胚胎著床前基因篩檢(PGS)的進階版(NGS)診斷出極小的染色體平衡轉位,經植入正常胚胎一顆健康足月活產,解決了五次習慣性流產。

本篇發表在國外影響因子2.163的期刊J Assist Reprod Genet. 2017 Sep 30.
寶醫師身為該患者的主治醫師擔責任作者,指導李怡萱醫師投稿刊登。李怡萱醫師在本篇論文的激勵下發奮考取台北醫學大學臨床醫學研究所博士班預攻讀基因醫學

中文題目
同時預測罕見的染色體畸變與次世代(NGS)基於序列的綜合人類植入前胚胎(PGS)中的染色體篩選於習慣性流產

中文摘要
摘要採用植入前基因檢測方法,近年來廣泛作為輔助生殖技術的一部分。由於脫氧核糖核酸的突破性發展酸(DNA)測序。隨著進步的技術,並提高下一代的分辨率測序(NGS),廣泛的全面染色體篩查以及小的臨床重大缺失並且可以同時執行重複。在這裡,我們提出罕見染色體畸變的病例:46,XY,dup(15)(q11.2q13),t(16; 18)(q23; p11.2),其中導致正常發育的成人但異常配子
導致復發性懷孕(RPL)。據我們所知,這是t(16; 18)易位的第一次報告。由NGS平台檢測到的小交換段MiSeq系統同時24染色體非整倍體

原文版

Title
Prediction of a rare chromosomal aberration simultaneously with next generation sequencing-based comprehensive chromosome screening in human preimplantation embryos for recurrent pregnancy loss
Author
Lee YX1, Chen CW1,2, Lin YH3,4, Tzeng CR1,5, CHEN CH 6,7
Abstract Preimplantation genetic testing has been used widely in recent years as a part of assisted reproductive technology (ART) owing to the breakthrough development of deoxyribonucleic acid (DNA) sequencing. With the advancement of technology and increased resolution of next generation sequencing (NGS), extensive comprehensive chromosome
screening along with small clinically significant deletions and duplications can possibly be performed simultaneously. Here, we present a case of rare chromosomal aberrations: 46,XY,dup(15)(q11.2q13),t(16;18)(q23;p11.2), which resulted in a normally developed adult but abnormal gametes leading to recurrent pregnancy loss (RPL). To our best knowledge, this is the first report of t(16;18) translocation with such a small exchanged segment detected by NGS platform of MiSeq system in simultaneous 24-chromosome aneuploidy screening.

NGS publised 2017

 

寶醫師發表最大型華人甲狀腺過氧化物酶抗體(Anti-TPO)與不孕症相關的研究

thyroid

 

 

期刊: Thyroid (甲狀腺) 2017年8月16.  

 

高影響因子期刊,

 impact factor: 5.515

 

寶醫師發表最大型華人甲狀腺過氧化物酶抗體(Anti-TPO)與不孕症相關的研究

 

 

 

題目

不明原因之卵巢庫存低下與甲狀腺過氧化酶抗體(Anti-TPO)陽性有關

 

陳芊彣1,2, 黃雅莉3, 黃瑞蘭1,

曾啟瑞2, 陳啟煌2,4

 

 

1衛生署部立雙和醫院婦產科,

2台北醫學大學附設醫院婦產部不孕科,

3台北醫學大學公共衛生學科,

4台北醫學大學醫學院婦產學科

 

 

摘要

 

背景:儘管已知甲狀腺過氧化酶抗體為卵巢早衰原因之一,甲狀腺自體免疫疾病與卵巢功能之關係仍然未明。已知甲狀腺自體免疫疾病之盛行率因人種而異,本研究旨在探討華人甲狀腺自體免疫疾病與卵巢功能之相關性。

 

方法:自2013年10月至2016年3月,執行於大學附設醫院不孕症門診之橫斷性研究,共收錄1044個初診資料齊全的病人。所有病人依卵巢功能分組,並於各組間比較甲狀腺功能,甲狀腺過氧化酶抗體以及甲狀腺球蛋白抗體盛行率。

 

