Hypoxia-inducible Factor-1α and mTOR as a Potential Therapeutic Target in Endometriosis: An Immunohistochemical Study.

BACKGROUND AND STUDY AIM: We aim to study the immunohistochemical expression of both hypoxia-inducible factor-1α (HIF-1α) and mammalian target of rapamycin (mTOR) in endometriosis to provide new evidence for a targeted endometriosis therapy. PATIENTS AND METHODS: This study comprised 106 endometriotic cases diagnosed clinically and histopathologically. The immunohistochemical method was done to determine the expression of HIF-1α and mTOR. RESULTS: Endometriotic glands showed significant cytoplasmic expression of both markers in patients with poor ovulation, severe endometriosis, and infertile for >2 years ( P <0.001). Also, patients with intense and worst pain show significant immunohistochemical expression of both markers ( P <0.001). There is a significant correlation between mTOR and HIF-1α expression in endometriotic tissue samples as P <0.001. CONCLUSIONS: Our data suggest that both mTOR and its downstream target HIF-1α transcription factor are both disrupted in patients with endometriosis, which is consistent with aberrant activation of these pathways and their possible contribution to the pathogenesis of endometriosis. These results could offer a promising novel opportunity to be blocked therapeutically. As new management options need to be refined in particular in severe cases and infertile patients with endometriosis, therefore future studies are warranted to investigate treating endometriosis with mTOR inhibitors; the latter are already in clinical trials in phase III and IV, treating solid tumors as well as non-neoplastic disorders.

Progesterone/Oestradiol ratio can Better Predict Intracytoplasmic Sperm Injection Outcomes than Absolute Progesterone Level.

BACKGROUND: Several parameters were proposed to predict the impact of premature luteinization on intracytoplasmic sperm injection (ICSI) outcomes such as isolated progesterone (P) level, progesterone to oocyte ratio, and progesterone/estradiol ratio (P/E2). AIM: The aim of this study is to compare the predictive value of P/E2 ratio and isolated P level on the ovulation triggering day for pregnancy outcomes in fresh GnRH antagonist ICSI cycles. SETTINGS AND DESIGN: A retrospective cohort study conducted in a university-affiliated in vitro fertilization center between January 2017 and April 2019. METHODS: The study included women who underwent their first- or second-ranked GnRH antagonist ICSI cycles with day-3 embryo transfer. P/E2 ratio was calculated as (P [ng/mL] × 1000)/E2 (pg/mL). Cutoff values of ≥1.5 ng/ml for high P (HP) and ≥0.55 for HP/E2 ratio were chosen based on the literature. STATISTICAL ANALYSIS: A receiver operating curve was performed to detect the predictability of serum P/E2 and P for the ongoing pregnancy rate. First, patients were divided according to either P level (low P < 1.5 ng/mL and HP ≥1.5 ng/mL) or P/E2 ratio (low P/E2 <0.55 and HP/E2 ≥ 0.55). Patients were further divided into four subgroups: (Group A: HP and HP/E2 ratio, Group B: low P and low P/E2 ratio, Group C: HP only, and Group D: HP/E2 only). A multivariate regression analysis models were used to account for the effect of the cycle confounders on the likelihood of pregnancy. RESULTS: A total of 402 ICSI cycles were analyzed. The area under the curve was 0.67 and 0.59 for P/E2 and P, respectively. P/E2 showed a significant association with ongoing pregnancy (adjusted odds ratios [aOR]: 0.409, 95% confidence interval [CI] 0.222-0.753, P = 0.004) while HP revealed no significant predictive value (aOR: 0.542, 95% CI 0.284-1.036, P = 0.064) after the multivariate analysis. CONCLUSIONS: P elevation may not present as an independent predictor for cycle outcomes. P/E2 ratio has a better prognostic value than P alone in predicting pregnancy of GnRH antagonist cycles.

Effect of Metformin on Premature Luteinization and Pregnancy Outcomes in Intracytoplasmic Sperm Injection-Fresh Embryo Transfer Cycles: A Randomized Double-Blind Controlled Trial.

