The Differential Role of Androgens in Early Human Sex Development

Overview

Journal BMC Med

Publisher Biomed Central

Specialty General Medicine

Date 2013 Jun 27

PMID 23800242

Citations 33

Authors

Olaf Hiort

Affiliations

Soon will be listed here.

Abstract

Sexual development in humans is only partly understood at the molecular level. It is dependent on genetic control primarily induced by the sex chromosomal differences between males and females. This leads to the development of the gonads, whereby afterwards the differentiation of the apparent phenotype is controlled by hormone action. Sex steroids may exert permanent and temporary effects. Their organizational features of inducing permanent changes in phenotype occur through genetic control of downstream genes. In this, androgens are the key elements for the differentiation of male internal and external genitalia as well as other sexual organs and general body composition, acting through a single androgen receptor. The androgen receptor is a nuclear transcription factor modulating DNA transcription of respective target genes and thereby driving development and growth in a stringent manner. The specificity of androgen action seems to be a strictly time-controlled process with the androgen receptor acting in concert with different metabolites and an array of cofactors modulating the cellular response and thereby permanently altering the phenotype of any given individual. For every cell programmed by androgens, a specific 'androgen response index' must be proposed.

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References

Han T, Goswami D, Trikudanathan S, Creighton S, Conway G . Comparison of bone mineral density and body proportions between women with complete androgen insensitivity syndrome and women with gonadal dysgenesis. Eur J Endocrinol. 2008; 159(2):179-85. DOI: 10.1530/EJE-08-0166. View

Shaffer P, Jivan A, Dollins D, Claessens F, Gewirth D . Structural basis of androgen receptor binding to selective androgen response elements. Proc Natl Acad Sci U S A. 2004; 101(14):4758-63. PMC: 387321. DOI: 10.1073/pnas.0401123101. View

Lonard D, Lanz R, OMalley B . Nuclear receptor coregulators and human disease. Endocr Rev. 2007; 28(5):575-87. DOI: 10.1210/er.2007-0012. View

Hoppe U, Holterhus P, Wunsch L, Jocham D, Drechsler T, Thiele S . Tissue-specific transcription profiles of sex steroid biosynthesis enzymes and the androgen receptor. J Mol Med (Berl). 2006; 84(8):651-9. DOI: 10.1007/s00109-006-0049-1. View

Holterhus P, Bebermeier J, Werner R, Demeter J, Richter-Unruh A, Cario G . Disorders of sex development expose transcriptional autonomy of genetic sex and androgen-programmed hormonal sex in human blood leukocytes. BMC Genomics. 2009; 10:292. PMC: 2713997. DOI: 10.1186/1471-2164-10-292. View

Bashamboo A, McElreavey K . Gene mutations associated with anomalies of human gonad formation. Sex Dev. 2012; 7(1-3):126-46. DOI: 10.1159/000342188. View

Hiort O . Androgens and puberty. Best Pract Res Clin Endocrinol Metab. 2002; 16(1):31-41. DOI: 10.1053/beem.2002.0178. View

Appari M, Werner R, Wunsch L, Cario G, Demeter J, Hiort O . Apolipoprotein D (APOD) is a putative biomarker of androgen receptor function in androgen insensitivity syndrome. J Mol Med (Berl). 2009; 87(6):623-32. PMC: 5518750. DOI: 10.1007/s00109-009-0462-3. View

Jurgensen M, Hiort O, Holterhus P, Thyen U . Gender role behavior in children with XY karyotype and disorders of sex development. Horm Behav. 2007; 51(3):443-53. DOI: 10.1016/j.yhbeh.2007.01.001. View

10.

Holterhus P, Hiort O, Demeter J, Brown P, Brooks J . Differential gene-expression patterns in genital fibroblasts of normal males and 46,XY females with androgen insensitivity syndrome: evidence for early programming involving the androgen receptor. Genome Biol. 2003; 4(6):R37. PMC: 193616. DOI: 10.1186/gb-2003-4-6-r37. View

11.

Werner R, Kulle A, Sommerfeld I, Riepe F, Wudy S, Hartmann M . Testosterone synthesis in patients with 17β-hydroxysteroid dehydrogenase 3 deficiency. Sex Dev. 2012; 6(4):161-8. DOI: 10.1159/000336605. View

12.

Berenbaum S, Beltz A . Sexual differentiation of human behavior: effects of prenatal and pubertal organizational hormones. Front Neuroendocrinol. 2011; 32(2):183-200. DOI: 10.1016/j.yfrne.2011.03.001. View

13.

Lonard D, OMalley B . Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation. Mol Cell. 2007; 27(5):691-700. DOI: 10.1016/j.molcel.2007.08.012. View

14.

Miyagawa S, Satoh Y, Haraguchi R, Suzuki K, Iguchi T, Taketo M . Genetic interactions of the androgen and Wnt/beta-catenin pathways for the masculinization of external genitalia. Mol Endocrinol. 2009; 23(6):871-80. PMC: 2725765. DOI: 10.1210/me.2008-0478. View

15.

Maimoun L, Philibert P, Cammas B, Audran F, Bouchard P, Fenichel P . Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: an extensive international experience of 55 patients. J Clin Endocrinol Metab. 2010; 96(2):296-307. DOI: 10.1210/jc.2010-1024. View

16.

DeFalco T, Capel B . Gonad morphogenesis in vertebrates: divergent means to a convergent end. Annu Rev Cell Dev Biol. 2009; 25:457-82. PMC: 4507502. DOI: 10.1146/annurev.cellbio.042308.13350. View

17.

Yamada G, Suzuki K, Haraguchi R, Miyagawa S, Satoh Y, Kamimura M . Molecular genetic cascades for external genitalia formation: an emerging organogenesis program. Dev Dyn. 2006; 235(7):1738-52. DOI: 10.1002/dvdy.20807. View

18.

de Zegher F, Francois I, Boehmer A, Saggese G, Muller J, Hiort O . Androgens and fetal growth. Horm Res. 1998; 50(4):243-4. DOI: 10.1159/000023284. View

19.

Werner R, Grotsch H, Hiort O . 46,XY disorders of sex development--the undermasculinised male with disorders of androgen action. Best Pract Res Clin Endocrinol Metab. 2010; 24(2):263-77. DOI: 10.1016/j.beem.2009.11.002. View

20.

Thiele S, Hoppe U, Holterhus P, Hiort O . Isoenzyme type 1 of 5alpha-reductase is abundantly transcribed in normal human genital skin fibroblasts and may play an important role in masculinization of 5alpha-reductase type 2 deficient males. Eur J Endocrinol. 2005; 152(6):875-80. DOI: 10.1530/eje.1.01927. View