結果:將所有病人納入分析發現,各卵巢功能組別間,甲狀腺功能、甲狀腺過氧化酶抗體以及甲狀腺球蛋白抗體盛行率皆無差異。然而,將已知有其他原因導致卵巢功能低下的病人剔除,分析其餘不明原因卵巢功能低下的病人,發現各卵巢功能組別間,僅有甲狀腺過氧化酶抗體盛行率有顯著差異:低卵巢功能(甲狀腺過氧化酶抗體陽性盛行率22.7%)、正常卵巢功能(14.0%)、高卵巢功能(10.3%),P=0.012。甲狀腺過氧化酶抗體數值高低則與卵巢功能無顯著相關(Spearman's
rho= -0.027, P=0.413)。針對不孕族群分析,只有不明原因不孕的族群,甲狀腺過氧化酶抗體陽性盛行率在各卵巢功能組別間有顯著差異:低卵巢功能(28.6%)、正常卵巢功能(15.7%)、高卵巢功能(9.5%),P=0.020。

 

結論:華人不明原因之卵巢庫存低下,與甲狀腺功能

(TSH)及甲狀腺球蛋白抗體(ATA)無關,僅僅與甲狀

腺過氧化酶抗體(Anti-TPO)陽性與否(非數值高低)有關。

 

 

 

這篇文章重大意義:

1. 國內未有華人最大型橫斷面研究卵巢庫存與更常見

的陽性TPO-Ab相關研究

 

2. 新陳代謝科,免疫科及生殖不孕科診斷治療分歧,尤其

部分醫師治療錯誤,用藥過重,導致患者免疫力下降

拼命降抗體的錯誤與荒謬。本篇重大發現: TPO-Ab

陽性與AMH低有顯著相關性,根據寶醫師的研究

Anti-TPO,高就要治療,只要適度

給予甲狀腺素(如昂特欣)就可以,

若甲狀腺亢進則由醫師建議,

也不一定貿然使用免生無謂的

副作用 , 不用刻意降抗體,

因為與anti-TPO的數據高低無

關,只要數字見紅,嚴重程度

與TPO的數據高低無關,

無謂的免疫治療花錢傷身,不

會讓anti-TPO紅字異常消失

 

 

刻意使用免疫藥物反而更容易導致流產

 

(Spearman's rho = -0.027,P = 0.413)。對於

不育症亞組,TPO-Ab陽性與不明原因不孕不育症的特

發性低卵巢庫存顯著相關(卵巢緩解率為28.6%,

正常:15.7%,高:9.5%,P = 0.020)。

 

 

 

 

3.本篇是內科內分泌及新陳代謝科重量級的世界級文

章,是華人最大,最具影響力的跨領域研究甲狀腺亢體與

卵巢之間的關係。

 

4.寶醫師用長時間的毅力及專注力收案三年的大數據,

 

特別感謝克大鼓勵我投稿挑戰甲狀腺期刊之王,一次攻

 

頂成功。

 

5.這篇陳啟煌醫師(寶醫師是責任作者),陳芊彣高徒在我指導

下是第一作者。陳芊彣高徒2017.09.01回雙和生殖中

心服務,是非常smart及謙虛的優秀台大醫科畢業生。

 

 

D5& D6的囊胚植入較第3天胚胎移植後單胎妊娠早產的風險增加

 D3 的胚胎
D5 & D6的囊胚



 

Human Reproduction  2013年1月24。搶鮮版 

 出處:第二名的不孕症期刊

 

 

D5& D6的囊胚植入較第3天胚胎移植後單胎妊娠早產的風險增加:加拿大試管嬰兒登錄系統於生育和男性不孕學會醫學會的分析。

抽象
研究的問題:卵裂期(D3)胚胎移植與(ET5/6天的囊胚階段所取得的成果比較單胎妊娠胎兒的生產影響>

摘要答:有一個風險顯著較高的早產(<37週)後,單身延長胚胎體外培養(5/6日)相比,卵裂期(3天)轉移。

什麼是已知的了:最近的兩項研究,從瑞典和美國,D5& D6的囊胚植入增加單胎妊娠早產的風險。美國的研究發現D5& D6的囊胚植入增加單胎妊娠
極度早產的風險,瑞典的研究顯示增加胎兒畸形

