：從實驗到臨床運用
陳啟煌醫師
台北醫學大學醫學系專任部定助理教授
台北醫學大學附設醫院生殖醫學中心主治醫師
中華民國駐查德共和國醫療團團長
Northwestern University & Johns Hopkins University試管嬰兒及
人工生殖研究員
中文演講摘要
癌症治療的進步已改善年輕癌症患者的長期生存率。生殖保存在任何威脅到生殖功能的情況下變成一個新興的需求與關心的議題。癌症生殖(Oncofertility)已成為一個跨學科領域銜接生物醫學與社會科學，根據個人生殖選項、選擇以及目標在癌症診斷、治療以及生存中需要檢視的問題。 放射線治療與化學治療對於生殖功能的影響與此類治療所引起的不孕症有關。Alkylating 藥物為化療藥物具有明確的性腺毒性，在現今臨床上常被拿來使用。女性癌症患者在化療或放療之後會喪失卵巢功能，因此如何保存其生育力已付出許多努力與關注。生育力保存對男性與女性都是最重要的，而不只是”女性的議題”。睪丸對放射線治療與化學治療的細胞毒性比卵巢更敏感，因此隨後的傷害對男性生育力的損傷比女性更為嚴重。 保存生育力之實驗與臨床策略包含外科手術卵巢移植以避免放射線傷害、子宮頸癌的環狀切除術、生育年齡使用生殖毒性較少之藥物、GnRHa的使用以減少化療造成的性腺傷害、標的抗凋零藥物使用以保護生殖細胞、冷凍保存配子與胚胎、體外促進未成熟卵子、性腺組織與完整性腺之成熟以及人工卵巢的組織工程等。 經由GnRH analogue抑制下視丘-腦下垂體-卵巢軸已被提出是一種非侵入性的方法以保護卵巢免受化療傷害。在動物模式中，促性腺釋放激素類似物在化療藥物引起的卵巢性腺毒性的保護效果已經拿來有效應用。在人類，GnRH類似物相對於化療的效果已被驗證。雖然看好GnRH類似物的效果，然而不同的追蹤時間、不同的治療策略、endpoint不易定義、不敏感的標記(例如懷孕率、經期恢復、血清中性荷爾蒙與促性腺激素的濃度)以及有限的樣本數都會影響所得到結論的可信度。在小鼠實驗我們於2010年發表證實GnRH類似物於化療的效果有效保存始基濾泡。 有鑑於一般癌症病患無法再承受額外的卵巢刺激的情況，IVM是一個可行的選項。此項技術只需要小量或不需要賀爾蒙的注射，而未成熟的卵子可以收集在實驗室中成熟。 從20世紀中開始，活細胞、組織以及器官的冷凍保存已經跨越醫學範圍應用在瀕臨絕種或有利經濟的物種上。隨著過去二十年來人工生殖技術成熟的到來，胚胎與配子的冷凍保存已成為最可行的策略，但其缺點是每次實施仍然受限於卵子與胚胎的數目。利用玻璃化冷凍成功保存卵子也將提供年輕女性有機會保存卵子。 從1990年起隨著卵巢組織開始冷凍保存的研究顯著增加，當完成癌症治療之後移植冷凍卵巢組織已被建議做為另一種恢復女性生育力的方法，這些女性在化療或放療後有很高的風險發生卵巢衰竭。截至2011年底，總共有18位利用慢速冷凍保存卵巢組織活產。我們在2006年發表兔子全卵巢慢速冷凍保存後自體異位移殖成功。然而人類整個卵巢冷凍保存以及卵巢組織玻璃化冷凍之後再移植已經有許多著墨但仍在發展初期尚無臨床成就。卵巢組織於同卵雙胞胎捐贈產子也提供卵巢組織於異體移植捐贈的是否產生強烈排斥與抗排斥藥物的成效缺乏進一步的研究 患有癌症的成年男性或青春期後男孩在化療或放療前可以將成熟精子冷凍保存。目前實驗技術也在發展保存青春期前男孩的生育力，這些技術經由生殖細胞移植、睪丸異體移植、自體移植或未成熟睪丸組織冷凍保存等。精蟲幹細胞與睪丸組織等男性生殖保存在小動物模式、非人類靈長類與人類中都有密集的研究，未來將可以應用在青春期前男孩，雖然到現在人類尚無成功孕育下一代的例子。 有鑑於生殖保存突飛猛進、癌症治療成功不斷增加使得目標在保存癌症病患生育力的實施與研究更形重要。
英文摘要講稿
Fertility Preservation Update: From Bench to Bedside
Chen, CH MD
Advances in cancer therapy have improved the long-term survival of young cancer patients. Fertility preservation has become an emergent need and the matter of concern for any case where the reproductive function is threatened. Oncofertility has emerged as an interdisciplinary field bridging biomedical, social sciences and examines issues regarding an individual’s fertility options, choice and goals in light of cancer diagnosis, treatment and survivorship.
