Single-chain human gonadotropin analogs induce follicle development in sheep

The biopotency of single-chain analogs of human hFSH, human chorionic gonadotropin (hCG), and a dually active gonadotropin construct (FcCGbetaalpha) was examined. Sheep (bwt=61.4+/-1.1 kg; n=6 ewes/treatment) received a single injection (5 IU/kg, i.v.) of the hFSH analog (Fcalpha), the hCG analog (CGbetaalpha), FcCGbetaalpha, or Fcalpha and CGbetaalpha. Control animals received conditioned media. Ovulation was induced 3 days after analog administration using hCG (1000 IU, i.v.). Basal serum concentrations of estradiol (E(2)) were maintained in control animals. Neither Fcalpha nor CGbetaalpha alone induced significant E(2) production during the pre-hCG period. Conversely, serum concentrations of E(2) were increased (P<0.05) 2 days after administration of FcCGbetaalpha or Fcalpha+ CGbetaalpha. Although P(4) concentrations were maintained at basal levels in control animals, significant increase was noted in all other treatment groups during the post-hCG period. Final ovarian weight was significantly increased (P<0.05) in animals receiving Fcalpha, Fcalpha+ CGbetaalpha, or FcCGbetaalpha, but not CGbetaalpha alone. Most of the ovarian enlargement was attributed to the formation of corpora lutea. Collectively, these observations demonstrate that the single-chain analogs of the human gonadotropins are active in sheep. The construct with singular FSH activity supports follicle development but not E(2) production. Conversely, the construct that incorporates beta-domains from both CG and FSH has dual activity. The long-lived nature of the single-chain constructs suggests that these recombinant gonadotropins may be effective alternatives to pituitary- or placenta-derived gonadotropins in out-of-season breeding and/or superovulation protocols.