Alessandro Conforti

A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept

The management of patients with impaired or poor ovarian response (POR) remains a controversial and complex clinical issue. A systematic review of 47 randomized controlled trials revealed 41 different definitions of POR (1). Notably, the number of oocytes retrieved was adopted as a criterion of POR in 40% of the trials, although the threshold number differed considerably among studies (1). To standardize the definition of POR, Ferraretti et al. (2) proposed new criteria, known as the ‘‘Bologna criteria,’’ based on three conditions: 1) advanced maternal age (R40 years) or any other POR risk factor; 2) a previous incident of POR; and 3) a low ovarian reserve test in terms of antim€ ullerian hormone (AMH) and antral follicle count (AFC). Two of these three criteria are required for a POR diagnosis. In addition, two cycles with POR after maximal stimulation are sufficient to classify a patient as a poor responder even in the absence of the other criteria mentioned. Although the Bologna criteria were found to be useful in predicting the outcome of IVF and for counseling purposes, their use in clinical trials has been questioned because they entail the risk of grouping together women who differ significantly in biologic characteristics (3). For example, according to the Bologna criteria, young women with a low ovarian reserve associated with a previous episode of POR, young women with a normal ovarian reserve and two POR episodes, and older women (R40 years) with a normal ovarian reserve and a previous episode of POR would be included in the same category even though the clinical management of these patients requires different strategies. In clinical terms, apart from the number of oocytes retrieved, various features that may affect treatment outcomes must be considered in the management of patients, namely: 1) the age-related embryo/blastocyst aneuploidy rate, which could dramatically change the prognosis in women that have the same oocyte yield; and 2) ovarian ‘‘sensitivity’’ to exogenous gonadotropins, which could be related to a specific genetic profile. To introduce a more nuanced picture of POR, we here propose clinically relevant criteria that can help to guide the physician in the management of patients. In detail, we suggest a more specific new definition of ‘‘low prognosis’’ patients that:

The management of Asherman syndrome: a review of literature

Asherman syndrome is a debatable topic in gynaecological field and there is no clear consensus about management and treatment. It is characterized by variable scarring inside the uterine cavity and it is also cause of menstrual disturbances, infertility and placental abnormalities. The advent of hysteroscopy has revolutionized its diagnosis and management and is therefore considered the most valuable tool in diagnosis and management. The aim of this review is to explore the most recent evidence related to this condition with regards to aetiology, diagnosis management and follow up strategies.

Techniques to reduce blood loss during open myomectomy: a qualitative review of literature.

Open myomectomy is the most adopted surgical strategy in the conservative treatment of uterine fibroids. According to several studies, the likelihood that a woman could develop uterine myomas is estimated around 75% by the age of 50. Open myomectomy is nonetheless a complicated surgery in terms of blood loss and need for transfusion. Many strategies have been published with the aim of limiting intra and post-operative bleeding complications. The scope of this review is to describe in detail the different techniques reported in literature focusing on their validity and safety.

Role of colonoscopy in the diagnostic work-up of bowel endometriosis

AIM To evaluate the accuracy of colonoscopy for the prediction of intestinal involvement in deep pelvic endometriosis. METHODS This prospective observational study was performed between September 2011 and July 2014. Only women with both a clinical and imaging diagnosis of deep pelvic endometriosis were included. The study was approved by the local ethics committee and written informed consent was obtained in all cases. Both colonoscopy and laparoscopy were performed by expert surgeons with a high level of expertise with these techniques. Laparoscopy was performed within 4 wk of colonoscopic examination. All hypothetical colonoscopy findings (eccentric wall thickening with or without surface nodularities and polypoid lesions with or without surface nodularities of endometriosis) were compared with laparoscopic and histological findings. We calculated the sensitivity, specificity, positive predictive value and negative predictive value for the presence of colonoscopic findings of intestinal endometriosis. RESULTS A total of 174 consecutive women aged between 21-42 years with a diagnosis of deep pelvic endometriosis who underwent colonoscopy and surgical intervention were included in our analysis. In 76 of the women (43.6%), intestinal endometrial implants were found at surgery and histopathological examination. Specifically, 38 of the 76 lesions (50%) were characterized by the presence of serosal bowel nodules; 28 of the 76 lesions (36.8%) reached the muscularis layer; 8 of the 76 lesions (10.5%) reached the submucosa; and 2 of the 76 lesions (2.6%) reached the mucosa. Colonoscopic findings suggestive of intestinal endometriosis were detected in 7 of the 174 (4%) examinations. Colonoscopy failed to diagnose intestinal endometriosis in 70 of the 76 women (92.1%). A colonoscopic diagnosis of endometriosis was obtained in all cases of mucosal involvement, in 3 of 8 cases (37.5%) of submucosal involvement, in no cases of muscularis layer involvement and in 1 of 38 cases (2.6%) of serosa involvement. The sensitivity, specificity, positive predictive and negative predictive values of colonoscopy for the diagnosis of intestinal endometriosis were 7%, 98%, 85% and 58%, respectively. CONCLUSION Being an invasive procedure, colonoscopy should not be routinely performed in the diagnostic work-up of bowel endometriosis.

