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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6738-6740
Copyright © 2005 by The Endocrine Society

Editorial

We All Remember Our First Kiss: Kisspeptin and the Male Gonadal Axis

Stephanie B. Seminara

Massachusetts General Hospital Reproductive Endocrinology Unit Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Dr. Stephanie B. Seminara, Massachusetts General Hospital, Reproductive Endocrinology Unit, Bartlett Hall, Extension 505, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: seminara.stephanie{at}mgh.harvard.edu.

The year 2003 was witness to a friendly collision between the fields of cancer and reproduction when a little known G protein-coupled receptor (GPR54) was pushed into the limelight. GPR54 was first cloned from rat brain in 1999 (1), but was an orphan receptor until 2001, when several groups discovered a high affinity ligand (2, 3, 4). This ligand, metastin, is derived from the proteolytic processing of a parent protein called kisspeptin-1 (metastin 1–54 = kisspeptin-1 68–121). Metastin’s name was so coined because of its role as a metastasis suppressor (5, 6). However, until 2003, there were few direct clues that the metastin/GPR54 pathway played a pivotal role in the reproductive cascade.

Meanwhile, on a backdrop of several decades of neurobiological research into the mechanisms of the onset of puberty, investigators in the 1990s began using genetic approaches to find novel neuromodulators of GnRH secretion using patients with idiopathic hypogonadotropic hypogonadism, a condition characterized by an absence of sexual development and low gonadotropin and sex steroid levels. Although these investigations uncovered genes whose protein products are involved in GnRH neuronal migration (KAL1, FGFR1) (7, 8, 9), gonadotrope sensitivity to GnRH (GNRHR, NROB1) (10, 11), and integrative signaling regarding peripheral energy stores (LEP, LEPR) (12, 13, 14), searches continued to find genes more directly involved in the triggering or inhibition of GnRH secretion.

In 2003, two groups independently discovered loss-of-function mutations in the gene encoding the G protein-coupled receptor GPR54 in patients with idiopathic hypogonadotropic hypogonadism (15, 16). Targeted deletion of Gpr54 in mice was also found to give rise to a phenocopy syndrome of delayed sexual development and hypogonadotropism (16). Suddenly, this receptor, and its ligand metastin, were pulled from their previous niches in cancer biology and thrust directly into long-standing questions within reproductive biology.

With the human genetic discoveries surrounding GPR54 creating unique opportunities for both basic investigators and animal physiologists, studies were published with lightening speed that further raised the possibility for compelling roles for metastin and GPR54 in reproduction. Expression levels of KISS1 mRNA were found to rise significantly across the pubertal transition in female and agonadal male monkeys (17). In vivo, the administration of metastin raises LH in adult male mice (18), adult male rats (19, 20, 21, 22), immature female rats (23), juvenile agonadal male monkeys (17), and mature, ovariectomized, estradiol-treated sheep (24). The effects of metastin on LH secretion can be observed with every method of administration including intracerebroventricular, iv, ip, and sc. Moreover, metastin appears to play an important role in normal pubertal development. Chronic central administration of metastin to sexually immature female rats induces early vaginal opening (23). In rat models of leptin insufficiency, metastin can also induce LH secretion (23).

Although the secretion of GnRH from the GnRH neuron has classically been considered the initiating event in the reproductive cascade, several lines of evidence suggest that metastin acts at a higher rung of the reproductive ladder, with its effects on LH secretion mediated through stimulation of GnRH release. In both rodents and monkeys, the effects of metastin on LH can be abrogated by a GnRH antagonist, demonstrating that metastin is acting through GnRH and its receptor to stimulate LH release (17, 18). Metastin induces c-fos immunoreactivity in GnRH neurons in rat hypothalamus (22) and stimulates the release of GnRH from hypothalamic explants (21).

In this issue of JCEM, we find by Dhillo et al. (25) the next important milestone in understanding the role of metastin in human reproductive physiology—metastin administration to normal healthy male volunteers. Because multiple representations of the same fragment are used in the literature, it is important to clarify that the authors use the term kisspeptin-54 to signify full-length metastin or metastin 1–54, which is equivalent to amino acids 68–121 of the parent compound, kisspeptin (kisspeptin 68–121). Similarly, the term kisspeptin-10 is used to signify the C-terminal fragment of metastin (metastin 45–54, which is equivalent to kisspeptin 112–121). Rather than using a single bolus approach, Dhillo et al. used 90-min infusions of full-length metastin in a dose-finding study (doses ranging from 0.125 to 40 pmol/kg·min). Because the dose of 4 pmol/kg·min (which yielded immunoreactive metastin levels of 300 pmol/liter) resulted in near-maximal LH release, the authors then used that dose as a starting point for a second set of infusions designed to map the time course of the kisspeptin response.

Dose-dependent increases in mean LH were observed using infusion rates ranging from 0.25 to 12 pg/kg·min. FSH also rose and testosterone trended in the same direction. At an infusion of 4 pmol/kg·min, mean LH, FSH, and testosterone levels were significantly increased at the 90-min time point compared with saline infusion (LH, 10.8 U/liter during peptide administration compared with 4.2 U/liter during saline; FSH, 3.9 vs. 3.2 U/liter; testosterone, 24.9 vs. 21.7 nmol/liter). These results echo the findings seen in rodents in which metastin administration has a more potent effect on LH than FSH release (21, 26). Inhibin B levels did not change, not a surprising finding given the short duration of the infusion. Overall, the work of Dhillo et al. (25) demonstrates that metastin can acutely increase circulating levels of gonadotropins and sex steroids in normal males. The administration of metastin appears safe; no adverse events in the human volunteers were noted.

This work clearly shows that administration of exogenous metastin 1–54 can be used to manipulate the hypothalamic-pituitary-gonadal axis in the human and therefore raises several intriguing possibilities. Exactly how metastin stimulates GnRH release and, conversely, what factors regulate kisspeptin expression, particularly across the pubertal transition, remain to be determined. In addition, metastin may play a critical role in other organ systems. For example, metastin levels are known to dramatically increase over the course of human pregnancy (27). Although evidence exists for a role in metastin in early trophoblast invasion in the human (28), it is unclear what role metastin might play, if any, in the later stages of pregnancy. In addition, it is unclear how ligand-receptor interactions in nonpregnant states (in which peripheral metastin levels are low) differ from that in pregnancy (in which levels are quite high). Obviously, future studies will be needed to determine whether metastin or analogous compounds can be used selectively to manipulate the reproductive cascade. Hopefully, the rapid pace of progress achieved in this field to date will continue for the next several years to come.

Received October 10, 2005.

Accepted October 21, 2005.

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