Table 1.
Clinical trials involving kisspeptin
| Author | Study design | Cohort | Intervention | Results |
|---|---|---|---|---|
| A, KP in healthy men | ||||
| Dhillo et al (2005) (13) | Double-blind placebo-controlled crossover | 6 men | KP54 (IV infusion 4 pmol/kg/min for 90 min) vs vehicle | KP54 increased LH (by 2.6-fold), FSH (by 1.2-fold), and testosterone |
| Chan et al (2011) (75) | Prospective study | 13 men | Baseline sampling (10 min for 6 h) followed by KP10 (IV bolus 0.24 nmol/kg) | KP10 induced immediate LH pulses, regardless of timing of previous endogenous pulse KP10 induced larger amplitude pulses than endogenous pulses (amplitude 5.0 ± 1.0 vs 2.1 ± 0.3 mIU/mL) |
| George et al (2011) (76) | Placebo-controlled | 6 men (acute studies) 4 men (chronic studies) |
KP10 (IV bolus 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 μg/kg) vs vehicle Baseline sampling (10 min for 9 h) followed by bolus KP10 (IV bolus 3.0 μg/kg) then (IV infusion 1.5 μg/kg/h for 22.5 h) |
KP10 (IV bolus 1 μg/kg) induced max LH response (4.1 ± 0.4 to 12.4 ± 1.7 IU/L) KP10 (IV infusion 1.5 μg/kg/h) increased
|
| Jayasena et al (2011) (77) | Single-blind placebo-controlled | 4 or 5 per group | KP10 (IV bolus at 0.3, 1.0, 3.0, or 10 nmol/kg) vs vehicle | KP10 elevated LH, FSH, and testosterone levels at doses as low as 0.3 and 1.0 nmol/kg, respectively |
| Jayasena et al (2015) (32) | Single-blind placebo-controlled | 5 men | KP10, KP54, GnRH, or vehicle (IV infusion 0.1, 0.3, and 1.0 nmol/kg/h for 3 h) |
Serum LH and FSH ∼3-fold higher during GnRH vs KP10 Serum LH and FSH ∼2-fold higher during GnRH vs KP54 |
| B, KP in healthy premenopausal women | ||||
| Dhillo et al (2007) (14) | Double-blind placebo-controlled | 8 women | KP54 (SC bolus 0.4 nmol/kg) | KP54 increased mean LH ± SEM (IU/L) during follicular (0.12 ± 0.17), preovulatory (20.64 ± 2.91), and luteal (2.17 ± 0.79) phases of menstrual cycle |
| Jayasena et al (2011) (77) | Single blind placebo-controlled | 4 or 5 per group | KP10 (IV bolus 1-10 nmol/kg) (SC bolus 2-32 nmol/kg) (IV infusion 20–720 pmol/kg/min) KP54 (IV bolus 1 nmol/kg) |
KP10 (all doses and routes) did not alter LH and FSH in follicular phase of menstrual cycle KP10 (IV bolus 10 nmol/kg) increased mean AUC LH (30.3 ± 7.7 h·IU/L) and FSH (6.9 ± 0.9 h·IU/L) in preovulatory phase |
| Chan et al (2012) (78) | Prospective study | 3-14 per group | KP 112-121 (IV bolus 0.24, 0.72 nmol/kg) | KP112-121 induced higher LH responses and LH pulses in luteal and preovulatory phases, but not early-mid follicular phase of menstrual cycle |
| George et al (2012) (79) | Prospective study | 10 women | KP10 (IV bolus 0.3 µg/kg) | KP10 increased LH but not FSH during early follicular phase of menstrual cycle |
| Jayasena et al (2013) (80) | Randomized single-blinded placebo-controlled trial | 6 women | KP54 (SC bolus 0.30, 0.60 nmol/kg) vs vehicle | KP54 increased mean LH pulses (KP54; −0·17 ± 0·54, saline; + 2·33 ± 0·56) during follicular phase |
