石明晴，周惠芳麗水市中醫(yī)院，浙江麗水33000；南京中醫(yī)藥大學(xué)第一臨床醫(yī)學(xué)院，江蘇南京009

Kisspeppttiinnss對(duì)下丘腦
--垂體--性腺軸作用機(jī)制新進(jìn)展

石明晴1，周惠芳21麗水市中醫(yī)院，浙江麗水3230002；2南京中醫(yī)藥大學(xué)第一臨床醫(yī)學(xué)院，江蘇南京210029

近年來，Kisspeptins的發(fā)現(xiàn)使人們對(duì)調(diào)控青春期和生殖的神經(jīng)內(nèi)分泌軸有了新的認(rèn)識(shí)。Kisspeptins不僅是促進(jìn)GnRH分泌的上游因子，而且調(diào)控下丘腦-垂體-卵巢軸，主要表現(xiàn)在促性腺激素分泌的調(diào)節(jié)、青春期的啟動(dòng)以及生殖功能的調(diào)控等方面。通過對(duì)健康人群及生殖內(nèi)分泌紊亂患者的觀察，發(fā)現(xiàn)Kisspeptins可以刺激GnRH分泌，后者誘導(dǎo)LH分泌，而且增強(qiáng)LH的脈沖頻率。這些研究表明Kisspeptins將成為生殖內(nèi)分泌研究的熱點(diǎn)，并為生殖內(nèi)分泌疾病提供新的治療策略。目前許多動(dòng)物試驗(yàn)研究證明Kisspeptins在以下幾個(gè)方面也存在潛在的作用，如卵巢的功能的調(diào)節(jié)、胚胎植入及胎盤的形成。本文將集中收集關(guān)于Kisspeptins調(diào)控GnRH的脈沖式分泌的現(xiàn)有的依據(jù)，特別是青春期啟動(dòng)及生殖內(nèi)分泌方面。

Kisspeptins；下丘腦-垂體-性腺軸；GnRH分泌；青春期啟動(dòng)；生殖內(nèi)分泌功能

如今普遍認(rèn)為下丘腦分泌的促性腺激素釋放激素（GnRH）是調(diào)控生殖功能的關(guān)鍵途徑［1］。但是這一途徑的局限性使得人們認(rèn)為：是否存在中間通路控制下丘腦-垂體-性腺軸。通過對(duì)GnRH神經(jīng)元中缺乏雌激素受體（ER-α）的大鼠研究，發(fā)現(xiàn)了一些上游通路介導(dǎo)性腺反饋［2］。

近年來，由于Kisspeptins的發(fā)現(xiàn)刷新了人們對(duì)調(diào)控青春期啟動(dòng)及生殖的神經(jīng)內(nèi)分泌軸的認(rèn)識(shí)［1］。Kisspeptins通過調(diào)節(jié)GnRH的分泌而對(duì)丘腦-垂體-性腺軸的調(diào)控，為闡明生殖中樞性和外周性調(diào)節(jié)機(jī)制復(fù)雜性提供理論依據(jù)［3］。Kisspeptin是一種多肽，由kiss-1基因編碼，存在于下丘腦中［4］。Kisspeptins作為促進(jìn)GnRH分泌的上游因子，在促進(jìn)促性腺激素分泌、青春期的啟動(dòng)及生殖內(nèi)分泌方面起關(guān)鍵性作用［5］。近來研究發(fā)現(xiàn)，除了Kisspeptin，還有以下神經(jīng)肽介入生殖內(nèi)分泌的調(diào)控，如：神經(jīng)激肽-Y（NPY）、nesfain-1［6-7］及神經(jīng)激肽-B［8］。分泌Kisspeptin和NPY的神經(jīng)元，也分泌強(qiáng)啡肽，共同構(gòu)成Kisspeptin-神經(jīng)激肽B-強(qiáng)啡肽（KNDy）神經(jīng)網(wǎng)絡(luò)［8］。本文重點(diǎn)關(guān)注有關(guān)Kisspeptin調(diào)控GnRH脈沖頻率的理論依據(jù)，但也不忽略調(diào)控KISS-1/kisspeptin/GPR54系統(tǒng)的其他因素。

