高浓度雄激素诱导KNDy神经内分泌紊乱在多囊卵巢综合征发病机制中的研究进展

doi:10.12280/gjfckx.20220496

摘要/Abstract

摘要：

多囊卵巢综合征（polycystic ovary syndrome,PCOS）是全世界女性最常见的生殖障碍性疾病之一,其症状主要表现为排卵、内分泌和代谢异常。尽管PCOS发病机制尚未明确,但是目前越来越多的研究证明高浓度雄激素诱导的神经内分泌紊乱在PCOS的发病中发挥作用,而下丘脑区域的KNDy神经元对女性的生殖功能有着重要的调控作用。近年研究发现,高浓度雄激素可能改变下丘脑区域KNDy神经元网络对促性腺激素释放激素的调节,从而干扰下丘脑-垂体-卵巢/肾上腺/脂肪细胞轴,使下游靶器官生成更多的雄激素即雄激素的恶性循环,加重PCOS的症状。因此,或许可通过在关键发育窗口期降低雄激素对神经内分泌的影响、恢复类固醇反馈的敏感性以及调整促性腺激素释放激素的分泌,进而使黄体生成素/卵泡刺激素（luteinizing hormone/follicle-stimulating hormone,LH/FSH）脉冲正常化来治疗PCOS。

关键词: 多囊卵巢综合征, 雄激素类, 神经分泌系统, 神经分泌, 神经内分泌紊乱, KNDy神经元

Abstract:

Polycystic ovary syndrome (PCOS) is one of the most common reproductive disorders in women worldwide, and its symptoms are mainly manifested as ovulation, endocrine and metabolic abnormalities. Although the pathogenesis of PCOS is not yet clear, more and more studies have demonstrated that high-concentration androgen-induced neuroendocrine disorders play a role in the pathogenesis of PCOS. The KNDy neurons in the hypothalamus play an important role in regulating female reproductive function. Recent studies have found that excessive concentrations of androgens may alter the regulation of GnRH by the KNDy neuronal network in the hypothalamus region, interfering with the hypothalamic-pituitary-ovarian/adrenal/adipocyte axis, which may increase the production of downstream target organs. The vicious cycle of excess androgens, aggravates the symptoms of PCOS. Therefore, it may be possible to treat PCOS patients by reducing androgen effects on neuroendocrine, restoring sensitivity to steroid feedback, and normalizing LH/FSH pulses by modulating GnRH secretion during critical developmental windows.

Key words: Polycystic ovary syndrome, Androgens, Neurosecretory systems, Neurosecretion, Neurosecretory disorder, KNDy neuron

王莹莹, 郑洲, 张秀明. 高浓度雄激素诱导KNDy神经内分泌紊乱在多囊卵巢综合征发病机制中的研究进展[J]. 国际妇产科学杂志, 2022, 49(5): 497-501.

WANG Ying-ying, ZHENG Zhou, ZHANG Xiu-ming. Research Progress of High-Concentration Androgen-Induecd KNDy Neuroendocrine Disorder in the Pathogenesis of PCOS[J]. Journal of International Obstetrics and Gynecology, 2022, 49(5): 497-501.

