title: Impaired reproduction in adult male, but not female, rats following juvenile treatment with the aromatase inhibitor, exemestane.
abstract: BACKGROUND
  Exemestane is an irreversible steroidal inhibitor of cytochrome-P450 aromatase required for estrogen synthesis. The safety of the drug in the pediatric population, particularly in males, has not previously been evaluated. Given the increased interest in treating children with aromatase inhibitors, we undertook a study in rats to assess the potential for exemestane to alter reproductive development and function when administered to juveniles.
  
  
  METHODS
  Male and female rats were treated with exemestane at doses anticipated to produce exposures approximately 2- and 35-fold the expected clinical plasma exposure in young adult males during the period of reproductive maturation. After maturation, treated rats were mated to evaluate the potential impact on reproductive function.
  
  
  CONCLUSIONS
  There were no effects on sexual maturation in either sex or on female reproductive function. Treatment of juvenile male rats caused increased cohabitation time and decreased copulation rates; pregnancy rates and litter size were not affected in rats that mated. Decreased testis (10-15%) and epididymis (20-30%) weights, and decreased Sertoli cell numbers were noted at all doses. This indicates that exemestane can reduce Sertoli cell proliferation during maturation. The sensitive window for this effect is expected to be limited to the period of Sertoli cell proliferation, which is completed by around postnatal day 15 in rats and before puberty in humans. Treatment beginning at a later time relative to the window for Sertoli cell proliferation or for a longer duration is not expected to have additional adverse effect as the effect was not shown to be degenerative.
authors.affiliation: Drug Safety Research and Development, Pfizer Inc.Groton Laboratories, Eastern Point Rd., Groton, CT 06340, USA. Gregg.d.cappon@pfizer.com
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Cappon
authors.forename: Robert E
authors.initials: RE
authors.lastname: Chapin
authors.forename: Mark E
authors.initials: ME
authors.lastname: Hurtt
authors.forename: Michael P
authors.initials: MP
authors.lastname: Wajnrajch
authors.forename: Leigh Ann
authors.initials: LA
authors.lastname: Burns-Naas
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000730:Androstadienes / Q000633:toxicity*; D000818:Animals; D047072:Aromatase Inhibitors / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D012708:Sertoli Cells / Q000187:drug effects; D012741:Sexual Maturation / Q000187:drug effects
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; C056516:exemestane