1 KISS-1/kisspeptin/GPR54系統(tǒng)的發(fā)現(xiàn)

Lee等［4］在研究人黑瘤素細(xì)胞不同轉(zhuǎn)移能力時(shí)，發(fā)現(xiàn)KISS-1基因。2001年，人們通過研究發(fā)現(xiàn)了KISS-1基因的產(chǎn)物肽-Kisspeptin，它們屬于同一蛋白質(zhì)前體不同水解過程的產(chǎn)物。Kisspeptin能裂解成Kisspeptin-14、-13、-10等，它們因?yàn)榫哂邢嗨频纳锾匦院凸δ埽唤y(tǒng)稱為Kisspeptins。主要的Kisspeptin肽是一個(gè)54個(gè)氨基酸的肽，被稱為metastin或Kisspeptin-54［9］。研究表明,Kisspeptin是GPR54的配體，Kisspeptins的C末端一般都有-Arg-Phe-NH2（-Rfamide）（精氨酸-苯丙氨酸酞胺基）序列，這對(duì)維持其生物活性具有重要意義［3］。GPR54是KISS-1蛋白的受體，屬G蛋白偶聯(lián)受體視紫紅質(zhì)家族成員,直到發(fā)現(xiàn)它與Kisspeptin具有非常高的親和力時(shí)，人們才開始才重視和研究它［10］。

2 Kisspeptins的生殖內(nèi)分泌功能

2003年，當(dāng)人們利用GPR54基因敲除小鼠和人類特發(fā)性促性腺激素分泌不足性腺機(jī)能減退癥（IHH）個(gè)體作為研究研究對(duì)象，研究KISS-1/GPR54系統(tǒng)對(duì)青春期的作用時(shí)，發(fā)現(xiàn)了Kisspeptins的生殖內(nèi)分泌功能，GPR54突變小鼠的表型與性腺類固醇激素分泌缺乏時(shí)一致，即突變的雌性小鼠沒有經(jīng)歷性成熟,當(dāng)與成熟雄性交配時(shí)，它們表現(xiàn)出陰道開張失敗，不能受孕；雄性突變個(gè)體表現(xiàn)為睪丸和陰莖很小，并且不能產(chǎn)生精子［11］。GPR54突變或受體缺失能造成人或小鼠的IHH疾病，因此可以表明GPR54發(fā)出的信號(hào)是性成熟的先決條件［12］。這些發(fā)現(xiàn)證實(shí)了Kisspeptin和GPR54是青春期啟動(dòng)和生殖內(nèi)分泌功能的關(guān)鍵環(huán)節(jié)，而且為揭開Kisspeptin與生殖功能之間的神秘關(guān)系的進(jìn)一步探索鋪平了道路。

