Kisspeptin and kisspeptin-10 (KP-10): mechanisms of action, studies in humans and new directions of research

Kisspeptin is a naturally occurring peptide signaling system in the body that plays an important role in regulating human reproductive functions [1]. It is one of the key elements of the hypothalamic-pituitary-gonadal axis (HPG), a hormonal network involved in sexual maturation, ovarian and testicular function, and fertility regulation. Within this system, hypothalamic neurons release gonadotropin-releasing hormone (GnRH), which stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These gonadotropins are involved in the development of ovarian follicles, ovulation, testosterone synthesis, and sperm production.

The KISS1 gene was first identified in 1996 during research into metastatic tumors. Its name refers to the city of Hershey in Pennsylvania, which is associated with the Hershey’s Kisses chocolate bar [1,2]. Subsequent discoveries have shown that kisspeptin signaling is an important regulator of the development of the reproductive system. Kisspeptins bind to the KISS1R receptor, also known as GPR54, which is present on neurons involved in the regulation of GnRH. Genetic and experimental studies have shown that disorders of this signaling system can disrupt sexual maturation and reproductive functions [1,2].

Kisspeptin neurons integrate feedback signals from sex hormones, including estradiol and testosterone, with metabolic signals such as leptin and insulin. They also interact with other signaling systems, including GABA, neuropeptide Y, and serotonin [1]. As such, kisspeptin serves as an important link between reproductive physiology, the body’s energy status, and neuronal communication.

Processing of the precursor protein encoded by the KISS1 gene leads to the formation of several active peptides, including kisspeptin-54, kisspeptin-14, kisspeptin-13, and kisspeptin-10. These fragments share a biologically important C-terminal region. Kisspeptin-10, abbreviated KP-10, is the shortest of the most frequently discussed active fragments and retains the ability to activate the KISS1R receptor [1,2].

How does kisspeptin-10 work?

Kisspeptin-10 activates the KISS1R receptor-dependent signaling associated with the release of GnRH and subsequently the secretion of LH and FSH. Depending on physiological conditions, these changes can affect the levels of estradiol and testosterone. The magnitude of the response depends, among other things, on gender, age, menstrual cycle phase, initial hormonal activity, and experimental conditions [1].

In human studies, KP-10 has been analyzed as a tool for understanding the physiology of reproductive hormones and assessing disorders of sexual maturation. Other studies have addressed its potential significance in reproductive medicine. However, the observation of a transient increase in the concentration of reproductive hormones is not equivalent to demonstrating an improvement in fertility or long-term clinical benefits.

In addition to the research, scientists have also studied kisspeptin signaling in the context of metabolism, pregnancy, bone biology, mood-related pathways, blood vessel function, and neuron activity. However, a significant portion of this broader evidence comes from cell culture or animal experiments, rather than from controlled clinical trials in humans.

Kisspeptin-10 in men: results of studies involving humans

Short-term and continuous hormonal response

George and colleagues (2011) studied the effect of intravenous exposure to KP-10 in healthy adult men using both short infusions and long-term infusions [3]. A single experimental exposure of 1 µg/kg resulted in approximately a threefold increase in LH within 30 minutes. FSH levels increased slightly, but no immediate increase in testosterone was observed. At a higher tested amount of 3 µg/kg, the LH response was weaker. This shows that the relationship between peptide amount and hormonal response was not simply linear.

During a 22.5-hour infusion at a rate of 4 µg/kg/h, the LH concentration remained elevated, and the testosterone level increased by 44%. The researchers did not observe a significant weakening of the hormonal response during this period. Infusion at a lower rate also increased the frequency and amplitude of LH pulses. The results indicate that KP-10 may affect both the amount of secreted LH and the temporal pattern of its release under controlled experimental conditions. However, they do not specify an appropriate clinical regimen or long-term treatment results [3].

Does age affect the response to kisspeptin-10?

Ullah and colleagues (2019) compared healthy young men, middle-aged men, and older participants after a single intravenous experimental exposure of 1 µg/kg [4]. LH levels increased in all three age groups, indicating preserved responsiveness within the hypothalamic-pituitary pathway. However, significant increases in testosterone were observed primarily in the younger participants.

This difference suggests that LH increase does not necessarily lead to the same testicular hormonal response at any age. One possible explanation is the age-related changes in Leydig cell function. However, the study itself does not allow determining the exact mechanism or predicting therapeutic efficacy [4].

Men with type 2 diabetes and mild hypogonadism

George and colleagues (2013) studied KP-10 in men with type 2 diabetes and mild biochemical confirmed hypogonadism, comparing them with healthy participants [7]. After intravenous study exposure of 0.3 µg/kg, the LH concentration increased from 5.5 to 13.9 IU/l in healthy men and from 4.7 to 10.7 IU/l in participants with diabetes. The magnitude of the response was essentially comparable between the groups.

