Mesenchymal stem cells (MSCs間葉幹細胞) 可有效應用於子宮內膜沾黏受損重建

https://onlinelibrary.wiley.com/doi/10.1002/rmb2.12339

Mesenchymal stem cells for restoring endometrial function: An infertility perspective

Background

Mesenchymal stem cells (MSCs) can be derived from several tissues such as bone marrow, placenta, adipose tissue, or endometrial tissue. MSCs gain a lot of attention for cell-based therapy due to their characteristics including differentiation ability and immunomodulatory effect. Preclinical and clinical studies demonstrated that MSCs can be applied to treat female infertility by improving of the functions of ovary and uterus. This mini- review focuses on the current study of treatment of endometrial infertility by using MSCs.

Methods

The present study performed a literature review focusing on the effect of MSCs for treatment of women infertility caused by endometrial dysfunction.

Results

Bone marrow-, umbilical cord-, adipose-, amniotic-, and menstruation-derived MSCs enhance endometrial cell proliferation, injury repairs as well as reducing scar formation. The beneficial mechanism probably via immunomodulatory, cell differentiation, stimulates endometrial cell proliferation and down-regulation of fibrosis genes. The major advantage of using MSCs is to improve endometrial functions resulting in increased implantation and pregnancy.

Conclusions

MSCs exhibit a potential for endometrial infertility treatment. Adipose- and menstruation-derived stem cells show advantages over other sources because the cells can be derived easily and do not causes graft rejection after autologous transplantation.

玻璃化冷凍單一載具之 (1)置入胚胎數量 , (2)放置方式  間距, (3)冷凍液殘留量

並不明顯影響溫度下降速度

Cryobiology

Volume 103, December 2021, Pages 22-31

Vitrifying multiple embryos in different arrangements does not alter the cooling rate☆

Author links open overlay panel

Vitrification is the most common method of cryopreservation of gametes in fertility clinics due to its improved survival rates compared to slow freezing techniques. For the Open Cryotop® vitrification device, the number of oocytes, or embryos, mounted onto a single device can vary.

In this work, a mathematical model is developed for the cooling of oocytes and embryos (samples). The model is solved computationally, to investigate whether varying the number of samples mounted onto the Open Cryotop® affects the cooling rates, and consequently the survival rates, of vitrified samples. Several realistic spatial arrangements of samples are examined, determining their temperature over time. In this way we quantify the effect of spatial arrangement on the cooling rate.

Our results indicate that neither the spatial arrangement nor the number of mounted samples has a large effect on cooling rates, so long as the volume of the cryoprotectant remains minimal. The time taken for cooling is found to be on the order of half a second, or less, regardless of the spatial arrangement or number of mounted samples. Hence, rapid cooling can be achieved for any number or arrangement of samples, as long as device manufacturer guidelines are adhered to.

卵巢注射RPR(血小板分離血漿)---仍處實驗階段 效果並不明確

. 2021 Jun 18;36(7):1737-1750.

 doi: 10.1093/humrep/deab106.

Intraovarian injection of platelet-rich plasma in assisted reproduction: too much too soon?

The prospect of ovarian rejuvenation offers the tantalising prospect of treating age-related declines in fertility or in pathological conditions such as premature ovarian failure. The concept of ovarian rejuvenation was invigorated by the indication of the existence of oogonial stem cells (OSCs), which have been shown experimentally to have the ability to differentiate into functional follicles and generate oocytes; however, their clinical potential remains unknown. Furthermore, there is now growing interest in performing ovarian rejuvenation in situ. One proposed approach involves injecting the ovary with platelet rich plasma (PRP). PRP is a component of blood that remains after the in vitro removal of red and white blood cells. It contains blood platelets, tiny anucleate cells of the blood, which are responsible for forming athrombus to prevent bleeding. In addition, PRP contains an array of cytokines and growth factors, as well as a number of small molecules.The utility ofPRP has been investigatedin a range of regenerative medicine approaches and has been shown to induce differentiation of a range of cell types, presumably through the action of cytokines. A handful ofcasereports have described the use of PRP injections into the ovaryin the human, and while these clinical data report promising results, knowledge on the mechanisms and safety of PRP injections into the ovary remain limited.In this article, we summarise some of the physiological detail of platelets and PRP, before reviewing the existing emerging literature in this area. We then propose potential mechanisms by which PRP may be eliciting any effects before reflecting on some considerations for future studies in the area. Importantly, on the basis of our existing knowledge, we suggest that immediate use of PRP in clinical applications is perhaps premature and further fundamental and clinical research on the nature of ovarian insufficiency, as well as the mechanism by which PRP may act on the ovary, is needed to fully understand this promising development.

鑲嵌染色體囊胚 活產率低於正常染色體囊胚

---46.6% vs. 59.1%, 

J Assist Reprod Genet. 2019 Jan; 36(1): 165–172.