The effects of radiation and chemotherapy on gonadal function are relevant to the morbidity induced by such treatments. Alkylating agents are the most reliably gonadaltoxics of chemotherapeutic agents in common clinical use currently. Much effort and attention has been paid to preserve fertility in women with cancer, who can lose their ovarian function after chemo- or radiotherapy. Fertility preservation is of utmost importance for both men and women and is not solely a “woman’s issue”. The testis is more sensitive than the ovary to cytotoxic therapy, so the ensuing injury is more damaging to male fertility than it is to female fertility.
Experimental and clinical strategies for preserving fertility include surgical ovarian translocation (oophoropexy) to avoid radiation, radical trachelectomy for cervical cancer, medical less gonadotoxic chemotherapy for the reproductive age, GnRHa to reduce gonadal damage from chemotherapy, targeted antiapoptotic agents for germ cell protection, cryopreservation of gamate, embryo, in vitro maturation of immature eggs, gonadal tissue or intact gonads and tissue engineering of artificial ovary.
Suppression of the hypothalamic–pituitary–ovarian axis by a GnRH analogue has been proposed to be a noninvasive method to protect the ovarian reserve from chemotherapy. Protective effect of a gonadotropin-releasing hormone analogue on
chemotherapeutic agent-induced ovarian gonadotoxicity in animal model lends weight to the effective application. In humans, the effect of GnRH analogues in parallel to chemotherapy has been examined. Despite the promising effects of GnRH analogues, the unequal follow-up time, different treatment protocols, poorly defined endpoints, less sensitive markers (such as pregnancy rate, resumption of menstruation, levels of serum sex steroids and gonadotropins) and limitation of sample size, all affect the strength of the conclusion.
Keeping in view the general condition of cancer patients who cannot be subjected to additional stress of ovarian stimulation, IVM is a feasible option. In this technique, minimal or no hormone injections are given and the immature oocytes are collected and matured in the lab.
Since the middle of the 20th century, cryopreservation of living cells, tissues, and organs has been applied across abroad range of medical applications for use with endangered or economically beneficial species. With the advent of mature assisted reproductive technology over the past two decades, cryopreservation of embryo and gamete becomes the most accessible strategy but the drawback of limited egg and embryo number for each practice remains. The successful preservation of oocytes by vitrification will also provide young women the opportunity to conceive and deliver using her own oocytes at the time she decides.
With the significant increase in studies on cryopreservation of ovarian tissue conducted since the 1990s, subsequent transplantation after completed cancer treatment has been suggested as an alternative to restore fertility for girls and women who are at high risk for ovarian failure after chemotherapy or radiotherapy. Until the end of 2011, a total of 18 live births have been reported by slow freezing of ovarian tissue preservation. The whole ovarian cryopreservation and vitrification of ovarian tissue followed by transplantation have been paid much effort and attention but still in infancy with limited clinical achievement.
Cryopreservation of mature spermatozoa for men or postpubertal boys with cancer is available before chemo- and radiotherapy. Experimental techniques are also under development for preserving the fertility of prepubertal boys by germ cell transplantation, testicular xenografting, autografting, or by the cryopreservation of immature testicular tissue. The intensive work of male fertility preservation for spermatogonial stem cell and testicular tissue in small animal model, non-human primates and humans raises the future application in prepubertal boys although not yet live birth in human nowadays.
In light of rapid advances in fertility preservation, the increasing successes of oncologic treatments make implementation of procedures aimed at preserving fertility for cancer patients even more crucial.
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