The hormone kisspeptin can enhance activity in brain regions associated with sexual arousal and romantic love, according to new research. 
 
 The scientists behind the early-stage study, from Imperial College London, are now keen to explore whether kisspeptin could play a part in treating some psychosexual disorders - sexual problems which are psychological in origin, and commonly occur in patients with infertility. The work was funded by the National Institute for Health Research (NIHR) the Wellcome Trust and the Medical Research Council. 
 
 Kisspeptin is a naturally occurring hormone that stimulates the release of other reproductive hormones inside the body. The study involved a double-blind, placebo-controlled trial in which 29 healthy heterosexual young men were given either an injection of kisspeptin or placebo. In an MRI scanner the men were shown a variety of images, including sexual and non-sexual romantic pictures of couples, whilst researchers scanned their brains to see how kisspeptin affected the brain's responses. 
 
 Ultimately, we are keen to look into whether kisspeptin could be an effective treatment for psychosexual disorders, and potentially help countless couples who struggle to conceive. – Professor Waljit Dhillo Department of Medicine 
 
 The researchers found that after the injection of kisspeptin, when the volunteers were shown sexual or romantic images of couples, there was enhanced activity in structures in the brain typically activated by sexual arousal and romance. 
 
 The team believe this shows kisspeptin boosts behavioural circuits associated with sex and love. They are particularly interested in how kisspeptin might be able to help people with psychosexual disorders and related problems with conceiving a baby. 
 
 NIHR Research Professor Waljit Dhillo, the lead author of the research from the Department of Medicine at Imperial College London, said: "Most of the research and treatment methods for infertility to date have focussed on the biological factors that may make it difficult for a couple to conceive naturally. These of course play a huge part in reproduction, but the role that the brain and emotional processing play in this process is also very important, and only partially understood." 
 
 As the research is at an early stage, the team of researchers now want to do a follow on study to analyse the effects of kisspeptin in a larger group, including women as well as men. 
 
 Professor Dhillo added: "Our initial findings are novel and exciting as they indicate that kisspeptin plays a role in stimulating some of the emotions and responses that lead to sex and reproduction. Ultimately, we are keen to look into whether kisspeptin could be an effective treatment for psychosexual disorders, and potentially help countless couples who struggle to conceive." 
 
 Volunteers in the study underwent MRI scans at the Imanova Centre for Imaging Sciences and were shown sexual and non-sexual romantic, negative, and neutral-themed images, and images of happy, fearful and neutral emotional faces. Kisspeptin did not appear to alter emotional brain activity in response to neutral, happy or fearful-themed images. However, when volunteers were shown negative images, kisspeptin did enhance activity in brain structures important in regulating negative moods, and study participants reported a reduction in negative mood in a post-scan questionnaires. As a result, the team are also interested in investigating the possibility that kisspeptin might be used for treating depression. 
 
 Left image: Orange highlights illustrate the enhanced activity in the brain when the subjects had the kisspeptin injection and looked at sexual images. These areas of the brain have often been associated with processing of sexual, emotional and rewarding stimuli. 
 
 Right image: Orange highlights show areas of the brain that were more responsive to couple-bonding images when the subjects had the kisspeptin injection.These areas of the brain have often been associated with memory and processing of romantic, emotional and rewarding stimuli. 
 
 Dr Alexander Comninos, first author of the study from the Department of Medicine at Imperial, said "'Our study shows that kisspeptin boosts sexual and romantic brain activity as well as decreasing negative mood. This raises the interesting possibility that kisspeptin may have uses in treating psychosexual disorders and depression which are major health problems which often occur together, but further studies would be needed to investigate this." 
 
 "Kisspeptin Modulates Sexual and Emotional Brain Processing in Humans" by Waljit S Dhillo et al is published in the Journal of Clinical Investigation. 
 
 See the press release of this article ||||| Kisspeptin The molecule of puberty 
 
 and sexual fertility Paul May 
 
 University of Bristol Molecule of the Month September 2010 
 
 Also available: JSMol version. 
 
 Surely nothing to do with Gene Simmons and Co.? 
 