In the second part of the study, involving an 11-hour infusion in men with diabetes, LH increased from 3.9 to 20.7 IU/l. The testosterone concentration increased by 34%, from 8.5 to 11.4 nmol/l. The LH pulse frequency also increased, and the total pulse secretion of this hormone was approximately four times higher. These short-term hormonal changes justify further research into hypothalamic regulation in metabolic diseases. However, they do not demonstrate a sustained correction of hypogonadism or equivalence with recognized treatment methods [7].

Comparison of KP-10, kisspeptin-54 and GnRH

Jayasena and colleagues (2015) directly compared gonadotropin response to kisspeptin-10, kisspeptin-54, and GnRH in healthy men [10]. Both kisspeptin fragments increased LH and FSH secretion with increasing experimental exposure. At an infusion rate of 1.0 nmol/kg/h, the area under the LH concentration curve was 10.8 h·IU/l for KP-10 and 14.4 h·IU/l for kisspeptin-54, compared with 34.1 h·IU/l for GnRH.

The results show that both fragments of kisspeptin can stimulate gonadotropin secretion, although in the studied conditions the LH response was weaker than after GnRH. Hypotheses regarding physiological signaling or reduced desensitization require separate evaluation and cannot be derived solely from a comparison of hormonal responses [10].

Differences between genders and the phases of the menstrual cycle

Jayasena and colleagues (2011) investigated differences in the response to KP-10 between men and women in different phases of the menstrual cycle [11]. In men, experimental doses starting at 0.3 nmol/kg resulted in rapid LH increases from approximately 4 IU/l to over 10 IU/l. At the same time, within 30 minutes, FSH levels increased by approximately 40%.

In women in the early follicular phase, no significant LH or FSH response was observed even at higher experimental exposure, which included amounts of up to 32 nmol/kg. However, in the preovulatory phase, exposure of 10 nmol/kg was associated with an increase in LH of approximately 3 IU/l and FSH of approximately 1 IU/l. These results underscore the importance of the hormonal environment, particularly estradiol concentrations, for the response to kisspeptin signaling [11].

Kisspeptin-10 in women: studies on the reproductive hormonal system

Lack of menstruation associated with hyperprolactinemia

Millar and colleagues (2017) studied two women with menstrual dysfunction associated with hyperprolactinemia, in whom treatment with dopamine agonists did not yield a sufficient response [13]. Each participant underwent a placebo-controlled observation period and a 12-hour infusion session of KP-10. During exposure to kisspeptin, LH levels increased by more than 200%, FSH by more than 100%, and estradiol by about four to six times. Pulsatile LH secretion also occurred again, which was not observed to the same extent during the placebo period.

The results show at a mechanistic level that stimulation of kisspeptin signaling can reactivate some elements of the hormonal reproductive system despite hyperprolactinaemia. However, a physiological study involving only two individuals does not allow confirmation of restoration of fertility, effectiveness in achieving pregnancy, or suitability for routine treatment [13].

Polycystic ovary syndrome and neurokinin B

Skorupskaite and colleagues (2020) studied ten women with polycystic ovary syndrome (PCOS) to investigate the interactions between kisspeptin signaling and neurokinin B (NKB). [14] For seven days, the participants received the neurokinin-3 receptor antagonist MLE4901, and then underwent an experimental infusion of KP-10. Blocking NKB signaling reduced LH and FSH levels and slowed the pulsatile secretion of LH. Subsequent exposure to KP-10 increased total LH secretion, pulse frequency, and the amount of hormone released in each pulse, despite the continued receptor blockade.

Compared to LH alone, FSH increased by more than 150% and FSH by about 40%. During NKB blockade, the typical relationship between estradiol and LH response also changed. The study helps distinguish the elements of the reproductive signaling network, but does not demonstrate an improvement in ovulation, pregnancy rates, or other clinical outcomes in women with PCOS [14].

The interaction of estradiol and NKB blocking

In a related cross-over study, Skorupskaite and colleagues (2016) included 20 healthy women before menopause. The researchers analyzed the effect of KP-10 during exposure to estradiol and the blocking of the neurokinin-3 receptor with AZD4901 [15]. LH levels increased from approximately 3 IU/l to over 16 IU/l at the end of the KP-10 infusion. Under the described conditions, the elevated level persisted for at least 16 hours. LH pulse frequency and volume, as well as FSH levels, also increased.

Blocking the NKB shortened the total time of sustained elevated LH levels, but did not eliminate the response to kisspeptin. The results indicate that these pathways are partially independent in the regulation of estrogen feedback loops. Their significance concerns primarily physiology, rather than confirmation of an effective method of treating ovulation disorders [15].

Hormonal status and the use of contraception

George and colleagues (2012) compared 34 women under four different hormonal conditions: in the early follicular phase, after menopause, during use of a combined oral contraceptive, and during use of a long-acting progestogen-containing implant [17]. LH levels increased significantly in women in the early follicular phase and in implant users, but not in women using a combined oral contraceptive. The highest LH response was observed in postmenopausal women, where levels increased more than twofold. This was also the only group in which a significant increase in FSH was observed.