BACKGROUND: Premature luteinization (PL) is not unusual in in vitro fertilization (IVF) and could not be wholly avoided by using either gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonist regimens. The study aims to evaluate metformin's efficacy in preventing PL in fresh GnRH antagonist intracytoplasmic sperm injection (ICSI) cycles with cleavage-stage embryo transfer. MATERIALS AND METHODS: This randomized, double-blind, placebo-controlled trial was conducted in a tertiary university IVF center. We recruited infertile women who were scheduled to perform their first or second ICSI trial. Eligible women were recruited and randomized in a 1:1 ratio into two groups. Metformin was administered in a dose of 1500 mg per day since the start of contraceptive pills in the cycle antecedent to stimulation cycle until the day of ovulation triggering, while women in the placebo group received a placebo for the same regimen and duration. The primary outcome was the incidence of PL, defined as serum progesterone (P) on the triggering day ≥1.5 ng/mL. Secondary outcomes comprised the live birth, ongoing pregnancy, implantation, and good-quality embryos rates. RESULTS: The trial involved 320 eligible participants (n=160 in each group). Both groups had comparable stimulation days, endometrial thickness, peak estradiol levels, number of oocytes retrieved, and number of mature oocytes. Metformin group experienced lower level of serum P (P<0.001) and incidence of PL (10 vs. 23.6%, P=0.001). Moreover, lower progesterone/estradiol (P/E) ratio and progesterone to mature oocyte index (PMOI) (P=0.002 and P=0.002, respectively) were demonstrated in women receiving metformin. Metformin group generated a better rate of goodquality embryos (P=0.005) and ongoing pregnancy (43.8 vs. 31.8%, P=0.026). A similar trend, though of borderline significance, was observed in the live birth rate in favor of metformin administration (38.15 vs. 27.5%, P=0.04). CONCLUSION: Metformin could be used in patients with potential PL to improve fresh cycle outcomes by preventing PL (Registration number: NCT03088631).

The safety and effectiveness of Bakri balloon in the management of postpartum hemorrhage: a systematic review.

Background: Postpartum hemorrhage (PPH) is a direct cause of maternal death all over the world. A Bakri balloon is recommended by American College of Obstetricians and Gynecologists (ACOG) and World Health Organization (WHO) as a treatment line for PPH unresponsive to uterotonics. We carried out a systematic review to assess the safety and effectiveness of Bakri balloon in the management of PPH.Methods: We searched PubMed, SCOPUS, central Cochrane, and Web of Science, from 2001 to 2018 for randomized controlled trials (RCTs) and observational studies to assess the safety and effectiveness of Bakri balloon on refractory PPH.Results: Twenty-eight articles were included for analysis. The primary indication for the use of a Bakri balloon tamponade was PPH. Only 67.9% (19/28) quantified the estimate blood loss necessary to use the balloon. Uterine atony was the underlying cause of PPH in 75% (21/28) of studies. Most of the studies on Bakri balloon are followed by vaginal birth (3/4). Bakri balloon displacement from the uterine cavity was reported by five publications, with the overall rate being 9% (95% CI: 5-15%). Hysterectomy was necessary for 1% (95% CI: 0-8%) of the women who required the balloon.Conclusions: Bakri balloon seems to be a less effective tool for management of PPH either after vaginal or cesarean delivery.

Revisiting debates of premature luteinization and its effect on assisted reproductive technology outcome.

The impact of the prematurely elevated serum progesterone on the late follicular phase, commonly known as premature luteinization (PL), is a matter of continuing debate. Available evidence supports that serum progesterone ≥ 1.5 ng/ml on the day of ovulation triggering could reduce the pregnancy potential in fresh in vitro fertilization (IVF) cycles by jeopardizing endometrial receptivity. Causes of PL during ovarian stimulation are unclear. Recent studies point toward the daily follicle-stimulating hormone dosage, duration of controlled ovarian stimulation, number of oocytes retrieved, and peak estradiol level as factors affecting the incidence of PL. Emerging data show additional influence on embryo quality. The prevention of PL has been challenging. The key elements in preventing PL include individualization of ovarian stimulation according to patient's ovarian reserve, proper ovulation trigger timing, and use of medications such as corticosteroids and metformin. Embryo cryopreservation with deferred embryo transfer is the established strategy to overcome PL, yet it is an extra burden to the IVF laboratory and increased cost for patients. Herein, we review the up-to-date knowledge of this frequent IVF problem including causes, proposed diagnostic criteria, and its impact on endometrial receptivity, embryo quality, and pregnancy outcomes. The preventive measures and rescue strategies are also discussed.

Human uterine leiomyoma contains low levels of 1, 25 dihdroxyvitamin D3, and shows dysregulated expression of vitamin D metabolizing enzymes.

