The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function

Owens, Lisa; Abbara, Ali; Lerner, Avi; O'floinn, S; Christopoulos, Georgios; Khanjani, Shirin; Islam, Rumana; Hardy, Kate; Hanyaloglu, Aylin C.; Lavery, Stuart; Dhillo, Waljit S.; Franks, Stephen

doi:10.1093/humrep/dex357

Cited by 37 publications

(28 citation statements)

References 50 publications

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“…Owens et al ( 216 ) investigated expression of genes involved in ovarian reproductive function, steroidogenesis, and OHSS in granulosa lutein cells following the use of hCG, GnRHa, or kisspeptin to induce oocyte maturation in 48 women undergoing IVF treatment. Kisspeptin-54 increased expression of genes involved in ovarian steroidogenesis, the FSH receptor, the LHCG receptor, steroid acute regulatory protein ( STAR ), aromatase, estrogen receptors α and β (ESR1, ESR2), 3 β -hydroxysteroid dehydrogenase type 2 ( 3BHSD2 ), and inhibin A, when compared with either hCG or GnRHa ( 216 ). Whereas in vitro treatment of granulosa lutein cells with hCG induced steroidogenic gene expression, kisspeptin-54 had no significant direct effects on either OHSS or steroidogenic genes ( 216 ).…”

Section: Endocrine Requirements For Oocyte Maturation and Ovulationmentioning

confidence: 99%

“…Kisspeptin-54 increased expression of genes involved in ovarian steroidogenesis, the FSH receptor, the LHCG receptor, steroid acute regulatory protein ( STAR ), aromatase, estrogen receptors α and β (ESR1, ESR2), 3 β -hydroxysteroid dehydrogenase type 2 ( 3BHSD2 ), and inhibin A, when compared with either hCG or GnRHa ( 216 ). Whereas in vitro treatment of granulosa lutein cells with hCG induced steroidogenic gene expression, kisspeptin-54 had no significant direct effects on either OHSS or steroidogenic genes ( 216 ).…”

Section: Endocrine Requirements For Oocyte Maturation and Ovulationmentioning

confidence: 99%

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Novel Concepts for Inducing Final Oocyte Maturation in In Vitro Fertilization Treatment

2018

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Infertility affects one in six of the population and increasingly couples require treatment with assisted reproductive techniques. In vitro fertilization (IVF) treatment is most commonly conducted using exogenous FSH to induce follicular growth and human chorionic gonadotropin (hCG) to induce final oocyte maturation. However, hCG may cause the potentially life-threatening iatrogenic complication “ovarian hyperstimulation syndrome” (OHSS), which can cause considerable morbidity and, rarely, even mortality in otherwise healthy women. The use of GnRH agonists (GnRHas) has been pioneered during the last two decades to provide a safer option to induce final oocyte maturation. More recently, the neuropeptide kisspeptin, a hypothalamic regulator of GnRH release, has been investigated as a novel inductor of oocyte maturation. The hormonal stimulus used to induce oocyte maturation has a major impact on the success (retrieval of oocytes and chance of implantation) and safety (risk of OHSS) of IVF treatment. This review aims to appraise experimental and clinical data of hormonal approaches used to induce final oocyte maturation by hCG, GnRHa, both GnRHa and hCG administered in combination, recombinant LH, or kisspeptin. We also examine evidence for the timing of administration of the inductor of final oocyte maturation in relationship to parameters of follicular growth and the subsequent interval to oocyte retrieval. In summary, we review data on the efficacy and safety of the major hormonal approaches used to induce final oocyte maturation in clinical practice, as well as some novel approaches that may offer fresh alternatives in future.

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Section: Endocrine Requirements For Oocyte Maturation and Ovulationmentioning

confidence: 99%

Section: Endocrine Requirements For Oocyte Maturation and Ovulationmentioning

confidence: 99%

Novel Concepts for Inducing Final Oocyte Maturation in In Vitro Fertilization Treatment

2018

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“…The expression of Star gene, which promotes the conversion of cholesterol into pregnenolone, is enhanced by androgen in rat GCs [ 59 ], and the KISS1 is likely to trigger the expression of Star in the granulosa lutein cells of humans [ 60 ]. The CYP17 gene encodes one member of the cytochrome P450 enzymes that produce androgens and estrogens, as well as impacting follicular development [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cells

