Kisspeptin: an alternative to hCG

Kisspeptin: an alternative to hCG October 2, 2020

Kisspeptins (formerly known as metastin) are peptides encoded by KISS1. The gene was first discovered in 1996, in Hershey, PA, USA, and was subsequently named after Hershey’s chocolate kisses. The peptide product of KISS1 is a 145 amino acid peptide that is cleaved into four shorter peptides: kisspeptin-54, kisspeptin-14, kisspeptin-13, and kisspeptin-10 (the numbers denote how many amino acids in each). All these isoforms activate the kisspeptin receptor. Kisspeptins produced in the hypothalamus stimulate neurons in the hypothalamus that secrete a gonadotropin-releasing hormone (GnRH), which subsequently stimulates the release of gonadotropins and sex steroid hormones.

Kisspeptin has been shown to have a crucial role in puberty. Inactivating mutations of the kisspeptin receptor or KISS1 gene lead to pubertal failure due to hypogonadotropic hypogonadism in mice and people. Conversely, activating mutations of the kisspeptin receptor in people leads to central precocious puberty. Exogenous kisspeptin stimulates gonadotropin release in all animal species studied and in people. This effect is mediated predominantly by stimulating GnRH release (because pretreatment with a GnRH antagonist completely blocks the ability of kisspeptin to stimulate gonadotropin release).

Recent evidence also suggests that the kisspeptin system is important in the generation of GnRH pulses, which are crucial for normal fertility. In a subpopulation of neurons in the hypothalamic arcuate nucleus, kisspeptin colocalizes with two other hormones known to affect GnRH release, namely neurokinin B (NKB) and dynorphin (DYN). This group of cells is often referred to as the KNDy neurons. Increasing data suggest that KNDy neurons have a key role in the mediation of pulsatile GnRH release. The evidence thus far suggests that kisspeptin has exciting therapeutic potential in people — i.e., acute use of kisspeptin for infertility could stimulate reproductive hormone release more naturally than by conventional methods.

Data for human beings also suggest that kisspeptin might stimulate pulses of luteinizing hormone, indicating its therapeutic potential for the treatment of women with anovulatory infertility. Chronic use of high doses of kisspeptin causes desensitization and reduces the secretion of gonadotropins. Hence, long-acting forms of kisspeptin are being developed to treat hormone-sensitive cancers, with promising early results in people.

Kisspeptin Timeline: A long road

1996: Kisspeptin gene (KISS1) discovered.

2001: Peptide products of KISS1 termed kisspeptins. Established that the three naturally occurring forms of kisspeptin are 54, 14, and 13 amino acids in length. These forms all share a common C-terminal decapeptide (kisspeptin-10), which is necessary for biological activity.

2003: Discovered that inactivation of the kisspeptin receptor in mice or people leads to pubertal failure, which is due to low circulating concentrations of gonadotropins, which in turn reduce sex hormone secretion (ie, hypogonadotropic hypogonadism). Kisspeptin-receptor knockout mice have normal amounts of GnRH in the hypothalamus and are responsive to exogenous gonadotropins or GnRH. These findings suggested that the kisspeptin receptor has a crucial role in the release of hypothalamic GnRH.

2003 forward: Studies of different species (eg, mice, rats, sheep, and monkeys) showed that central or peripheral administration of kisspeptin potently stimulates gonadotropin release, which is predominantly mediated by stimulation of GnRH release (pretreatment with a GnRH antagonist completely blocks the ability of kisspeptin to stimulate gonadotropin release). Chronic, intermittent kisspeptin can lead to sustained stimulation of gonadotropin release. However, chronic infusion of high doses of kisspeptin can lead to an initial stimulation of gonadotropin release followed by suppression due to desensitization at the kisspeptin receptor.

Hypothalamic kisspeptin expression was shown to be regulated by sex steroids.

Kisspeptin knockout mice were shown to have a similar (but perhaps milder) phenotype to kisspeptin-receptor knockout mice.

Kisspeptin was shown to play a part in the induction of the preovulatory surge of luteinizing hormone and regulation of the estrous cycle in female animals.

Kisspeptin shown to have a role in the mediation of hypogonadotropic hypogonadism, in association with fasting, leptin deficiency, stress, and hyperprolactinemia.

Hypothalamic kisspeptin secretion was shown to be pulsatile and to have a role in modulation of GnRH pulses.

2005: The first-in-man study showed that kisspeptin potently stimulates gonadotropin release without side-effects.

2007: The first study in healthy women showed that kisspeptin potently stimulates gonadotropin release and that the effects are greatest in the preovulatory phase of the menstrual cycle.

An animal study showed that, in a subpopulation of neurons in the hypothalamic arcuate nucleus, kisspeptin colocalizes with two other hormones known to affect GnRH release — namely, neurokinin B and dynorphin. This subpopulation is often referred to as the KNDy neurons.

2008: Activating mutation in the kisspeptin receptor shown to cause central precocious puberty.

2009: Kisspeptin shown to potently stimulate gonadotropin release in women with infertility due to hypothalamic amenorrhea.

Kisspeptin antagonist developed. • Established that blockade of kisspeptin action disrupts GnRH pulsatility in animals.

Patients with inactivating mutations in the gene encoding neurokinin B or its receptor (NK3) shown to have a similar phenotype to patients with kisspeptin-receptor mutations— namely, hypogonadotropic hypogonadism.

Animal data suggest that KNDy neurons have a key role in the mediation of pulsatile GnRH release.

2011: Human studies suggested that kisspeptin could reset the hypothalamic GnRH clock and that an infusion of kisspeptin in healthy men can stimulate pulses of luteinizing hormone.

2012: Inactivating mutations in the kisspeptin gene shown to cause pubertal failure due to hypogonadotropic hypogonadism.

2013: Human studies showed that kisspeptin can stimulate pulses of luteinizing hormone in healthy women, patients with mutations in neurokinin B or its receptor, patients with mild biochemical hypogonadism due to diabetes, and in women with hypothalamic amenorrhea.

Further human studies are underway to investigate the therapeutic potential of kisspeptin infertility and hormone-sensitive cancers.

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