Metastin/
kisspeptin, a hypothalamic
peptide, plays a pivotal role in controlling
GnRH neurons. Here we studied the effect of chronic sc administration of two
kisspeptin analogs, KISS1-305 and
TAK-448, on hypothalamic-pituitary-gonadal function in male rats in comparison with a
GnRH analogue
leuprolide or bilateral
orchiectomy (ORX). The prototype
polypeptide, KISS1-305 (1-4 nmol/h), caused substantial elevations of plasma LH and
testosterone, followed by abrupt reductions of both
hormone levels. Notably,
testosterone levels were reduced to castrate levels within 3 d and remained depleted throughout the 4-wk dosing period, an effect that was faster and more pronounced than
leuprolide (1 nmol/h) dosing. KISS1-305 also reduced genital organ weight more profoundly than
leuprolide. In mechanistic studies, chronic KISS1-305 administration only transiently induced c-Fos expression in
GnRH neurons, suggesting that
GnRH-neural response was attenuated over time. Hypothalamic
GnRH content was reduced to 10-20% of control at 3 wk without any changes in
Gnrh mRNA expression. Dosing with the investigational
peptide TAK-448 was also studied to extend our understanding of hypothalamic-pituitary functions. Similar to ORX,
TAK-448 (0.1 nmol/h) depleted
testosterone and decreased
GnRH content by 4 wk. However, in contrast to ORX,
TAK-448 decreased
gonadotropin levels in pituitary and plasma samples, implying the suppression of
GnRH pulses. These results suggest that chronic administration of
kisspeptin analogs disrupts endogenous
kisspeptin signals to suppress intrinsic
GnRH pulses, perhaps by attenuating
GnRH-neural response and inducing continuous
GnRH leakage from the hypothalamus. The potential utility of
kisspeptin analogs as novel agents to treat
hormone-related diseases, including
prostate cancer, is discussed.