【摘要】 隨著社會(huì)的快速發(fā)展,多孩政策的實(shí)施,以及女性個(gè)人成長與職業(yè)規(guī)劃的變化,女性的結(jié)婚及生育的年齡呈現(xiàn)出逐漸增加的趨勢(shì)。這種變化導(dǎo)致卵巢儲(chǔ)備功能減退在育齡女性中的發(fā)病率逐年上升,從而引起了大眾及醫(yī)務(wù)人員的廣泛關(guān)注。卵巢儲(chǔ)備功能減退是指隨著年齡的增加,卵母細(xì)胞的數(shù)量及質(zhì)量逐漸降低,卵巢儲(chǔ)備功能減退的女性,生育能力往往下降,自然流產(chǎn)發(fā)生風(fēng)險(xiǎn)較高,這是針對(duì)生殖醫(yī)學(xué)領(lǐng)域的一大挑戰(zhàn)。卵巢儲(chǔ)備功能減退對(duì)女性的生育能力和生活質(zhì)量產(chǎn)生顯著影響。因此,針對(duì)這一問題,提供及時(shí)、有效的計(jì)劃生育和生育治療指導(dǎo)至關(guān)重要,故本文旨在對(duì)造成卵巢儲(chǔ)備功能減退的高危因素的最新研究進(jìn)展做一綜述,為卵巢儲(chǔ)備功能減退的臨床治療和預(yù)防提供一定的參考依據(jù)。
【關(guān)鍵詞】 卵巢儲(chǔ)備功能減退 年齡 女性不孕癥 育齡期女性
Research Progress on the Etiology of Diminished Ovarian Reserve/ZHANG Wenya, Tuerxunguli Haimudula, HAN Lili, WANG Fen. //Medical Innovation of China, 2024, 21(35): -178
[Abstract] With the rapid development of society, the implementation of the multi-child policy, and the changes of women's personal growth and career planning, the age of women's marriage and childbirth has shown a gradual increase. This change leads to an increase in the incidence of diminished ovarian reserve in women of childbearing age year by year, which has aroused widespread concern of the public and medical personnel. Diminished ovarian reserve function means that with the increase of age, the number and quality of oocytes gradually decrease, and the fertility of women with diminished ovarian reserve often shows a decline trend, and the risk of spontaneous abortion is higher, which is a major challenge in the field of reproductive medicine. Diminished ovarian reserve has a significant impact on a woman's fertility and quality of life. Therefore, it is very important to provide timely and effective family planning and fertility treatment guidance in response to this