The LH increase in postmenopausal participants was 2.3 times greater than in the follicular group, whereas in women using combined oral contraceptives, the LH response was about 60% weaker. These observations confirm that the response to kisspeptin depends on the hormonal context. However, they should not be generalized as a universal rule that low estrogen levels always increase or always decrease sensitivity to kisspeptin, because the studies included different populations and conditions [17].

Symptom of ovarian cysts and infertility

Blasco and colleagues (2020) analyzed germ cells and cumulus ovarii cells from 56 women treated for infertility. The results were compared with samples from 30 healthy egg donor women [21]. The group treated for infertility included women of advanced reproductive age, with endometriosis and a poor ovarian response. The expression of the KISS1 mRNA was approximately 52% lower in germ cells of the uterine wall in participants with disorders, particularly in older women. The expression of TAC3 and TACR3, associated with NKB signaling, was even twentyfold lower in some subgroups.

Molecular differences suggest a link between impaired local signaling and abnormal ovarian function. Since the study concerned gene expression rather than KP-10 intervention, it does not allow determining whether the administration of kisspeptin improves the quality of ovarian cells, fertilization, or embryo development [21].

Beyond development: research in animals and in the laboratory

The results below refer to experimental systems. They do not represent confirmed clinical effects of KP-10 in humans.

Bone remodeling and osteoclast activity

Li and colleagues (2024) studied mice with defects in signaling related to Kiss1, Gpr54, or Dusp18 [22]. In the animals, significant bone tissue loss developed, and the reported reduction in bone volume and density approached 40%. Over eight weeks, KP-10 and its bone-directed analog (DSS)₆-Kp-10 improved measured bone parameters in experimental models. Osteoclast activity decreased by approximately 30–50%, and the bone-directed compound resulted in relatively minor hormonal changes.

Mechanistic studies indicated the involvement of GPR54, Dusp18, and impaired Src signaling in the regulation of osteoclasts. The results identify a potentially important pathway in bone biology, but do not confirm the efficacy of osteoporosis treatment or safety in humans [22].

Pituitary signals related to appetite

Orlando and colleagues (2018) used a mouse hypothalamus cell model to investigate the effect of KP-10 on appetite-regulating molecules [23]. At higher experimental concentrations, the expression of the neuropeptide Y gene increased more than twofold, while the level of BDNF decreased by about 35%. Dopamine and serotonin concentrations decreased by about 30–35%, accompanied by an increase in the levels of their metabolites.

Results obtained at the cellular level suggest changes in neurotransmitter metabolism and appetite-related signaling. However, they do not indicate increased food intake, weight gain, or lasting metabolic effects in humans [23].

Development of adipocytes and lipid metabolism

Pruszyńska-Oszmałek and colleagues (2017) studied KP-10 in 3T3-L1 cells and isolated adipocytes from rats [24]. The researchers observed a decrease in cell proliferation or parameters related to their development by approximately 25–35%, as well as lower expression of adipogenic factors such as PPAR-γ and C/EBP-β. Lipolysis increased by approximately 30%, while the expression of proteins associated with lipid breakdown, including perilipins and hormone-sensitive lipase, increased more than twofold.

Insulin sensitivity and glucose storage decreased by approximately 20–25%. Leptin levels increased by approximately 25%, while adiponectin decreased by approximately 30%. These diverse results indicate that KP-10 may affect the biology of adipocytes in experimental systems, but do not confirm a beneficial effect in weight control [24].

Models of brain aneurysms

Yu and colleagues (2025) studied KP-10 in mouse models of the brain vessel endothelium and in experiments on human brain endothelial cells [25]. After four weeks, the size of the vessels and the inflammatory status were approximately 40–60% lower in the treated mice. The expression of MMP-9 and VEGF-A decreased, the structure of the vessel wall was better preserved, and the accumulation of inflammatory cells was reduced.

These effects were not replicated in mice lacking GPR54, indicating a role for the receptor. Experiments on endothelial cells also suggested inhibition of Egr-1-related signaling. These are promising mechanistic observations, but do not provide evidence that KP-10 can prevent aneurysm rupture or replace established clinical practice [25].

Aging of cartilage cells and inflammatory stress

Qiu and colleagues (2025) studied mouse chondrocytes subjected to TNF-α treatment as a model of inflammatory-related cellular aging [26]. Over 55% cells exposed to stress showed aging-related characteristics, and telomerase activity decreased by about 45%. At an exposure to KP-10 at 100 nM, the percentage of aging cells decreased to about 29%, while telomerase activity returned to about 90% of the reference level.

The SIRT1 protein level increased 2.1-fold, and p53 and p21 decreased by approximately 40% and 55%, respectively. Inhibiting SIRT1 eliminated a significant portion of the observed response. Expression of GPR54, previously reduced by approximately 60% after exposure to TNF-α, also recovered. The results concern cellular pathways and do not confirm a slowdown in the progression of osteoarthritis in patients [26].

Behavior related to mood in rats

Serhatlioglu and colleagues (2024) studied KP-10 in a rat behavioral model [27]. Experimental administration to the central nervous system shortened the time to immobility in the forced-swimming test by approximately 45%. Blocking the kisspeptin receptor eliminated the observed effect. Disrupting α₂-adrenergic or serotonergic signaling reduced the response by approximately 40%, while overall locomotor activity remained largely unchanged.