 No, not the rock band Kiss, although it has similarities it that it also sends teenagers wild. Kisspeptin is a protein that when released from the brain triggers the cascade of biochemical changes that leads to puberty, turning children into adults. Puberty is still one of the great unsolved mysteries in biology. Scientists have known for years that puberty begins when a child's brain releases hormones that cascade through the body leading to the maturing of testes in boys and ovaries in girls. However, the exact nature of the hormones wasn't fully understood until a few years ago, when kisspeptin was discovered. Adolescents who lack a functioning kisspeptin system fail to achieve puberty. We now know that, almost literally, ‘puberty begins with a kiss’! 
 
 It started with a kiss... 
 
 Kisspeptins are actually a group of proteins with similar structure, and are products of the KiSS-1 gene. This gene was discovered in 1996 [Lee et al., 2006] when scientists were searching for a gene that prevents cancer from spreading. This groundbreaking work took place in research labs in the town of Hershey, Pennsylvania, the location also famous for the Hershey's chocolate factory. Since Hershey's most popular product is a chocolate confectionary called a Hershey's Kiss (photo, right), the discoverers' of the gene named it KiSS-1 after this chocolate. However, the nomenclature also has a scientific grounding as the inclusion of SS in the name also indicates that the gene is a suppressor sequence, i.e. it prevents some biological process from occurring (such as cancer spreading). Kisspeptin was first given the name metastin, because it was thought to play a role in tumor metastasis, but later named kisspeptin after its gene pecursor. The receptor for kisspeptin in the brain was identified only recently and was given the rather less whimsical name GPR54 (G-Protein Coupled Receptor 54). 
 
 The KiSS-1 gene is found on the long-arm of chromosome 1. The protein it makes is a peptide containing 145 amino-acids, which are then cleaved into smaller, 54-amino-acid chunks. These may also be further truncated down to 14, 13 or even 10 amino-acids fragments with carboxylic acid terminations. These N-terminally truncated peptides are known as the family of kisspeptins. Kisspeptin-10 is shown below. 
 
 ...never thought it would come to this 
 
 A single injection of kisspeptin in animals has been found to stimulate a huge increase in the secretion of gonadotropins (hormones that stimulate the production of testosterone in men and estradiol in women). Repeated injections into immature rats has been shown to advance the age of puberty. 
 
 Very recently, a group of Japanese scientists delivered an antibody directed against kisspeptin into the brain of female rats. This stopped the rats' reproductive cycle demonstrating that inhibiting the effect of kisspeptin, even after puberty, still blocks reproductive function. Therefore, as well as being vital to initiate puberty, kisspeptin is necessary for reproductive function to continue later in life. Later, Spanish scientists discovered that administering kisspeptin in food-restricted rats still stimulated the release of gonadotropins. This is a remarkable discovery, since normally when a mammal is facing starvation its reproductive system becomes dormant to conserve the body's stored food supply. Kisspeptin injections over-ride this defence mechanism, and can kick-start normally dormant reproductive systems. 
 
 It has also been discovered that kisspeptin plays a role in seasonal-breeding animals. Many mammals only become fertile during the annual breeding season, and this is controlled by the duration of daylight per day. During short winter days, these anmials have a reduced amount of kisspeptin in certain parts of the brain, and sexual activity is switched off (or greatly reduced). But in the long summer days, kisspeptin amounts increase, stimulating the animals to breed. Artificially injecting animals (such as ewes) with kisspeptin during the winter months causes ovulation even in the non-breeding season [Dhilo 2008]. This has implications for farmers, who may soon be able to choose when their livestock reproduce rather than be restricted by the natural annual cycle. 
 
 The kiss of life? 
 
 Because of its link with the KiSS-1 gene, kisspeptin has been suggested as a possible treatment for some forms of cancer. In particular, when breast and prostate cancers develop, they are nurtured by the sex hormones oestrogen and testosterone. If the production of these hormones could be switched off the tumours should shrivel and die. One way to do this might be to block the kisspeptin-receptor in the brain. Scientists are now actively looking for molecules that can block this receptor. 
 
 Kisspeptin's role in switching-on sexual hormones could be vital in controlling the timing of puberty when this goes wrong. There are a number of conditions where children that reach puberty much too early (five or six years old) could possibly be treated by simply taking pills containing kispeptin derivatives. Conversely, for young people in which puberty does not begin as normal in their teenage years, it may be possible to administer kisspeptin to kick-start the process. 
 
