In vivo effects of follicle-stimulating hormone-related synthetic peptides on the mouse estrous cycle.

Abstract

We have previously shown that a synthetic peptide amide corresponding to residues 34-37 (TRDL) of the human (h) FSH beta-subunit inhibited binding of [125I]hFSH to bovine calf testis membrane receptors and antagonized FSH-stimulated estradiol biosynthesis in primary cultures of rat Sertoli cells. These in vitro effects would have additional significance if they could be confirmed in an in vivo model system. We have obtained several lines of evidence supporting in vivo effects of TRDL on the mouse estrous cycle. 1) A single i.p. injection of 200 microg/g BW TRDL induced persistent vaginal estrus, characterized by the complete absence of epithelial casts in 87% of the mice treated, as determined by vaginal cytology. 2) A synthetic peptide representing a larger receptor-binding domain of the hFSH beta-subunit, hFSHbeta-(33-53), that contains the TRDL sequence had a similar effect, but hFSHbeta-(38-53) lacking the TRDL sequence, did not. 3) A series of unrelated synthetic peptides, tested at a comparable dose (200 microg/g BW), were also without effect, as was a D-amino acid analog of TRDL, TR(D)DL. 4) Serum estradiol levels at proestrus in TRDL-treated mice were significantly lower than those in vehicle-injected control mice. 5) The effect of estrogen on uterine ballooning and weight gain, seen in all vehicle-injected control mice at proestrus, did not occur in 97% of the mice treated with TRDL. 6) The ovaries of TRDL-treated mice taken during persistent vaginal estrus contained a greater number of large hemorrhagic preovulatory follicles and fewer corpora lutea than those in ovaries taken at estrus from vehicle-injected control mice. Taken together, these results indicate disruption of the normal mouse estrous cycle by the TRDL peptide and represent the first demonstration of in vivo effects of gonadotropin-related synthetic peptides on reproductive processes.