| Jayasena et al (2013) (81) | Prospective single-blinded, placebo-controlled 1-way crossover trial | 5 women | KP54 (SC bolus 6.4 nmol/kg, twice daily, during d 7-14 of menstrual cycle) vs vehicle | KP54 does not cause tachyphylaxis KP54 induced a shorter menstrual cycle length (d 26.8 vs d 28.6), earlier LH peak (d 13 vs d 15.2), and earlier luteal phase vs saline (d 15.8 vs d 18) vs vehicle |
| Narayanaswamy et al (2016) (82) | Prospective single-blinded placebo-controlled trial | 4 women | KP54 (SC infusion 0.3-1.0 nmol/kg/h for 8 h) during early follicular phase of 4 menstrual cycles | KP54 induced mean rise in LH (>8 IU/L) KP54 positively correlated with baseline E2 levels (KP54 dose of 1.0 nmol/kg/h → 100 pmol/L rise in baseline E2 associated with 1.0-IU/L increase in LH) |
| Abbara et al (2020) (83) | Single-blinded randomized controlled trial | 9 women | MVT-602 (SC bolus 0.01, 0.03 nmol/kg) KP-54 (SC bolus 9.6 nmol/kg) during early follicular phase |
MVT-602 and KP54 had similar LH amplitude increases LH peak delayed with MVT-602 vs KP54 (21.4 vs 4.7 hrs) AUC of LH exposure increased with MVT-602 vs KP54 (169 vs 38.5 IU·h/L) MVT-602 induced longer duration of GnRH neuronal firing than KP54 (115 vs 55 min) |
| C, KP in delayed puberty | ||||
| Chan et al (2014) (84) | Longitudinal cohort study, proof of concept | 11 CHH (adult) 1 with reversal of CHH |
KP10 (IV bolus 0.24 nmol/kg) GnRH (IV bolus 75 ng/kg) |
KP10 (unlike GnRH) failed to induce LH response in CHH, but produced LH response in reversal of CHH |
| Lippincott et al (2016) (85) | Single-blinded randomized controlled trial | 4 with reversal of CHH 2 with relapsed CHH |
KP10 (IV bolus 0.24-2.4 nmol/kg) GnRH (IV bolus 75 ng/kg) |
KP10 stimulated LH pulses in reversal of CHH (within 30 min) but not in relapsed CHH |
| Chan et al (2020) (86) | Longitudinal cohort study | 16 with delayed puberty | KP10 (IV bolus 0.313 µg/kg) GnRH (IV bolus 75 ng/kg) |
KP10 increased LH in CDGP (≥0.8 mIU/mL) but not in CHH (≤0.4 mIU/mL) |
| Abbara et al (2021) (87) | Single-blinded randomised controlled trial | 21 CHH 21 controls |
KP54 (IV bolus 6.4 nmol/kg) GnRH (IV 100 mcg) |
KP54 had reduced LH responses in CHH (0.4 IU/L) than controls (12.5 IU/L), and had an AUCROC of 100% (95% CI, 100%-100%) to differentiate CHH from healthy |
| D, KP in precocious puberty | ||||
| Cintra et al (2021) (88) | Systematic review | Systematic review and meta-analysis 316 CPP 251 controls |
KP measurement | KP increased in CPP vs controls (std MD and [95% CI] = 1.53 [0.56-2.51]) KP positively correlated with age and was associated with precocious thelarche |
| Vuralli et al (2023) (89) | Cross-sectional study | 51 CPP 48 PT 42 controls |
KP measurement (ng/mL) | KP increased in CPP (0.43 ± 0.16) vs PT (0.26 ± 0.10) vs controls (0.18 ± 0.07) |
| E: KISSPEPTIN IN HYPOTHALAMIC AMENORRHOEA | ||||
| Podfigurna et al (2020) (90) | Prospective cohort | HA: 58 low LH 13 normal LH |
KP measurement (ng/mL) | KP reduced in HA women with low LH (1.7 ± 0.1) vs normal LH (2.6 ± 0.3) |
| Podfigurna et al (2020) (90) | Prospective cohort | 41 HA 40 controls |
KP measurement (ng/mL) | KP reduced in HA (0.17 ± 0.11) vs controls (0.3 ± 0.36) |
| Hofmann et al (2017) (91) | Prospective cohort | 38 HA (anorexia) | KP measurement | KP negatively correlated with physical activity (r = −0.41) |
