The KiSS-1/GPR54 system: putative target for endocrine disruption of reproduction at hypothalamic-pituitary unit?

The hypothalamic-pituitary (HP) unit, key element in the control of development and function of the reproductive axis, is highly sensitive to the organizing and activational effects of endogenous and exogenous compounds with sex steroid activity. Thus, inappropriate sex steroid input during early critical periods of their maturation can induce immediate or delayed defects in the neuroendocrine systems governing reproduction, which might eventually lead to alterations in the timing of puberty onset and/or infertility. Similarly, later inadequate exposures can cause dysfunctions of the gonadotropic axis. In recent years, kisspeptins (the products of KiSS-1 gene that operate through the G protein-coupled receptor 54) have emerged as fundamental regulators of puberty onset and gonadotropin secretion, and neurons in the hypothalamus expressing KiSS-1 have been demonstrated as essential conduits for the dynamic control of the gonadotropic axis by a number of hormonal factors. In this context, the hypothalamic KiSS-1 system has been proven sensitive to the early organizing effects, as well as to the acute regulatory actions, of gonadal steroids: phenomena which are likely to play fundamental roles in the sexual differentiation of gonadotropin secretion, and its feedback regulation by androgen and oestrogen. These observations raise the question on whether the hypothalamic KiSS-1 system might constitute a potential target for endocrine disruption of puberty onset and reproductive function at the HP unit by compounds with oestrogenic, androgenic or anti-androgenic activity. We review herein the physiological basis and initial, albeit so far scarce, experimental evidence supporting such possibility.