problem. Therefore, this paper aims to review the latest research progress on the high-risk factors causing the decline of ovarian reserve function, and provide certain reference for the clinical treatment and prevention of the decline of ovarian reserve function.
[Key words] Low ovarian reserve function Age Female infertility Women of childbearing age
First-author's address: Graduate School of Xinjiang Medical University, Urumqi 830017, China
doi:10.3969/j.issn.1674-4985.2024.35.039
卵巢儲(chǔ)備功能減退(diminished ovarian reserve,DOR)是導(dǎo)致育齡期女性不孕癥發(fā)生的最常見原因之一。DOR是指隨著年齡增加,卵母細(xì)胞的數(shù)量及質(zhì)量下降,導(dǎo)致卵巢儲(chǔ)備功能不足,引起女性生育能力下降及女性激素分泌的減少[1]。有8%~15%的育齡期女性可因種種原因?qū)е侣殉矁?chǔ)備功能減退,而在gt;40歲的女性人群中DOR的患病率則可能會(huì)超過50%[2]。根據(jù)波塞冬共識(shí),DOR被定義為血清抗米勒管激素(anti-Müllerian tube hormone,AMH)水平lt;1.2 ng/mL或竇卵泡計(jì)數(shù)(antral follicle count,AFC)lt;5枚[3]。根據(jù)2022年專家共識(shí):AMHlt;1.1 ng/mL,提示DOR;兩側(cè)卵巢AFClt;5~7枚,提示DOR;連續(xù)兩個(gè)月經(jīng)周期的基礎(chǔ)卵泡刺激素(FSH)≥10 IU/L提示DOR[4]。
卵巢儲(chǔ)備不足是一個(gè)日益嚴(yán)重的社會(huì)問題,需要我們從多個(gè)方面進(jìn)行預(yù)防和干預(yù)。目前,導(dǎo)致DOR發(fā)病的高危因素可能與年齡、基因遺傳、醫(yī)源性、自身免疫因素、感染因素等有關(guān)。通過了解高危因素并采取相應(yīng)的措施,我們可以幫助女性提高生育能力,減緩卵巢儲(chǔ)備功能減退的速度,從而提高她們的生活質(zhì)量。本綜述擬圍繞近些年來對(duì)卵巢儲(chǔ)備功能減退相關(guān)的最新的危險(xiǎn)因素及其相關(guān)研究成果總結(jié),旨在為DOR預(yù)防提供更加有新意的視角。
1 DOR的危險(xiǎn)因素
1.1 年齡
年齡是導(dǎo)致DOR發(fā)病的一個(gè)最主要的因素,高齡的DOR的發(fā)生是生理性的,但是年齡lt;40歲的女性發(fā)生DOR被認(rèn)為是病理性的,在人類女性中,卵母細(xì)胞的發(fā)育在胎兒時(shí)期開始并達(dá)到最大值[5],隨后卵母細(xì)胞開始不斷凋亡。大多數(shù)卵泡會(huì)隨著年齡的增長發(fā)生細(xì)胞凋亡而退化,最終導(dǎo)致卵泡閉鎖[6]。卵巢儲(chǔ)備和女性年齡與卵巢卵泡的數(shù)量和質(zhì)量密切相關(guān),這反映了女性的生殖潛力和不孕癥發(fā)生概率。