3 Kisspeptin系統(tǒng)的功能性神經(jīng)解剖

通過對(duì)人類及其他各種物種的研究發(fā)現(xiàn)，Kisspeptin主要存在于下丘腦的漏斗/弓狀核。人體標(biāo)本的研究證實(shí)，人類的Kisspeptin神經(jīng)元主要位于漏斗區(qū)（其他物種位于弓狀核）和延髓視前區(qū)（POA）［13］。通過GnRH神經(jīng)元對(duì)KisspeptinRmRNA的表達(dá)［14］，發(fā)現(xiàn)Kisspeptin直接參與GnRH的分泌。后來亦有研究發(fā)現(xiàn)，位于人類漏斗區(qū)/嚙齒類動(dòng)物弓狀核的Kisspeptin神經(jīng)元也表達(dá)其他的神經(jīng)肽，命名為神經(jīng)激肽-B和強(qiáng)啡肽，被統(tǒng)稱為KNDy神經(jīng)元［13,15］，而位于POA的神經(jīng)元并未參與表達(dá)［1］。通過KNDy神經(jīng)元對(duì)強(qiáng)啡肽受體（k-阿片肽受體）和神經(jīng)激肽-B受體的表達(dá)證明，KNDy神經(jīng)元調(diào)節(jié)Kisspeptin和GnRH的脈沖式分泌［16-17］；（2）這就意味，通過強(qiáng)啡肽和神經(jīng)激肽-B的抑制和刺激作用，KNDy神經(jīng)元調(diào)節(jié)Kisspeptin的分泌，進(jìn)而調(diào)節(jié)GnRH和LH脈沖釋放［16］。也有研究認(rèn)為，KNDy神經(jīng)元調(diào)節(jié)Kisspeptin的分泌，主要是依賴于類固醇激素的正負(fù)反饋調(diào)節(jié)［18］。

4 Kisspeptins調(diào)控GnRH分泌的生理功能

研究表明，Kisspeptin通過與GnRH受體的相互作用，直接作用于GnRH神經(jīng)元，并促進(jìn)GnRH釋放。而GnRH又刺激垂體分泌促卵泡雌激素（FSH）和LH的分泌［1］。Oakley等［18-19］已經(jīng)證實(shí)Kisspeptin可使GnRH神經(jīng)元對(duì)GnRH的表達(dá)增強(qiáng)。

5 Kisspeptin對(duì)GnRH脈沖產(chǎn)生的作用

Kisspeptin對(duì)GnRH脈沖式分泌的控制，對(duì)于將來有關(guān)生殖的藥物治療，具有巨大的潛力［20］。Kisspeptin神經(jīng)元作為一種GnRH脈沖發(fā)生器，可能在兩性生殖功能方面起作用，如卵泡的發(fā)育、性激素的分泌和精子的產(chǎn)生［20］。有證據(jù)表明，Kisspeptin神經(jīng)元大量存在于弓狀核（ARC）被認(rèn)為是GnRH脈沖產(chǎn)生的中心，因?yàn)榘袺isspeptin拮抗劑注入ARC能消除GnRH脈分泌，而把Kisspeptin拮抗劑注入POA，則不能出現(xiàn)上述情況［21-22］。亦有藥理研究提示，人體注射Kisspeptin-10和Kisspeptin-54，能增加促性腺激素的分泌，尤其是LH［23-24］。

6 Kisspeptin神經(jīng)元作為性激素的負(fù)反饋通路

有假說提出，可能有一些神經(jīng)元作為中間橋梁，介導(dǎo)類固醇激素的反饋信號(hào)與不能表達(dá)雌激素類受體的GnRH神經(jīng)元之間的傳遞。近來研究表明，KNDy神經(jīng)元能介導(dǎo)類固醇激反饋調(diào)節(jié)GnRH神經(jīng)元［5］。Kisspeptin神經(jīng)元的顯著特征是，幾乎全部都表達(dá)ER-α，部分表達(dá)雌激素受體-β［25］。Kisspeptin神經(jīng)元調(diào)節(jié)性激素的負(fù)反饋的證據(jù)來源于對(duì)雄性和去勢(shì)雌性大鼠的研究，該研究揭示了下丘腦中Kiss-1mRNA的高表達(dá)，并且與循環(huán)中性激素水平的增加呈平行水平。亦有研究表明，雌激素的負(fù)反饋主要是通過Kisspeptin神經(jīng)元介導(dǎo)的ER-α［25］，而不是GnRH神經(jīng)元。這一說法在以下研究中也得到了證實(shí)，在選擇性去除雌激素受體的小鼠模型中，發(fā)現(xiàn)KISS-1mRNA表達(dá)增多與LH水平明顯增加呈相關(guān)性［26］。并有證據(jù)表明，神經(jīng)激肽-BK和kisspeptin對(duì)雌激素的負(fù)反饋有協(xié)同作用［18］。也有研究表明強(qiáng)啡肽介導(dǎo)性激素的負(fù)反饋，主要是通過絕經(jīng)后婦女漏斗核［27］及去勢(shì)動(dòng)物弓狀核中強(qiáng)啡肽原mRNA的表達(dá)增強(qiáng)而發(fā)現(xiàn)［28］。以上研究均表明，類固醇激素負(fù)反饋調(diào)節(jié)GnRH神經(jīng)元，主要是通過刺激強(qiáng)啡肽的分泌和抑制神經(jīng)激肽-B及Kisspeptin神經(jīng)元的分泌。