The results indicate the involvement of receptor-dependent mechanisms and neurotransmitter-related mechanisms in the behavioral model under study. However, the result of the forced swimming test is not equivalent to clinical diagnosis or confirmation of antidepressant efficacy in humans [27].

Experimental activation of reproductive hormones in rats

Thompson and colleagues (2004) demonstrated a strong hormonal response to KP-10 in rats [28]. After administration to the central nervous system, LH increased by about 400%, FSH by 60%, and testosterone levels more than doubled within an hour. Intramuscular administration also caused hormonal changes. In hypothalamic preparations, GnRH release increased by about 200–300%, but in these specific experiments, no direct effect on the pituitary gland was observed.

The observations confirm the central role of hypothalamic signaling, while leaving the possibility of differences depending on the species and type of preparation in the direct response of the pituitary gland [28].

Oxidative stress of the testes in rats with hypothyroidism

Santos and colleagues (2024) evaluated KP-10 in a rat model of chronic thyroid insufficiency [29]. The studied intervention was associated with restoring the expression of the SOD1 and GPx1 genes, associated with antioxidant protection, towards reference values. Oxidative stress parameters associated with superoxide decreased by approximately 50%, and apoptosis of reproductive cells was reduced. However, KP-10 did not reverse the reduced expression of the genes responsible for responding to misfolded proteins.

The results indicate selective changes in the oxidative stress pathways, without a full normalization of all the studied cellular processes. They do not confirm fertility in men with thyroid diseases [29].

Damage to neurons caused by L-methionine

Akkaya and colleagues (2014) investigated KP-10 after chemically induced neuronal damage in rats [30]. Compared to untreated animals with the damage, they observed less DNA fragmentation, about 40–60% lower lipid peroxidation, approximately twice the glutathione concentration, and superoxide dismutase activity closer to the control values.

These biochemical endpoints suggest an effect on the redox balance in an experimental model of damage. However, they do not allow for confirmation of neuroprotective effects in neurological diseases in humans [30].

α-Synuclein and cellular models associated with Parkinson's disease

Simon and colleagues (2023) studied KP-10 in neuronal cells derived from SH-SY5Y lines that had been subjected to α-synuclein-related toxic effects [31]. KP-10 reduced apoptosis by about half, improved mitochondrial parameters, and reduced α-synuclein accumulation by about 30%. Some effects persisted despite the inhibition of KISS1R, suggesting a mechanism that may not be entirely dependent on the classic kisspeptin receptor.

Observations from cell culture studies are important for studying the mechanisms of neurodegeneration. However, they do not prove the effectiveness of treating Parkinson's disease in humans [31].

Brain ischemia and reperfusion

Akkaya and colleagues (2022) investigated KP-10 exposure before ischemia in mice subjected to ischemia-reperfusion injury [32]. Under the described experimental conditions, dopamine release was approximately 40% lower, and in addition, changes in glial cell responses were observed. However, the parameters of oxidative damage and lipid changes did not show a consistent improvement.

The inconsistent results suggest that KP-10 may affect selected elements of the injury response, while not preventing the widespread tissue damage. Drawing conclusions regarding stroke in humans would be premature [32].

Testicular damage associated with methionine

In young rats exposed to oxidative stress caused by methionine, Akkaya and colleagues (2017) observed that KP-10 was associated with the preservation of structural characteristics of the germinal canals, a partial restoration of LH levels, and an improvement in the activity of antioxidant enzymes, including superoxide dismutase and catalase [33]. Changes in the expression of genes associated with oxidative stress were also observed.

The results describe a specific toxicological model and do not allow to confirm an improvement in the course of sexual maturation or fertility in humans [33].

The toxic effects of arsenic on the reproductive system

Fatima and Qureshi (2022) studied adult male mice exposed to sodium arsenate [34]. In groups receiving KP-10, selected markers of oxidative damage, including malonylaldehyde and protein carbonyl groups, decreased by approximately 40–60%. The activity of antioxidant enzymes improved, while testosterone levels and the content of fructose in the semen increased by approximately 25–40%. Compared to control animals exposed to arsenic, the number, motility, and morphology of the sperm, as well as the appearance of the canalicular tissue of the sperm were also improved.

The results justify further research into the mechanisms of oxidative stress in the reproductive system of animals, but do not constitute a basis for clinical claims regarding the treatment of the effects of exposure to toxic metals [34].

Sexual behavior of females and neuronal circuits

Experimental studies discussed by Hellier and colleagues (2019) linked kisspeptin neurons in the anterior-abdominal preoptic and preoptic areas (AVPV/PeN) with sexual behaviors in female mice [35]. Removal of these neurons disrupted partner preference and lordosis posture despite maintaining the remaining hormonal conditions. Some behaviors returned after exposure to KP-10 or experimental neuron activation.

Studies distinguish signaling associated with KISS1R–GnRH from nitric oxide-dependent neuronal pathways involved in various elements of behavior. However, the results do not confirm the effectiveness of therapy for sexual disorders in women [35].