| Jayasena et al (2009) (43) | Prospective, randomized, double-blinded | 10 HA | KP54 (SC bolus 6.4 nmol/kg, twice daily for 2 wk) vs vehicle | Acute KP54 (after 4 h) increased LH (to 24 IU/L) and FSH (to 9.1 IU/L) Chronic KP54 (after 2 wk) lowered LH (to 1.5 U/L) and FSH (to 0.5 IU/L) due to tachyphylaxis |
| Jayasena et al (2010) (43) | Randomized, double-blinded, placebo-controlled | 20 HA | KP54 (SC bolus 6.4 nmol/kg, twice weekly for 8 wk) | KP54 (after 1d) increased LH (to 21.5 IU/L) and FSH (to 6.4 IU/L) KP54 (after 2 wk) reduced LH (to 10 IU/L) and FSH (to 2.7 IU/L) KP54 (after 4 wk) maintained LH (9 IU/L) and FSH (2.6 IU/L) KP54 (after 6 wk) maintained LH (8.9 IU/L) and FSH (2.4 IU/L) KP54 (after 8 wk) maintained LH (7.9 IU/L) and FSH (2.7 IU/L) |
| Jayasena et al (2014) (92) | Randomised single-blinded placebo-controlled | 5 HA | KP54 (IV infusion 0.01-0.3 nmol/kg/h, for 8 h; 1.0 nmol/kg/h for 10 h) | Highest dose of KP54 increased LH greater than 10-fold vs placebo (placebo 1.26 ± 0.56, KP54 15.42 ± 3.57 IU/L) Highest dose of KP-54 increased LH pulses by 3-fold (No. of LH pulses over 8 h: placebo 1.6 ± 0.4, KP54 5.0 ± 0.5) |
| Abbara et al (2020) (83) | Single-blinded RCT | 6 HA 9 controls |
MVT-602 (SC bolus 0.03 nmol/kg) | MVT-602 increased LH sooner in HA (6.2 h) vs controls (15.1 h) MVT-602 increased FSH and E2 levels in HA |
| F, KP in PCOS | ||||
| Tang et al (2019) (93) | Systematic literature review | 12 studies | KP measurement | KP increased in PCOS than controls in 9 studies |
| Varikasuvu et al (2019) (94) | Meta-analysis | 23 studies | KP measurement | KP increased in PCOS than controls (std MD and [95% CI] = 0.47 [0.17-0.77]) Diagnostic OR 13.71, AUC 0.835 to differentiate PCOS from controls |
| Ibrahim et al (2020) (95) | Prospective | 60 PCOS 40 controls |
KP measurement (ng/mL) | KP increased in PCOS (1.79 ± 0.98) than controls (1.05 ± 0.86) |
| Akad et al (2022) (96) | Prospective case-control | 37 PCOS 24 controls |
KP measurement (pg/mL) | KP increased in PCOS (130.5) than controls (76.2), 95% CI, 7.55-11.50 |
| Romero-Ruiz et al (2019) (97) | Pilot exploratory cohort | 12 PCOS | KP54 (SC bolus 3.2-12.8 nmol/kg for 21 d) | KP54 increased LH (from 10.8 to 13.4 IU/L) and E2 levels, but did not change FSH |
| Skorupskaite et al (2020) (98) | Single-blinded placebo-controlled trial | 15 PCOS | KP10 (IV infusion 4 μg/kg/h for 7 h) | KP10 increased LH (from 5.2 to 7.8 IU/L) and E2 levels, but did not change FSH |
| Abbara et al (2020) (83) | Single-blinded RCT | 6 PCOS 9 controls |
MVT-602 (SC bolus 0.01–0.03 nmol/kg) | MVT-602 did change LH, FSH, or E2 concentrations in PCOS |
| G, KP in hyperprolactinemia | ||||
| Millar et al (2017) (99) | Prospective exploratory study | 2 women with high PRL | KP10 (IV infusion 1.5 mg/kg/h for 12 h) vs vehicle | KP10 increased LH from 5.3 to 25.4 IU/L and from 1.22 to 5.2 IU/L in each patient |
| Hoskova et al (2022) (100) | Prospective study | 11 high PRL (F) | KP112-121 (IV bolus 0.24 nmol/kg, every h for 11 h) | KP112-121 increased LH pulses from 4.5 ± 0.9 to 7.5 ± 0.5 pulses KP112-121 decreased LH interpulse interval from 2.7 ± 0.5 h to 1.3 ± 0.1 h KP112-121 did not change LH pulse amplitude, FSH, E2, or PRL levels |
