Open Access Research article

Disorders of sex development expose transcriptional autonomy of genetic sex and androgen-programmed hormonal sex in human blood leukocytes

Paul-Martin Holterhus1*, Jan-Hendrik Bebermeier2, Ralf Werner3, Janos Demeter4, Annette Richter-Unruh5, Gunnar Cario6, Mahesh Appari6, Reiner Siebert7, Felix Riepe6, James D Brooks8 and Olaf Hiort3

Author Affiliations

1 Department of Pediatrics, Christian Albrechts University of Kiel, Germany

2 Eppendorf Biochip Systems, Hamburg, Germany

3 Department of Pediatric and Adolescent Medicine, University of Lübeck, Lübeck, Germany

4 Department of Biochemistry, Stanford University School of Medicine, CA, USA

5 Department of Pediatrics, University of Essen, Essen, Germany

6 Department of Pediatrics, Christian Albrechts University of Kiel, Kiel, Germany

7 Institute of Human Genetics, Christian Albrechts University of Kiel, Kiel, Germany

8 Department of Urology, Stanford University School of Medicine, CA, USA

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BMC Genomics 2009, 10:292  doi:10.1186/1471-2164-10-292

Published: 1 July 2009



Gender appears to be determined by independent programs controlled by the sex-chromosomes and by androgen-dependent programming during embryonic development. To enable experimental dissection of these components in the human, we performed genome-wide profiling of the transcriptomes of peripheral blood mononuclear cells (PBMC) in patients with rare defined "disorders of sex development" (DSD, e.g., 46, XY-females due to defective androgen biosynthesis) compared to normal 46, XY-males and 46, XX-females.


A discrete set of transcripts was directly correlated with XY or XX genotypes in all individuals independent of male or female phenotype of the external genitalia. However, a significantly larger gene set in the PBMC only reflected the degree of external genital masculinization independent of the sex chromosomes and independent of concurrent post-natal sex steroid hormone levels. Consequently, the architecture of the transcriptional PBMC-"sexes" was either male, female or even "intersex" with a discordant alignment of the DSD individuals' genetic and hormonal sex signatures.


A significant fraction of gene expression differences between males and females in the human appears to have its roots in early embryogenesis and is not only caused by sex chromosomes but also by long-term sex-specific hormonal programming due to presence or absence of androgen during the time of external genital masculinization. Genetic sex and the androgen milieu during embryonic development might therefore independently modulate functional traits, phenotype and diseases associated with male or female gender as well as with DSD conditions.