Testicular damage associated with methotrexate

Güvenç and Aksakal (2018) studied KP-10 in rats exposed to the toxic effects of methotrexate on the reproductive system [36]. The study described lower levels of markers of oxidative stress, such as malondialdehyde, sperm motility exceeding 70% in one of the experimental groups, and a reduction in the percentage of abnormal sperm forms by approximately 50%. Changes in the mass of the seminal vesicles and the tail of the epididymis were also noted.

Animal studies do not show that KP-10 prevents fertility complications during chemotherapy in humans [36].

Maintaining mitochondrial function in models of brain aging

Mattam and colleagues (2021) investigated KP-10 in the hippocampal tissue of aging rats and in human neuronal cell models [37]. The results indicated the involvement of the CaMKKβ–AMPK–ULK1 pathway in autophagy and mitophagy, with the described effects being independent of mTOR. Autophagy parameters increased approximately twofold, the number of mitochondria increased by 35%, the activity of the I complex by 40%, and the ATP content by 25% in the hippocampal tissue of older animals.

The measurements suggest a possible role of KP-10 in the mechanisms of mitochondrial quality control. However, they do not confirm improvement in cognitive function, delay of brain aging, or prevention of neurodegenerative diseases in humans [37].

Growth hormone and LH in rabbits

Kadokawa and colleagues (2008) studied the single-dose experimental intravenous exposure to 1 mg of KP-10 in Holstein heifers before they reached sexual maturity [38]. LH concentration increased over approximately 30 minutes, and the peak of growth hormone secretion occurred after approximately 75 minutes. In the group receiving saline, no equivalent changes were observed.

The results suggest interactions between hormonal signaling related to development and growth in cattle. However, they do not confirm the effectiveness of interventions aimed at accelerating the growth or sexual maturation of livestock animals [38].

Direct effect on the pituitary cells in farm animals

Suzuki and colleagues (2008) studied isolated anterior pituitary cells derived from cattle and pigs [39]. In cattle cells, significant LH secretion was observed at KP-10 concentrations of 1000 and 10,000 nM, whereas porcine cells responded at 100 and 1000 nM concentrations. The LH response was approximately 30–50% times that of GnRH in the described conditions.

The results suggest that in some species and cell preparations, a direct response from the pituitary gland is possible, although the GnRH hypothalamic signaling remains a central element of the broader reproductive regulation system [39].

Signaling associated with sexual maturation in young sheep

Redmond and colleagues (2011) studied repeated experimental exposure to KP-10 in 28-week-old female pigs [40]. Administration every hour for 24 hours increased LH and estradiol concentrations and induced short-term ovulatory responses in some animals. However, luteal activity was short-lived, and the time to reach permanent sexual maturity did not accelerate compared to the control group.

This distinction is important: the short-term stimulation of the secretion of reproductive hormones does not mean the achievement of full sexual maturity [40].

Experimental exposition and formulations used in published studies

Various routes of administration and experimental exposure conditions were used in the studies on KP-10. The information below describes the way researchers design studies. It does not constitute dosage recommendations or instructions for use.

In published studies in healthy men, single intravenous experimental exposures ranged from 0.01 to 3.0 µg/kg. George and colleagues observed a pronounced LH response at 1 µg/kg and a weaker response at 3 µg/kg [3]. The 1 µg/kg condition was also analyzed in a study comparing age groups [4]. In pediatric diagnostic studies, an intravenous sample with a volume of 0.313 µg/kg was used [8].

Continuous infusion protocols in source studies included rates of approximately 1.5–4 µg/kg/h for several hours. For example, an experimental bolus of 3 µg/kg was administered followed by a 1.5 µg/kg/h infusion for nine hours, or a 4 µg/kg/h infusion for 22.5 hours in healthy men [3]. An eleven-hour infusion was studied in men with type 2 diabetes [7], while seven-hour infusion conditions were analyzed in women with PCOS and in estrogen-related experiments [14,15]. A twelve-hour study infusion was administered in two women with menstrual dysfunction associated with hyperprolactinemia [13].

In other studies, subcutaneous administration was used. Shamas and colleagues analyzed a single subcutaneous trial with KP-10 in lean men and obese men, while Jayasena and colleagues studied different exposure conditions in women, including experimental subcutaneous administration [9,11]. In animal experiments, additional delivery routes adapted to the study designs were used [28,34,40].

Such diverse protocols cannot be combined into a single standard clinical dose. Differences between species, study populations, endpoints evaluated, and administration routes also make it impossible to simply compare efficacy or safety.

Kisspeptin-10 as a tool for diagnostic research

Distinguishing the causes of delayed sexual maturation

Chan and colleagues (2018) investigated the response to kisspeptin in 15 children with delayed or arrested sexual maturation [5]. In participants with a preserved, developing hypothalamic GnRH response, an increase in LH and nocturnal pulsatile LH secretion was observed, which in some cases was consistent with a constitutional delay in maturation. In other participants, the LH response to kisspeptin was minimal, although their pituitary gland responded to GnRH under test conditions.

