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JAMA Network Open Feb 2023The human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to low sexual desire; the most prevalent psychological form is hypoactive sexual desire disorder (HSDD), which affects 8% of men but currently has no effective pharmacological treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target, owing to emerging understanding of its role in reproductive behavior.
OBJECTIVE
To determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD.
DESIGN, SETTING, AND PARTICIPANTS
This double-blind, 2-way crossover, placebo-controlled randomized clinical trial was performed at a single academic research center in the UK. Eligible participants were right-handed heterosexual men with HSDD. Physiological, behavioral, functional magnetic resonance imaging (fMRI), and hormonal analyses were used to investigate the clinical and mechanistic effects of kisspeptin administration in response to visual sexual stimuli (short and long video tasks). The trial was conducted between January 11 and September 15, 2021, and data analysis was performed between October and November 2021.
INTERVENTIONS
Participants attended 2 study visits at least 7 days apart, in balanced random order, for intravenous infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes or for administration of a rate-matched placebo.
MAIN OUTCOMES AND MEASURES
Changes in (1) brain activity on whole-brain analysis, as determined by fMRI blood oxygen level-dependent activity in response to visual sexual stimuli during kisspeptin administration compared with placebo, (2) physiological sexual arousal (penile tumescence), and (3) behavioral measures of sexual desire and arousal.
RESULTS
Of the 37 men randomized, 32 completed the trial. Participants had a mean (SD) age of 37.9 (8.6) years and a mean (SD) body mass index of 24.9 (5.4). On viewing sexual videos, kisspeptin significantly modulated brain activity in key structures of the sexual-processing network on whole-brain analysis compared with placebo (mean absolute change [Cohen d] = 0.81 [95% CI, 0.41-1.21]; P = .003). Furthermore, improvements in several secondary analyses were observed, including significant increases in penile tumescence in response to sexual stimuli (by up to 56% more than placebo; mean difference = 0.28 units [95% CI, 0.04-0.52 units]; P = .02) and behavioral measures of sexual desire-most notably, increased happiness about sex (mean difference = 0.63 points [95% CI, 0.10-1.15 points]; P = .02).
CONCLUSIONS AND RELEVANCE
Collectively, this randomized clinical trial provides the first evidence to date showing that kisspeptin administration substantially modulates sexual brain processing in men with HSDD, with associated increases in penile tumescence and behavioral measures of sexual desire and arousal. These data suggest that kisspeptin has potential as the first pharmacological treatment for men with low sexual desire.
TRIAL REGISTRATION
isrctn.org Identifier: ISRCTN17271094.
Topics: Male; Humans; Adult; Penile Erection; Kisspeptins; Sexual Behavior; Sexual Dysfunctions, Psychological; Brain
PubMed: 36735255
DOI: 10.1001/jamanetworkopen.2022.54313 -
Peptides Apr 2023Optical systems and genetic engineering technologies have made it possible to control neurons and unravel neuronal circuit behavior with high temporal and spatial...
Optical systems and genetic engineering technologies have made it possible to control neurons and unravel neuronal circuit behavior with high temporal and spatial resolution. The application of optogenetic strategies to understand the physiology of kisspeptin neuronal circuits has evolved in recent years among the neuroendocrine community. Kisspeptin neurons are fundamentally involved in controlling mammalian reproduction but also are implicated in numerous other physiological processes, including but not limited to feeding, energy expenditure, core body temperature and behavior. We conducted a review aiming to shed light on the novel findings obtained from in vitro and in vivo optogenetic studies interrogating kisspeptin neuronal circuits to date. Understanding the function of kisspeptin networks in the brain can greatly inform a wide range of clinical studies investigating infertility treatments, gender identity, metabolic disorders, hot flushes and psychosexual disorders.
Topics: Humans; Animals; Female; Male; Kisspeptins; Optogenetics; Gender Identity; Neurons; Brain; Mammals
PubMed: 36731655
DOI: 10.1016/j.peptides.2023.170961 -
Cancer Metastasis Reviews Mar 2023Present therapeutic approaches do not effectively target metastatic cancers, often limited by their inability to eliminate already-seeded non-proliferative,... (Review)
Review
Present therapeutic approaches do not effectively target metastatic cancers, often limited by their inability to eliminate already-seeded non-proliferative, growth-arrested, or therapy-resistant tumor cells. Devising effective approaches targeting dormant tumor cells has been a focus of cancer clinicians for decades. However, progress has been limited due to limited understanding of the tumor dormancy process. Studies on tumor dormancy have picked up pace and have resulted in the identification of several regulators. This review focuses on KISS1, a metastasis suppressor gene that suppresses metastasis by keeping tumor cells in a state of dormancy at ectopic sites. The review explores mechanistic insights of KISS1 and discusses its potential application as a therapeutic against metastatic cancers by eliminating quiescent cells or inducing long-term dormancy in tumor cells.