 It has recently been found that kisspeptin can restart the female reproductive system in women who have stopped ovulating due to an imbalance in their sex hormones. Kisspeptin is therefore a potential basis for a new infertility treatment. 
 
 References 
 
 W.S. Dhillo, J. Neuroendocrin . 20 (2008) 963 - a good review paper. 
 
 . (2008) 963 - a good review paper. J.H. Lee, M.E. Miele, D.J. Hicks, et al . "KiSS-1, a novel human malignant melanoma metastasis-suppressor gene.", J. Natl. Cancer Inst . 88 (1996) 1731–7. 
 
 . "KiSS-1, a novel human malignant melanoma metastasis-suppressor gene.", . (1996) 1731–7. Sciencewatch - lots of references here to the current scientific literature. 
 
 Wikipedia 
 
 kisspeptin.com 
 
 kisspeptin.org 
 
 Women's health 
 
 Back to Molecule of the Month page. [DOI:10.6084/m9.figshare.5255167] ||||| Mental Viagra’ is on the horizon after scientists discovered that a hormone which surges during puberty can activate lust signals in the brain. 
 
 The hormone kisspeptin essentially switches on the desire to reproduce and is linked to feeling sexy, romantic and turned on. It is thought to be responsible for the voracious sexual appetite of young people. 
 
 Now scientists at Imperial College London have found that an injection of kisspeptin can trigger chemicals in the brain which occur when people feel amorous and aroused. 
 
 They believe that pills containing the hormone could one day be used to treat sexual problems which are psychological – rather than physical. 
 
 It could even help couples recapture the spark in a failing relationship. ||||| In this study, we demonstrate that the reproductive hormone kisspeptin enhances limbic brain activity specifically in response to sexual and bonding stimuli and that these responses correlate with psychometric measures of sexual and emotional processing. Sexual and emotional responses are fundamental drivers of human behavior, and the links among sex, bonding, and reproduction ultimately ensure the survival of most mammalian species (20). However, the pathways involved are multiple, complex, relatively poorly understood, and involve reproductive and metabolic hormones, pheromones, neuronal networks, peripheral organs, and various sensory signals, among others. Our data suggest a potential role for kisspeptin as an important neuromodulator, linking sexual and emotional brain processing with the reproductive axis. 
 
 Visually evoked sexual arousal is a frequent occurrence in men, and brain activity associated with visual sexual stimuli have been explored in several previous studies. These studies have examined a wide range of brain structures in response to sexual-themed images and revealed a processing network involving structures including the hypothalamus, amygdala, thalamus, cingulate, insula, precentral gyrus, and occipital cortex (13–15, 21–28). Furthermore, activations in structures including the thalamus and cingulate correlate with physiological sexual arousal (as assessed by penile tumescence) (13). The involvement of these structures therefore suggests cognitive (cingulate, thalamus), emotional (amygdala, insula), motivational (precentral gyrus), and physiological (thalamus) components to sexual arousal from the appraisal of a stimulus as sexual through to the autonomic activation in readiness for sexual behavior (13, 27, 28). 
 
 Kisspeptin sits at the apex of the reproductive axis, above gonadal hormones such as testosterone that are known to be involved in sexual and emotional processing (29). Kisspeptin signaling is also essential in the “timing” of reproduction, from regulating gonadotropin-releasing hormone (GnRH) pulsatility, oestrous cyclicity, and sexual development to aging (30). In our study, kisspeptin enhanced activity in key limbic and paralimbic structures when heterosexual young men viewed sexual images. These included the anterior and posterior cingulate as well as the left amygdala, consistent with areas of activation observed in the above studies (13–15, 21–28) and with regions expressing kisspeptin and kisspeptin receptors (4–10). Therefore, we demonstrate that kisspeptin administration enhances activation in key established areas of the sexual-processing network. 
 
 It is interesting that, although kisspeptin enhanced activity in both the right and left amygdala, this only reached statistical significance on the left. Although the right amygdala often shows greater enhancement during image-related emotion stimulation (31, 32), the left amygdala is more often engaged in sexual (14) and emotional processing in men (33), and so in this study, kisspeptin may be preferentially acting on the left amygdala in keeping with these studies. Future studies may seek to examine whether there is a lateralization of kisspeptin and kisspeptin receptor expression in the amygdala to address this further. 
 
