two common XY DSD conditions seen in sports, androgen insensitivity syndrome (AIS) and 5α-reductase type 2 deficiency (5ARD), are still not fully understood. A joint study conducted by researchers at the University of Sydney (Australia) and the Health and Science Department of World Athletics (Monaco) that was initiated to define the serum androgen profiles of individuals participating in elite athletic (specifically track and field) events provided by liquid chromatography-mass spectrometry (LCMS) analysis of serum androgen profiles collected during routine antidoping tests in World Anti-Doping Agency (WADA)-accredited laboratories. A paper based on their research was published in the Journal of Clinical Endocrinology & Metabolism.¹

What Biological and Genetic Factors Contribute to Physical Advantages in Sports Performance?

Physical advantages develop during male puberty because testosterone levels rise dramatically and stay much higher than in females. This leads to larger and stronger muscles and bones, greater heart and lung capacity, higher hemoglobin levels, and other physical differences.² Smaller testosterone-related effects may also come from exposure before birth during male development, as well as from the short period in the first six months of life, sometimes referred to as “mini-puberty,” when baby boys, but not girls, have testosterone levels similar to adults.^3,4 Other natural genetic differences can also affect athletic ability. For example, some genetic variations influence muscle performance, oxygen use, height, or limb length. These kinds of physical advantages or disadvantages are generally accepted as part of an athlete’s natural talent because they can occur in both men and women.^5,6

What Did the Study Find About Hormone Levels and XY Differences in Sex Development (DSD) Among Elite Athletes?

In this study, researchers tested blood samples from 1689 elite athletes (889 men and 800 women), using more than 5500 samples overall. The samples were analyzed in 19 laboratories approved by the to measure hormones such as testosterone, dihydrotestosterone (DHT), and androstenedione. The researchers compared hormone levels across athletes while accounting for repeated testing and incomplete data. Among the female athletes, some were found to have XY differences in sex development (DSD), identified by testosterone levels typically seen in adult males. These athletes had conditions such as 5α-reductase type 2 deficiency (5ARD), androgen insensitivity syndrome (AIS), or other unclassified XY DSDs. After excluding samples linked to pregnancy or testosterone doping, the study found that male athletes generally had much higher testosterone levels and higher testosterone-to-DHT ratios than female athletes. Athletes with XY DSD showed hormone patterns that were more like those of male athletes.¹

“The prevalence of XY DSD in elite female athletes,” write the authors of the paper,¹ “greatly exceeds that of the community with a high proportion androgen sensitive 5ARD. Serum T/DHT ratio by LCMS to characterize 5ARD can be extended to elite athletes.”

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References

1. Handelsman, D. J.; Bermon, S. Serum Androgen Profile of Elite Athletes. J Clin Endocrinol Metab. 2026, dgag196. DOI: 10.1210/clinem/dgag196
2. Handelsman, D. J.; Hirschberg, A. L.; Bermon, S. Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance. Endocr Rev 2018, 39, 803-829. DOI: 10.1210/er.2018-00020
3. Rohayem, J.; Alexander, E. C.; Heger, S. et al. Mini Puberty, Physiological and Disordered: Consequences, and Potential for Therapeutic Replacement. Endocr Rev 2024, 45, 460-492. DOI: 10.1210/endrev/bnae003
4. Tharabenjasin, P.; Pabalan, N.; Jarjanazi, H. Association of the ACTN3 R577X(rs1815739) Polymorphism with Elite Power Sports: A Meta-Analysis. PLoS One 2019, 14, e0217390.DOI: 10.1371/journal.pone.0217390
5. de la Chapelle, A.; Traskelin, A. L.; Juvonen, E. Truncated Erythropoietin ReceptorCauses Dominantly Inherited Benign Human Erythrocytosis. Proc Natl Acad Sci U S A 1993, 90, 4495-4499. DOI: 10.1073/pnas.90.10.4495
6. Murray, T. H. Good Sport; Oxford University Press, 2018.