此外有相關(guān)研究發(fā)現(xiàn)高齡還可能增加發(fā)生染色體異常的可能,與20~32歲的年輕女性相比,32歲以上患有DOR的女性的染色體畸變更常見[7],并且取卵時(shí),與年輕女性相比,高齡女性的卵子在減數(shù)分裂前經(jīng)歷了更多的有絲分裂,這可能與氧化損傷導(dǎo)致端??s短、減數(shù)分裂紊亂有關(guān),并增加了染色體為非整倍體的卵母細(xì)胞數(shù)量,最終使不孕和流產(chǎn)率增加[8]。目前越來越多的新型DOR致病機(jī)制被揭示出來,包括氧化應(yīng)激損傷、線粒體功能障礙、能量代謝損傷、自噬和內(nèi)質(zhì)網(wǎng)應(yīng)激等[9]。隨著女性年齡的增加,女性卵母細(xì)胞數(shù)量及質(zhì)量在不斷下降,女性機(jī)體開始出現(xiàn)老化,卵巢環(huán)境隨之發(fā)生變化,導(dǎo)致女性的卵巢儲(chǔ)備功能減退。
1.2 遺傳因素
遺傳因素是導(dǎo)致DOR發(fā)病的重要原因之一,基因突變和染色體異??赡芘c過早發(fā)生DOR有關(guān)[10]。目前已經(jīng)發(fā)現(xiàn)一些基因的變異可能會(huì)導(dǎo)致患DOR的風(fēng)險(xiǎn)增加[11],比如BRCA1/2、H19等基因[12]。目前被證實(shí)導(dǎo)致DOR發(fā)病的一些基因,是既往已被證實(shí)導(dǎo)致是發(fā)性卵巢功能不全(POI)發(fā)病的基因,例如FMR1、FSHR、GDF9和NR5A1,DOR和POI的遺傳背景之間可能存在重疊,故卵巢儲(chǔ)備功能過早下降可能是由多基因相互作用形成的[13]。此外還有一些研究證據(jù)表明遺傳因素與環(huán)境因素兩者之間存在復(fù)雜的相互影響機(jī)制。
1.3 自身免疫因素
自身免疫性疾病可能導(dǎo)致DOR的過早發(fā)生[14]。有研究表明,自身免疫性疾病可能會(huì)導(dǎo)致卵巢儲(chǔ)備減少,甚至導(dǎo)致卵巢功能不全,并且與較低水平的AMH有關(guān),如橋本甲狀腺炎、系統(tǒng)性紅斑狼瘡(SLE)和1型糖尿病(T1DM)等[15]。此外還有一些研究發(fā)現(xiàn),通過對(duì)AMH的檢測(cè),在一些患有自身免疫性疾病的青少年中,沒有出現(xiàn)卵巢儲(chǔ)備功能受損的情況,這提示自身免疫性抗體可能需要一定時(shí)間才能對(duì)卵巢儲(chǔ)備功能產(chǎn)生不利影響[16]。自身免疫性疾病可能導(dǎo)致卵巢炎癥的發(fā)生[17],還可能影響下丘腦-垂體-卵巢(HPO)軸疾病,使激素分泌失調(diào)最終導(dǎo)致卵巢儲(chǔ)備功能減退[18]。許多研究闡明了自身免疫抗體與卵巢儲(chǔ)備功能減退之間的密切關(guān)系,這主要由淋巴細(xì)胞性卵巢炎和卵巢自身抗體的存在及其他自身免疫相關(guān)疾病所導(dǎo)致[19],因?yàn)槁殉矝]有免疫保護(hù),故卵巢容易受到自身免疫抗體攻擊,卵母細(xì)胞是常見的自身免疫抗體攻擊的靶細(xì)胞之一,大量的抗體產(chǎn)生,損傷卵母細(xì)胞,加之炎癥的影響,使卵泡數(shù)量減少,導(dǎo)致DOR過早發(fā)病,所以患有自身免疫性相關(guān)疾病的女性,更應(yīng)該盡早完成生育目標(biāo)。
1.4 醫(yī)源性因素
醫(yī)源性因素是導(dǎo)致卵巢儲(chǔ)備功能減退的一個(gè)重要原因。主要見于有卵巢手術(shù)史、化療史、放療史的患者。有研究發(fā)現(xiàn),卵巢子宮內(nèi)膜異位癥對(duì)患者的生育能力有負(fù)面影響,并可能影響卵巢儲(chǔ)備功能[20],導(dǎo)致AMH降低。并且一些盆腹腔的手術(shù)也會(huì)引起AMH的顯著下降,如腹腔鏡下子宮肌瘤剔除術(shù)及腹腔鏡下卵巢囊腫剝除術(shù),并且有研究結(jié)果發(fā)現(xiàn),卵巢囊腫剝除手術(shù)可能在術(shù)后會(huì)進(jìn)一步導(dǎo)致卵巢儲(chǔ)備功能減退,這種情況可能持續(xù)至術(shù)后6個(gè)月[21]。