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

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。     

神经激肽B与子痫前期

子痫前期是妊娠期特有的疾病，是导致孕产妇和围生儿病率及死亡率增高的主要原因。对其病因学和发病机制的研究一直是产科学中的重要课题。自Page发现胎盘神经激肽B（neurokinin B，NKB）mRNA及其多肽，并提出胎盘分泌过多的NKB导致子痫前期发生后，NKB和子痫前期的关系日益受到重视。综述NKB与速激肽家族、在胎盘组织的分布、在生理妊娠中的作用及其与子痫前期相关性研究。     

下丘脑-垂体轴外GnRH—R研究现状

促性腺激素释放激素（GnRH）是下丘脑神经内分泌细胞合成的十肽激素，以脉冲形式分泌，通过垂体门脉系统进入垂体，与垂体前叶促性腺细胞上的特异性高亲和力促性腺激素释放激素受体（GnRH—R）结合，刺激黄体生成素（LH）和卵泡刺激素（FSH）的合成与分泌，作用于性腺，从而维持正常的内分泌和生殖系统功能。GnRH—R是介导GnRH功能必不可少的物质，主要分布于垂体，20世纪70年代始下丘脑-垂体轴外GnRH及GnRH—R相继被发现，在下丘脑-垂体轴外许多正常组织和病变组织发现有GnRH—R的表达，     

神经激肽B及胎盘生长因子与妊娠期高血压疾病

妊娠期高血压疾病是常见的妊娠并发症,是孕产妇及嗣生儿死亡的主要原因之一。探讨其发病机制一直是产科领域研究的主要课题。胎盘滋养细胞可分泌胎盘生长因子（PLGF）和神经激肽B（NKB）,两者可能在滋养细胞浸润、胎盘血管重铸和血管舒缩调控等方面起一定作用。妊娠期高血压疾病患者胎盘PLGF水平显著降低而NKB水平明显升高,二者的异常变化可能是导致该疾病血管损伤、滋养细胞功能异常的原因之一。     

神经激肽B与子痫前期

子痫前期是妊娠期特有的疾病,是导致孕产妇和围生儿病率及死亡率增高的主要原因.对其病因学和发病机制的研究一直是产科学中的重要课题.自Page发现胎盘神经激肽B(neurokinin B,NKB)mRNA及其多肽,并提出胎盘分泌过多的NKB导致子痫前期发生后,NKB和子痫前期的关系日益受到重视.综述NKB与速激肽家族、在胎盘组织的分布、在生理妊娠中的作用及其与子痫前期相关性研究.     

GnRH-a的临床应用进展

促性腺激素释放激素（gonadotropin releasing hormones，GnRH）是由下丘脑神经元细胞体合成并由其末端直接分泌入垂体门脉系统的一种十肽化合物。GnRH选择性的刺激促性腺细胞释放促性腺激素LH和FSH，接下来LH和FSH分别刺激性腺细胞产生性激素并促进配子形成。GnRH具有以下几个显著的生理特征：     

神经内分泌在多囊卵巢综合征发病机制中的研究进展

多囊卵巢综合征(PCOS)是最常见的女性生殖障碍疾病,影响全球育龄期女性,发病机制尚未明确。研究发现神经内分泌疾病患者PCOS的发生率较高,PCOS患者脑脊液γ氨基丁酸(GABA)和血液Kisspeptin水平升高,Neurokinin B受体(NK3R)拮抗剂治疗后,PCOS患者睾酮和黄体生成激素(LH)水平下降,提示神经内分泌紊乱是PCOS的发病机制之一。常用的PCOS动物模型包括产前雄激素模型、产前抗苗勒管激素(AMH)模型、产后雄激素模型和芳香化酶抑制剂模型。不同模型模拟了PCOS的不同亚型,其中芳香化酶抑制剂模型较好地反映了PCOS的神经内分泌改变。临床及动物模型研究显示促性腺激素释放激素(GnRH)神经元、GABA能神经元、Kisspeptin神经元和雄激素等参与了PCOS的神经内分泌调节。     

Kisspeptin对女性生殖功能调控机制的研究进展

在女性生殖活动中,kisspeptin参与调控下丘脑-垂体-性腺(HPG)轴的功能,并通过介导雌激素的正负反馈调节促性腺激素释放激素(Gn RH)的分泌,解除促性腺激素抑制激素(Gn IH)对HPG轴的负性调控作用,继而调节促性腺激素(Gn)的分泌及类固醇甾体激素的分泌,并与多种卵巢功能异常疾病的病理过程密切相关。Kisspeptin可调控卵泡发育和排卵发生,并影响子宫内膜容受性的形成。此外,在辅助生殖技术(ART)过程中kisspeptin可代替传统h CG扳机,并降低接受ART治疗的不孕症女性卵巢过度刺激综合征(OHSS)的发生。     

神经激肽B及胎盘生长因子与妊娠期高血压疾病

妊娠期高血压疾病是常见的妊娠并发症,是孕产妇及围生儿死亡的主要原因之一.探讨其发病机制一直是产科领域研究的主要课题.胎盘滋养细胞可分泌胎盘生长因子(PLGF)和神经激肽B(NKB),两者可能在滋养细胞浸润、胎盘血管重铸和血管舒缩调控等方面起一定作用.妊娠期高血压疾病患者胎盘PLGF水平显著降低而NKB水平明显升高,二者的异常变化可能是导致该疾病血管损伤、滋养细胞功能异常的原因之一.     

