Kisspeptin – a Promising Candidate to Treat Reproductive Disorders
Hypogonadism is a common reproductive system disorder where the male testes and female ovaries produce less or no sex hormones. One of the forms of hypogonadism is called hypogonadotropic hypogonadism where patients suffer from hypogonadism due to under functioning of the pituitary gland or hypothalamus (1).
The usual hormone cycle begins when the hypothalamus releases the gonadotropin releasing hormones (GnRH). Once released, GnRH stimulates the pituitary gland to release follicle stimulating hormone (FSH) and luteinizing hormone (LH). Both FSH and LH then stimulate the female ovaries or male testes thereby leading to sexual development during puberty and normal estrogen levels (in women) and sperm production (in men)(1).
Lack of these hormones, i.e. GnRH, FSH, and LH, are the main causes of hypogonadotropic hypogonadism that evidently affects the sexual development in patients.
What is Kisspeptin
Kisspeptin is a naturally occurring peptide protein encoded by the KISS1 gene in the human body (2).
Kisspeptin is a product of the KISS1 gene, which is produced due to the cleavage of the original 145 amino acid peptide to a smaller peptide composed of 54 amino acids (6).
KISS1 is a gene that suppresses metastases of the melanomas and breast carcinomas, thereby inhibiting abnormal cell growth and preventing cancer (2).
Initially thought to be a metastasis suppressor, Kisspeptin was later discovered to possess a different expression profile which also allows it to function on the hypothalamus and pituitary gland, and thereby positively affect the reproductive system (3).
In the mid-1990s, a cancer cell was isolated and inserted with human chromosome 6, and it was found that this human chromosome (later named KISS1 gene) inhibited the metastasis development and the spreading of cancer in the cell (4).
It was only after 10 years since then that a breakthrough discovery was made regarding the functioning of Kisspeptin peptide.
Several independent studies in the mid-2000s suggested that Kisspeptin plays a vital role in hypogonadotropic hypogonadism as Kisspeptin is a ligand of the G-protein coupled receptor 54 (GPR54)(5). Research continues till date to explore this aspect of the Kisspeptin peptide.
How Does Kisspeptin Work?
GPR54, also called KISS1 receptor (KISS1R)(7), is an important GnRH receptor, which plays an important role in mammals for puberty to occur (5).
Kisspeptin binds to these GPR54 receptors that activate the reproductive axis by stimulating the release of GnRH and gonadotropin neurons in the body. By centrally applying Kisspeptin in the body (i.e., in the central nervous system), it stimulates more than 85% of GnRH neurons, which thereby secrete FSH and LH in the body (7).
As stated above, Kisspeptin is a 54 amino acid peptide product of the KISS1 gene. Besides this, there are other smaller peptide fragments such as Kisspeptin 10, 13, and 14, which all have a biological activity towards GPR54 (7). These smaller peptides bind with a low affinity to the GPR54 receptors and stimulate calcium mobilization, arachidonic acid release, and extracellular protein kinase phosphorylation (7). These events depolarize the Kisspeptin neurons, which leads to the depolarization of the GnRH neurons and thereby modulates the gonadotropin release (9).
In humans, GPR54 is expressed in the pituitary gland and in GnRH neurons, and Kisspeptin stimulates the release of GnRH through direct stimulation of the GnRH neurons and not through pituitary stimulation.
Kisspeptin is the most potent and effective peptide, which excites a vast majority of the GnRH neurons (7) and thereby regulates the reproductive system.
Clinical Uses of Kisspeptin
Reports show that Kisspeptin is a key regulator of the reproductive functions in both animals and humans, throughout their life.
Kisspeptin is a key regulator because of its following advantages (8):
- Stimulates GnRH release in healthy human candidates and animals
- Stimulates endogenous gonadotropin release in lesser fertile candidates
- High dose administration of the peptide causes desensitization and suppression of the hypothalamus, pituitary gland, and gonadal axis
- Possesses the potency to act differently during different phases of the reproductive life cycle (puberty, fertility, pregnancy, and menopause)
These factors make Kisspeptin a promising candidate to treat reproductive disorders and ailments dependent on sex hormones.
As the key regulator, Kisspeptin can also be used to treat the following conditions (9):
- Delayed onset of puberty
- GnRH deficiency
- Treatment of tumors related to the use of sex steroids
- Treatment of metastatic carcinoma
Research and Clinical Studies
Role in the Female Reproductive System
As part of this 2017 study (10), a literature review was conducted for all articles published during 1999 to 2016.
