Effects of finasteride, a type 2 5-alpha reductase inhibitor, on fetal development in the rhesus monkey (Macaca mulatta)

Prahalada, S.; Tarantal, Alice F.; Harris, G.; Ellsworth, Kenneth; Clarke, Anthony; Skiles, Gary L.; MacKenzie, Kathleen I.; Kruk, L. F.; Ablin, Deborah S.; Cukierski, Mark A.; Peter, C. P.; Vanzwieten, M. J.; Hendrickx, Andrew G.

doi:10.1002/(sici)1096-9926(199702)55:2<119::aid-tera1>3.0.co;2-z

Cited by 66 publications

(37 citation statements)

References 28 publications

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“…The present data indicated an increased Srd5a2 mRNA expression in the long-term exposure as counter-regulation to the assumed inhibition of 5-a reductase enzyme activity. This result is in line with the fact that FIN is a specific inhibitor of 5-a reductase type 2 enzyme activity in mammals (Prahalada et al 1997, Ellsworth et al 1998. Accordingly, specific inhibition of 5-a reductase enzyme activity was reported in sea urchins (Wasson & Watts 1998) suggesting that FIN is acting specifically in vertebrates and non-vertebrates.…”

Section: Discussionsupporting

confidence: 85%

“…R URBATZKA and others 215 type 1 enzyme (Prahalada et al 1997, Ellsworth et al 1998. Aro mRNA expression stayed at the same expression level indicating no interference of FIN with oestrogen synthesis.…”

Section: Discussionmentioning

confidence: 90%

“…DHT promotes in humans and mammals the development of external genitalia or androgenic tissues like prostate, while testosterone is responsible for the development of male internal genitalia. Finasteride (FIN), a well-known inhibitor of 5-a reductase activity with higher potency to Srd5a2 than to Srd5a1 (George et al 1989, Prahalada et al 1997, Ellsworth et al 1998, was frequently used to experimentally unravel functions of 5-a reductases being involved in male pattern hair loss (Kawashima et al 2004) or benign prostate hyperplasia or prostate cancer (Luo et al 2003). If administered in utero, external genitalia were feminized in rats (ImperatoMcGinley et al 1992) or developed abnormalities in rhesus monkeys (Prahalada et al 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Finasteride (FIN), a well-known inhibitor of 5-a reductase activity with higher potency to Srd5a2 than to Srd5a1 (George et al 1989, Prahalada et al 1997, Ellsworth et al 1998, was frequently used to experimentally unravel functions of 5-a reductases being involved in male pattern hair loss (Kawashima et al 2004) or benign prostate hyperplasia or prostate cancer (Luo et al 2003). If administered in utero, external genitalia were feminized in rats (ImperatoMcGinley et al 1992) or developed abnormalities in rhesus monkeys (Prahalada et al 1997). Humans with deficiency of Srd5a2 developed feminized genitalia (Imperato-McGinley et al 1981), and polymorphisms in Srd5a2 gene were associated with differences in sperm concentration and motility (Elzanaty et al 2006).…”

Section: Introductionmentioning

confidence: 99%

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Exposure of Xenopus laevis tadpoles to finasteride, an inhibitor of 5-α reductase activity, impairs spermatogenesis and alters hypophyseal feedback mechanisms

Urbatzka¹,

Watermann²,

Lutz³

et al. 2009

Journal of Molecular Endocrinology

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Sexual steroids have major regulatory functions in gonadal development, maturation of gametes and sexual differentiation in vertebrates. Previous studies in amphibians provided evidence that dihydrotestosterone and activity of 5-a reductases might play a significant role in androgen-mediated reproductive biology. To test the involvement of 5-a reductases in maturation of gametes in amphibians, Xenopus laevis was exposed to finasteride (FIN), a known inhibitor of 5-a reductase enzyme activity. In a long-term exposure from stage 46 to 66, severe disruption of spermatogenesis was observed in histological analysis of testes as detected by occurrence of empty spermatocysts, while ovaries remained unaffected. Real-time PCR analyses of male and female brain revealed an increase of LHb mRNA and a decrease of FSHb mRNA in males, suggesting a signalling on testes that could result in increased steroidogenesis and reduced Sertoli cell proliferation. Accordingly, the mRNA expression of P450 side chain cleavage enzyme and 5-a reductase type 2 was increased in testes, while no effects could be observed on steroidogenic genes in ovaries. A short-term exposure to testosterone, FIN and testosteroneCFIN showed that transient effects of FIN targeted males selectively and, in particular, interfered with the hypothalamus-pituitary-gonad axis. Furthermore, a negative feedback of testosterone on LHb was observed on males and females. This study provides evidence that exposure of X. laevis to FIN, an inhibitor of 5-a reductases, impaired spermatogenesis and involved sex-specific hypophyseal feedback mechanisms.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Exposure of Xenopus laevis tadpoles to finasteride, an inhibitor of 5-α reductase activity, impairs spermatogenesis and alters hypophyseal feedback mechanisms

Urbatzka¹,

Watermann²,

Lutz³

et al. 2009

Journal of Molecular Endocrinology

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“…It inhibits human type 2 5α-reductase, responsible for converting 5α testosterone to DHT (62). This drug is used to treat benign prostatic hyperplasia because it decreases circulating and tissue levels of DHT.…”

Section: Etiologymentioning

confidence: 99%

Hypospadias and endocrine disruption: is there a connection?

Baskin

Himes

Colborn

2001

Environ Health Perspect

248

131

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Hypospadias is one of the most common congenital anomalies in the United States, occurring in approximately 1 in 250 newborns or roughly 1 in 125 live male births. It is the result of arrested development of the urethra, foreskin, and ventral surface of the penis where the urethral opening may be anywhere along the shaft, within the scrotum, or in the perineum. The only treatment is surgery. Thus, prevention is imperative. To accomplish this, it is necessary to determine the etiology of hypospadias, the majority of which have been classified as idiopathic. In this paper we briefly describe the normal development of the male external genitalia and review the prevalence, etiology, risk factors, and epidemiology of hypospadias. The majority of hypospadias are believed to have a multifactorial etiology, although a small percentage do result from single gene mutations. Recent findings suggest that some hypospadias could be the result of disrupted gene expression. Discoveries about the antiandrogenic mechanisms of action of some contemporary-use chemicals have provided new knowledge about the organization and development of the urogenital system and may provide additional insight into the etiology of hypospadias and direction for prevention.

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