Inhibition of gonadotropin secretion by gonadotropin‐inhibitory hormone: it's all in your head

The seminal work of Geoffery Harris cemented neural substances of hypothalamic origin as key in the control of gonadal function (Harris, 1950). Subsequently, Amoss et al. (1971) and Schally et al. (1971) independently isolated the neuropeptide that directly simulates pituitary gonadotropin secretion and thus, it was termed gonadotropin releasing-hormone (GnRH). Since that time, the search has been underway to identify the location (Wintermantel et al. 2006) and phenotype of neurotransmitters and neuropeptides which allow the GnRH-containing neurons to respond to the multiple internal and external cues (Herbison, 2006) regulating GnRH secretion and by extension controlling sexual reproduction. Tsutsui et al. (2000) provided a new perspective on the control of gonadotropin secretion when they reported a hypothalamic peptide whose inhibitory action on gonadotropin release from quail anterior pituitaries as indicated in figure 1, was consistent with it being a gonadotropin inhibitory hormone. The neuropeptide was termed GnIH for its direct but converse effect (from GnRH) on pituitary gonadotropin secretion (fig. 1). Figure 1 GnIH directly inhibits the activity of GnRH neurons rendering it a putative GnRH-IH in rodents Until most recently, GnIH remained a pituitary GnIH as evidence for hypothalamic site of action was lacking. Now, the groups of Allan Herbison (Ducret et al. 2009) and in this issue of The Journal of Physiology Meenakshi Alreja (Wu et al. 2009) have independently shown that GnIH has direct inhibitory actions on GnRH neurons. The GnIH reduces rates of firing and induces hyperpolarization in substantial portions of the total population of GnRH neurons. Moreover, since GnIH neurons in rats are not neurosecretory (Rizwan et al. 2009), it appears at least in rodents that the GnIH in other vertebrates, may have largely a hypothalamic site of action on gonadotropin secretion (fig. 1). Therefore, the long repudiated GnRH-IH neuropeptide seems to be GnIH. The question remains as to which of the multiple internal and external cues that inhibit activity of GnRH neurons are mediated by activation of GnIH-containing neurons. For example, pulsatile GnRH release is regulated by a negative feedback system. Since the GnRH neurons themselves do not contain classical steroid receptors, gonadal steroids must act through alternative mechanisms such as direct membrane effects or steroid-sensitive presynaptic inputs to GnRH neurons (see Kelly & Ronnekleiv 2008 for review). If GnIH neurons are steroid sensitive, then they could play a pivotal role in inhibition of GnRH secretion via gonadal steroids. Likewise, stress inhibits reproduction. Preliminary evidence suggests that GnIH expression increases in rats during exposure to acute stressors (Kirby et al. 2007). Perhaps the most intriguing aspect of the GnIH peptide is its impact on reproductive behaviour. In male rats, GnIH-related peptides reduce the full sequela of male sexual behaviours (Johnson et al. 2007). Accordingly, input to GnRH neurons from GnIH-containing neurons may provide the link between reproductive hormone secretion and reproductive behaviour (Coquelin & Bronson, 1980). The above speculation notwithstanding, the neurons containing GnIH are poised to exert control of gonadotropin secretion from within the hypothalamus. Thus, the GnIH peptide is likely to emerge as a key regulator of GnRH secretion through its direct actions on GnRH neurons.