中枢神经系统激素与功能性下丘脑性闭经

功能性下丘脑性闭经（FHA）是由于下丘脑促性腺激素释放激素（GnRH）的脉冲分泌受损导致的一种可逆性非器质性疾病。已发现中枢神经系统分泌的多种激素参与GnRH分泌的调控,并在功能性下丘脑性闭经的发病过程中起重要的作用。就目前认为与下丘脑性闭经相关的中枢神经系统激素进行综述,以探讨其治疗新策略。     

The role of kisspeptin/neurokinin B/dynorphin neurons in pathomechanism of vasomotor symptoms in postmenopausal women: from physiology to potential therapeutic applications

Abstract

Women during perimenopausal period experience a range of symptoms, which interfere with physical, sexual, and social life. About 65–75% of symptoms connected with postmenopausal period are vasomotor symptoms (VMS), such as hot flushes and night sweats. Hot flushes are subjective sensation of heat associated with cutaneous vasodilatation and drop in core temperature. It is suspected that VMS are strongly correlated with pulsatile oversecretion of gonadotropin-releasing hormone (GnRH) and subsequently luteinizing hormone (LH). Evidence has accumulated in parallel showing that lack of negative feedback of steroid hormones synthesized in ovary causes overactivation of hypertrophied kisspeptin/neurokinin B/dynorphin (KNDy) neurons, located in infundibular nucleus. Oversecretion of both kisspeptin (KISS1) and neurokinin B (NKB), as well as downregulation of dynorphin, plays dominant role in creation of GnRH pulses. This in turn causes VMS. Administration of senktide, highly potent and selective NK3R agonist, resulted in increase of serum LH concentration, induction of VMS, increase in heart rate, and skin temperature in postmenopausal women. These finding suggest that modulation of KNDy neurons may become new therapeutic approach in the treatment of VMS.     

Paracrine/autocrine control of female reproduction.

Neuropeptides, growth factors and cytokines are expressed in reproductive organs and tissues, where they interact with afferent endocrine messages to modulate cell proliferation and differentiation, local hormone secretion and vascular function. These events regulate complex processes such as gonadotropin pulsatility, ovulation, implantation and parturition. During reproductive life, a number of neuropeptides produced within the hypothalamus play a modulatory role in the control of gonadotropin-releasing hormone (GnRH) release, hence characterizing a hypothalamic paracrine system. The pituitary gland is a source and target of inhibin-related proteins, and these typical 'gonadal' products, once secreted by the pituitary cells, acquire the function of paracrine modulators of follicle-stimulating hormone (FSH) secretion. In the ovary, the effect of gonadotropins is locally modulated by growth factors acting in an autocrine/paracrine manner, although their precise role in folliculogenesis remains uncertain. Numerous local factors are involved in the control of endometrial growth, differentiation, receptivity and menstruation. Alterations in the paracrine endometrial system may underlie pathological processes such as infertility or endometrial neoplasia. The human placenta and its related membranes produce cytokines, hormones and growth factors that participate in the control of gestational development as well as in the maternal-fetal adaptation to gestational diseases. There is increasing evidence that paracrine signaling plays a fundamental role in all spheres of female reproductive function, and future research will concentrate on clarifying which of these local mechanisms play a decisive role in both physiology and disease, thus giving rise to new therapeutic strategies.     

Paracrine/autocrine control of female reproduction

Neuropeptides, growth factors and cytokines are expressed in reproductive organs and tissues, where they interact with afferent endocrine messages to modulate cell proliferation and differentiation, local hormone secretion and vascular function. These events regulate complex processes such as gonadotropin pulsatility, ovulation, implantation and parturition.

During reproductive life, a number of neuropeptides produced within the hypothalamus play a modulatory role in the control of gonadotropin-releasing hormone (GnRH) release, hence characterizing a hypothalamic paracrine system. The pituitary gland is a source and target of inhibin-related proteins, and these typical ‘gonadal’ products, once secreted by the pituitary cells, acquire the function of paracrine modulators of follicle-stimulating hormone (FSH) secretion. In the ovary, the effect of gonadotropins is locally modulated by growth factors acting in an autocrine/paracrine manner, although their precise role in folliculogenesis remains uncertain. Numerous local factors are involved in the control of endometrial growth, differentiation, receptivity and menstruation. Alterations in the paracrine endometrial system may underlie pathological processes such as infertility or endometrial neoplasia. The human placenta and its related membranes produce cytokines, hormones and growth factors that participate in the control of gestational development as well as in the maternal–fetal adaptation to gestational diseases.

