The<i>GPR54</i>Gene as a Regulator of Puberty

Seminara, Stephanie B.; Messager, Sophie; Chatzidaki, Emmanouella E.; Thresher, Rosemary R.; Acierno, James S.; Shagoury, Jenna K.; Bo-Abbas, Yøusef; Kuohung, Wendy; Schwinof, Kristine M.; Hendrick, Alan G.; Zahn, Dirk; Dixon, John; Kaiser, Ursula B.; Slaugenhaupt, Susan A.; Gusella, James F.; O’Rahilly, Stephen; Carlton, Mark; Crowley, William F.; Aparicio, Samuel; Colledge, William H

doi:10.1056/nejmoa035322

Cited by 2,225 publications

(777 citation statements)

References 34 publications

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“…In the present comparison of the plasma FSH level, a statistically significant difference was not found between the female Pkr2 Ϫ/Ϫ mice and their control wild-type littermates. We surmise that, because, in rodents, the plasma FSH level is generally lower in females than in males (25,26), individual variability in the plasma FSH level masked the true difference between the mutant and wild-type mice. A similar explanation could be applied to our result that the plasma LH level showed no statistically significant difference (25).…”

Section: Discussionmentioning

confidence: 86%

“…We surmise that, because, in rodents, the plasma FSH level is generally lower in females than in males (25,26), individual variability in the plasma FSH level masked the true difference between the mutant and wild-type mice. A similar explanation could be applied to our result that the plasma LH level showed no statistically significant difference (25). In view of the fact that PKR2 is also expressed in the gonads (4, 5, 18), we cannot exclude the possibility that the hypoplasia of the reproductive systems arose from the loss of a direct role of PKR2 in the development of these tissues.…”

Section: Discussionmentioning

confidence: 86%

“…Our Pkr2 Ϫ/Ϫ mouse is a genetically engineered murine line that shows hypoplasia in both the OB and the reproductive system. Recent reports demonstrated that knockout mice lacking Gpr54 (Gpr54 Ϫ/Ϫ mice) showed a striking phenotype of isolated hypothalamic hypogonadism (25,41). Similar to PKRs, GPR54 is also a member of the G protein-coupled receptor family.…”

Section: Discussionmentioning

confidence: 99%

“…GPR54 activation leads to direct release of GnRH from hypothalamic GnRH neurons and is essential for mammalian puberty, including in man (26,(42)(43)(44). In Gpr54 Ϫ/Ϫ mice, which possess intact hypothalamic GnRH neurons (45), decreased pituitary LH͞FSH secretion causes the characteristic hypogonadism due to the loss of GPR54 activation (25,43). In view of the fact that neither agenesis of the OB nor abnormality of the hypothalamic GnRH neurons was observed in the Gpr54 Ϫ/Ϫ mice, we surmise that the physiological roles of GPR54 are different from those of PKR2.…”

Section: Discussionmentioning

confidence: 99%

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Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2

Matsumoto

Yamazaki²,

Masumoto³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

248

237

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Prokineticins, multifunctional secreted proteins, activate two endogenous G protein-coupled receptors PKR1 and PKR2. From in situ analysis of the mouse brain, we discovered that PKR2 is predominantly expressed in the olfactory bulb (OB). To examine the role of PKR2 in the OB, we created PKR1-and PKR2-gene-disrupted mice (Pkr1 ؊/؊ and Pkr2 ؊/؊ , respectively). Phenotypic analysis indicated that not Pkr1 ؊/؊ but Pkr2 ؊/؊ mice exhibited hypoplasia of the OB. This abnormality was observed in the early developmental stages of fetal OB in the Pkr2 ؊/؊ mice. In addition, the Pkr2 ؊/؊ mice showed severe atrophy of the reproductive system, including the testis, ovary, uterus, vagina, and mammary gland. In the Pkr2 ؊/؊ mice, the plasma levels of testosterone and follicle-stimulating hormone were decreased, and the mRNA transcription levels of gonadotropin-releasing hormone in the hypothalamus and luteinizing hormone and follicle-stimulating hormone in the pituitary were also significantly reduced. Immunohistochemical analysis revealed that gonadotropin-releasing hormone neurons were absent in the hypothalamus in the Pkr2 ؊/؊ mice. The phenotype of the Pkr2 ؊/؊ mice showed similarity to the clinical features of Kallmann syndrome, a human disease characterized by association of hypogonadotropic hypogonadism and anosmia. Our current findings demonstrated that physiological activation of PKR2 is essential for normal development of the OB and sexual maturation.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2

Matsumoto

Yamazaki²,

Masumoto³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

248

237

View full text Add to dashboard Cite

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“…Instead, genetic abnormalities that preclude puberty have provided the major insights into the pathways that are critical for the development and maturation of the reproductive axis (2,3). Perhaps the best candidate for regulating the onset of puberty is kisspeptin, the ligand for the receptor encoded by GPR54, a gene identified as a cause of recessive hypogonadotropic hypogonadism (4,5). The report by Pitteloud et al (6) in this issue of PNAS identifies loss-of-function mutations in the prokineticin 2 (PROK2) gene, which encodes a secreted peptide that regulates the development and migration of the olfactory tract and GnRH neuron progenitors.…”

mentioning

confidence: 99%

Rites of passage through puberty: A complex genetic ensemble

Jameson

2007

Proc. Natl. Acad. Sci. U.S.A.

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Effects of Kisspeptin on Sexual Brain Processing and Penile Tumescence in Men With Hypoactive Sexual Desire Disorder

et al. 2023

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ImportanceThe 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.ObjectiveTo determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD.Design, Setting, and ParticipantsThis 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.InterventionsParticipants 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 MeasuresChanges 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.ResultsOf 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 RelevanceCollectively, 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 Registrationisrctn.org Identifier: ISRCTN17271094

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TheGPR54Gene as a Regulator of Puberty

Abstract: Mutations in GPR54, a G protein-coupled receptor gene, cause autosomal recessive idiopathic hypogonadotropic hypogonadism in humans and mice, suggesting that this receptor is essential for normal gonadotropin-releasing hormone physiology and for puberty.

Cited by 2,225 publications

References 34 publications

Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2

Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2

Rites of passage through puberty: A complex genetic ensemble

Effects of Kisspeptin on Sexual Brain Processing and Penile Tumescence in Men With Hypoactive Sexual Desire Disorder

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