In Estimated Good Prognosis Patients Could Unexpected “Hyporesponse” to Controlled Ovarian Stimulation be Related to Genetic Polymorphisms of FSH Receptor?

It has been reported that 10% to 15% of young normogonadotrophic women show suboptimal response to standard gonadotropin-releasing hormone—a long protocol. These patients require higher doses of exogenous follicle-stimulating hormone (FSH). This phenomenon could be associated with genetic characteristics. In this study, FSH receptor polymorphism was retrospectively evaluated in 42 normoresponder young women undergoing an in vitro fertilization/intracytoplasmic sperm injection cycle; patients were stratified according to recombinant human FSH (r-hFSH) consumption. We selected 17 normoresponder young patients who required a cumulative dose of recombinant FSH (rFSH) >2500 UI (group A). A control group was randomly selected among patients who required a cumulative dose of rFSH <2500 UI (group B). Follicle-stimulating hormone receptor (FSH-R) 307Ala and 680Ser variants were analyzed in all our patients. Our results show that the mean number of rFSH vials (36.3 ± 7.5 vs 28.6 ± 4.5, P = .0001) and days of stimulation (12.7 ± 2.4 vs 10.8 ± 2.8, P = .03) were significantly lower in group B, whereas the number of oocytes retrieved (7.1 ± 1.5 vs 9.6 ± 2.4; P = .0005) and the average number of embryos transferred (2.1 ± 0.7 vs 2.7 ± 0.4; P = .001) were significantly lower in group A. Estradiol serum levels on the human chorionic gonadotrophin day were significantly lower in group A (997.8 ± 384.9 pg/mL vs 1749.1 ± 644.4; P = .0001). The incidence of the Ser/Ser genotype was higher in patients with higher r-hFSH consumption (group A; P = .02). Based on our results, we hypothesize an association between the FSH-R polymorphisms and a “hyporesponse” to exogenous FSH.

Successful direct bipolar resection of 6th week cesarean scar pregnancy: case report and literature review.

Cesarean scar pregnancy is a specific ectopic pregnancy implanted in the scar tissue of a previous cesarean section. To date, no clear consensus exists regarding its management and treatment. Timely diagnosis of this condition is fundamental, owing to the high rate of life-threatening complications and massive hemorrhage. The use of high-definition transvaginal ultrasound is strongly recommended as a first-line diagnostic approach. A wide range of medical and surgical strategies has been described in the literature, including methotrexate administration, local injection of embryocides, uterine curettage, and laparoscopic surgery. The treatment goal should be complete and efficient without compromising the chance of future pregnancies. Recently, many cases were successfully treated through the hysteroscopic route. Illustrating the case of an early detected cesarean scar pregnancy originally treated in our institution with direct bipolar resection, we reviewed the literature regarding the advantages and efficacy of the hysteroscopic approach in terms of fertility preservation, rapid recovery, and safety. In conclusion, the use of a direct hysteroscopic approach could represent a valuable strategy in the first stage of cesarean scar pregnancy.

Impact of Mutations and Polymorphisms of Gonadotrophins and Their Receptors on the Outcome of Controlled Ovarian Stimulation

Controlled ovarian stimulation is a mainstay of assisted reproductive technologies and leads to optimal follicular growth and steroidogenesis in the majority of cases. Nonetheless, some women defined as “hyporesponders” require higher amount of exogenous gonadotrophin to achieve an adequate number of oocytes retrieved despite an apparently good prognosis. Clinical observational trials suggest that hyporesponse to exogenous gonadotrophins, including initial poor response, could be a genetically determined trait with specific genotype profile associated with this condition. Specifically, mutation and polymorphisms involving luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and their receptors LH-R and FSH-R have been thoroughly investigated. Among all the mutations discovered, it seems that that carriers of common LH variant and FSH receptor Ser/680 variants require higher doses of exogenous FSH to achieve a normal ovarian response.