Topics: Humans; Kisspeptins; Neoplasms; Genes, Tumor Suppressor; Neoplasm Metastasis
PubMed: 36720764
DOI: 10.1007/s10555-023-10090-6 -
The Science of the Total Environment Apr 2023Kisspeptin has been proposed as an effect biomarker to understand the mechanisms by which some environmental chemicals adversely affect the human reproductive system.
BACKGROUND
Kisspeptin has been proposed as an effect biomarker to understand the mechanisms by which some environmental chemicals adversely affect the human reproductive system.
OBJECTIVE
To ascertain whether kisspeptin serum protein and DNA methylation levels are associated with exposure to several environmental chemicals (individually and as a mixture) and serum reproductive hormone levels in adolescent males.
METHODS
Three phenols (bisphenol A [BPA], methyl-paraben [MPB], and benzophenone-3 [BP3]); two toxic metals (arsenic and cadmium); and four metabolites of non-persistent pesticides, including insecticides (2-isopropyl-6-methyl-4-pyrimidinol [IMPy], malathion diacid [MDA], and dimethylcyclopropane carboxylic acid [DCCA]) and fungicides (ethylene thiourea [ETU]) were measured in first-morning urine samples of 133 adolescent males aged 15-17 years from the INMA-Granada cohort. In blood samples collected on the same day, KISS1 gene DNA methylation was measured at four CpGs from the Exon IV, as well as serum levels of kiss54 protein, total testosterone (T), estradiol (E), sex hormone binding-globulin, dehydroepiandrosterone sulfate, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Multiple linear regression and mixture (quantile g-computation) models were fit.
RESULTS
Urinary MDA and DCCA concentrations were associated with higher kiss54 levels [% change (95%CI) for each log-unit increase in concentration = 2.90 (0.32;5.56), and 1.93 (0.45,3.43), respectively]; IMPy with lower DNA methylation percentage at CpG1 and total CpGs [% change (95%CI) = -1.15 (-1.96;-0.33): -0.89 (-1.73;-0.01), respectively]; and BP3 and DCCA with lower total CpGs methylation [-0.53 (-1.04;-0.01) and - 0.69 (-1.37;-0.01), respectively]. The pesticide mixture and the whole chemical mixture were associated with higher kiss54 [% change (95%CI) = 9.09 (3.29;15.21) and 11.61 (3.96;19.82), respectively] and lower methylation levels at several CpGs. Additionally, serum kiss54 in the third tertile was associated with higher LH levels [% change (95%CI) = 28.69 (3.75-59.63)], and third-tertile CpG1, CpG2, and total CpG methylation percentages were associated with lower FSH and E.
CONCLUSION
The findings of the present study and the negative correlation between serum kiss54 levels and KISS1 DNA methylation percentages suggested that kisspeptin may be a promising effect biomarker.
Topics: Male; Humans; Adolescent; Kisspeptins; Pilot Projects; Luteinizing Hormone; Follicle Stimulating Hormone; Testosterone
PubMed: 36657687
DOI: 10.1016/j.scitotenv.2023.161668 -
American Journal of Physiology.... Apr 2023Kisspeptin and γ-amino butyric acid (GABA), synthesized in the central nervous system, are critical for reproduction. Both are also expressed in peripheral...
Kisspeptin and γ-amino butyric acid (GABA), synthesized in the central nervous system, are critical for reproduction. Both are also expressed in peripheral organs/tissues critical to metabolic control (liver/pancreas/adipose). Many kisspeptin neurons coexpress GABAB receptors (GABABR) and GABA controls kisspeptin expression and secretion. We developed a unique mouse lacking GABABR exclusively from kisspeptin cells/neurons (-GABAB1KO) to evaluate the impact on metabolism/reproduction. We confirmed selective deletion of GABABR from cells in the anteroventral periventricular nucleus/periventricular nucleus continuum (AVPV/PeN; immunofluorescence and PCR) and arcuate nucleus (ARC), medial amygdala (MeA), pituitary, liver, and testes (PCR). Young -GABAB1KO males were fertile, with normal LH and testosterone. expression was similar between genotypes in AVPV/PeN, ARC, MeA, bed nucleus of the (BNST), and peripheral organs (testis, liver, pituitary). -GABAB1KO males presented higher fasted glycemia and insulin levels, an impaired response to a glucose overload, reduced insulin sensitivity, and marked insulin resistance. Interestingly, when -GABAB1KO males got older (9 mo old) their body weight (BW) increased, in part due to an increase in white adipose tissue (WAT). Old -GABAB1KO males showed higher fasted insulin, increased pancreatic insulin content, insulin resistance, and significantly decreased pancreatic kisspeptin levels. In sum, lack of GABABR specifically in cells severely impacts glucose homeostasis in male mice, reinforcing kisspeptin involvement in metabolic regulation. These alterations in glucose homeostasis worsened with aging. We highlight the impact of GABA through GABABR in the regulation of the pancreas kisspeptin system in contrast to liver kisspeptin that was not affected. We developed a unique mouse lacking GABAB receptors specifically in cells to evaluate the impact on reproduction and metabolism. Knockout males showed a severe impact on glucose homeostasis, which worsened with aging. These results reinforce the proposed kisspeptin involvement in metabolic regulation and highlight the impact of GABA through GABABR in the regulation of the peripheral pancreas kisspeptin system.