7 Kisspeptin神經(jīng)元作為性激素的正反饋通路，以及在排卵前的作用

令人信服的嚙齒類動(dòng)物研究表明，雌激素刺激AVPV（腹側(cè)腦室周圍白質(zhì)核）神經(jīng)元，并與活性孕激素受體（PRs）協(xié)同作用，通過誘導(dǎo)排卵前LH峰體現(xiàn)正反饋?zhàn)饔茫?］。去勢(shì)后的雌性及雄性小鼠AVPV區(qū)的Kiss-1 mRNA的表達(dá)均下降，但是給予性激素替代治療后，其表達(dá)均增加［25］。對(duì)大鼠的進(jìn)一步研究表明，AVPV區(qū)的Kisspeptin神經(jīng)元的活性增加［29］早于雌激素誘導(dǎo)的LH排卵峰。最近在嚙齒動(dòng)物研究也表明，位于AVPV區(qū)的Kisspeptin神經(jīng)元活性同步于雌激素依賴性晝夜節(jié)律［30-32］。研究表明，在卵泡發(fā)育晚期，雌激素能增加Kiss-1 mRNA在豬側(cè)腦室旁核和羊POA/ARC區(qū)的表達(dá)，與體內(nèi)的雌激素高峰對(duì)應(yīng)，但早于GnRH激增［33-34］。

首個(gè)大鼠藥理研究通過發(fā)現(xiàn)KP-10可以導(dǎo)致排卵期LH最大量分泌，證明了類固醇激素對(duì)Kisspeptin的反應(yīng)［35］。最近動(dòng)物藥理研究表明，Kisspeptin可導(dǎo)致早期LH峰［36］，但是Kisspeptin拮抗劑卻減弱排卵期LH和FSH峰［37］。人類注射Kisspeptin-54產(chǎn)生LH峰，可使卵母細(xì)胞成熟［38］。另一項(xiàng)研究表明，Kisspeptin-54可產(chǎn)生LH峰，并縮短女性月經(jīng)周期［39］。另外，給去勢(shì)大鼠注射Kisspeptin-10，只有在雌孕激素替代治療后，才能對(duì)促性腺激素起反應(yīng)［35］。進(jìn)一步的研究發(fā)現(xiàn)選擇性阻斷大鼠ER-α，明顯抑制LH反應(yīng)，外周注射KP-10后，并不能出現(xiàn)排卵前LH峰值［40-41］。這些研究還觀察到，給去勢(shì)大鼠補(bǔ)充孕激素及選擇性雌激素受體-激動(dòng)劑有利于他們的潛在誘導(dǎo)排卵期促性腺激素的激增［5］。