Intact removal of spontaneous twin ectopic Caesarean scar pregnancy by office hysteroscopy: case report and literature review

Caesarean scar pregnancy is a dangerous condition that occurs when an embryo is implanted in a previous Caesarean scar. This condition has become more frequent as a direct consequence of the increased number of Caesarean sections reported worldwide. Timely diagnosis of this condition is fundamental, and allows a conservative approach to preserving fertility. A wide range of medical and surgical strategies has been described, with no consensus on preferred management. Recently, hysteroscopic surgery has been proposed as a conservative strategy, with interesting results in reproductive outcome, postoperative course and success rate. Most cases of Caesarean scar pregnancy reported worldwide involve a singleton pregnancy. A peculiar case of fully documented office hysteroscopic removal of twin Caesarean scar pregnancy is presented in this paper. This procedure took place in a tertiary care university hospital without cervix dilatation, under conscious sedation, after failure of systemic methotrexate administration. Complete removal of the ectopic pregnancy was obtained without intra- and postoperative complications.

Influence of cryopreservation on perinatal outcome after blastocyst- vs cleavage-stage embryo transfer: systematic review and meta-analysis

To compare the perinatal outcomes of singleton pregnancies resulting from blastocyst‐ vs cleavage‐stage embryo transfer and to assess whether they differ between fresh and frozen embryo transfer cycles.

Clinical relevance of genetic variants of gonadotrophins and their receptors in controlled ovarian stimulation: a systematic review and meta-analysis

BACKGROUND Genotype has been implicated in the outcome of ovarian stimulation. The analysis of patient-specific genotypes might lead to an individualized pharmacogenomic approach to controlled ovarian stimulation (COS). However, the validity of such an approach remains to be established. OBJECTIVE AND RATIONALE To define the impact of specific genotype profiles of follicle-stimulating hormone, luteinizing hormone and their receptors (FSHR, LHR and LHCGR) on ovarian stimulation outcome. Specifically, our aim was to identify polymorphisms that could be useful in clinical practice, and those that need further clinical investigation. SEARCH METHODS A systematic review followed by a meta-analysis was performed according to the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines without time restriction. We searched the PubMed/MEDLINE, Cochrane Library, SCOPUS and EMBASE databases to identify all relevant studies published before January 2017. Only clinical trials published as full-text articles in peer-reviewed journals were included. The primary outcome was the number of oocytes retrieved. OUTCOMES Fifty-seven studies were assessed for eligibility, 33 of which were included in the qualitative and quantitative analyses. Data were independently extracted using quality indicators. COS outcomes related to seven polymorphisms (FSHR [rs6165], FSHR [rs6166], FSHR [rs1394205], LHB [rs1800447], LHB [rs1056917], LHCGR [rs2293275] and LHCGR [rs13405728]) were evaluated. More oocytes were retrieved from FSHR (rs6165) AA homozygotes (five studies, 677 patients, weighted mean difference [WMD]: 1.85, 95% CI: 0.85-2.85, P < 0.001; I2 = 0%) than from GG homozygotes and AG heterozygotes (four studies, 630 patients, WMD: 1.62, 95% CI: 0.28-2.95, P = 0.020; I2 = 56%). Moreover, stimulation duration was shorter in FSHR (rs6165) AA homozygotes than in AG carriers (three studies, 588 patients, WMD -0.48, 95% CI: -0.87 to -0.10, P = 0.010, I2 = 44%). A higher number of oocytes (21 studies, 2632 patients WMD: 0.84, 95% CI: 0.19 to 1.49, P = 0.01, I2 = 76%) and metaphase II oocytes (five studies, 608 patients, WMD: 1.03, 95% CI: 0.01-2.05, P = 0.050, I2 = 0%) was observed in AA than in GG homozygote carriers. FSH consumption was significantly lower in FSHR (rs1394205) GG homozygotes (three studies, 411 patients, WMD: -1294.61 IU, 95% CI: -593.08 to -1996.14 IU, P = 0.0003, I2 = 99%) and AG heterozygotes (three studies, 367 patients, WMD: -1014.36 IU, 95% CI: -364.11 to -1664.61 IU, P = 0.002, I2 = 99%) than in AA homozygotes. WIDER IMPLICATIONS These results support the clinical relevance of specific genotype profiles on reproductive outcome. Further studies are required to determine their application in a pharmacogenomic approach to ovarian stimulation.