研究設計,大小和持續時間進行了回顧性隊列研究。數據收集新鮮IVF / ICSI ET週期(2001-2009)的所有單胞胎後,從加拿大ART註冊數據庫。

參加者/材料,設置方法:一共有12 712單胞胎都包括在內。這些,9506單胎妊娠來自第3天胚胎移植,3206單胎妊娠來自囊胚(5/6天)胚胎移植。

主要結果和作用的機會:早產率<37週(未經調整潛在的混雜因素)5/ 6與日3傳輸(17.2%比14.1%,P <0.001)。使用logistic回歸分析調整混雜因素,<37週的早產率是5/6天與第3天轉移(比值比為1.3295%可信區間1.17-1.49)相比,顯著增加後的唯一結果。下面的混雜因素進行了調整:一年的治療,產婦年齡(連續),奇偶(0
1出生),診斷類別,數量的卵母細胞檢索(2001-2009[2020(高反應組) ,人工授精的方法(IVFICSI),移植胚胎數(123)和存在的消失雙(1胎兒心臟上的初始超聲檢查)。

限制,需要注意的原因:產後隨訪研究,以確定如果我們觀察到這種差異轉化為長期的不利影響,這些後代。早期的早產率(<32週)在5/6日與第3天高,但數量很少的情況下,在這一類沒有顯示出差異(3.02.7%,P = 0.34)。

廣泛影響的調查結果:我們發現一個風險顯著較高的早產(<37週)D5& D6的囊胚植入較第3天胚胎移植後單胎妊娠早產的風險增加,單身延長胚胎體外培養(5/6日)相比,卵裂期(第3天)傳輸,即使在調整混雜因素。我們的研究結果與前兩個研究,但是,我們並沒有表現出美國的研究發現D5& D6的囊胚植入增加單胎妊娠
極度早產的風險,瑞典的研究顯示增加胎兒畸形。我們推測,有可能是一個長期的有害影響,在隨後的胎盤在體外胚胎培養。將需要更長的長期隨訪研究,以確定如果長時間在體外培養到囊胚階段相較較短的卵裂階段的胚胎培養有不利影響的長期健康的後代。

 

醫師的Comment:

來自文明進步的國家如美國、瑞典及加拿大的權威研究顯示:D5&D6的囊胚植入較第3天胚胎移植後單胎妊娠早產的風險增加,可能來自長時間在體外培養到囊胚階段相較較短的卵裂階段的胚胎培養有不利影響的長期健康的後代。IVF前的充份諮詢,產前遺傳診斷及高水準的產檢照顧在醫病間會的認知是非常重要的。

 

Hum Reprod. 2013 Jan 24. [Epub ahead of print]

Increased risk of preterm birth in singleton pregnancies after blastocyst versus Day 3 embryo transfer: Canadian ART Register (CARTR) analysis.

Dar SLibrach CLGunby JBissonnette FCowan Lon behalf of the IVF Directors Group of the Canadian Fertility and Andrology Society.

Source

CReATe Fertility Center , 790 Bay Street, Suite 1100 , Toronto , Ontario , Canada M 5G 1N8 .

Abstract

STUDY QUESTION:

Are the fetal outcomes of singleton pregnancies that result from cleavage stage embryo transfer (ET) different from the outcomes from Day 5/6 blastocyst stage ET?

SUMMARY ANSWER:

There was a significantly higher risk of preterm birth (<37 weeks) in singletons after extended embryo culture (Day 5/6) compared with cleavage stage (Day 3) transfer.

WHAT IS KNOWN ALREADY:

Two recent studies, from Sweden and the USA , reported an increased risk of preterm birth in singleton pregnancies after Day 5/6 ET compared with Day 3 ET. The US study also showed increased early preterm births and the Swedish study showed increased fetal malformations in this group.

STUDY DESIGN, SIZE AND DURATION:

A retrospective cohort study was performed. Data were collected from the Canadian ART Register database for all singleton births after fresh IVF/ICSI ET cycles (2001-2009).

PARTICIPANTS/MATERIALS, SETTING, METHODS:

A total of 12 712 singleton births were included. Of these, 9506 resulted from a Day 3 ET and 3206 resulted from a blastocyst (Day 5/6) ET.

