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Reproductive Endocrine Unit (S.B.S.), Massachusetts General Hospital and Harvard Medical School, and Division of Endocrinology, Diabetes, and Hypertension (U.B.K.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Ursula B. Kaiser, M.D., Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: ukaiser{at}partners.org.
Last year, a little known G protein-coupled receptor, GPR54, was unexpectedly catapulted to a key regulatory position within the hypothalamic-pituitary-gonadal axis. Several lines of evidence supported the role of GPR54 as gatekeeper of the reproductive cascade. In the human, loss-of-function point mutations and deletions within the coding sequence of the GPR54 gene were identified in patients with idiopathic hypogonadotropic hypogonadism, a condition characterized by the absence of spontaneous pubertal development, low sex steroids, and inappropriately low gonadotropins (1, 2). Mice carrying null mutations of Gpr54 (Gpr54–/–) recapitulated the human phenotype and have provided clues that the defects occur at the level of GnRH processing or secretion (1, 3).
These discoveries cast a new eye not only to GPR54 but also to its endogenous ligands, derived from the KiSS-1 gene. The KiSS-1 gene encodes a 145-amino-acid peptide that is proteolytically cleaved into a family of peptides referred to as kisspeptins, the most abundant of which is an amidated 54-amino-acid protein, kisspeptin-54, also known as metastin (4, 5, 6). KiSS-1 is highly expressed in the placenta and is also expressed in the brain, particularly the hypothalamus and basal ganglia, whereas GPR54 demonstrates a somewhat broader pattern of expression, including the brain, particularly the hypothalamus, and the pituitary. Metastin was so named based on its original characterization as a suppressor of tumor metastasis (7, 8). Other studies have suggested that metastin may play a role in the developing placenta (9). Although these biological stories are themselves intriguing, the recognition of the potential role of the KiSS-1/GPR54 system in the initiation of puberty has led several investigators to initiate the exploration of its role in the regulation of GnRH and gonadotropin secretion.
Features of the Gpr54–/– mice have helped to set the stage for direct kisspeptin administration studies in intact animals, including the report by Navarro et al. (10) featured in this issue of Endocrinology. The normal hypothalamic content of GnRH in the Gpr54–/– mice indicates that the pathways of GnRH neuronal migration and GnRH synthesis remain intact and suggests a defect in the processing or secretion of GnRH. Although several recent studies examining the effects of kisspeptin administration to intact animals have focused on LH rather than FSH secretion, it is important to look at the work of Navarro et al. in this context. Several themes are emerging from the recent literature (11, 12, 13, 14, 15, 16, 17, 18):
1. Kisspeptins are potent stimulators of LH secretion. This has been demonstrated in both mice and rats, in both males and females, and in prepubertal, pubertal, and adult rats, as well as in a juvenile agonadal male monkey model.
2. Kisspeptins exhibit a dose-dependent and time-dependent effect upon LH secretion, with effects observed as soon as 10 min after central administration and with as little as 1 fmol.
3. The stimulatory effects of kisspeptins are observed after both central (intracerebroventricular) and systemic (ip and iv) administration, which suggests an action on GnRH nerve terminals at the median eminence-arcuate nucleus complex, outside the blood-brain barrier.
4. Kisspeptins are effective whether administered as the full 54-amino-acid peptide (metastin) or as just the C-terminal decapeptide (kisspeptin-10).
5. In both rodents and nonhuman primates, the effects of kisspeptins on LH can be blocked by a GnRH antagonist, demonstrating that kisspeptins are acting through GnRH and its receptor to stimulate LH release (i.e. hypothalamic effect).
Additional evidence supporting a direct action of kisspeptins on GnRH neurons includes the distribution of KiSS-1 mRNA in areas of the hypothalamus implicated in the neuroendocrine regulation of gonadotropin secretion, including the anteroventral periventricular nucleus, the periventricular nucleus, and the arcuate nucleus (11), and the detection of GPR54 expression in GnRH neurons (17). Moreover, hypothalamic expression of both KiSS-1 and GPR54 mRNA are developmentally and hormonally regulated, with increased levels at puberty in both male and female rats, changes throughout the estrous cycle in adult females, and increases after gonadectomy that are prevented by sex steroid replacement in both males and females (12, 17). Kisspeptins have been shown to stimulate transcriptional activity in GnRH neurons, as evidenced by the induction of c-Fos immunoreactivity in GnRH neurons after intracerebroventricular metastin administration (15, 17).