| H, KP in IVF | ||||
| Jayasena et al (2014) (101) | Phase 2 randomized | 53 undergoing IVF | KP54 (SC bolus 1.6-12.8 nmol/kg) | ≥1 mature oocyte: 51/53 (96.2%) ≥ 1 fertilized egg: 49/53 (92.5%) Embryo transfer: 49/53 (92.5%) Clinical pregnancy rate per transfer: 12/49 (24.5%) Live birth rate per transfer: 10/49 (20.4%) Moderate to severe OHSS: 0 |
| Abbara et al (2015) (102) | Phase 2, open-label, randomized | 60 with high risk of OHSS undergoing IVF | KP54 (SC bolus 3.2-12.8 nmol/kg) | ≥1 mature oocyte: 57/60 (95.0%) ≥ 1 fertilized egg: 54/60 (90.0%) Embryo transfer: 51/60 (85.0%) Clinical pregnancy rate per transfer: 27/51 (52.9%) Live birth rate per transfer: 23/51 (45.1%) Moderate to severe OHSS: 0 |
| Abbara et al (2017) (103) | Phase 2, placebo-controlled, randomized | 62 with high risk of OHSS undergoing IVF | KP54 (SC bolus 9.6 nmol/kg, 1 dose vs 2 doses) | ≥1 mature oocyte: 61/62 (98.4%) ≥ 1 fertilized egg: 61/62 (98.4%) Embryo transfer: 60/62 (96.8%) Clinical pregnancy rate per transfer: 19/60 (31.7%) Live birth rate per transfer: 18/60 (30.0%) Moderate to severe OHSS: 1/62 (1.6%) |
| I, KP in healthy pregnancy | ||||
| Abbara et al (2021) (104) | Case-control trial | 39 pregnant 10 nonpregnant |
KP measurement (pmol/L) | KP increased linearly with advancing pregnancy |
| J: KISSPEPTIN IN MISCARRIAGE | ||||
| Silva et al (2023) (105) | Systematic review | 7 case-control studies | KP measurement | KP is reduced in miscarriage KP had better discriminatory score than b-hCG to differentiate miscarriage from healthy pregnancy (in 3/7 studies) |
| K, KP in hypertensive disorders of pregnancy | ||||
| Perez-Lopez et al (2021) (106) | Meta-analysis | 7 studies 214 Preeclampsia/gestational hypertension 263 normotensive |
KP measurement | KP is reduced in preeclampsia or gestational hypertension than in normotensive pregnancies (SMD −0.68); I2 = 77% |
| Abbara et al (2022) (107) | Case-control | 265 controls 20 preeclampsia 12 Gestational hypertension |
KP measurement | KP reduced in all hypertensive disorders (at 28-40 wk of gestation) KP increased in late-onset preeclampsia and reduced in early-onset preeclampsia (at 9-13 wk gestation) |
| L, KP in other pregnancy complications | ||||
| i. GDM | ||||
| Cetcovic (2012) (108) | Prospective case-control | 25 controls 20 GDM |
KP measurement (nmol/L) | KP is reduced in GDM (21-25 wk; 4.51, 32-36 wk; 11.64) than controls (21-25 wk; 10.33, 32-36 wk; 20.48) |
| Bowe et al (2019) (109) | Case-control | 62 controls 26 GDM |
KP measurement (pmol/L) | KP is reduced in GDM (889) than controls (1270) at 26-34 wk of gestation |
| Arslan et al (2020) (110) | Cross sectional | 82 controls 76 GDM |
KP measurement (pmol/L) | KP remained unchanged in GDM vs controls at 24-26 wk of gestation |
| Abbara et al (2022) (107) | Case-control | 265 controls 35 GDM |
KP measurement | KP remained unchanged in GDM vs controls in all trimesters |
| ii. Preterm birth | ||||
| Torricelli et al (2008) (111) | Observational | 30 controls 10 preterm |
KP measurement (ng/mL) | KP remained unchanged in preterm birth |
| Abbara (2022) (107) | Case-control | 265 controls 11 preterm |
