title: Development of the external genitalia: perspectives from the spotted hyena (Crocuta crocuta).
abstract: This review/research paper summarizes data on development of the external genitalia of the spotted hyena, a fascinating mammal noted for extreme masculinization of the female external genitalia. The female spotted hyena is the only extant mammal that mates and gives birth through a pendulous penis-like clitoris. Our studies indicate that early formation of the phallus in both males and females is independent of androgens; indeed the phallus forms before the fetal testes or ovaries are capable of synthesizing androgens. Likewise, pre- and postnatal growth in length of the penis and clitoris is minimally affected by "androgen status". Nonetheless, several internal morphologies, as well as external surface features of the phallus, are androgen-dependent and thus account for dimorphism between the penis and clitoris. Finally, estrogens play a critical role in penile and clitoral development, specifying the position of the urethral orifice, determining elasticity of the urethral meatus, and facilitating epithelial-epithelial fusion events required for proper formation of the distal urethra/urogenital sinus and prepuce. Accordingly, prenatal inhibition of estrogen synthesis via administration of letrozole (an aromatase inhibitor) leads to malformations of the glans as well as the prepuce (hypospadias). The effects of prenatal androgens, anti-androgens and impaired estrogen synthesis correlated with the tissue expression of androgen and estrogen receptors.
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, United States; Department of Anatomy & Developmental Biology, Monash University, Clayton Campus, Building 76 Level 3, Wellington Road, Clayton, VIC, Australia. Electronic address: cunhag@urology.ucsf.edu.
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Cunha
authors.affiliation: Department of Anatomy & Developmental Biology, Monash University, Clayton Campus, Building 76 Level 3, Wellington Road, Clayton, VIC, Australia.
authors.forename: Gail
authors.initials: G
authors.lastname: Risbridger
authors.affiliation: Department of Anatomy & Developmental Biology, Monash University, Clayton Campus, Building 76 Level 3, Wellington Road, Clayton, VIC, Australia.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, United States.
authors.forename: Ned J
authors.initials: NJ
authors.lastname: Place
authors.affiliation: Department of Pediatrics, University of California San Francisco, Box 0434, San Francisco, CA 94143, United States.
authors.forename: Mel
authors.initials: M
authors.lastname: Grumbach
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, United States.
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Cunha
authors.affiliation: Departments of Psychology and Integrative Biology, University of California, Berkeley, CA 94720, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Weldele
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, United States.
authors.forename: Al J
authors.initials: AJ
authors.lastname: Conley
authors.affiliation: Monte Vista High School, Cupertino, CA 95014, United States.
authors.forename: Dale
authors.initials: D
authors.lastname: Barcellos
authors.affiliation: Monte Vista High School, Cupertino, CA 95014, United States.
authors.forename: Sanjana
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Monte Vista High School, Cupertino, CA 95014, United States.
authors.forename: Argun
authors.initials: A
authors.lastname: Bhargava
authors.affiliation: Departments of Evolutionary Anthropology and Biology, Duke University, Durham, NC 27708, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Drea
authors.affiliation: Department of Cellular & Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Hammond
authors.affiliation: Department of Obstetrics and Gynecology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, United States.
authors.forename: Penti
authors.initials: P
authors.lastname: Siiteri
authors.affiliation: Salesian High School, Richmond, CA 94804, United States.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Coscia
authors.affiliation: University of Texas Southwestern, Division of Endocrinology and Metabolism, 5323 Harry Hines Blvd., Dallas, TX, 75390-8857 and Quest Diagnostics, Endocrine Division, 33608 Ortega Highway, San Juan Capistrano, CA 92675, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McPhaul
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, United States.
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Baskin
authors.affiliation: Departments of Psychology and Integrative Biology, University of California, Berkeley, CA 94720, United States.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Glickman
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D002987:Clitoris / Q000254:growth & development; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005836:Genitalia, Female / Q000254:growth & development*; D045968:Hyaenidae / Q000235:genetics / Q000254:growth & development*; D008297:Male; D010053:Ovary / Q000254:growth & development; D010413:Penis / Q000254:growth & development; D013737:Testis / Q000254:growth & development
chemical_list: D000728:Androgens; D004967:Estrogens
keywords: Androgens; Clitoris; Estrogens; Hyena; Penis; Urogenital sinus