Topics: Mice; Animals; Male; Kisspeptins; Insulin Resistance; Estradiol; Mice, Knockout; Reproduction; Homeostasis; gamma-Aminobutyric Acid; Insulins
PubMed: 36652400
DOI: 10.1152/ajpendo.00129.2022 -
Journal of Ovarian Research Jan 2023Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, anovulation, and polycystic ovaries. Electroacupuncture (EA) can effectively improve...
Effects of electroacupuncture on the kisspeptin-gonadotropin-releasing hormone (GnRH) /luteinizing hormone (LH) neural circuit abnormalities and androgen receptor expression of kisspeptin/neurokinin B/dynorphin neurons in PCOS rats.
BACKGROUND
Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, anovulation, and polycystic ovaries. Electroacupuncture (EA) can effectively improve hyperandrogenism and increase ovulation frequency in patients with PCOS. Pieces of suggest that androgen activity in the brain is associated with impaired steroid negative feedback in such patients. Studies have shown that EA regulated androgen receptor (AR) expression and local factor levels (such as anti-Müllerian hormone and inhibin B) in the ovary of PCOS rats. However, few studies have explored the effect of EA on androgen activity in the brain.
OBJECTIVE
This study investigated the effect of EA on the kisspeptin-gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) neural circuit and sex hormone receptor expression in the hypothalamus of PCOS rats.
METHODS
PCOS signs were induced by letrozole administration, and the induced rats were treated with low-frequency EA at Guan Yuan acupoint (CV4). The effect of EA on PCOS-like signs was evaluated by observing changes in the body weight, ovarian quality, ovarian morphology, and serum sex hormone levels in rats. To explore the mechanism of the effect of EA on PCOS-like signs, the neuropeptide content of the kisspeptin-GnRH/LH neural circuit was assessed using enzyme-linked immunosorbent assay(ELISA); AR and estrogen receptor α (ERα) coexpression on kisspeptin/neurokinin B/dynorphin (KNDy) neurons was determined via triple-label immunofluorescence; and protein and mRNA expression of Kiss1, Ar, Esr1, and kisspeptin receptor (Kiss1r) was evaluated via western blotting and Reverse Transcription-Polymerase Chain Reaction (RT-PCR).
RESULTS
The results revealed that the estrous cycle of rats in the EA treatment group recovered, and their body and ovary weight reduced; ovarian morphology improved; serum testosterone and LH levels significantly decreased; and kisspeptin, GnRH, and dynorphin levels in hypothalamic arcuate nucleus significantly decreased. Compared with controls, the number of AR/Kiss1-positive cells increased, number of ERα/Kiss1-positive cells decreased, and protein and mRNA expression of Kiss1, Ar, and Kiss1r significantly increased in PCOS rats. However, EA treatment reversed these changes and reduced the expression of Kiss1, Ar, and Kiss1r significantly.
CONCLUSION
Improvement in the reproductive hallmarks of PCOS rats via EA may be achieved by regulating the kisspeptin-GnRH/LH circuit via androgen activity attenuation. Thus, the results provide an experimental basis for acupuncture as an adjuvant medical therapy on PCOS.
Topics: Animals; Female; Humans; Rats; Androgens; Dynorphins; Electroacupuncture; Estrogen Receptor alpha; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Hyperandrogenism; Kisspeptins; Luteinizing Hormone; Neurokinin B; Neurons; Polycystic Ovary Syndrome; Rats, Sprague-Dawley; Receptors, Androgen; Receptors, Kisspeptin-1; RNA, Messenger
PubMed: 36650561
DOI: 10.1186/s13048-022-01078-x -
Cell Reports Jan 2023The mechanism by which arcuate nucleus kisspeptin (ARN) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to...