et al. 2020

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Background In mammals, it is known that the estradiol-17β (E2) is mainly synthetized in ovarian granulosa cells (GCs), and the excessive apoptosis of GCs induces the follicular atresia. Many studies have implicated the essential role of KISS1, with the pro-synthetic effect of E2 and the anti-apoptotic effect on GCs, in the mammalian folliculogenesis, and several STAT4 potential binding sites were previously predicted on the promoter of KISS1 in pigs. However, the biological effects of STAT4 on GCs and the molecular regulation between STAT4 and KISS1 remained largely unknown. Methods Using the porcine GCs as the cellular model, the overexpression plasmid, small interfering RNA, 5′-deletion and luciferase assay were applied to investigate the molecular mechanisms for STAT4 regulating the expression of KISS1. Results In this study, the STAT4 negatively regulated the mRNA and protein levels of KISS1 in porcine GCs, and the mRNA level of STAT4 was observed to significantly decrease from immature to mature follicles, which was inversed with that of KISS1. The relative luciferase activity of KISS1 promoter was significantly increased with deletion of the fourth potential binding site (− 305/− 295), and ChIP further confirmed that the STAT4 bound at − 305/− 295 region of KISS1. Besides, the STAT4 significantly regulated the mRNA levels of PDK1, FOXO3 and TSC2 of PI3K signaling pathway to promote the cell apoptosis and the percentage of cells at G0/G1 phase of cell cycle in GCs. Alternatively, the STAT4 significantly decreased the mRNA levels of CYP17, 3B-HSD, 17B-33 HSD, ESR1, and ESR2, as well as the concentration of E2 in GCs. Furthermore, interfering with the expression of STAT4 was observed to significantly stimulate the pro-synthetic effect of E2 and anti-apoptotic effect of KISS1 in GCs. Conclusions Collectively, the STAT4 might directly target at − 305/− 295 region of KISS1 to negatively regulate the transcription of KISS1, promote the cell apoptosis via PI3K signaling pathway, suppress the synthesis of E2 through the estrogen signaling pathway in porcine GCs. These proposed works could provide useful insight in further investigations on the molecular functionalities of STAT4 and KISS1 in the folliculogenesis of mammals.

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“…5 Owens and colleagues 38 examined the in vivo and in vitro actions of using kisspeptin-54 trigger on gene expression relating to ovarian reproductive function, steroidogenesis, and OHSS in granulosa lutein cells, compared with current triggers. 38 They observed that triggering oocyte maturation with kisspeptin-54 increased the expression of genes involved in ovarian steroidogenesis such as LH/hCG and FSH receptor, steroid acute regulatory (STAR) protein, aromatase, and estrogen receptors. 38 In summary, kisspeptin stimulates release of an LH surge sufficient to induce effective oocyte maturation and achieve at least comparable pregnancy rates in subfertile women undergoing IVF treatment.…”

Section: Kisspeptin During In Vitro Fertilizationmentioning

confidence: 99%

“…38 They observed that triggering oocyte maturation with kisspeptin-54 increased the expression of genes involved in ovarian steroidogenesis such as LH/hCG and FSH receptor, steroid acute regulatory (STAR) protein, aromatase, and estrogen receptors. 38 In summary, kisspeptin stimulates release of an LH surge sufficient to induce effective oocyte maturation and achieve at least comparable pregnancy rates in subfertile women undergoing IVF treatment. Crucially, rates of OHSS are dramatically reduced by kisspeptin triggering, and this could in part be achieved by a further direct ovarian action of kisspeptin on VEGF production.…”

Section: Kisspeptin During In Vitro Fertilizationmentioning

confidence: 99%

Clinical Translational Studies of Kisspeptin and Neurokinin B

Hunjan

Abbara

2019

Semin Reprod Med

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Kisspeptin and neurokinin B (NKB) are hypothalamic neuropeptides that are vital for reproductive health. An absence of either kisspeptin or NKB signaling results in hypogonadotrophic hypogonadism and a failure to proceed through puberty. In recent years, several studies have demonstrated potential avenues for the clinical utility of medications that act through these pathways in the assessment and treatment of reproductive disorders. Kisspeptin acts to stimulate hypothalamic gonadotrophic-releasing hormone (GnRH) secretion from the hypothalamus. Kisspeptin induces gonadotrophin secretion in both healthy men and women, and in women with reproductive disorders such as hypothalamic amenorrhea (HA). Kisspeptin-based treatments hold promise for use during in vitro fertilization (IVF) treatment; a bolus of kisspeptin-54 induces an LH surge of 12 to 14 hours of duration sufficient to induce oocyte maturation, but with markedly reduced rates of the most significant complication of IVF treatment, ovarian hyperstimulation syndrome (OHSS). Kisspeptin could also be used chronically to restore reproductive health in patients with functional hypogonadism, such as those with HA. Furthermore, kisspeptin has potential as a diagnostic test of hypothalamic function; a “kisspeptin test” could be used in children with delayed puberty to identify the subset with genetically determined deficits in hypothalamic pathways (congenital hypogonadotrophic hypogonadism [CHH]). In addition to its role in hypothalamic GnRH pulse generation, NKB plays a critical role in the occurrence of one of the most troubling symptoms of the menopause, the “hot flush.” Neurokinin-3 receptor (NK3R) antagonists are highly effective as treatments for hot flushes in postmenopausal women, with several compounds now in late-phase development. Furthermore, NK3R antagonism leads to a reduction in LH secretion by reducing GnRH pulsatility in the hypothalamus and has been shown to reduce androgen levels in women with polycystic ovary syndrome (PCOS) (in whom GnRH pulsatility is often increased). In summary, although further detailed evaluation in several clinical settings is ongoing, medications based on kisspeptin and NKB pathways have prodigious potential in the assessment and treatment of reproductive disorders.

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The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function

Abstract: ClinicalTrials.gov NCT01667406.

Cited by 37 publications

References 50 publications

Novel Concepts for Inducing Final Oocyte Maturation in In Vitro Fertilization Treatment

Novel Concepts for Inducing Final Oocyte Maturation in In Vitro Fertilization Treatment

STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cells

Clinical Translational Studies of Kisspeptin and Neurokinin B

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