 We then proceeded to correlate modulations in brain activity with our psychometric data to provide functional relevance. Interestingly, kisspeptin’s enhancement of several structures of the sexual-processing network (including the cingulate, putamen, and globus pallidus) correlated with reduced sexual aversion, suggesting a role for kisspeptin in sexual disinhibition. 
 
 Drive and reward traits are primary components of BAS, which has key functions in bringing the individual together with biological rewards such as sex and food (34, 35). Furthermore, previous studies have shown that these traits predict fMRI responses to appetizing foods (36) and sexual images (37). The neural substrate of the BAS comprises structures belonging to the mesolimbic reward and fronto-striatal-amygdala-midbrain networks (36, 37). Intriguingly, in our study, kisspeptin activated key components related to these networks (including the hippocampus, amygdala, and cingulate) more in participants with lower baseline drive and reward traits in response to viewing sexual images. It is interesting to speculate as to a functional reason for this. Kisspeptin was able to enhance activity in components of this reward circuitry more in participants who were less reward responsive. This could serve as a functional mechanism for enhancing reward-system activity during sexual arousal (in those generally less responsive to reward), so as to drive a desire for reproduction in these individuals. 
 
 Collectively, these data suggest that kisspeptin not only enhances activation in established structures of sexual arousal, but that this activation correlates with behavioral measures of reward, drive, and sexual aversion. Consistent with the expression pattern of kisspeptin and its cognate receptor in these regions (4–10), we provide evidence for kisspeptin as a neuroendocrine modulator of the human brain sexual-processing network. 
 
 In addition to sexual stimulation, an important precursor to reproduction is the desire to bond with a partner. Studies of bonding have examined different types: romantic love, maternal love, and unconditional love. Studies of romantic love demonstrate activations in dopamine-rich and basal ganglia structures such as the putamen, thalamus, and globus pallidus (17, 38, 39), which are associated with reward (40), pair-bonding (41), and euphoria (16). In addition, activations are commonly seen in areas associated with mental associations (e.g., hippocampus and thalamus) and emotional areas also implicated in sexual processing (e.g., cingulate and amygdala) (17, 38, 39, 42). There is substantial overlap with the processing networks in maternal love, including the cingulate, globus pallidus, amygdala, and dopaminergic brain areas (43). Activations are also observed in reward and dopamine-rich areas (e.g., globus pallidus and cingulate) in unconditional love (44). Taken together, these studies suggest a common subcortical dopaminergic reward-related brain system as well as higher-order cortical cognitive centers driving love and bonding. 
 
 In the current study, kisspeptin modulated the response to bonding images in regions similar to those seen with sexual images, including the anterior and posterior cingulate and amygdala, with the addition of activation in the thalamus and globus pallidus. These activations by kisspeptin match regions implicated in romantic love, maternal love, and even unconditional love in the aforementioned studies as well as being sites of kisspeptin and kisspeptin receptor expression (4–10). Furthermore, we observed that kisspeptin’s enhanced activation of the amygdala in response to bonding images correlated with improvements in positive mood. Taken together, these data demonstrate that kisspeptin enhanced activity in key “romance and bonding” structures in response to viewing couple-bonding images and that this correlated with improved positive mood. We therefore provide evidence in humans of a role for kisspeptin in the processing of sexual and bonding stimuli, both of which are critical in driving reproduction at a behavioral level. 
 
 Consistent with the correlation between kisspeptin’s enhancement of amygdala activity and improvements in positive mood in humans above, recent rodent data suggest antidepressant-like effects for kisspeptin via the serotonergic system (45). In our study, kisspeptin enhanced prefrontal activity in response to negative images; a region expressing kisspeptin receptors (9). This is consistent with studies of negative-evoked stimuli, demonstrating predominant activation in prefrontal regions commonly implicated in response inhibition and self-control. Greater activity in these regions assists internalized representations of safety to minimize fear and anxiety to negative stimuli (19). In keeping with this, we observed that kisspeptin administration elicited a reduction in negative mood, providing human evidence of an antidepressant-like effect for kisspeptin, a finding with clear clinical implications. 
 