The mechanism by which arcuate nucleus kisspeptin (ARN) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to generate pulsatile hormone secretion remains unknown. An acute brain slice preparation maintaining synchronized ARN neuron burst firing was used alongside in vivo GCaMP GRIN lens microendoscope and fiber photometry imaging coupled with intra-ARN microinfusion. Studies in intact and gonadectomized male mice revealed that ARN neuron synchronizations result from near-random emergent network activity within the population and that this was critically dependent on local glutamate-AMPA signaling. Whereas neurokinin B operated to potentiate glutamate-generated synchronizations, dynorphin-kappa opioid tone within the network served as a gate for synchronization initiation. These observations force a departure from the existing "KNDy hypothesis" for ARN neuron synchronization. A "glutamate two-transition" mechanism is proposed to underlie synchronizations in this key hypothalamic central pattern generator driving mammalian fertility.
Topics: Mice; Male; Animals; Neurokinin B; Dynorphins; Kisspeptins; Arcuate Nucleus of Hypothalamus; Neurons; Glutamates; Hormones; Mammals
PubMed: 36640343
DOI: 10.1016/j.celrep.2022.111914 -
Endocrinology Jan 2023
Topics: Mice; Animals; Dynorphins; Gonadotropin-Releasing Hormone; Kisspeptins; Rodentia; Sexual Maturation; Neurokinin B; Fertility
PubMed: 36639244
DOI: 10.1210/endocr/bqad005 -
BMC Women's Health Jan 2023The development of polycystic ovary syndrome (PCOS) is closely correlated with apoptosis and oxidative stress in ovarian granulosa cells. Kisspeptin plays an important...
BACKGROUND
The development of polycystic ovary syndrome (PCOS) is closely correlated with apoptosis and oxidative stress in ovarian granulosa cells. Kisspeptin plays an important role in reproductive organ function. This study aimed to explore the role of kisspeptin in PCOS and oxidative stress-triggered apoptosis of ovarian granular cells.
METHODS
A PCOS rat model was established by injecting dehydroepiandrosterone (DHEA) and feeding the rats a high-fat diet. The RNA and protein levels of kisspeptin were analysed by quantitative PCR, western blotting, and histological staining. Tissue damage was evaluated using haematoxylin and eosin (H&E) staining. The viability and proliferation of human granulosa cell KGN were measured using the cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell cycle and apoptosis were analysed by flow cytometry. Oxidative stress was analysed by measuring reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) levels.
RESULTS
Kisspeptin was downregulated in the ovarian granulosa cells of PCOS rats compared to those of control rats. Kisspeptin overexpression enhanced KGN cell proliferation and inhibited apoptosis. ROS generation was suppressed by kisspeptin, along with decreased levels of MDA and increased levels of the antioxidants GSH, SOD, and CAT. Kisspeptin activates PI3K/AKT and ERK signalling, and inactivation of ERK1/2 suppresses the protective role of kisspeptin in ovarian granulosa cells.
CONCLUSION
Kisspeptin improves proliferation and alleviates apoptosis and oxidative stress in ovarian granulosa cells by activating PI3K/AKT and ERK signalling.
Topics: Female; Rats; Humans; Animals; Polycystic Ovary Syndrome; Proto-Oncogene Proteins c-akt; Kisspeptins; Phosphatidylinositol 3-Kinases; Reactive Oxygen Species; Apoptosis; Cell Proliferation; Granulosa Cells; Superoxide Dismutase
PubMed: 36627631
DOI: 10.1186/s12905-022-02154-6 -
The Lancet. Diabetes & Endocrinology Mar 2023Puberty is a major maturational event; its mechanisms and timing are driven by genetic determinants, but also controlled by endogenous and environmental cues.... (Review)
Review
Puberty is a major maturational event; its mechanisms and timing are driven by genetic determinants, but also controlled by endogenous and environmental cues. Substantial progress towards elucidation of the neuroendocrine networks governing puberty has taken place. However, key aspects of the mechanisms responsible for the precise timing of puberty and its alterations have only recently begun to be deciphered, propelled by epidemiological data suggesting that pubertal timing is changing in humans, via mechanisms that are not yet understood. By integrating basic and clinical data, we provide a comprehensive overview of current advances on the physiological basis of puberty, with a particular focus on the roles of kisspeptins and other central transmitters, the underlying molecular and endocrine mechanisms, and the pathways involved in pubertal modulation by nutritional and metabolic cues. Additionally, we have summarised molecular features of precocious and delayed puberty in both sexes, as revealed by clinical and genetic studies. This Review is a synoptic up-to-date view of how puberty is controlled and of the pathogenesis of major pubertal alterations, from both a clinical and translational perspective. We also highlight unsolved challenges that will seemingly concentrate future research efforts in this active domain of endocrinology.
Topics: Male; Female; Humans; Puberty; Kisspeptins; Puberty, Precocious
PubMed: 36620967
DOI: 10.1016/S2213-8587(22)00339-4