madman
Super Moderator
Figure 1. Effects of kisspeptin on reproductive behavior in rodents and humans. Figure illustrates the diverse roles of kisspeptin in modulating behaviors related to sexual partner preference, sexual motivation, arousal/copulatory behaviors, pair bonding, and mood (anxiety/depression) in male and female rodents and humans (created using BioRender.com).
Abstract
Reproductive success and ultimately species survival at a population level is contingent on a plethora of neuroendocrine signals working in concert to regulate gonadal function and reproductive behavior. Among these, the neuropeptide kisspeptin (encoded by the KISS1/Kiss1 gene) has emerged as the master regulator of the hypothalamic-pituitary-gonadal axis. Besides the hypothalamus, both kisspeptin and its cognate receptor are extensively expressed throughout cortico-limbic brain structures in rodents and humans, which are regions traditionally implicated in behavioral and emotional responses. Thus, there exists a neuroanatomical framework through which kisspeptin can integrate reproductive behavior and emotional regulation with the reproductive axis. Accordingly, this sets the scene for recent findings derived from an assortment of species, including humans, unveiling kisspeptin as an important gatekeeper of reproductive behavior and emotional control. Herein, we summarize the major preclinical animal and human experimental evidence identifying kisspeptin as a key neuromodulator of reproductive behavior and emotional state. Such findings have laid the foundations for clinical applications of kisspeptin-based therapies for patients with related reproductive and psychosexual disorders.
Conclusions and Future Directions
Over the last 2 decades, kisspeptin has emerged as the master regulator of reproduction due to its position at the apex of the reproductive axis. Beyond the hypothalamus, both kisspeptin and its receptor are extensively distributed throughout important cortico-limbic brain regions (ie, the behavioral and emotional control centers of the brain) in rodents and humans. As detailed throughout this review, this provides a neuroanatomical framework for an expanding pool of preclinical animal evidence derived from Kiss1 and Kiss1r knockout models (largely performed in combination with sexsteroid replacement to facilitate investigation of primary defects in kisspeptin signaling on reproductive behavior, rather than as a result of a hypogonadal state), as well as chemogenetic approaches and pharmacological kisspeptin administration studies. Together, these experimental models validate kisspeptin signaling as an essential neuromodulator of reproductive behavior including sexual-partner preference, sexual motivation, and copulatory behavior, while also optimizing mood and emotions in an integrated fashion that is positive toward reproduction (summarized in Fig. 1). While several of these behavior and mood-altering effects are due to direct actions of kisspeptin on its receptor in specific cortico-limbic brain regions, other effects are due to kisspeptin’s unique ability to interplay and orchestrate other important neuropeptides and neurotransmitter systems residing downstream of kisspeptin neurons, such as GABA, serotonin, NO, GnRH, and of course downstream sex-steroids.
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Regarding humans, clinical studies in healthy volunteers have provided valuable insights into the influence of kisspeptin in modulating sexual and emotional brain processing. Indeed, these preclinical animal and human findings have laid the foundations for recent studies in people with distressing low sexual desire, demonstrating that kisspeptin acutely and safely restores sexual brain activity, which ultimately enhances sexual desire and arousal. Given this, further human studies (including in women) are now warranted to investigate broader patient cohorts, such as other psychosexual disorders. Moreover, in order to capitalize on the clinical utility of kisspeptin-based medicines, simpler routes of administration to parenteral injection are required. Combined with the current literature, these data would provide further fundamental mechanistic and pharmacological insights for kisspeptin’s importance in reproductive behavior. To this end, the available research has helped unlock kisspeptin-based therapy as an exciting, much-needed, andwell-tolerated potential addition to the treatment armamentarium for managing psychosexual disorders.