一項(xiàng)橫斷面研究發(fā)現(xiàn),只有年齡和既往卵巢手術(shù)(而非卵巢子宮內(nèi)膜異位囊腫本身)與AMH水平lt;1 ng/mL有關(guān)[22]。在卵巢囊腫剝除術(shù)中,尤其是卵巢子宮內(nèi)膜異位囊腫剝除術(shù)。隨著現(xiàn)代醫(yī)學(xué)的進(jìn)步,針對(duì)患有惡性腫瘤的患者的治療方式的多樣性發(fā)展,許多療法都可能導(dǎo)致卵巢儲(chǔ)備功能減退及提前絕經(jīng)。有相關(guān)研究發(fā)現(xiàn),針對(duì)惡性腫瘤患者化療中所使用的化療藥物會(huì)消耗患者現(xiàn)存的卵泡而引起卵巢儲(chǔ)備功能減退,化療藥物的種類、使用計(jì)量及初始化療的年齡決定卵巢儲(chǔ)備功能減退的程度[23]。一些相關(guān)研究發(fā)現(xiàn),化療導(dǎo)致DOR發(fā)生的最主要的兩個(gè)相關(guān)預(yù)測(cè)因素是基線卵巢儲(chǔ)備和烷化劑的使用劑量,并且該研究發(fā)現(xiàn)初始化療前較高的AMH可能會(huì)減少DOR的發(fā)生[24]。一些其他相關(guān)研究也證實(shí)了這個(gè)觀點(diǎn),并且認(rèn)為開始化療時(shí)年齡越低發(fā)生DOR的可能性越小[25]。但也有一些其他研究發(fā)現(xiàn),未成年的惡性腫瘤患者進(jìn)行相關(guān)的化療及放療治療后,可能會(huì)導(dǎo)致卵巢儲(chǔ)備功能減退甚至卵巢早衰,認(rèn)為這可能是化療及放療治療對(duì)于下丘腦-垂體和性腺軸的破壞所導(dǎo)致的[26]。此外放療也是導(dǎo)致卵巢儲(chǔ)備功能減退的一個(gè)危險(xiǎn)因素,當(dāng)患者處于放療射線的照射范圍內(nèi)時(shí),可能會(huì)發(fā)生卵巢衰竭,放療射線對(duì)卵巢損傷的程度取決于患者的年齡及所用性腺毒性藥物的照射劑量和類型[27],并且由于卵母細(xì)胞對(duì)電離輻射損傷敏感,輻射射線可能會(huì)對(duì)卵泡細(xì)胞造成不可逆的損害,例如卵母細(xì)胞丟失和卵泡數(shù)量下降,表現(xiàn)為月經(jīng)不調(diào)和卵巢衰竭,因此,針對(duì)患有惡性腫瘤及需要進(jìn)行卵巢手術(shù)治療的育齡期婦女,在進(jìn)行治療之前,應(yīng)考慮到這些治療方式對(duì)卵巢儲(chǔ)備功能及生育能力的影響,在進(jìn)行治療的同時(shí)積極保存女性生育能力。
1.5 感染因素
感染因素也是導(dǎo)致卵巢儲(chǔ)備功能減退的一個(gè)重要因素。一些病毒或細(xì)菌可直接侵襲女性的生殖系統(tǒng),引起卵巢炎癥的發(fā)生、卵巢儲(chǔ)備功能減退。一些研究發(fā)現(xiàn),在青少年時(shí)感染腮腺炎病毒可能會(huì)累及卵巢組織,導(dǎo)致病毒性卵巢炎[28],在一些發(fā)生卵巢早衰并在青少年時(shí)期有過腮腺炎感染史的患者中,發(fā)現(xiàn)卵巢纖維化病灶,進(jìn)一步證實(shí)腮腺炎病毒可能會(huì)引起卵巢儲(chǔ)備功能減退[29]。其他病原體如結(jié)核桿菌、帶狀皰疹病毒、巨細(xì)胞病毒、人類免疫缺陷病毒(HIV)及高危型人乳頭瘤病毒(HPV)等病原體也可侵害卵巢組織,引起卵巢組織的炎癥發(fā)生,導(dǎo)致卵巢儲(chǔ)備功能減退[30]。
1.6 其他因素