参考文献 31

[1]	Tang Y, Huang T, Pan Y. Correlation Analysis of Vaspin Gene Polymorphisms and Polycystic Ovary Syndrome Based on Intelligent Medicine[J]. Comput Intell Neurosci, 2022, 2022:6154233. doi: 10.1155/2022/6154233. doi: 10.1155/2022/6154233
[2]	Zhang J, Bao Y, Zhou X, et al. Polycystic ovary syndrome and mitochondrial dysfunction[J]. Reprod Biol Endocrinol, 2019, 17(1):67. doi: 10.1186/s12958-019-0509-4. doi: 10.1186/s12958-019-0509-4
[3]	Moore AM, Lohr DB, Coolen LM, et al. Prenatal Androgen Exposure Alters KNDy Neurons and Their Afferent Network in a Model of Polycystic Ovarian Syndrome[J]. Endocrinology, 2021, 162(11):bqab158. doi: 10.1210/endocr/bqab158. doi: 10.1210/endocr/bqab158
[4]	Yan X, Yuan C, Zhao N, et al. Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats[J]. J Endocrinol, 2014, 222(1):73-85. doi: 10.1530/JOE-14-0021. doi: 10.1530/JOE-14-0021 pmid: 24829217
[5]	Silva MS, Prescott M, Campbell RE. Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS[J]. JCI Insight, 2018, 3(7):e99405. doi: 10.1172/jci.insight.99405. doi: 10.1172/jci.insight.99405
[6]	Caldwell A, Edwards MC, Desai R, et al. Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome[J]. Proc Natl Acad Sci U S A, 2017, 114(16):E3334-E3343. doi: 10.1073/pnas.1616467114. doi: 10.1073/pnas.1616467114
[7]	Abbott DH, Vepraskas SH, Horton TH, et al. Accelerated Episodic Luteinizing Hormone Release Accompanies Blunted Progesterone Regulation in PCOS-like Female Rhesus Monkeys (Macaca Mulatta) Exposed to Testosterone during Early-to-Mid Gestation[J]. Neuroendocrinology, 2018, 107(2):133-146. doi: 10.1159/000490570. doi: 10.1159/000490570 pmid: 29949806
[8]	Sanchez-Garrido MA, Tena-Sempere M. Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies[J]. Mol Metab, 2020, 35:100937. doi: 10.1016/j.molmet.2020.01.001. doi: 10.1016/j.molmet.2020.01.001
[9]	Witchel SF, Plant TM. Intertwined reproductive endocrinology: Puberty and polycystic ovary syndrome[J]. Curr Opin Endocr Metab Res, 2020, 14:127-136. doi: 10.1016/j.coemr.2020.07.004. doi: 10.1016/j.coemr.2020.07.004 pmid: 33102929
[10]	Herde MK, Iremonger KJ, Constantin S, et al. GnRH neurons elaborate a long-range projection with shared axonal and dendritic functions[J]. J Neurosci, 2013, 33(31):12689-12697. doi: 10.1523/JNEUROSCI.0579-13.2013. doi: 10.1523/JNEUROSCI.0579-13.2013 pmid: 23904605
[11]	Lehman MN, He W, Coolen LM, et al. Does the KNDy Model for the Control of Gonadotropin-Releasing Hormone Pulses Apply to Monkeys and Humans?[J]. Semin Reprod Med, 2019, 37(2):71-83. doi: 10.1055/s-0039-3400254. doi: 10.1055/s-0039-3400254 pmid: 31847027
[12]	Navarro VM. Metabolic regulation of kisspeptin - the link between energy balance and reproduction[J]. Nat Rev Endocrinol, 2020, 16(8):407-420. doi: 10.1038/s41574-020-0363-7. doi: 10.1038/s41574-020-0363-7 pmid: 32427949
[13]	Brown R, Khant Aung Z, Phillipps HR, et al. Acute Suppression of LH Secretion by Prolactin in Female Mice Is Mediated by Kisspeptin Neurons in the Arcuate Nucleus[J]. Endocrinology, 2019, 160(5):1323-1332. doi: 10.1210/en.2019-00038. doi: 10.1210/en.2019-00038 pmid: 30901026
[14]	Cheng G, Coolen LM, Padmanabhan V, et al. The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep[J]. Endocrinology, 2010, 151(1):301-311. doi: 10.1210/en.2009-0541. doi: 10.1210/en.2009-0541 pmid: 19880810
[15]	Gorkem U, Togrul C, Arslan E, et al. Is there a role for kisspeptin in pathogenesis of polycystic ovary syndrome?[J]. Gynecol Endocrinol, 2018, 34(2):157-160. doi: 10.1080/09513590.2017.1379499. doi: 10.1080/09513590.2017.1379499 pmid: 28933574
[16]	Osuka S, Iwase A, Nakahara T, et al. Kisspeptin in the Hypothalamus of 2 Rat Models of Polycystic Ovary Syndrome[J]. Endocrinology, 2017, 158(2):367-377. doi: 10.1210/en.2016-1333. doi: 10.1210/en.2016-1333 pmid: 27983870
