Deficits in reproduction and pro-gonadotropin-releasing hormone processing in male Cpefat mice

Endocrinology. 2004 Apr;145(4):2023-34. doi: 10.1210/en.2003-1442. Epub 2004 Jan 8.


Cpe(fat/fat) mice are obese, diabetic, and infertile. These animals have a point mutation in carboxypeptidase E (CPE), an exopeptidase that removes C-terminal basic amino acids from peptide intermediates. The mutation renders the enzyme unstable, and it is rapidly degraded. Although the infertility of Cpe(fat/fat) mice has not been systematically investigated, it is thought to be due to a deficit in GnRH processing. We have evaluated this hypothesis and found hypothalamic GnRH levels to be reduced by 65-78% and concentrations of pro-GnRH and C-terminal-extended intermediates to be high. Basal serum gonadotropin contents are similar among wild-type, heterozygous, and homozygous mice. Testis morphology and function are abnormal in older obese Cpe(fat/fat) mice. Matings between homozygous mutants yield a 5% pregnancy rate. By comparison, when 50-d-old Cpe(fat/fat) males are paired with heterozygous females, rates increase to 43%, and they rapidly decrease to negligible levels by 120 d. As fertility declines without accompanying changes in the hypothalamic-pituitary-gonadal axis and before obesity is evident, reproduction is more complex than originally thought. This suspicion is confirmed in 90-d-old Cpe(fat/fat) males, who readily interact with females, but rarely mount and fail to show intromission or ejaculation behaviors. Together, these findings show that CPE is a key enzyme for pro-GnRH processing in vivo; however, the reproductive deficits in Cpe(fat/fat) males appear to be due primarily to abnormal sexual behavior.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carboxypeptidase H / genetics*
  • Diabetes Mellitus / genetics
  • Female
  • Fertility
  • Genitalia / pathology
  • Gonadotropin-Releasing Hormone / metabolism*
  • Homozygote
  • Hypothalamus / metabolism
  • Infertility / genetics
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mutation*
  • Obesity / genetics
  • Organ Size
  • Pituitary Gland, Anterior / physiopathology
  • Pregnancy
  • Protein Precursors / metabolism*
  • Protein Processing, Post-Translational*
  • Reproduction / genetics*
  • Sexual Behavior, Animal


  • Protein Precursors
  • progonadoliberin I
  • Gonadotropin-Releasing Hormone
  • Carboxypeptidase H