The study suggests that the attempt with kisspeptin may provide information about the functional status of GnRH neurons, and not only about the pituitary gland's ability to respond. Its diagnostic value requires interpretation in a broader clinical context [5].

Return of reproductive axis function in idiopathic hypogonadotropic hypogonadism

Lippincott and colleagues (2016) studied six men with idiopathic hypogonadotropic hypogonadism who had previously shown signs of return of reproductive function [6]. In men whose regained gonad function persisted, a LH pulse was present after exposure to kisspeptin. In participants with a recurrence of disorders, the response to kisspeptin was minimal, although the pituitary gland continued to respond to GnRH.

The observations support the concept that the response to kisspeptin may help characterize the activity of the hypothalamic reproductive system. However, the small sample size does not allow this to be considered a universally valid diagnostic test [6].

Predicting the progression of sexual maturation

In a 2020 study, Chan and colleagues evaluated 16 young individuals with delayed sexual maturation using a kisspeptin trial [8]. In eight participants, the LH concentration change was at least 0.8 mIU/ml, and subsequent maturation of sexual maturation was observed in them. In the remaining eight, the changes were 0.4 mIU/ml or less, and these participants did not begin maturation until the age of 18. In this small group, the reported classification achieved 100% sensitivity and specificity (P = 0.0002), surpassing several comparative tests.

The result deserves attention, but it should be presented along with the number of trials. The excellent effectiveness of classification in 16 participants does not mean 100% accuracy in routine practice. Independent validation is necessary [8].

Kisspeptin binding to metabolism in human studies

Iryzina after exposure to KP-10

Shamas and colleagues (2019) compared lean men with a mean body mass index of about 23 with obese men with a mean BMI of about 32 [9]. After experimental subcutaneous exposure to KP-10, the irysin concentration increased from 59 to 96 ng/ml in the lean group of participants, which corresponds to an increase of 63%, and from 41 to 76 ng/ml in the obese group, which corresponds to an increase of 84%. The peak concentration occurred earlier in obese men.

Irysin is studied in the context of skeletal muscle signaling and energy metabolism. However, the short-term increase in this biomarker does not indicate a loss of fat tissue, an improvement in metabolic health, or the effectiveness of treatment for obesity [9].

Kisspeptin circulating in the blood, body mass and insulin resistance

Sitticharoon and colleagues (2021) measured the concentration of kisspeptin in serum and cerebrospinal fluid in 40 men undergoing scheduled surgical procedures [12]. The mean serum concentration was 0.26 ng/ml in participants with normal body weight, 0.31 ng/ml in overweight individuals, and 0.49 ng/ml in obese men (P < 0.01).

The serum concentration of kisspeptin was positively correlated with BMI (r = +0.51), leptin (r = +0.53), fasting insulin (r = +0.46), and the HOMA-IR index (r = +0.44). A negative correlation was noted with LH (r = −0.35), while no significant association was found with total testosterone or blood glucose concentration. In the cerebrospinal fluid samples, kisspeptin remained undetectable under the measurement conditions used in the study.

The results suggest associations between the concentration of kisspeptin in the blood and metabolic status. However, they do not prove that an increased amount of adipose tissue causes the observed hormonal changes, that kisspeptin circulating in the blood comes exclusively from outside the brain, or that modifying its concentration will help treat insulin resistance [12].

Kisspeptin in pregnancy and studies of reproductive biomarkers

Prepubertal stage: hormonal dependencies

Al-Kaabi and colleagues (2020) studied 100 women who were in their first pregnancy. In 60 of them, preeclampsia developed, while 40 remained in the control group [16]. The levels of CK-10 in the mothers were lower in the preeclampsia group in both the second and third trimesters. The ROC curve (AUC) area under the curve in the second trimester was 0.662, with a sensitivity of 55% and a specificity of 87.5%. In the third trimester, the AUC was 0.747, with a sensitivity of 83.3% and a specificity of 67.5%.

The study also noted changing relationships with estradiol, LH, FSH, and β-hCG, while progesterone showed no such pattern. Positive predictive values ranged from approximately 22–33%, and negative predictive values exceeded 94% under the described study conditions. These values depend on the population being studied and the frequency of the disease. Therefore, they do not confirm that KP-10 measurement alone can safely rule out preeclampsia in general obstetric practice [16].

Fetal growth and severity of preeclampsia

Ziyaraa and colleagues (2016) evaluated 100 pregnancies after 20 weeks, including 60 with preeclampsia—32 mild and 28 severe—and 40 normal pregnancies constituting the control group [18]. In the later period of pregnancy, the mean KP-10 concentration was approximately 310 pg/ml in the control group, 215 pg/ml in the mild preeclampsia, and 145 pg/ml in the severe preeclampsia. This corresponded to a reduction of approximately 30% and 55% in both groups with complications.