Rates of live birth after mosaic embryo transfer compared with euploid embryo transfer

Purpose

Mosaicism is a prevalent characteristic of human preimplantation embryos. This retrospective cohort study aimed to investigate pregnancy outcomes after transfer of mosaic or euploid embryos.

Methods

The embryos, which had been transferred as “euploidy,” were processed using array-based comparative genomic hybridization (aCGH). The original aCGH charts of the transferred embryos were reanalyzed. Mosaic and control euploid embryos were defined according to log2 ratio calls.

Results

Overall, 102 embryos were determined to be mosaic, of which 101 were estimated to harbor no more than 50% aneuploid mosaicism. Additionally, 268 euploid embryos were matched as controls. The rates of live birth (46.6% vs. 59.1%, odds ratio (OR) 0.60, 95% confidence interval (CI) 0.38–0.95), and biochemical pregnancy (65.7% vs. 76.1%, OR 0.60, 95% CI 0.37–0.99) per transfer cycle were significantly lower after mosaic embryo transfer than after euploid embryo transfer. The rates of clinical pregnancy and pregnancy loss and the risks of obstetric outcomes did not differ significantly between the two groups.

Conclusions

Compared with euploid embryo transfer, mosaic embryo transfer is associated with a lower rate of live birth, which is mainly attributed to a decreased rate of conception. However, as mosaic embryo transfer yielded a live birth rate of 46.6%, patients without euploid embryos could be counseled regarding this alternative option.

 凍胚植入黃體期補充黃體素

----合併注射黃體素 優於  純粹陰道黃體素

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. 2021 Sep;116(3):633-643.

 doi: 10.1016/j.fertnstert.2021.04.013. Epub 2021 May 13.

Intramuscular progesterone optimizes live birth from programmed frozen embryo transfer: a randomized clinical trial

Objective: To determine whether vaginal progesterone for programmed endometrial preparation is noninferior to intramuscular progesterone in terms of live birth rates from frozen embryo transfer (FET).

Design: Three-armed, randomized, controlled noninferiority trial.

Setting: Multicenter fertility clinic.

Patient(s): A total of 1,346 volunteer subjects planning vitrified-warmed transfer of high-quality nonbiopsied blastocysts were screened, of whom 1,125 subjects were ultimately enrolled and randomly assigned to treatment.

Intervention(s): The subjects were randomly assigned to receive, in preparation for FET, 50 mg daily of intramuscular progesterone (control group), 200 mg twice daily of vaginal micronized progesterone plus 50 mg of intramuscular progesterone every third day (combination treatment), or 200 mg twice daily of vaginal micronized progesterone.

Main outcome measure(s): The primary outcome was live birth rate per vitrified-warmed embryo transfer. The secondary outcomes were a positive serum human chorionic gonadotropin test 2 weeks after FET, biochemical pregnancy loss, clinical pregnancy, clinical pregnancy loss, total pregnancy loss, serum luteal progesterone concentration 2 weeks after FET, and patient's experience and attitudes regarding the route of progesterone administration, on the basis of a survey administered to the subjects between FET and pregnancy test.

Result(s): A total of 1,060 FETs were completed. The live birth rate was significantly lower in women receiving only vaginal progesterone (27%) than in women receiving intramuscular progesterone (44%) or combination treatment (46%). Fifty percent of pregnancies in women receiving only vaginal progesterone ended in miscarriage.

Conclusion(s): The live birth rate after vaginal-only progesterone replacement was significantly reduced, due primarily to an increased rate of miscarriage. Vaginal progesterone supplemented with intramuscular progesterone every third day was noninferior to daily intramuscular progesterone, offering an effective alternative regimen with fewer injections.

最適合植入時間:  使用黃體素5-6天

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238935/

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Figure 1

Endometrial receptivity status frequencies along different days of progesterone administration as assessed by ER Map. Frequencies of receptive, pre-receptive and post-receptive samples after a variable number of days of progesterone administration. N = 2828 biopsies.

胚胎植入時間不宜早於預期月經來之11.5天前

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558300/

Go to:

Abstract

Objective:

The aim of this study was to assess whether the time from the menstrual day at embryo transfer to expected menstrual cycle (TETEMC) is associated with the implantation in women with regular cycles or not.

Materials and Methods:

Forty women with successful implantation and forty women without implantation with regular cycles were randomly selected from prospectively collected database of assisted reproductive technology clinic of Zeynep Kamil Women And Children’s Health Training and Research Hospital. TETEMC was calculated for each case to assess relationship with the successful implantation.

Results:

Comparison of groups revealed significant differences with regard to TETEMC and the menstrual period (p<0.05).

In ROC analyses both the TETEMC (AUC=0.824, p<0.001) and the menstrual period (AUC=0.797, p<0.001) were significant predictors for clinical pregnancy. Cut off value for the menstrual period was found to be 27.5 days with 82.6% sensitivity and 65% specificity. Cut off value for TETEMC was 11.5 days with 75% sensitivity and 63.2% specificity.

