In the Journals

Analysis: Marked, bimodal distribution of testosterone between genetic males, females

Normal testosterone ranges for adult women and men differ markedly with a bimodal distribution, with the lower limit of the male range approximately four- to fivefold higher vs. the upper limit of the female range, according to a literature review published in Clinical Endocrinology.

Richard V. Clark

In the review, designed to compare testosterone levels associated with disorders of sex development with reference to average testosterone levels in healthy men and women, the researchers noted that the findings could inform the discussion regarding the influence of elevated endogenous testosterone levels on athletic performance.

“Recently, a few athletes competing in events classified for women have been found to have a male genotype with variable degrees of androgenization, that can vary from a nearly normal female to male phenotype, with testosterone levels in the adult male range,” Richard V. Clark, MD, PhD, FACP, a member of the board of directors for the U.S. Anti-Doping Agency, and colleagues wrote. “This can occur in genetic males with a disorder of sex development (46,XY DSD). These are rare conditions in which a genetic mutation affects cellular enzymes involved in the production of testosterone and the more potent androgen, dihydrotestosterone (DHT), or impairs androgen receptors that control cellular and tissue responses to androgens.”

Clark and colleagues analyzed data from 24 studies reporting on testosterone levels for healthy men and women, men with disorders of sex development — specifically, 5-alpha reductase deficiency, type 2 (5ARD2) and complete or partial androgen insensitivity syndrome — and women with polycystic ovary syndrome or 21-hydroxylase deficiency, the most common form of congenital adrenal hyperplasia. Included studies used liquid chromatography mass spectrometry-based testosterone assays exclusively for the references ranges in normal men and women and for women with PCOS or congenital adrenal hyperplasia. Studies reporting testosterone levels in genetic males with 5ARD2 or androgen insensitivity syndrome only reported values measured via immunoassays.

Testosterone ranges

In healthy men and women, the average weighted testosterone values ranged from 8.8 nmol/L to 30.9 nmol/L for men and from 0.4 nmol/L to 2 nmol/L for women. The low value for testosterone in men was four- to fivefold greater vs. the high value in women based on a normal range of 2.5% to 97.5%, according to the researchers.

Most genetic males with 5ARD2 and androgen insensitivity syndrome showed virilization with apparent male external genitalia; however, some presented with a more female phenotype, with testosterone in the normal male range, the researchers wrote. Mean testosterone levels for genetic males with 5ARD2 ranged from 13.4 nmol/L to 31.2 nmol/L and the absolute range of individual values was between 3.6 nmol/L and 47.2 nmol/L. Mean testosterone levels for genetic males with androgen insensitivity syndrome ranged from 11.9 nmol/L to 55.7 nmol/L, with the overall absolute range between 4.8 nmol/L and 68.3 nmol/L. There were no between-group differences for genetic males with partial or complete androgen insensitivity syndrome.

“Some of the reports included pubertal males for both 5ARD2 and [androgen insensitivity syndrome], and their ranges overlapped with the postpubertal males,” the researchers wrote.

The median testosterone range for women with PCOS was higher vs. those in women without the condition, ranging from 1.22 nmol/L to 1.71 nmol/L, and the absolute range between 0.34 nmol/L and 5.5 nmol/L. The researchers noted that some women with marked PCOS can have testosterone levels approaching the low end of male values.

In a mixed population of genetic females with 21-hydroxylase deficiency, the median testosterone level was 2.78 nmol/L and the interquartile range was between 1.32 nmol/L and 5.62 nmol/L, overlapping with testosterone levels observed in women with PCOS and approximately 3.5-fold higher vs. controls. The researchers noted that adrenal androgens such as dehydroepiandrosterone and its sulfate form are the more abundant androgens in these women, making comparison of testosterone levels with other conditions difficult.

‘There is no continuum’

The researchers noted that ranges of testosterone for genetic males with 5ARD2 and complete or partial androgen insensitivity syndrome are mostly within the normal male range and “well beyond the range for normal females,” whereas the range of testosterone levels in women with PCOS extends beyond the normal female range, but not into the normal male range.

“The weighted average lower limit of testosterone level in healthy males is 8.8 nmol/L, roughly four- to fivefold higher than the average upper limit of testosterone level in healthy females, 2 nmol/L,” the researchers wrote. “There is no continuum of testosterone levels from normal females to normal males.”

As children, genetic males with 5ARD2 and partial androgen insensitivity syndrome, in particular, may be raised either as boys or girls, depending upon whether the female or male phenotype predominates, the researchers wrote. That choice has come into question in elite sports, the researchers noted, and recent cases have been highlighted in which genetic males with a 46,XY DSD competed as females in women’s events. These competitors, they wrote, have been challenged as having a competitive advantage due to elevated testosterone levels in the normal male range.

“Existing studies strongly support a clear, bimodal distribution of serum testosterone levels in females compared to males,” the researchers wrote. “This data should be considered in the discussion of female competition eligibility and classification of genetic males with possible DSDs or genetic females with hyperandrogenism.” – by Regina Schaffer

Disclosures: Clark reports that he serves on the board of directors for the U.S. Anti-Doping Agency. Please see the study for the other authors’ relevant financial disclosures.