 The hippocampus is heavily involved in producing emotions. In our study, sexual- and bonding-themed stimuli resulted in positive increases in activity in the hippocampus (i.e., increases in mean percentage of blood-oxygen-level–dependent [BOLD] signal change) in line with previous studies (25, 46). In other words, the images were able to stimulate hippocampal activity. However, there was no significant difference in this increased activity between kisspeptin and vehicle administration. Overall, these data suggest that kisspeptin may have a greater effect on other limbic structures involved in emotional processing, such as the amygdala, cingulate, thalamus, and globus pallidus rather than the hippocampus. 
 
 It is salient to note that the effects of kisspeptin on the limbic system were confined to sexual and couple-bonding images, with no limbic effects in response to negative-, neutral-, happy-, or fearful-themed images. In addition, kisspeptin had no effect on brain activity during a battery of nonlimbic tasks (visual, auditory, motor, language, calculation). These data highlight that kisspeptin acts specifically to enhance limbic activity only to sexual and couple-bonding stimulation in our study, which is particularly pertinent given its established role as a potent reproductive hormone (1–3). It is also noteworthy that kisspeptin administration had no effect in the current study on other relevant hormones that could affect limbic activity, including testosterone, oxytocin, and cortisol as well as attention and anxiety. Furthermore, previous studies demonstrate that kisspeptin administration has no effect on other endocrine hormones, including growth hormone, prolactin, and thyroid-stimulating hormone in humans (47). 
 
 It is important to consider the physiological implications of our findings using the experimental paradigm employed in this study. Physiologically, kisspeptin is predominantly synthesized and secreted from kisspeptin neurones in the infundibular nucleus of the hypothalamus in humans (48) and the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV) in rodents (49). This kisspeptin then activates kisspeptin receptors on GnRH neurones, stimulating pulsatile GnRH release into the hypophyseal-portal circulation and downstream reproductive hormones. This secretion does appear to be pulsatile in rodents (49), and work in monkeys demonstrates pulsatile kisspeptin secretion (every 30 to 90 minutes) into the hypophyseal-pituitary circulation (50). In this study, kisspeptin was administered peripherally, as it is obviously not possible to administer it into the hypothalamus in humans, and we acknowledge that this differs from physiological kisspeptin release. However, the levels of kisspeptin achieved in this study are similar to those observed physiologically in normal pregnancy (51, 52). In addition, the kisspeptin levels observed in this study were similar to the kisspeptin levels achieved in previous studies in which peripheral kisspeptin administration stimulated oocyte maturation in in vitro fertilization protocols (53) and restored luteinizing hormone (LH) pulsatility in women with hypothalamic amenorrhoea (54). Furthermore, our study and others have demonstrated that peripheral kisspeptin administration does not result in downregulation of the reproductive axis in the time frame used in this study in healthy men (54–57). As such, while our protocol does not precisely mimic normal physiology, in the current study, we administered doses of kisspeptin that have previously been shown to have physiological and sustained reproductive effects. 
 
 Another important point to consider is whether peripherally administered kisspeptin can get into the brain. Peripheral kisspeptin can access GnRH neurones via their dendritic terminals in the organum vasculosum of the lamina terminalis (OVLT) outside the blood-brain barrier (58, 59). To examine other brain areas, we administered radiolabeled kisspeptin peripherally to male mice and demonstrated that it can access the brain, including limbic structures (Supplemental Figure 6). Although this study was performed in mice, it suggests that peripheral kisspeptin can cross the blood-brain barrier and directly access brain regions expressing kisspeptin and kisspeptin receptors (4–10). Future work will no doubt examine the neuronal pathways involved, expanding on established interactions among kisspeptin (6), GABA (60), and nitric oxide (61) pathways. 
 
