Efficacy of Immunization against a Novel Synthetic 13-Amino Acid Betaglycan-Binding Peptide Sequence of Inhibin α Subunit on Promoting Fertility in Female Rats

Inhibins suppress the FSH production in pituitary gonadotrope cells by robustly antagonizing activin signaling by competitively binding to activin type II receptors (ACTR II). The binding of inhibin A to ACTR II requires the presence of its co-receptor, namely, betaglycan. In humans, the critical binding site for betaglycan to inhibin A was identified on the inhibin alpha subunit. Through conservation analysis, we found that a core 13-amino-acid peptide sequence within the betaglycan-binding epitope on human inhibin alpha subunit is highly conserved across species. Based on the tandem sequence of such a conserved 13-amino-acid betaglycan-binding epitope (INH alpha 13AA-T), we developed a novel inhibin vaccine and tested its efficacy in promoting female fertility using the female rat as a model. Compared with placebo-immunized controls, INH alpha 13AA-T immunization induced a marked (p < 0.05) antibody generation, enhanced (p < 0.05) ovarian follicle development, and increased ovulation rate and litter sizes. Mechanistically, INH alpha 13AA-T immunization promoted (p < 0.05) pituitary Fshb transcription and increased (p < 0.05) serum FSH and 17 beta-estradiol concentrations. In summary, active immunization against INH alpha 13AA-T potently increased FSH levels, ovarian follicle development, ovulation rate and litter sizes, thus causing super-fertility in females. Therefore, immunization against INH alpha 13AA is a promising alternative to the conventional approach of multiple ovulation and super-fertility in mammals.

Automated summary

Inhibins suppress FSH production by binding to ACTR II receptors and their co-receptor betaglycan. A 13-amino-acid peptide sequence in the inhibin alpha subunit, which is conserved across species, was identified as the critical binding site for betaglycan. Immunization with a novel inhibin vaccine based on this peptide sequence increased FSH levels, ovarian follicle development, ovulation rate, and litter sizes in female rats.