Normal testosterone ranges for adult women and men differ markedly with a bimodal distribution, with the lower limit of the male range approximately four- to fivefold higher vs. the upper limit of the female range, according to a literature review published in Clinical Endocrinology.

Richard V. Clark

In the review, designed to compare testosterone levels associated with disorders of sex development with reference to average testosterone levels in healthy men and women, the researchers noted that the findings could inform the discussion regarding the influence of elevated endogenous testosterone levels on athletic performance.

“Recently, a few athletes competing in events classified for women have been found to have a male genotype with variable degrees of androgenization, that can vary from a nearly normal female to male phenotype, with testosterone levels in the adult male range,” Richard V. Clark, MD, PhD, FACP, a member of the board of directors for the U.S. Anti-Doping Agency, and colleagues wrote. “This can occur in genetic males with a disorder of sex development (46,XY DSD). These are rare conditions in which a genetic mutation affects cellular enzymes involved in the production of testosterone and the more potent androgen, dihydrotestosterone (DHT), or impairs androgen receptors that control cellular and tissue responses to androgens.”

Clark and colleagues analyzed data from 24 studies reporting on testosterone levels for healthy men and women, men with disorders of sex development — specifically, 5-alpha reductase deficiency, type 2 (5ARD2) and complete or partial androgen insensitivity syndrome — and women with polycystic ovary syndrome or 21-hydroxylase deficiency, the most common form of congenital adrenal hyperplasia. Included studies used liquid chromatography mass spectrometry-based testosterone assays exclusively for the references ranges in normal men and women and for women with PCOS or congenital adrenal hyperplasia. Studies reporting testosterone levels in genetic males with 5ARD2 or androgen insensitivity syndrome only reported values measured via immunoassays.

Testosterone ranges

In healthy men and women, the average weighted testosterone values ranged from 8.8 nmol/L to 30.9 nmol/L for men and from 0.4 nmol/L to 2 nmol/L for women. The low value for testosterone in men was four- to fivefold greater vs. the high value in women based on a normal range of 2.5% to 97.5%, according to the researchers.

Most genetic males with 5ARD2 and androgen insensitivity syndrome showed virilization with apparent male external genitalia; however, some presented with a more female phenotype, with testosterone in the normal male range, the researchers wrote. Mean testosterone levels for genetic males with 5ARD2 ranged from 13.4 nmol/L to 31.2 nmol/L and the absolute range of individual values was between 3.6 nmol/L and 47.2 nmol/L. Mean testosterone levels for genetic males with androgen insensitivity syndrome ranged from 11.9 nmol/L to 55.7 nmol/L, with the overall absolute range between 4.8 nmol/L and 68.3 nmol/L. There were no between-group differences for genetic males with partial or complete androgen insensitivity syndrome.

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“Some of the reports included pubertal males for both 5ARD2 and [androgen insensitivity syndrome], and their ranges overlapped with the postpubertal males,” the researchers wrote.

The median testosterone range for women with PCOS was higher vs. those in women without the condition, ranging from 1.22 nmol/L to 1.71 nmol/L, and the absolute range between 0.34 nmol/L and 5.5 nmol/L. The researchers noted that some women with marked PCOS can have testosterone levels approaching the low end of male values.

In a mixed population of genetic females with 21-hydroxylase deficiency, the median testosterone level was 2.78 nmol/L and the interquartile range was between 1.32 nmol/L and 5.62 nmol/L, overlapping with testosterone levels observed in women with PCOS and approximately 3.5-fold higher vs. controls. The researchers noted that adrenal androgens such as dehydroepiandrosterone and its sulfate form are the more abundant androgens in these women, making comparison of testosterone levels with other conditions difficult.

‘There is no continuum’

The researchers noted that ranges of testosterone for genetic males with 5ARD2 and complete or partial androgen insensitivity syndrome are mostly within the normal male range and “well beyond the range for normal females,” whereas the range of testosterone levels in women with PCOS extends beyond the normal female range, but not into the normal male range.

“The weighted average lower limit of testosterone level in healthy males is 8.8 nmol/L, roughly four- to fivefold higher than the average upper limit of testosterone level in healthy females, 2 nmol/L,” the researchers wrote. “There is no continuum of testosterone levels from normal females to normal males.”

As children, genetic males with 5ARD2 and partial androgen insensitivity syndrome, in particular, may be raised either as boys or girls, depending upon whether the female or male phenotype predominates, the researchers wrote. That choice has come into question in elite sports, the researchers noted, and recent cases have been highlighted in which genetic males with a 46,XY DSD competed as females in women’s events. These competitors, they wrote, have been challenged as having a competitive advantage due to elevated testosterone levels in the normal male range.

“Existing studies strongly support a clear, bimodal distribution of serum testosterone levels in females compared to males,” the researchers wrote. “This data should be considered in the discussion of female competition eligibility and classification of genetic males with possible DSDs or genetic females with hyperandrogenism.” – by Regina Schaffer

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Disclosures: Clark reports that he serves on the board of directors for the U.S. Anti-Doping Agency. Please see the study for the other authors’ relevant financial disclosures.