The decrease in concentration by 100 pg/ml was associated with an estimated fetal weight difference of 120 g. Correlations with fetal growth parameters were approximately r = 0.4–0.45. The dependence on Doppler blood flow indices was also described. The results suggest the potential importance of kisspeptin as a biomarker, but do not prove that a lower KP-10 concentration causes fetal growth disorders or that a single measurement can replace standard pregnancy monitoring [18].

Frontal joint and local expression of kisspeptin

Katirci and colleagues (2024) investigated kisspeptin-related parameters in serum and placenta in women with a pre-existing placenta [19]. The reported serum concentrations were more than twice lower than in uncomplicated pregnancies constituting the comparison group. Kisspeptin expression in the placenta was approximately 96% lower, while KisspeptinR expression increased by approximately 170%.

The results may reflect altered signaling or compensatory regulation of receptors. However, they do not prove that reduced kisspeptin levels cause anterior placenta, nor do they confirm the usefulness of KISS1 or KISS1R as clinical screening tests [19].

Transfer of thawed embryos and early pregnancy

Hu and colleagues (2019) measured kisspeptin and hCG concentrations in serum on the 14th and 21st day after the transfer of previously frozen and thawed embryos in 133 women [20]. In properly developing pregnancies, the concentration of kisspeptin roughly doubled between these time points, whereas in biochemical pregnancies it remained relatively unchanged. The lowest kisspeptin concentrations on the 14th day were observed in twin pregnancies.

Although kisspeptin appeared to reflect some aspects of early embryonic activity, hCG better predicted the evaluated outcomes related to miscarriage. The observations support further research on biomarkers, rather than the routine use of kisspeptin to predict in vitro fertilization outcomes [20].

General interpretation of the studies on kisspeptin-10

Kisspeptin-10 is an active fragment of the kisspeptin signaling system and an important experimental tool for studying the hypothalamic-pituitary-gonadal axis. Studies in humans consistently show that it can induce short-term changes in LH levels, and in some conditions also in FSH, estradiol, or testosterone. These responses depend on age, gender, menstrual cycle phase, hormonal status, and the study design [3,4,7,10,11,13–17].

Studies on delayed sexual maturation and the return of reproductive hormone function suggest that attempts with kisspeptin may provide information about the functioning of GnRH neurons. In small studies, very good ability to distinguish specific diagnostic conditions was observed, but before generalizing the results, broader validation is necessary [5,6,8].

Other studies have shown relationships with irisin, metabolic markers associated with obesity, placental function, and pregnancy outcomes [9,12,16,18–20]. These are promising directions for research, but not established clinical applications. Similarly, experiments in mice, rats, farm animals, and cell cultures describe potential effects on bone remodeling, oxidative stress, neurobiology, adipocytes, and vascular pathways, but do not confirm equivalent effects in patients [22–40].

The most important distinction concerns biological activity and clinical benefits. KP-10 undoubtedly participates in reproductive signaling. However, determining whether a specific intervention improves long-term fertility, pregnancy outcomes, the course of metabolic diseases or other health problems requires separate, appropriately designed clinical studies. Its long-term safety and optimal role in medical practice remain largely unknown.

Frequently asked questions about kisspeptin-10 (FAQ)

Where is kisspeptin-10 naturally produced?

Kisspeptins are produced from the precursor protein KISS1 in several tissues, particularly the hypothalamus, the placenta, and the reproductive organs. Signaling associated with kisspeptin has also been studied in the pancreas and other peripheral tissues. KP-10 is one of the active fragments of this broader family of peptides, and not a hormone encoded by a completely separate gene [1,2].

What is kisspeptin-10 used for in medical research?

KP-10 is primarily used to study hormonal regulation of reproduction and the response of the GnRH–LH/FSH pathway. Human studies included delayed sexual maturation, hypogonadotropic disorders, and hormonal responses in men and women. Research applications should not be equated with the widely approved method of treating infertility or hormonal disorders [3–8,13–17].

Can kisspeptin-10 help treat infertility?

KP-10 can stimulate the release of reproductive hormones under certain experimental conditions, but this in itself does not prove an improvement in fertility. Some methods based on kisspeptin are being studied in reproductive medicine, however the results regarding a specific peptide fragment, formulation, and protocol must be evaluated independently. The studies presented in this article focus primarily on hormonal responses, rather than on the frequency of achieving pregnancy or delivering a live baby [7,10,13–15].

How was kisspeptin-10 administered in the studies?

Depending on the research question, researchers used single-dose intravenous administration, infusions, and subcutaneous administration. Other methods characteristic of laboratory research were also used in animal experiments. These descriptions refer to controlled experimental procedures and do not constitute instructions for self-administration [3,9,11,28].

Is there a fixed clinical dose of kisspeptin-10?

No one universally established clinical dose can be determined based on the presented studies. Scientists analyzed different levels of experimental exposure depending on the population, route of administration, and evaluated results. The published amounts are not equivalent to therapeutic recommendations, and the source material does not specify a standard routine dosing schedule [3,4,7,8,14,15].

What side effects can kisspeptin-10 cause?

The studies presented do not include a comprehensive, systematically defined characteristic of the adverse reactions of KP-10. Short-term experiments analyzed hormonal responses, but do not allow a full assessment of rare events, interactions, or the risk associated with repeated exposure. Claims that serious adverse reactions occur rarely require confirmation in appropriately large safety studies.