Conclusion:

Turk J Obstet Gynecol. 2016 Sep; 13(3): 116–122.

Published online 2016 Sep 15. doi: 10.4274/tjod.34651

Non-invasive prediction of implantation window in controlled hyperstimulation cycles: Can the time from the menstrual day at embryo transfer to expected menstrual cycle give a clue?

Objective:

The aim of this study was to assess whether the time from the menstrual day at embryo transfer to expected menstrual cycle (TETEMC) is associated with the implantation in women with regular cycles or not.

Materials and Methods:

Forty women with successful implantation and forty women without implantation with regular cycles were randomly selected from prospectively collected database of assisted reproductive technology clinic of Zeynep Kamil Women And Children’s Health Training and Research Hospital. TETEMC was calculated for each case to assess relationship with the successful implantation.

Results:

Comparison of groups revealed significant differences with regard to TETEMC and the menstrual period (p<0.05).

In ROC analyses both the TETEMC (AUC=0.824, p<0.001) and the menstrual period (AUC=0.797, p<0.001) were significant predictors for clinical pregnancy. Cut off value for the menstrual period was found to be 27.5 days with 82.6% sensitivity and 65% specificity. Cut off value for TETEMC was 11.5 days with 75% sensitivity and 63.2% specificity.

Conclusion:

Longer menstrual cycle and the TETEMC seem to be associated with the implantation failure.

 長期凍胚(>1y)  vs  短期凍胚(<1y)  懷孕率無差異

Review

 

. 2022 Feb 4.

 doi: 10.1007/s10815-022-02405-3. Online ahead of print.

The effect of extended cryo-storage following vitrification on embryo competence: a systematic review and meta-analysis

Purpose: Few studies explored whether prolonged cryo-storage after vitrification affects embryo competence and perinatal outcomes. This systematic review and meta-analysis aims at highlighting any putative impact of cryo-storage duration on cryo-survival, miscarriage, live birth and major malformations.

Methods: A systematic review was performed using MEDLINE (PubMed), ISI Web of Knowledge, Scopus and Embase databases up to June 2021. Data were combined to obtain a pooled OR, and meta-analysis was conducted using a random effects model. Out of 1,389 screened abstracts, 22 papers were assessed for eligibility, and 5 studies were included (N = 18,047 embryos). Prolonged cryo-storage was defined as > 12 months (N = 3389 embryos). Subgroup analysis was performed for untested vitrified cleavage stage embryos (N = 1739 embryos) and for untested and euploid vitrified blastocysts (N = 13,596 and 2712 embryos, respectively).

Results: Survival rate, miscarriage, live birth and major malformation rates were all similar in the two groups.

Conclusion: These data further support the safety of long-term cryo-storage of human embryos beyond 12 months. This is reassuring for good prognosis patients with surplus embryos, couples seeking a second child from supernumerary embryos and women postponing the transfer for clinical or personal reasons.

自體血小板RPR卵巢注射-----可改善FSH, AMH and AFC & 提高 IVF-ET早期懷孕率  但無法明顯提高活產率

. 2020 Apr;37(4):855-863.

 doi: 10.1007/s10815-020-01710-z. Epub 2020 Feb 7.

The use of autologous platelet-rich plasma (PRP) versus no intervention in women with low ovarian reserve undergoing fertility treatment: a non-randomized interventional study

Purpose: To investigate the impact of a 3-month course of intracortical injections of autologous platelet-rich plasma (PRP) upon ovarian reserve markers versus no intervention in women with low ovarian reserve prior to undergoing assisted reproductive technology (ART).

Methods: Prospective controlled, non-randomized comparative study conducted in a private fertility clinic, in Venezuela. Women with abnormal ovarian reserve markers (FSH, AMH and AFC) who declined oocyte donation were allocated to one of the following groups according to patient choice: monthly intracortical ovarian PRP injections for three cycles, or no intervention. Primary outcomes were the change in FSH, AMH and AFC pre- and post-treatment. Secondary outcomes included the number of oocytes collected and fertilized, biochemical/clinical pregnancy rates and miscarriage and live birth rates.

Results: Eighty-three women were included, of which 46 received PRP treatment and 37 underwent no intervention. Overall median age was 41 years (IQR 39-44). There were no demographic differences between the study groups. At the 3-month follow-up, women treated with PRP experienced a significant improvement in FSH, AMH and AFC, whereas there was no change in the control group. Furthermore, overall rates of biochemical (26.1% versus 5.4%, P = 0.02) and clinical pregnancy (23.9% versus 5.4%, P = 0.03) were higher in the PRP group, while there was no difference in the rates of first trimester miscarriage and live birth between groups.

Conclusion: PRP injections are effective and safe to improve markers of low ovarian reserve prior to ART, although further evidence is required to evaluate the impact of PRP on pregnancy outcomes.