Upon review of the articles, it was established that there is compelling evidence to support that the Kisspeptin system (KISS1 gene and its products, GPR54 receptors) are vital for the onset of puberty and thereby regulate the release of gonadotropin hormones.
Furthermore, there were reports stating that certain studies were conducted on experimental animal models representing similar characteristics as hypogonadotropic hypogonadism (HH) and polycystic ovarian syndrome (PCOS) in humans. These reports suggested that reproductive disorders such as HH and PCOS occur due to abnormalities in the KISS1 and GPR54 system.
The outcome of this literature review suggested that Kisspeptin is a principal neuropeptide that regulates GnRH release and is a prerequisite to maintain a normal, healthy reproductive system in females.
Role in Children with Delayed Puberty
The main goal of this study (13) was to evaluate the effects of Kisspeptin peptide in children with stalled puberty. Based on the functioning of the peptide, it was hypothesized that the peptide would help stimulate the gonadal hormonal release and regulate the reproductive system in children with a delayed onset of puberty.
Eleven boys and four girls were enrolled for this 2018 study where they were all administered with either a single intravenous bolus of Kisspeptin or of gonadotropin releasing hormone (GnRH). The levels of luteinizing hormone (LH) were monitored overnight.
All subjects were then administered with GnRH for 6 days and were then again examined for the levels of LH.
Out of the 15 children, 7 children showed positive results to Kisspeptin with increased levels of LH hormone, 1 child showed an intermediate response, and the other 7 showed no response to peptide.
While the results were varied amongst the subjects, these children should be subject to other follow up studies to determine whether peptide administration impacts future pubertal onset in these children. Further studies are ongoing to fully determine the effects.
Role in Modulating Emotions in Humans
The main purpose of this study (14) was to understand the role of Kisspeptin on the limbic brain activity. The limbic brain processing plays a vital role in the sexual and emotional behavior of humans.
Kisspeptin peptide was exogenously administered in 29 healthy heterosexual men and their effects were examined via neuroimaging and psychometric analysis.
The results of the study showed that the peptide administration led to enhanced limbic brain activity. The subjects showed an increased response towards sexual and bonding stimuli. What’s more, the elevated brain activity also showed improved responses toward sexual drive, mood, and elated behavior. Kisspeptin administration reduced the negative mood in the subjects.
The results further demonstrate the Kisspeptin can be potentially used to treat common reproductive disorders (possibly to improve sex drive) in humans.
Role in Reproductive Hormone Release
The key objective of this study (15) was to establish the effects of Kisspeptin on reproductive hormone release in both healthy men and women.
Kisspeptin was administered intravenously in both men and women at the doses of 0.3, and 1.0 nmol/kg. The peptide was also administered subcutaneously and as intravenous infusion in women at maximal doses of 10, and 32 nmol/kg and 720pmol/kg per minute (for intravenous infusion).
Results in men demonstrated that the levels of FSH and LH were increased at both doses of intravenous peptide administration.
In women, no alterations were observed in the levels of LH and FSH at any of the doses during the follicular phase of the menstrual cycle (i.e., during 2 to 10 days of the menstrual cycle). However, during the preovulatory phase (i.e., during 15 to 16 days before the upcoming cycle), the levels of FSH and LH were elevated in women.
Thus, these results proved that Kisspeptin elevates FSH and LH levels in men and women during their preovulatory phase. These results show the sexual dimorphism in the responses of the healthy volunteers toward Kisspeptin administration.
Role in Food Intake
Kisspeptin is widely distributed in the body in brain sites including hippocampus, cerebellum, posterior hypothalamus, and septum. Owing to its vast distribution, and presence in the food intake regulating nuclei such as Arc found in the hypothalamus, this study (11) was conducted with the aim to examine the effects of Kisspeptin on food intake.
This experiment was conducted on adult male mice aged between 6 and 8 weeks, which were caged under normal temperatures and conditions. These mice were subjected to a standard rodent diet and tap water.
Overnight fasted mice and the experimentally fed mice were administered with different doses of Kisspeptin 10 (3, 1 or 0.3 microgram dose) or placebo either via intraperitoneal (IP) route or intracerebroventricular (ICV) route.