[17]	Iwata K, Kunimura Y, Matsumoto K, et al. Effect of androgen on Kiss1 expression and luteinizing hormone release in female rats[J]. J Endocrinol, 2017, 233(3):281-292. doi: 10.1530/JOE-16-0568. doi: 10.1530/JOE-16-0568
[18]	Abbara A, Dhillo WS. Targeting Elevated GnRH Pulsatility to Treat Polycystic Ovary Syndrome[J]. J Clin Endocrinol Metab, 2021, 106(10):e4275-e4277. doi: 10.1210/clinem/dgab422. doi: 10.1210/clinem/dgab422 pmid: 34117885
[19]	Szeliga A, Podfigurna A, Bala G, et al. Kisspeptin and neurokinin B analogs use in gynecological endocrinology: where do we stand?[J]. J Endocrinol Invest, 2020, 43(5):555-561. doi: 10.1007/s40618-019-01160-0. doi: 10.1007/s40618-019-01160-0 pmid: 31838714
[20]	Gutiérrez-Pascual E, Martínez-Fuentes AJ, Pinilla L, et al. Direct pituitary effects of kisspeptin: activation of gonadotrophs and somatotrophs and stimulation of luteinising hormone and growth hormone secretion[J]. J Neuroendocrinol, 2007, 19(7):521-530. doi: 10.1111/j.1365-2826.2007.01558.x. doi: 10.1111/j.1365-2826.2007.01558.x pmid: 17532794
[21]	Grachev P, Li XF, Kinsey-Jones JS, et al. Suppression of the GnRH pulse generator by neurokinin B involves a κ-opioid receptor-dependent mechanism[J]. Endocrinology, 2012, 153(10):4894-4904. doi: 10.1210/en.2012-1574. doi: 10.1210/en.2012-1574 pmid: 22903614
[22]	Weems PW, Coolen LM, Hileman SM, et al. Evidence That Dynorphin Acts Upon KNDy and GnRH Neurons During GnRH Pulse Termination in the Ewe[J]. Endocrinology, 2018, 159(9):3187-3199. doi: 10.1210/en.2018-00435. doi: 10.1210/en.2018-00435 pmid: 30016419
[23]	Goodman RL, Hileman SM, Nestor CC, et al. Kisspeptin, neurokinin B, and dynorphin act in the arcuate nucleus to control activity of the GnRH pulse generator in ewes[J]. Endocrinology, 2013, 154(11):4259-4269. doi: 10.1210/en.2013-1331. doi: 10.1210/en.2013-1331 pmid: 23959940
[24]	Mimouni N, Paiva I, Barbotin AL, et al. Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process[J]. Cell Metab, 2021, 33(3):513-530. doi: 10.1016/j.cmet.2021.01.004. doi: 10.1016/j.cmet.2021.01.004 pmid: 33539777
[25]	Abbott DH, Dumesic DA, Levine JE. Hyperandrogenic origins of polycystic ovary syndrome - implications for pathophysiology and therapy[J]. Expert Rev Endocrinol Metab, 2019, 14(2):131-143. doi: 10.1080/17446651.2019.1576522. doi: 10.1080/17446651.2019.1576522 pmid: 30767580
[26]	Cui P, Ma T, Tamadon A, et al. Hypothalamic DNA methylation in rats with dihydrotestosterone-induced polycystic ovary syndrome: effects of low-frequency electro-acupuncture[J]. Exp Physiol, 2018, 103(12):1618-1632. doi: 10.1113/EP087163. doi: 10.1113/EP087163 pmid: 30204276
[27]	Febri RR, Hestiantoro A. DNA methylation of the androgen receptor gene promoter in the granulosa cells of polycystic ovary syndrome patients[J]. J Phy Conference Series, 2018, 1073(3):032078. doi: 10.1088/1742-6596/1073/3/032078. doi: 10.1088/1742-6596/1073/3/032078
[28]	Javier B, Magdalena B, Roberto S, et al. Acute and fulminant hepatitis induced by flutamide: case series report and review of the literature[J]. Ann Hepatol, 2011, 10(1):93-98. doi: 10.1016/S1665-2681(19)31595-9. doi: 10.1016/S1665-2681(19)31595-9 pmid: 21301018
[29]	Echiburú B, Milagro F, Crisosto N, et al. DNA methylation in promoter regions of genes involved in the reproductive and metabolic function of children born to women with PCOS[J]. Epigenetics, 2020, 15(11):1178-1194. doi: 10.1080/15592294.2020.1754674. doi: 10.1080/15592294.2020.1754674
[30]	Fraser GL, Obermayer-Pietsch B, Laven J, et al. Randomized Controlled Trial of Neurokinin 3 Receptor Antagonist Fezolinetant for Treatment of Polycystic Ovary Syndrome[J]. J Clin Endocrinol Metab, 2021, 106(9):e3519-e3532. doi: 10.1210/clinem/dgab320. doi: 10.1210/clinem/dgab320 pmid: 34000049
[31]	Sucquart IE, Nagarkar R, Edwards MC, et al. Neurokinin 3 Receptor Antagonism Ameliorates Key Metabolic Features in a Hyperandrogenic PCOS Mouse Model[J]. Endocrinology, 2021, 162(5):bqab020. doi: 10.1210/endocr/bqab020. doi: 10.1210/endocr/bqab020