Evaluating the contraceptive potential of active immunization against gonadotropin-releasing hormone

Humans and rhesus macaques are known to express two molecular forms of gonadotropin-releasing hormone (GnRH-I and GnRH-II), which appear to differentially contribute to the regulation of the menstrual cycle. Specifically, there is evidence to suggest that GnRH-I is the primary mediator of negative estrogen feedback to the hypothalamus and pituitary gland, while GnRH-II is the primary mediator of the positive feedback that stimulates the preovulatory surge of luteinizing hormone. Therefore, it is plausible that selective silencing of GnRH-II would block ovulation and lay the platform for development of a novel contraceptive. To test this possibility female rhesus macaques were actively immunized against GnRH-II (and/or GnRH-I), and serum estradiol and progesterone concentrations were monitored for an additional ∼2.5 years. Despite multiple booster immunizations every ∼6 weeks, and elevated GnRH antibody titers, none of the animals ceased ovulating (i.e., revealed by monthly peaks of serum progesterone concentrations followed by menstruation). Taken together, these findings question the efficacy of GnRH vaccines as a stratagem for selectively blocking ovulation in humans. However, they do not negate the potential value of pharmacological interventions aimed at selectively silencing GnRH-II function and its involvement in stimulating the preovulatory luteinizing hormone surge.