KP measurement | KP increased in preterm birth than controls in all trimesters |
| iii. FGR | ||||
| Smets et al (2008) (112) | Case-control | 31 controls 31 SGA |
KP measurement (pmol/L) | KP is reduced in SGA (1376) than controls (2035) |
| Armstrong et al (2009) (113) | Retrospective case-control | 317 controls 118 IUGR |
KP measurement (pg/mL) | KP is reduced in IUGR (1164) than controls (1188) |
| Khaled et al (2018) (114) | Case-control | 10 controls 10 PE and IUGR 10 IUGR |
KP measurement (ng/mL) | KP is reduced in IUGR (with PE, 1640; and without PE, 1630) than controls (2900) |
| Abbara et al (2022) (107) | Case-control | 265 controls 17 FGR |
KP measurement | KP is reduced in FGR in all trimesters |
| M, KP in glucose control | ||||
| Izzi-Engbeaya et al (2018) (115) | Randomized, blinded, 2-way crossover | 15 healthy men | KP54 (IV infusion 1 nmol/kg/h for 2 h) vs vehicle | KP induced:
|
| Izzi-Engbeaya et al (2023) (116) | Single-blinded, crossover study | 17 women with overweight or obesity | KP54 (IV infusion 1 nmol/kg/h for 2 h) | KP had no effect on preprandial and postprandial insulin and glucose levels |
| N, KP in appetite regulation and obesity | ||||
| Izzi-Engbeaya et al (2018) (115) | Randomized, blinded, 2-way crossover | 15 healthy men | KP54 (IV infusion 1 nmol/kg/h for 2 h) vs vehicle | KP had no effect on self-reported hunger (assessed by visual analog scores) or objective food intake |
| Yang et al (2021) (117) | Double-blinded, randomized, placebo-controlled, crossover study | 27 healthy men | KP54 (IV infusion 1 nmol/kg/h for 75 min) vs vehicle | KP did not elicit brain responses to visual food stimuli or psychometric parameters |
| Izzi-Engbeaya et al (2023) (116) | Single-blinded, crossover study | 17 women with overweight or obesity | KP54 (IV infusion 1 nmol/kg/h for 2 h) | KP had no effect on self-reported hunger (assessed by visual analog scores) or objective food intake |
| O, KP in MAFLD | ||||
| Guzman et al (2022) (118) | Observational | 31T2DM 34 NAFL 25 NASH 31 healthy men |
KP measurement (pmol/L) | KP increased in NAFL (19.2 ± 2.6) and NASH (18.9 ± 2.4) compared with controls (6.6 ± 0.8) or patients with type 2 diabetes (7.1 ± 0.7) |
| P, KP in bone disorders | ||||
| Comninos et al (2022) (119) | Randomized, placebo-controlled, double-blind, 2-way crossover | 26 healthy men | KP54 (IV infusion 1 nmol/kg/h for 90 min) | KP54 increased osteoblast activity (20.3% increase in osteocalcin, 24.3% increase in carboxylated osteocalcin) |
| Q, KP in psychosexual dysfunction | ||||
| Comninos et al (2017) (120) | Randomized, double-blind, 2-way crossover, placebo-controlled, fMRI study | 29 healthy heterosexual men | KP54 (IV infusion 1 nmol/kg/h, for 75 min) vs vehicle | In response to sexual stimuli, KP54 enhanced brain activity in amygdala, globus pallidus, posterior cingulate, putamen and thalamus, compared to placebo. Correlation between baseline reward scores and KP hippocampal enhancement, and change in sexual aversion and KP putamen enhancement |