MAIN RESULTS AND THE ROLE OF CHANCE:

Preterm birth rate <37 weeks (unadjusted by potential confounding factors) was higher with Day 5/6 versus Day 3 transfers (17.2 versus 14.1%, P < 0.001). Using logistic regression analysis to adjust for confounding factors, preterm birth rate <37 weeks was the only outcome significantly increased after Day 5/6 compared with Day 3 transfer (odds ratio 1.32, 95% confidence interval 1.17-1.49). The following confounding factors were adjusted for: year of treatment (2001-2009), maternal age (continuous), parity (0 versus ≥1 birth), diagnosis category, number of oocytes retrieved [≤20 versus >20 (high responder group)], insemination method (IVF versus ICSI), number of embryos transferred (1, 2 or ≥3) and the presence of a vanishing twin (≥1 fetal heart on the initial ultrasonographic examination).

LIMITATIONS, REASONS FOR CAUTION:

Post-natal follow-up studies will be required to determine if this difference we observed translates into adverse long-term effects on these offspring. The rate of early preterm births (<32 weeks) was higher in Day 5/6 versus Day 3, but the low number of cases in this category did not have the power to show a difference (3.0 versus 2.7%, P = 0.34).

WIDER IMPLICATIONS OF THE FINDINGS:

We found a significantly higher risk of preterm birth (<37 weeks) in singletons after extended embryo culture (Day 5/6) compared with cleavage stage (Day 3) transfer, even when adjusting for confounding factors. Our findings are in agreement with the previous two studies; however, we did not show a difference in the very preterm deliveries (unlike the US study) or in fetal malformations (as in the Swedish study). We hypothesize that there may be a deleterious effect of prolonged in vitro embryo culture on subsequent placentation. Longer term follow-up studies will be required to determine if prolonged in vitro culture to the blastocyst stage has an adverse effect on the long-term health of offspring when compared with shorter cleavage stage culture.

 

2017.05.05.今日最新文獻:服用DHEA有助於卵巢功能不佳者會增強卵巢對排卵針藥物的反應

DHEA

白藜蘆醇保護高齡小鼠不孕


 

Human Reproduction  201314日。搶鮮版  

 

出處:第二名的不孕症期刊

 

 

白藜蘆醇保護高齡小鼠不孕

 

 

細胞生物學與遺傳學系,藥物化學生物學國家重點實驗室,生命科學學院,南開大學,天津 300071,中國。

抽象
研究的問題:
白藜蘆醇抵消年齡相關的不孕生殖衰老小鼠模式的嗎?
摘要答案:
長期口服白藜蘆醇對減少生育與生殖衰老小鼠的保護。
什麼是已知的了:卵巢老化和不育的卵母細胞和卵泡及卵母細胞質量下降的損失歸因於與年齡老化。隨著年齡的增長自由基的積累導致DNA突變,蛋白質損傷,端粒縮短,細胞凋亡,加速卵巢衰老。越來越多的證據表明,白藜蘆醇,豐富了某些食物,例如紅葡萄和葡萄酒,體細胞具有抗腫瘤和抗衰老的作用,通過影響不同的信號轉導通路,包括抗氧化,以及激活SIRT1和端粒酶。我們研究了潛在的白藜蘆醇,以延緩卵巢衰老的近交系的C57/BL6小鼠模型。
研究設計,大小,持續時間:
年輕C57/BL6女性(年齡在2-3個月)被餵食白藜蘆醇添加到飲用水在30毫克/升〜7.0毫克/公斤/天,6個月或12個月的生育和卵巢功能比較帶或不帶白藜蘆醇治療的老鼠,與年輕小鼠生殖控制。實驗重複3次,每個重複,女25例,隨機平均分配到每個治療組。
參加者/材料,設置方法:
雌性小鼠的繁殖性能是決定產仔數,卵巢內的卵泡及卵母細胞的數量和質量,並與年齡匹配的對照比較。白藜蘆醇對端粒和端粒酶的活性,並與細胞衰老相關基因的表達的影響也進行了評估。
主要結果和角色的機會:
年輕老鼠餵食白藜蘆醇12個月,保留了生育能力,而年齡匹配的對照組沒有子代,為12個月餵白藜蘆醇的小鼠表現出較大的卵泡池比對照組(P <0.05)。此外,端粒酶活性,端粒長度與年齡有關的基因在餵白藜蘆醇的小鼠卵巢中的表達相似,那些年輕的老鼠,但是從這些
年齡相匹配的老年小鼠差異(P <0.05)。白藜蘆醇改善(P <0.05)卵母細胞的數量和質量,就證明了紡錘體形態和染色體定位。此外,白藜蘆醇在體外以劑量依賴性的方式受影響的胚胎發育。
限制,謹慎的理由:
的劑量白藜蘆醇的實驗條件下使用不同的研究小組有各種不同的影響很大,而且劑量的白藜蘆醇的有效性和毒性。微調劑量的白藜蘆醇可能對卵巢功能優化其抗衰老的作用。
更廣泛的影響的研究結果:
我們的數據提供了一個證明的原則,在雌性小鼠的白藜蘆醇的保留生育功能的影響。雖然消耗的卵巢儲備功能的高品質的卵母細胞,也有助於增加女性不孕不育與生殖衰老,獲得的數據使用的小鼠模型可能無法直接推斷到人類的繁衍,如果任何臨床試驗嘗試。以及更廣泛的研究是必要的。

