SMC 資料庫

Background：

Expert reaction:

2024/08/07

Dr. Meng-Che Tsai
Associate Professor of the Department of Pediatrics /Visiting Staff of Division of Genetics Metabolism and Endocrinology, Department of Pediatrics, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

First, I understand that this issue has arisen due to athletes, particularly those from our country. Based on my training as a physician, unless the individuals choose to disclose their condition, they are just like any other person to me, not patients with chromosomal abnormalities or those with Differences in Sex Development (DSD).

To me, chromosomal abnormalities refer to conditions such as Down syndrome (trisomy 21), Cri du Chat syndrome (chromosome 5p deletion), Turner syndrome (45X), or Klinefelter syndrome (47XXY). DSD, on the other hand, encompasses a spectrum of genital development (Prader classification, as shown in the attached image), which sometimes includes conditions like hypospadias or incomplete uterine development.

Figure :Prader and Quigley Scales for visual grading of external genital virilization. In Stage 3 a single urogenital orifice can be observed.（from: Ambiguous Genitalia in the Newborn）

Flück CE, Güran T. Ambiguous Genitalia in the Newborn. [Updated 2023 Nov 13]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Figure 7. [Prader and Quigley Scales for...]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279168/figure/ambig-genital-newbrn.F7/

With this premise established, instead of discussing the athletes, I would focus on the DSD.

Q1: What are the currently known sex tests? What is the scientific basis behind these tests? (For example, what can be detected through blood tests? Do differences in XY chromosomes and testosterone levels affect athletic performance?)

To test for sex, one must first define what "sex" is. Is it gender identity or biological sex? If it is gender identity, a questionnaire can be administered to the individual. As for the definition of "biological sex," it is also diverse. If referring to anatomical sex, physical or imaging examinations can be performed; if referring to gonadal sex, biopsies of the testes, ovaries, or gonads can be done; if referring to chromosomal or SRY gene (sex-determining region Y gene) sex, blood tests or buccal swabs for chromosome or SRY gene analysis can be conducted. These different definitions of sex can show in various combinations in individuals, so the specific tests to be used depend on the purpose of the testing.

Q2: What factors, besides differences in XY chromosomes, influence the process of sexual development? What are the various forms of sexual development? What are the issues with using only XY or XX chromosomes to determine sex?

The process of sexual development is regulated by numerous genes, many of which have not been fully elucidated by science. Besides the known SRY gene on the Y chromosome, many other genes on the autosomes (non-sex chromosomes) also influence sexual development. These gene variations cannot be detected solely by chromosomal analysis, as the XY chromosomes may appear normal. It means that anatomical sex can be male, but the individual has XX chromosomes and testes; or anatomical sex can be female, but the individual has XY chromosomes and a uterus.

Q3: What is "Differences in Sex Development (DSD)"? Is there sufficient scientific research to help us understand whether DSD affects athletic performance?

Many factors influence an individual's athletic performance, including nutrition, training, genetics, psychology, and diseases. The extent to which each factor influences performance may vary from person to person. DSD affects sexual development but it is not a direct cause of differences in athletic performance. Athletic performance should be considered with  factors such as nutrition, training, genetics, psychology, and diseases.

Q4: Does the amount of testosterone vary inherently due to differences in XY chromosomes?

Typically, adult males with a Y chromosome and normally developed testes produce large amounts of testosterone compared to adult females who do not have a Y chromosome and testes. However, some females with hyperfunctioning adrenal gland or polycystic ovary syndrome can produce high levels of testosterone. Conversely, even with XY chromosomes, if the testes do not develop properly (e.g., Kallmann syndrome), there can be a deficiency in testosterone.

Q5: What are the standards for testing testosterone levels? Does high testosterone necessarily indicate that a person is male or that banned substances are being used?

Testosterone levels should follow a normal distribution within a population, providing reference ranges influenced by sex and other factors, such as age. For example, testosterone levels in middle-aged men are lower than those in men in their twenties. These varying reference ranges allow for rough standards to detect banned substance use in sports. However, high testosterone levels do not necessarily indicate that a person is male or that banned substances are being used. For example, individuals with androgen resistance may have high testosterone levels but have female anatomical sex.

Q6: What additional scientific evidence do we need to understand the diversity and differences in sexual development? How can we discuss sex differences and athletic performance based on science?

Sexual development is very complex, with diverse definitions of sex. I am not an expert in sports science, so it is difficult for me to answer this question comprehensively. However, in competitive sports, considering factors beyond sex/gender might simplify matters, as biomedical science is very complex and there are many unknown yet to be discovered.  

2024/08/09

Mei-Chich Hsu, Ph.D

Professor of the Department of Sports Medicine, Kaohsiung Medical University./ Emeritus Professor, National Taiwan Sports University. 

Q: Does the amount of testosterone vary inherently due to differences in XY chromosomes?

The amount of testosterone is primarily determined by the development and function of the gonads, rather than being directly influenced by the Y chromosome. Some individuals with a Y chromosome may have lower testosterone concentrations if they have an impaired synthesis of sex hormones (endogenous steroids). Some individuals, even with high testosterone levels, may not see its effects because their androgen receptors are less sensitive and can't effectively respond to the testosterone. 

Q: What are the standards for testing testosterone levels? Does high testosterone necessarily indicate that a person is male or that banned substances are being used?

It is not appropriate to use testosterone levels as a definitive criterion for determining male or female, as there are females who naturally have high testosterone levels.

Testosterone levels are typically interpreted within reference ranges that account for age, sex, and health status. For the general male population, normal testosterone concentrations range from 10 to 35 nanomoles per liter (nmol/L), while for females, the normal range is lower, typically below 2.5 nmol/L. These ranges can vary depending on the laboratory and testing methods used. It is crucial that any interpretation of testosterone levels should consider the individual's overall health status and medical background.

It is noteworthy that a study published in 2014 involving 693 elite athletes revealed that 16.5% of "male" athletes had testosterone levels below the normal range, while 13.7% of "female" athletes had levels above the normal range, indicating a significant overlap in testosterone concentrations between male and female. Therefore, it is untenable to conclude that someone is not female based on their high testosterone levels.  

High testosterone does not necessarily indicate the use of banned substances.

The primary reason elite athletes might use testosterone, androgens, or synthetic anabolic steroids is to enhance muscle strength and improve athletic performance. However, the scientific evidence linking testosterone directly to improved performance in various sports remains insufficient.

Currently, internationally accredited laboratories can effectively detect known synthetic anabolic steroids by using liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS). Additionally, using carbon-12 and carbon-13  in isotope ratio mass spectrometry (IRMS) can distinguish between endogenous testosterone and its precursors from exogenous anabolic steroids used to enhance performance. This helps laboratory inspectors determine whether high testosterone levels are of natural origin or due to the use of prohibited substances.

For elite athletes, the World Anti-Doping Agency (WADA) has introduced the "biological passport" system. By collecting a series of urine samples from athletes, this system continuously tracks the concentrations and ratios of endogenous steroids in the body over time, which can reveal the use of exogenous anabolic steroids. 

Reference:

Healy, Marie-Louise, et al. "Endocrine profiles in 693 elite athletes in the postcompetition setting." Clinical endocrinology 81.2 (2014): 294-305.