| Comninos et al (2018) (121) | Randomized, double-blind, 2-way crossover, placebo-controlled, fMRI study | 29 healthy heterosexual men | KP54 (IV infusion 1 nmol/kg/h, for 75 min) vs vehicle | KP's modulation of default mode network correlated with increased limbic activity in response to sexual stimuli. KP's DMN modulation was greater in men with less reward drive and predicted reduced sexual aversion |
| Yang et al (2020) (122) | Randomized, double-blind, 2-way crossover, placebo-controlled, fMRI study | 33 healthy heterosexual men | KP54 (IV infusion 1 nmol/kg/h, for 75 min) vs vehicle | In response to feminine olfactory stimulus, KP54 enhanced brain activity in amygdala, caudate, globus pallidus, putamen, and thalamus, compared to placebo. In response to female faces, KP54 enhanced brain activity in medial prefrontal cortex and superior frontal gyrus, compared to placebo |
| Comninos et al (2021) (123) | Randomized, double-blind, 2-way crossover, placebo-controlled, MR spectroscopy study | 19 healthy heterosexual men | KP54 (IV infusion 1 nmol/kg/h, for 75 min) vs vehicle | Significant decrease (14.1%-15.7%) in total endogenous GABA levels in anterior cingulate cortex during KP, compared to vehicle |
| Thurston et al (2022) (124) | Randomized, double-blind, 2-way crossover, placebo-controlled, fMRI study | 32 eugonadal women with hypoactive sexual desire disorder | KP54 (IV infusion 1 nmol/kg/h, for 75 min) vs vehicle | In response to erotic videos, KP54 deactivated inferior frontal and middle frontal gyri and activated postcentral and supramarginal gyri, compared to placebo. In response to male faces, KP54 deactivated temporoparietal junction, compared to placebo |
| Mills et al (2023) (125) | Randomized, double-blind, 2-way crossover, placebo-controlled, fMRI study | 32 eugonadal men with hypoactive sexual desire disorder | KP54 (IV infusion 1 nmol/kg/h, for 75 min) vs vehicle | In response to erotic videos, KP54 deactivated parahippocampus, precuneus, frontal pole, and posterior cingulate, while activating anterior cingulate, middle frontal gyrus, fusiform gyrus, visual cortex Associated with significant increases in penile tumescence (by 56% more than placebo) and behavioral measures of sexual desire, most notably increased “happiness about sex.” |
Abbreviations: AUC, area under the curve; AUCROC, area under receiver operating characteristic curve; CDGP, constitutional delay of growth and puberty; CHH, congenital hypogonadotropic hypogonadism; CPP, central precocious puberty; E2, estradiol; EP, ectopic pregnancy; F, female; FSH, follicle-stimulating hormone; GA, gestational age; GABA, γ-aminobutyric acid; GDM, gestational diabetes mellitus; fMRI, functional magnetic resonance imaging; GnRH, gonadotropin-releasing hormone; HA, hypothalamic amenorrhea; HCG, human chorionic gonadotropin, IUGR, intrauterine growth restriction; IV, intravenous; IVF, in vitro fertilization; IVGTT-DI, intravenous glucose tolerance test—disposition index; KP, kisspeptin; LH, luteinizing hormone; M, male; NAFL, nonalcoholic fatty liver; MAFLD, metabolic fatty liver disease; NASH, nonalcoholic steatohepatitis; OHSS, ovarian hyperstimulation syndrome; PE, preeclampsia; PRL, prolactin; RCT, randomized controlled trial; SC, subcutaneous, SGA, small for gestational age.