There is increasing evidence that paracrine signaling plays a fundamental role in all spheres of female reproductive function, and future research will concentrate on clarifying which of these local mechanisms play a decisive role in both physiology and disease, thus giving rise to new therapeutic strategies.     

促性腺激素释放激素在女性生殖系统的分布与作用

促性腺激素释放激素(gonadotropin releasing hormone,GnRH)是下丘脑分泌的十肽激素,对生殖调控具有重要意义。人体中存在2种亚型,即GnRH-I和GnRH-II,以及2种相应的受体GnRHR-I和GnRHR-II。GnRH除了通过垂体性腺轴控制女性的发育、生殖功能外,同时还以自分泌和旁分泌的方式作用于垂体外组织,如乳腺、胎盘、卵巢、子宫内膜等。GnRH或许可作为乳腺癌的一种有效治疗和预防恶化的方法。GnRH类似物已经用于治疗许多激素相关的疾病,尤其是与子宫相关的疾病,如子宫内膜增生、子宫内膜癌、子宫内膜异位症(EMs),可降低子宫颈癌的风险等。胎盘自身可生成GnRH或GnRH样多肽物质,离体的胎盘组织体外培养表明,GnRH可显著增加胎盘组织人绒毛膜促性腺激素(hCG)的释放。局部的GnRHs对维持卵巢功能具有重要的作用;卵巢GnRHs参与正常和异常生殖组织的内分泌调控。     

The effect of oxytocin and Kisspeptin-10 in ovary and uterus of ischemia-reperfusion injured rats

Objective

Ischemia/reperfusion (I/R) injuries result in damage to endothelial and parenchymal cells. Oxytocin (OXY) stimulates uterine contraction during parturition and myoepithelial cells during suckling. OXY has been used as a protective antioxidant. Kisspeptin plays a key role in the central control of reproductive functions and onset of puberty. Recent studies show that these reproductive hormones have protective potential as antioxidant. The aim of this study is to investigate the potential protective effects of Kisspeptin and OXY as antioxidants on I/R injured ovary and uterus of female rats.

The genetics of hypogonadotropic hypogonadism

An up-to-date review of the genetic aspects of idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS) is presented. Because proper development of the neuroendocrine axis must occur for normal puberty and reproductive function, gonadotropin-releasing hormone (GnRH) neuron migration is outlined first, followed by an introduction to the in vitro analysis of GnRH neuron migration. The normal hypothalamic-pituitary-gonadal (HPG) axis at different ages is discussed, along with a brief overview of normal and delayed puberty in both boys and girls. The phenotype of IHH/KS is discussed in detail, with its relation to Mendelian inheritance and chromosomal translocations. The molecular basis of IHH/KS is reviewed, with particular emphasis on the three most common genes ( KAL1, FGFR1, and GNRHR) that possess mutations in these patients. However, all other known genes for which mutations occur are also addressed briefly. The goal of this review is to provide a comprehensive discussion of IHH/KS, and to include both basic science and clinical findings that should allow a more complete understanding of hypothalamic-pituitary neuroendocrinology that is important in puberty and reproduction.     

Endocrine disorders and medically assisted procreation

A normal endocrine environment is imperative to maintain normal reproduction in women. The major endocrine organs that play a part in the reproductive system include hypothalamic pituitary axis, adrenal gland, thyroid gland, and the ovary. Each endocrine organ is in close communication and relationship with one another. Any endocrine disorders that significantly affect any of these organs would disrupt reproduction resulting in infertility. In this review, we will provide an overview of the common endocrine disorders and the available medical management including assisted reproductive technology (ART) and hormonal supplementation to overcome the endocrine disorders in order to achieve fertility for the female patients.     

The usefulness of circulating levels of leptin,kisspeptin, and neurokinin B in obese girls with precocious puberty

This study investigated the relationships of circulating leptin, kisspeptin, and neurokinin B (NKB) levels with precocious puberty (PP) in overweight/obese girls and evaluated the usefulness of these markers in the initiation of puberty. One hundred and twenty-eight girls aged 7.0–8.9?years with PP (group A, normal-weight; group B, overweight/obese) and 30 age-matched normal controls (NC) were enrolled. Serum levels of leptin, kisspeptin, and NKB were measured by commercial kits. Serum leptin levels were higher in group A (4.21?ng/mL) and B (5.64?ng/mL) compared to the NC (2.35?ng/mL, p?p?=?.018). Serum NKB levels were not different among the three groups. The predictive value of leptin (AUC =0.791) was lower than that of IGF-1 (AUC =0.917, p?=?.009), although both were significant markers for PP in the regression analysis. BMI z-score (AUC =0.806) was a predictive factor of PP. In conclusion, a higher level of leptin, IGF-1, and fatness in overweight/obese girls with PP compared to the NC confirms their roles in the regulation of puberty. Further research is needed if the effects of kisspeptin and NKB on puberty are limited at the levels of neurons or target tissue.