Results showed that the peptide injection in the overnight fasted mice led to a dose-dependent decrease in food intake during the first 3-to-12-hour period. The food intake then increased during the 12-to-16-hour period, which resulted in overall similar food intake compared to the placebo group. This result suggested that ICV administration led to decrease in meal frequency and total meal time, and increased internals between meals. However, meal size and eating rate was almost similar to that of the placebo treated mice.
When observed in experimentally fed (or fasted) mice, the peptide administration did not alter the food intake, but it exerted similar effects of reduced meal frequency and increased inter-meal intervals.
Impaired Kisspeptin System Consequences
Kisspeptin is widely distributed in the body, especially the brain, which suggests that the peptide has additional functions besides regulating the reproduction system.
As part of this study (12), the energetic and metabolic effects were compared between healthy mice and mice with impaired Kisspeptin system.
Results showed that female mice with impaired Kisspeptin system showed dramatic increase in their body weight and significantly impaired glucose tolerance levels. While the peptide impaired female mice ate less than the healthy female mice, they were more obese, with reduced locomotor activity and respiratory rate.
Interestingly, there was no difference found in the healthy male mice and male mice with impaired Kisspeptin system. Both demonstrated normal body weight and glucose levels.
While one would assume that the effects in female mice were due to the absence of gonadotropin estrogen, it was confirmed that this was not the case. This was because even the female mice with chronically increased levels of estrogen (another form of impaired Kisspeptin system) showed similar outcomes.
These results show that alterations in the Kisspeptin system also influence the metabolic rate, body weight, energy expenditure and glucose regulation mechanisms in the body.
Side Effects of Kisspeptin
The above listed studies so far have demonstrated no side effects towards Kisspeptin administration. Furthermore, reports (16) have shown that increased levels of Kisspeptin does not alter the heart rate and blood pressure.
That being said, it should be noted that impaired levels of Kisspeptin can lead to increased body weight, decreased metabolism, and impaired glucose regulation, especially in women (12).
As seen with other peptides, some common side effects of the peptide may be redness and itchiness at the site of administration, nausea, headache, and fatigue.
The Kisspeptin peptides are available in different lengths of 10, 13, 14 and 54 amino acids, all containing the same 10 amino acid structure at the C-terminal. While all possess biological activities, Kisspeptin 54 and 10 are more effective towards stimulating the reproductive axis. However, the extent of their impact differs (17).
As part of their analysis (17), researchers systemically administered Kisspeptin 54 and 10 in male mice and examined the levels of LH hormones in their bloodstream.
Upon examining the LH levels at 10 minutes and 2 hours after administration, it was seen that Kisspeptin 54 sustained the LH release for a prolonged period as compared to Kisspeptin 10.
Further analysis showed that this was possibly because Kisspeptin 54 had a longer half-life (32 minutes) as compared to Kisspeptin 10 (5 minutes). In addition, scientific data suggested that Kisspeptin 54 possessed the ability to cross the blood brain barrier, while Kisspeptin 10 may not be able to do so as easily.
Kisspeptin is a by-product of the KISS1 gene naturally found in the human system. Originally thought to inhibit the metastasis development in the body, Kisspeptin was later discovered to have a significant impact on the reproductive axis and regulates the secretion of gonadotropins in the body – primarily via binding to the GRP54 receptors.
Studies so far have demonstrated that this peptide protein has a significant effect on the reproductive system in humans. While the results are varied amongst women (depending on the phases of their menstrual cycle) and children with delayed puberty, the results so far seem promising with minimal side effects. It should be noted that impaired Kisspeptin levels can have significant adverse effects, especially in women, leading to increased body weight and weakened glucose regulation.
Since the breakthrough discovery of the correlation between Kisspeptin and reproductive axis is relatively new, clinical trials are still underway to fully explore the potency of this peptide and thereby potentially establish its use as a therapeutic agent in treating common reproductive disorders.
