Emerging Functions Of Gonadotropin‐Releasing Hormone II in Mammalian Physiology and Behaviour

Abstract

Gonadotropin-releasing hormone (GnRH) is the central neuroendocrine regulator of the hypothalamic-pituitary-gonadal axis. Multiple structural variants of GnRH are present in vertebrates. The first isoform isolated in the mammalian brain (GnRH I) was shown to regulate the release of pituitary gonadotropins. Recently, a second form has been discovered in mammals (GnRH II), both in the brain and periphery. Although it is unlikely to be a primary regulator of gonadotropin release, the highly conserved GnRH II variant appears to have a wide array of physiological functions. In the periphery, GnRH I and II have similar roles in regulating cell proliferation and mediating hormonal secretion from the ovary and placenta in an autocrine/paracrine manner. In the brain, GnRH I and II apparently modulate mammalian reproductive behaviours in different but complementary ways: GnRH I stimulates luteinizing hormone/follicle-stimulating hormone secretion (and thus gonadal steroids) and promotes sexual behaviour in ad libitum fed animals. By contrast, GnRH II acts as a permissive regulator of female reproductive behaviour based on energy status, as well as a modifier of short-term food intake. GnRH II has also been implicated in the regulation of calcium and potassium channels in nervous systems of amphibians, functions which may also be present in mammals. Increasing evidence suggests that the effects of GnRH II in both the periphery and brain may be mediated by GnRH receptor subtypes distinct from the type-1 GnRH receptor. It is likely that this evolutionarily conserved peptide has been co-opted over evolutionary time to possess multiple regulatory functions in a broad range of biological aspects, including, but not limited to, reproduction. Here, the proposed actions of both neural and peripheral GnRH II in affecting physiology and behaviour are summarized, and an outline of critical directions for future research is proposed.

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

“…The manner in which local GnRH action modulates the physiology and patho-physiology of reproductive tissues is a focus of investigation [23,48,139]. More specialized roles in blastocyst implantation, physiological changes occurring during pregnancy, including modulation of the cellular immune system, and influences on reproductive and parental behavior are also regarded as possibilities in certain mammalian species [15,19,22,40,59,61]. Many mechanistic questions concerning the precise involvement of GnRH in such diverse processes remain unanswered.…”

“…This conclusion is further supported by the demonstration that antide which is an antagonist at the type I receptor but is inactive at type II receptors, had no effect on GnRH II stimulation of behavior. Interestingly, these effects could only be demonstrated after food restriction and GnRH II itself was found to inhibit feeding behavior in musk shrews [59,60]. Thus, it appears that under normal conditions when animals are satiated the endogenous GnRH II system is fully activating reproductive behavior and exogenous GnRH II is not required.…”

Gonadotropin-releasing hormone neuropeptides and receptor in human breast cancer: Correlation to poor prognosis parameters

“…The second differs by three amino acids [6,27] and is widely distributed in the central and peripheral nervous system. It is also expressed at significantly higher than GnRH I levels outside the brain and it has been shown to act as a neuromodulator in the behavioral components of reproduction [16,27,28].…”

Mechanisms of Neuromodulation by a Nonhypophysiotropic GnRH System Controlling Motivation of Reproductive Behavior in the Teleost Brain

“…In addition to GnRH3, GnRH2 peptide is also reported to influence reproductive behaviors without physiologically regulating pituitary gonadotropins. The administration of GnRH2 peptide facilitated reproductive behavior and inhibited short-term food intake in female musk shrews [62] and goldfish [63].…”

“…In addition to GnRH3, GnRH2 peptide is also reported to influence reproductive behaviors without physiologically regulating pituitary gonadotropins. The administration of GnRH2 peptide facilitated reproductive behavior and inhibited short-term food intake in female musk shrews [62] and goldfish [63].As partly mentioned above, various environmental and internal states regulate neuromodulatory GnRH neuronal systems. In Indian major carp (Cirrhinus mrigala), for example, GnRH immunoreactivity in the TN changes seasonally, peaking during the prespawning season [64].…”