The studies by Navarro et al. (10) in this issue of Endocrinology focus on FSH and echo many of the findings for LH secretion. Kisspeptins stimulate FSH secretion in prepubertal male and female rats as well as in adult male rats. Prepubertal animals exhibit an earlier response to metastin stimulation (maximal 15 min after injection), whereas adult rats exhibit only a marginal rise in FSH at that time point but rise further at 60 min. Thompson et al. (16) described similar findings with the same dose (1 nmol) of the same formulation (kisspeptin-10) in male rats in the same reproductive stage (adult), with a significant rise in FSH levels at 60 min, but three other doses tested at that time point failed to reach significance (0.1–3 nmol). Furthermore, when Thompson et al. administered higher doses of kisspeptin (10–100 nmol) ip, no significant response was observed. Therefore, subtleties of dose, route of administration, and stage of the animal under study may impact metastin sensitivity and, by extension, gonadotropin secretion, possibly also reflecting changes in GPR54 levels or endogenous ligand levels at different stages (12).
When directly compared, Navarro et al. found kisspeptin to be a more potent stimulator of LH than FSH, with ED50 values of 4 and 400 pmol, respectively. Viewed in this comparative mode, kisspeptin does not appear to act as a selective FSH-releasing factor. Endogenous GnRH receptor blockade using a GnRH receptor antagonist results in a significant drop in the FSH levels achieved after kisspeptin administration. Therefore, kisspeptins exert their effects on both LH and FSH secretion by acting through the GnRH receptor, pointing once again to the hypothalamus as a pivotal site of action for this protein with respect to reproductive axis dynamics. Interestingly, in this context, one might expect FSH secretion to be more sensitive to kisspeptins than LH, given prior observations that the amount of GnRH required to induce FSH secretion is less than for LH (19, 20, 21). We can speculate that kisspeptins may elicit dose-dependent patterns of pulsatile GnRH release that favor LH at lower concentrations (22, 23).
To investigate the level of action of the KiSS-1/GPR54 system in the regulation of GnRH in the hypothalamic pathways, Navarro et al. studied the effects of kisspeptin on FSH release in the presence of inhibitors of other pivotal neuroendocrine regulators of GnRH secretion, including excitatory amino acids, nitric oxide, and leptin. Pharmacological inhibitors of ionotropic glutamate receptors of both the N-methyl-D-aspartate and non-N-methyl-D-aspartate types, or inhibitors of nitric oxide synthases, did not interfere with kisspeptin stimulation of FSH secretion. Similarly, the FSH response to kisspeptin was preserved in three different models of leptin insufficiency: food deprivation, leptin immunoneutralization, and leptin resistance. Importantly, these observations point to a site of action of the KiSS-1/GPR54 system downstream of (or independent of) glutamate, nitric oxide, and leptin actions in modulation of GnRH release.
The studies to date support a primary action of the KiSS-1/GPR54 system in the reproductive axis at the top of the reproductive cascade, regulating GnRH secretion. Nonetheless, the high expression levels of GPR54 in the pituitary raise the question: does an independent regulatory role for either KiSS-1 or GPR54 exist at the level of the pituitary? Navarro et al. demonstrate effects of kisspeptin on GnRH-stimulated, but not on basal, FSH release in cultured primary rat pituitary cells. Similar effects were observed on LH secretion, in this case in the absence of GnRH (14). On the other hand, others have observed no direct effect of kisspeptin on LH or FSH secretion in cultured primary rat pituitary cells and anterior pituitary fragments (15, 16). Although the major actions of metastin appear to occur at the level of the hypothalamus to regulate GnRH release, potential modifier effects at the level of gonadotropin secretion in response to GnRH cannot be excluded.
In conclusion, based on the article by Navarro et al. (10) in this issue of Endocrinology, placed in the context of the recent literature, it can be surmised that metastin, acting downstream of other neuroendocrine regulators, stimulates GnRH release from hypothalamic GnRH neurons, which in turn effects both LH and FSH secretion. The next chapter in the emerging biologies of both metastin and GPR54 waits to be written.
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Received January 18, 2005.
Accepted for publication January 18, 2005.
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