1. Hypogonadotropic hypogonadism. US National Library of Medicine. https://medlineplus.gov/ency/article/000390.htm
2. KISS1 KiSS-1 metastasis suppressor [Homo sapiens (humans)]. https://www.ncbi.nlm.nih.gov/gene/3814
3. Hussain, Mehboob A et al. “There is Kisspeptin – And Then There is Kisspeptin.” Trends in endocrinology and metabolism: TEM vol. 26,10 (2015): 564-572. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587393/
4. Pasquier, J., Kamech, N., Lafont, A., Vaudry, H., Rousseau, K., & Dufour, S. (2014). MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors, Journal of Molecular Endocrinology, 52(3), T101-T117. https://jme.bioscientifica.com/view/journals/jme/52/3/T101.xml
5. Messager, S., Chatzidaki, E. E., Ma, D., Hendrick, A. G., Zahn, D., Dixon, J., Thresher, R. R., Malinge, I., Lomet, D., Carlton, M. B., Colledge, W. H., Caraty, A., & Aparicio, S. A. (2005). Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proceedings of the National Academy of Sciences of the United States of America, 102(5), 1761–1766. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC545088/
6. Mead, E. J., Maguire, J. J., Kuc, R. E., & Davenport, A. P. (2007). Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system. British journal of pharmacology, 151(8), 1143–1153. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189831/
7. Rønnekleiv, O. K., & Kelly, M. J. (2013). Kisspeptin excitation of GnRH neurons. Advances in experimental medicine and biology, 784, 113–131. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019505/
8. Prague JK, Dhillo WS. Potential Clinical Use of Kisspeptin. Neuroendocrinology. 2015;102(3):238-45. doi: 10.1159/000439133. Epub 2015 Aug 7. https://pubmed.ncbi.nlm.nih.gov/26277870/
9. Tng E. L. (2015). Kisspeptin signalling and its roles in humans. Singapore medical journal, 56(12), 649–656. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678402/
10. Zeydabadi Nejad, S., Ramezani Tehrani, F., & Zadeh-Vakili, A. (2017). The Role of Kisspeptin in Female Reproduction. International journal of endocrinology and metabolism, 15(3), e44337. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702467/
11. Stengel, A., Wang, L., Goebel-Stengel, M., & Taché, Y. (2011). Centrally injected kisspeptin reduces food intake by increasing meal intervals in mice. Neuroreport, 22(5), 253–257. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063509/
12. Kristen P. Tolson et.al, Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. The Journal of Clinical Investigation. Published June 17, 2014. https://www.jci.org/articles/view/71075
13. Chan, Y. M., Lippincott, M. F., Kusa, T. O., & Seminara, S. B. (2018). Divergent responses to kisspeptin in children with delayed puberty. JCI insight, 3(8), e99109. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931121/
14. Comninos, A. N., Wall, M. B., Demetriou, L., Shah, A. J., Clarke, S. A., Narayanaswamy, S., Nesbitt, A., Izzi-Engbeaya, C., Prague, J. K., Abbara, A., Ratnasabapathy, R., Salem, V., Nijher, G. M., Jayasena, C. N., Tanner, M., Bassett, P., Mehta, A., Rabiner, E. A., Hönigsperger, C., Silva, M. R., Dhillo, W. S. (2017). Kisspeptin modulates sexual and emotional brain processing in humans. The Journal of clinical investigation, 127(2), 709–719. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272173/
15. Jayasena, C. N., Nijher, G. M., Comninos, A. N., Abbara, A., Januszewki, A., Vaal, M. L., Sriskandarajah, L., Murphy, K. G., Farzad, Z., Ghatei, M. A., Bloom, S. R., & Dhillo, W. S. (2011). The effects of kisspeptin-10 on reproductive hormone release show sexual dimorphism in humans. The Journal of clinical endocrinology and metabolism, 96(12), E1963–E1972. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232613/
16. G. M. K. Nijher, O. B. Chaudhri, R. Ramachandran et al., “The effects of kisspeptin-54 on blood pressure in humans and plasma kisspeptin concentrations in hypertensive diseases of pregnancy,” The British Journal of Clinical Pharmacology, vol. 70, no. 5, pp. 674–681, 2010. https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2010.03746.x
17. d’Anglemont de Tassigny X, Jayasena CN, Murphy KG, Dhillo WS, Colledge WH. Mechanistic insights into the more potent effect of KP-54 compared to KP-10 in vivo. PLoS One. 2017 May 2;12(5):e0176821. doi: 10.1371/journal.pone.0176821. Erratum in: PLoS One. 2018 Jan 25;13(1):e0192014. PMID: 28464043; PMCID: PMC5413024. https://pubmed.ncbi.nlm.nih.gov/28464043/
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