Is long-term exposure to kisspeptin-10 safe?

Long-term safety has not been sufficiently established in the studies discussed in the article. Most human studies were short-term and focused on hormonal measurements. Changes in the concentration of reproductive hormones observed over a few hours do not allow determining the consequences of repeated or prolonged exposure.

What is the biological mechanism of action of kisspeptin-10?

KP-10 activates signaling associated with the KISS1R/GPR54 receptor, which can stimulate GnRH release in the hypothalamus. GnRH then stimulates the pituitary gland to secrete LH and FSH, affecting the continued function of the gonads. Kisspeptin signaling also interacts with the feedback of sex hormones and metabolic signals, so the magnitude of the response depends on physiological conditions [1,2].

Does kisspeptin-10 directly increase testosterone?

Its main documented hormonal action is to stimulate the earlier stages of reproductive signaling, particularly LH secretion. LH then acts on Leydig cells in the testes, supporting the synthesis of testosterone. Studies in humans show that the testosterone response differs depending on age and physiological status, even when LH levels increase [3,4,7].

How quickly can kisspeptin-10 affect reproductive hormones?

In some controlled intravenous studies in humans, LH increased over approximately 15–30 minutes. Testosterone changes did not always occur immediately and varied between experimental conditions. These observations describe short-term research responses, rather than a predictable time for the onset of clinical benefits [3,11].

Does kisspeptin-10 cause tachyphylaxis?

In some short-term infusion studies, elevated LH levels persisted without any apparent rapid decline in the response during the observation period. However, the absence of short-term desensitization under these conditions does not prove that repeated or prolonged exposure will always elicit the same effect [3].

Has kisspeptin-10 been studied in children?

Yes. Small specialized studies included trials with kisspeptin in young individuals with delayed sexual maturation. They evaluated hormonal responses and the subsequent course of maturation. However, they do not confirm the validity of routine pediatric treatment or the widely understood long-term safety [5,8].

Does kisspeptin-10 work in older people?

Studies in men suggest that LH may respond to kisspeptin in different age groups, whereas testosterone levels in older participants may be lower or may not be present. This difference shows why the response of the hypothalamus and pituitary should be evaluated separately from the gonad response [4].

Can kisspeptin-10 help diagnose delayed puberty?

Trials with kisspeptin have demonstrated the potential to distinguish constitutional delay of puberty from impaired reproductive signaling in the hypothalamus. This is still an area of specialized research, and the results should be interpreted in conjunction with clinical history, other hormonal tests, and further observation [5,8].

How accurate is the kisspeptin test?

In one study involving 16 participants, 100% sensitivities and specificities were recorded using the accepted response thresholds. However, this impressive result was based on a small sample and should not be considered a guarantee of the same accuracy in larger populations. Independent validation is needed [8].

Has kisspeptin-10 been studied in men with diabetes?

Yes. In a short-term study, men with type 2 diabetes and mild hypogonadism observed an increase in LH secretion, an intensification of pulsatile LH secretion, and an increase in testosterone during experimental exposure. The results confirm the ability of the hormonal system to respond, but do not prove sustained therapeutic efficacy [7].

Can kisspeptin-10 support weight loss?

The presented studies do not confirm weight loss as a clinical effect of KP-10. In experiments, changes in the concentration of irisin were observed in men, and changes in adipocyte signaling were observed in cell or animal models. None of these results indicate a reduction in body weight in humans [9,24].

Is kisspeptin associated with pre-pubertal syndrome?

In some observational studies, lower concentrations of kisspeptin-related compounds were observed in the blood of women whose pregnancies were complicated by preeclampsia. Correlations with disease severity and fetal growth parameters were also described. The results suggest possible significance as a biomarker, but do not confirm a causal relationship or the usefulness of the diagnostic test alone [16,18].

Can kisspeptin predict the results of in vitro fertilization?

In one study, serum kisspeptin levels changed during early pregnancy after the transfer of previously frozen and thawed embryos. However, hCG provided more useful information about the evaluated outcomes related to miscarriage. Kisspeptin is therefore not considered a suitable substitute for standard pregnancy monitoring [20].

Is kisspeptin-10 available as an approved drug?

The studies discussed in the article do not confirm that KP-10 is a widely marketed and routinely prescribed drug. Its main documented uses in the presented material relate to scientific research and specialized clinical trials. Regulatory status should be verified for the specific product, indication, and country, and not be derived solely from the biological activity of the peptide.

Disclaimer

This article presents the results of published scientific studies and information contained in the source material. It is intended solely for educational and scientific information purposes and does not constitute medical advice. Experimental doses and routes of administration are described solely to illustrate the research methodology. The results of laboratory studies, animal experiments, short-term hormonal changes, and the relationship between biomarkers should not be interpreted as evidence of clinical efficacy or safety. Decisions regarding fertility, sexual maturation, pregnancy, and hormonal disorders require evaluation by a suitably qualified specialist.

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