8 Kisspeptin與生殖內(nèi)分泌疾病的關(guān)系

研究表明Kisspeptin與臨床上許多引起不孕的疾病密切相關(guān)，如多囊卵巢綜合癥，多囊卵巢綜合癥是一種具有代謝異常及內(nèi)分泌異常表現(xiàn)的疾病,而Kisspeptin與體內(nèi)代謝狀況與內(nèi)分泌環(huán)境存在關(guān)聯(lián)［42］,因此與多囊卵巢綜合癥的發(fā)生發(fā)展密切相關(guān)，Jeon等［43］研究發(fā)現(xiàn)多囊卵巢綜合癥患者血清中Kisspeptin水平明顯升高；再如影響排卵的高泌乳素血癥，易導(dǎo)致月經(jīng)失調(diào)和不孕，Charlotte［44］等利用小鼠作為模式動(dòng)物，他們發(fā)現(xiàn)在小鼠中，高泌乳素血癥不僅直接抑制kisspeptin分泌，而且通過阻止GnRH的分泌而有效地阻斷卵巢周期性。此外，Kisseptin與其他生殖內(nèi)分泌疾病也存在一定關(guān)聯(lián)，如GPR-54基因敲除的小鼠表現(xiàn)出IHH等［45］。由此推Kisspeptin與卵巢功能存在潛在聯(lián)系。此外Kisspeptin作為GnRH的上游調(diào)節(jié)因子,國(guó)外已有研究表明Kisspeptin可用于誘導(dǎo)排卵,并減少卵巢過度刺激綜合癥的發(fā)生［46-47］。

9 結(jié)論

目前已有充分證據(jù)支持kisspeptins作為GnGH脈沖分泌中央調(diào)制器，在控制青春期啟動(dòng)和在人類兩性生殖中起著舉足輕重的作用。也有明顯的證據(jù)表明kisspeptins作為生殖和人體代謝之間的重要紐帶，介導(dǎo)性激素的正、負(fù)反饋信號(hào)來調(diào)節(jié)GnRH神經(jīng)元。

人類外周注射的kisspeptin，也被視為一個(gè)潛在的新的治療方案，在促性腺激素脈沖分泌紊亂的疾病治療方面，而且是目前研究的一個(gè)熱點(diǎn)。目前相關(guān)領(lǐng)域已作了大量的工作，但仍需要制定一個(gè)合適的方案，使kisspeptin可以用于人類不孕不育和生殖障礙的治療。Kisspeptin對(duì)外周生殖器官的作用，表明其在調(diào)節(jié)重要生理過程中的作用確定，包括卵巢功能、胚胎植入和胎盤形成。但是，對(duì)于這些研究結(jié)果與人類有相關(guān)性，還需要更有力的證據(jù)，因?yàn)槟壳暗难芯績(jī)H涉及動(dòng)物模型。

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New progress in the mechanism of Kisspeptins on hypothalamic pituitary gonadal axis

SHI Mingqing1,ZHOU Huifag21Lishui Hospital of Traditional Chinese Medicine,Zhejiang Province,Lishui 323000,China;2The first clinical medical college of Nanjing University of Chinese Medicine,Jiangsu province,Nangjing 210023,China

In recent years,the discovery of Kisspeptins makes people have a new understanding of the neuroendocrine axis regulating puberty and reproduction.Kisspeptins is not only the upstream factor that promotes the secretion of GnRH,but also regulates the hypothalamic pituitary ovary axis,which is mainly manifested in the regulation of gonadotropin secretion, the initiation of puberty and the regulation of reproductive function.By observing the healthy population and reproductive endocrine disorders,we found that Kisspeptins can stimulate the secretion of GnRH,which induces LH secretion,and enhance the pulse frequency of LH.At present,many animal experiments have proved that Kisspeptins has the potential function in the following aspects,such as the function of ovary,embryo implantation and placenta formation.This article will focus on the existing basis for the Kisspeptins regulation of GnRH pulse type secretion,in particular,the initiation of puberty and reproductive endocrine aspects.

kisspeptins;hypothalamic pituitary gonadal axis;GnRH secretion;puberty initiation;reproductive and endocrine function

2016-07-14

石明晴，碩士，主治醫(yī)師，E-mail:936391460@qq.com

周惠芳，主任醫(yī)師，教授，博士研究生導(dǎo)師，E-mail: zhouhuifang2011301@163.com