環(huán)境因素、生活方式及社會(huì)心理因素等也可能對(duì)卵巢儲(chǔ)備功能產(chǎn)生影響,有相關(guān)研究發(fā)現(xiàn),甲醛可能會(huì)使卵泡凋亡,影響卵巢功能[31]?,F(xiàn)如今處于全球變暖環(huán)境中,有相關(guān)研究發(fā)現(xiàn),長期處于溫度較高的環(huán)境中可能會(huì)導(dǎo)致女性的卵巢儲(chǔ)備功能減退,導(dǎo)致女性生殖系統(tǒng)的衰老加速[32]。在一項(xiàng)針對(duì)患有不孕癥的韓國女性的研究中,發(fā)現(xiàn)環(huán)境中PM濃度與卵巢儲(chǔ)備能力之間呈負(fù)相關(guān)的關(guān)系,這說明空氣污染可能對(duì)女性生育能力有潛在不利影響[33]。有相關(guān)研究發(fā)現(xiàn),環(huán)境中存在很多物質(zhì)可能會(huì)導(dǎo)致女性卵巢儲(chǔ)備功能減退,如現(xiàn)代工業(yè)生產(chǎn)產(chǎn)生的持久性有機(jī)污染物(POPs)可能與女性卵巢儲(chǔ)備功能減退有關(guān),此外如有機(jī)氯農(nóng)藥(OCPs)、10種多氯聯(lián)苯(PCBs)、3種多溴聯(lián)苯醚(PBDEs)和9種全氟烷基物質(zhì)(PFAS)可能會(huì)導(dǎo)致健康卵泡密度下降[34]。根據(jù)一些研究結(jié)果表明,不良的生活習(xí)慣可能會(huì)對(duì)卵巢儲(chǔ)備功能產(chǎn)生不良影響[35]。比如高體重指數(shù)(BMI)對(duì)卵巢有負(fù)面影響,會(huì)減少竇卵泡數(shù)量和降低AMH水平,并且降低卵母細(xì)胞質(zhì)量[36]。此外如過大的生活壓力及過快的生活節(jié)奏、吸煙、肥胖、體重過低與厭食、過量飲酒、吸毒及攝入過量咖啡因等不良生活習(xí)慣也可能導(dǎo)致卵巢儲(chǔ)備功能減退[37]。此外有研究發(fā)現(xiàn),心理因素同樣也能對(duì)卵巢儲(chǔ)備功能產(chǎn)生影響,長期處在焦慮及抑郁等不良心理狀態(tài)下的女性可能會(huì)出現(xiàn)卵巢儲(chǔ)備功能減退的情況[38],并且有研究發(fā)現(xiàn)長期保持這種負(fù)面情緒可能會(huì)對(duì)HPO軸功能的產(chǎn)生影響,從而導(dǎo)致卵巢儲(chǔ)備功能減退[39]。所以長期暴露于不良環(huán)境中、長期處于不良心理狀態(tài)及有不良生活習(xí)慣的女性應(yīng)盡快改善這種不良情況,避免對(duì)女性生育能力產(chǎn)生影響。
2 總結(jié)
綜上所述,隨著年齡的增長,卵巢功能下降是一個(gè)自然而然的生理過程,但病理性的DOR發(fā)病率逐年攀升,發(fā)病機(jī)制尚不能完全明了,且致病因素復(fù)雜呈進(jìn)行性發(fā)展。多種因素均能導(dǎo)致病理性的DOR發(fā)生,例如遺傳因素、自身免疫性因素、醫(yī)源性因素、感染因素等。針對(duì)有易感因素的高危人群應(yīng)盡早進(jìn)行干預(yù),盡快完成生育目的。對(duì)于這類人群,應(yīng)在早期完成卵巢儲(chǔ)備功能的相關(guān)評(píng)估;若發(fā)現(xiàn)卵巢功能下降,則應(yīng)積極干預(yù),必要時(shí)使用輔助生殖技術(shù)完成生育目標(biāo)。對(duì)于需要行盆腔手術(shù)治療及放化療治療且有生育要求的女性,在臨床治療方法的選擇在中也應(yīng)盡可能地降低對(duì)卵巢儲(chǔ)備功能的影響,盡量避免醫(yī)源性卵巢損傷,最大限度上保護(hù)卵巢儲(chǔ)備功能,并且積極指導(dǎo)生育,盡早完成生育目標(biāo),應(yīng)針對(duì)不同患者選擇個(gè)體化治療方法。對(duì)于處在不良生活環(huán)境及不良生活模式的患者,應(yīng)盡早幫助患者改善生活環(huán)境及生活模式,積極保存患者生育能力。
希望未來更多優(yōu)質(zhì)科研數(shù)據(jù)的產(chǎn)生,為DOR的早期診斷及預(yù)防提供更多證據(jù),幫助更多DOR患者保存生育力,達(dá)成生育目的。
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(收稿日期:2024-10-22) (本文編輯:田婧)