 

陳醫師的意見

 

儘管這是用年紀大的小鼠的動物實驗,研究證實高齡老鼠卵巢功能不足,而長期服用白藜蘆醇改善(P <0.05)卵母細胞的數量和質量,就證明了紡錘體形態和染色體穩定。人類尚無此研究

 

Hum Reprod. 2013 Jan 4. [Epub ahead of print]

Resveratrol protects against age-associated infertility in mice.

Liu MYin YYe XZeng MZhao QKeefe DLLiu L.

Source

Department of Cell Biology and Genetics, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences; Nankai University, Tianjin 300071, China.

Abstract

STUDY QUESTION:

Does resveratrol counteract age-associated infertility in a mouse model of reproductive aging?

SUMMARY ANSWER:

Long-term-oral administration of resveratrol protects against the reduction of fertility with reproductive aging in mice.

WHAT IS KNOWN ALREADY:

Loss of oocytes and follicles and reduced oocyte quality contribute to age-associated ovarian aging and infertility. Accumulation of free radicals with age leads to DNA mutations, protein damage, telomere shortening, apoptosis and accelerated ovarian aging. Increasing evidence shows that resveratrol, enriched in certain foods, for example red grapes and wine, has anti-tumor and anti-aging effects on somatic tissues by influencing various signaling pathways, including anti-oxidation, as well as activating Sirt1 and telomerase. We investigated the potential of resveratrol to stave off ovarian aging in the inbred C57/BL6 mouse model.

STUDY DESIGN, SIZE, DURATION:

Young C57/BL6 females (aged 2-3 months) were fed with resveratrol added to drinking water at 30 mg/l (providing 7.0 mg/kg/day) for 6 or 12 months, and the fertility and ovarian functions were compared among mice treated with or without resveratrol, and young mice served as reproductive controls. Experiments were repeated three times, with an average of 25 females randomly allocated to each treatment group for each repeat.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Reproductive performance of female mice was determined by litter size, ovarian follicles and oocyte quantity and quality, and compared with age-matched controls. The impact of resveratrol on telomeres and telomerase activity, and expression of genes associated with cell senescence also was evaluated.

MAIN RESULTS AND THE ROLE OF CHANCE:

Young mice fed with resveratrol for 12 months retained the capacity to reproduce, while age-matched controls produced no pups. Consistently, mice fed with resveratrol for 12 months exhibited a larger follicle pool than controls (P < 0.05). Furthermore, telomerase activity, telomere length and age-related gene expression in ovaries of mice fed with resveratrol resembled those of young mice, but differed (P < 0.05) from those of age-matched old mice. Resveratrol improved (P < 0.05) the number and quality of oocytes, as evidenced by spindle morphology and chromosome alignment. Also, resveratrol affected embryo development in vitro in a dose-dependent manner.

LIMITATIONS, REASONS FOR CAUTION:

The doses of resveratrol and the experimental conditions used by different research groups have varied considerably, and the dosage influences both the effectiveness and toxicity of resveratrol. Fine-tuning the dosage of resveratrol likely will optimize its anti-aging effects on ovarian function.

WIDER IMPLICATIONS OF THE FINDINGS:

Our data provide a proof of principle of the fertility-sparing effect of resveratrol in female mice. Although depletion of the ovarian reserve of high-quality oocytes also contributes to increased infertility with reproductive aging in women, the data obtained using a mouse model may not extrapolate directly to human reproduction, and more extensive research is needed if any clinic trials are to be attempted.