 In conclusion, we implicate kisspeptin as a modulator of reproductive hormones, limbic brain activity, and behavior. This is supported by the findings of kisspeptin and kisspeptin receptor expression in limbic and paralimbic structures (4–10). We demonstrate that kisspeptin administration enhances limbic responses to sexual and bonding stimuli and that this activity correlates with reward measures, improved positive mood, and reduced sexual aversion. In addition, kisspeptin attenuates negative mood. This suggests that kisspeptin, in addition to its established role in the reproductive hormonal cascade, can also influence related sexual and emotional brain processing, thereby providing integration among reproduction, sexual responses, and bonding. These findings have important ramifications for our understanding of reproductive biology. Delineation of the precise neuronal networks by which kisspeptin exerts these effects will be an exciting field of future study, and recent advances in the use of optogenetics to stimulate endogenous kisspeptin neurones may serve as useful tools (49). Furthermore, in rodents, the kisspeptin receptor is necessary for male olfactory partner preference (62), with limbic kisspeptin neurones integrating into olfactory and reproductive circuits (6). This suggests that in humans, kisspeptin-olfactory processing may provide another area of future study. 
 
 We observed that kisspeptin’s enhancement of brain activity correlated with improvements in positive mood and reduced sexual aversion while kisspeptin also reduced negative mood. Therefore, this raises interesting directions for the pharmacological use of kisspeptin in disorders of sexual and emotional processing. For example, studies of kisspeptin administration in patients with depression and psychosexual disorders may prove fruitful as well as informing current work to develop kisspeptin as a potential therapeutic for common reproductive disorders, including male hypogonadism (56), hypothalamic amenorrhoea (54), and hyperprolactinaemia (63), and as a trigger for ovulation in in vitro fertilization (53). Therefore, our data also have important clinical relevance given the continued development of kisspeptin as a potential therapeutic. ||||| Oxytocin, a hormone often referred to as the "cuddle chemical" for its role in helping to foster intimate relationships—particularly between mothers and their newborns—may help people with autism to read and react to social cues, according to the preliminary results of a small study published in the Proceedings of the National Academy of Sciences. Individuals with autism spectrum disorders often have trouble engaging and interacting in social situations, frequently avoiding eye contact, for example, and previous research has also shown that people who are autistic often have lower levels of the hormone oxytocin. In this recent study, researchers from France's Center of Cognitive Neuroscience used nasal inhalers to give oxytocin to 13 individuals with high-functioning autism or Asperger's syndrome. Afterwards, the researchers examined the study participants' reactions to social stimuli. They found that, after the oxytocin, the subjects showed significant improvement on social tasks—including making more eye contact when shown pictures of faces, and responding to other players in a ball tossing game. 
 
 Oxytocin, sometimes referred to as the "love hormone", is one powerful chemical: during physical intimacy, it increases for both men and women; it acts as a hormone to help induce labor and lactation in mothers; and it also serves as a nuerotransmitter in the brain—research suggests that it influences everything from our ability to fall in love, to our tendency toward monogamous relationships and ability to trust others. Should these initial findings be confirmed, they may suggest a potential therapeutic use of oxytocin for individuals with autism spectrum disorders. What's more, it could even increase opportunities for early intervention for children diagnosed with autism. As Angela Sirigu, lead author of the study, told the Washington Post, "It's possible it can become a cure, if it's given early when the problems are detected in the little kids... We can change the way these patients interact with people from childhood."
– Kisspeptin, a naturally occurring hormone that kicks off puberty and is thought to fuel what the Telegraph describes as the "voracious sexual appetites of young people," could well be a sort of "mental Viagra" for people with psychosexual disorders—that is, disorders that are psychological as opposed to physical. And because these disorders can occur in patients who are infertile, researchers from Imperial College London report in the Journal of Clinical Investigation that kisspeptin could even play a role in helping couples struggling to conceive. The early-stage study began to lay the groundwork for that theory by testing how kisspeptin affects the brain's responses to sexual situations. To achieve this, researchers injected kisspeptin or a placebo into 29 healthy young men, explains a press release. When shown arousing images, MRI scans of the kisspeptin group revealed enhanced activity in brain regions associated with arousal compared to the placebo group. There was no such activity observed when non-sexual romantic images were shown. The lead author notes that most research and treatments for infertility focus on important biological factors, but that emotional processing is also key and "only partially understood." Next up, they plan to expand the study's size and include women. Bonus trivia: Kisspeptin's name comes from Hershey, Pa., which is home to both Hershey’s Kisses and the lab that in 1996 discovered the KiSS-1 gene that encodes kisspeptins, reports the New Statesman. (After the most extreme tragedy, this couple is pregnant with twins.)