OBJECTIVES: To evaluate tissue concentration of 1, 25 dihydroxyvitamin D3, and gene expression level of CYP27B1 that codes for 1-α hydroxylase (vitamin D activating enzyme), and CYP24A1 that codes for 24-hydroxylase (vitamin D catabolizing enzyme) in human uterine leiomyoma (ULM), its adjacent myometrium (Myo-F), and normal myometrium (Myo-N). STUDY DESIGN: Levels of 1, 25 dihydroxyvitamin D3 were measured using HPLC and Diode detectors whereas CYP27B1, and CYP24A1 expressions were assessed using Real-Time PCR in ULM, Myo-F, and Myo-N. Non-parametric statistics were used. RESULTS: ULMs contained significantly less 1, 25 dihydroxy vitamin D3 compared to Myo-F (3.0, IQR: 1.0-9.0 versus 6.0, IQR: 3.0-13.0 µg/ kg, P value is 0.03). No significant difference was detected between ULM and Myo-N, or Myo-F and Myo-N. Intratumoral level of the active form of vitamin D did not differ according to the type of ULM (submucous or interstitial/subserous), or to the ULM volume. CYP27B1 was expressed in ULM (2.17, IQR: 0.65-4.9), Myo-F (4.94, IQR: 1.04-22.59), and Myo-N (0.99, IQR: 0.49-1.71) to a comparable level. CYP24A1 expression was significantly higher in ULM compared to Myo-N (2.00, IQR: 0.69-10.77 versus 0.22, IQR: 00- 0.96, respectively, P value is 0.04). CONCLUSIONS: Human ULMs contain significantly lower 1, 25 dihydroxyvitamin D3 than its adjacent myometrium. ULM, Myo-F, and Myo-N express CYP27B1 and CYP24A1. ULMs express significantly higher level of CYP24A1 than normal myometrium indicating that over expression of 24-hydroxylase is a mechanism by which ULMs sustain a relative state of hypovitaminosis D.

Clinical efficacy of neoadjuvant chemotherapy with irinotecan (CPT-11) and nedaplatin followed by radical hysterectomy for locally advanced cervical cancer.

OBJECTIVE: To investigate the clinical efficacy of neoadjuvant chemotherapy (NAC) with irinotecan (CPT-11) and nedaplatin (NED) followed by radical hysterectomy. METHODS: Patients with locally advanced cervical cancer (stage Ib2-IIb) were treated with NAC followed by surgery, primary surgery or primary radiotherapy. NAC was usually performed using transuterine arterial chemotherapy (TUAC) or intravenous CPT-11/NED. Survival rates were analysed in the three treatment groups; response rates and adverse events associated with NAC, TUAC and CPT-11/NED were compared, along with previously reported adverse events of chemoradiotherapy. RESULTS: A total of 165 patients with cervical cancer were recruited. Of these, 70 were treated with NAC followed by surgery (48 with CPT-11/NED, 18 with TUAC and four with other types of chemotherapy), 73 were treated with primary surgery and 22 with primary radiotherapy (including chemoradiotherapy). There were no significant differences in progression-free survival or overall survival rates between the three treatment groups. The response rates for the NAC regimen of CPT-11/NED and TUAC were high (75% and 78%, respectively). The frequency of severe thrombocytopenia was lower in patients receiving CPT-11/NED compared with TUAC, and the incidence of severe anaemia, vomiting and cystitis was lower in patients receiving CPT-11/NED compared with chemoradiotherapy. CONCLUSIONS: The use of CPT-11/NED as a NAC regimen shows favourable activity, with lower toxicity compared with NAC using TUAC or chemoradiotherapy, for the treatment of locally advanced cervical cancer.

Stem cell applications for pathologies of the urinary bladder.

New stem cell based therapies are undergoing intense research and are widely investigated in clinical fields including the urinary system. The urinary bladder performs critical complex functions that rely on its highly coordinated anatomical composition and multiplex of regulatory mechanisms. Bladder pathologies resulting in severe dysfunction are common clinical encounter and often cause significant impairment of patient's quality of life. Current surgical and medical interventions to correct urinary dysfunction or to replace an absent or defective bladder are sub-optimal and are associated with notable complications. As a result, stem cell based therapies for the urinary bladder are hoped to offer new venues that could make up for limitations of existing therapies. In this article, we review research efforts that describe the use of different types of stem cells in bladder reconstruction, urinary incontinence and retention disorders. In particular, stress urinary incontinence has been a popular target for stem cell based therapies in reported clinical trials. Furthermore, we discuss the relevance of the cancer stem cell hypothesis to the development of bladder cancer. A key subject that should not be overlooked is the safety and quality of stem cell based therapies introduced to human subjects either in a research or a clinical context.