Nikos F. Vlahos

Prevention and management of ovarian hyperstimulation syndrome.

Abstract:u2002 The Ovarian Hyperstimulation Syndrome (OHSS) represents one of the biggest nightmares of all physicians involved in Assisted Reproductive Technologies (ART). Every year, several hundreds of women are hospitalized and to date several deaths have been reported. The pivotal event in the development of OHSS is the disruption of capillary integrity that results in leakage of intravascular fluid and proteins into third space. On the molecular level, human chorionic godadotropin (HCG) either exogenous or endogenous, functions as the triggering point for the production of vascular endothelial growth factor (VEGF) that is the main mediator to increase permeability on the vascular bed. Spontaneous OHSS has also been reported, either due to inappropriate activation of a mutant FSH receptor or due to very high levels of HCG during pregnancy. The available evidence on the several preventive and therapeutic approaches with special attention to level 1 evidence when available is also presented. OHSS is a self‐resolving condition and the main role of the physician is to correct and maintain the intravascular volume, to support renal function and respiration and prevent thrombotic events. An algorithm on the management of OHSS on an outpatient basis and in the hospital is based on the previous mentioned principles.

Endometriosis, in vitro fertilisation and the risk of gynaecological malignancies, including ovarian and breast cancer.

There is evidence that endometriosis as well as drugs used in the process of in vitro fertilisation appear to associate with increased risk for gynaecological cancer. In this review, we attempt to describe this relationship according to the most recent epidemiologic data and to present the possible mechanisms on the molecular level that could potentially explain this correlation. There are data to support that ovarian endometriosis could have the potential for malignant transformation. Epidemiologic and genetic studies support this notion. It seems that endometriosis is associated with specific types of ovarian cancer (endometrioid and clear cell). There is no clear association between endometriosis and breast or endometrial cancer. More studies are needed to establish the risk factors that may lead to malignant transformation of this condition and to identify predisposed individuals who may require closer surveillance. Currently, there is no proven relationship between any type of gynaecological cancer and drugs used for infertility treatment. In principle, infertile women have increased risk for gynaecologic malignancies. Nulligravidas who received treatment are at increased risk for malignancy compared with women who had conceived after treatment. There is limited evidence that clomiphene citrate use for more than six cycles or 900mg or treatment of women over the age of 40 could increase their risk for ovarian and breast cancer. More studies with the appropriate statistical power and follow-up time are required to evaluate accurately the long-term effects of these drugs and procedures.

Continuous versus cyclic oral contraceptives for the treatment of endometriosis: a systematic review

PurposeRecurrence of endometriosis after conservative surgery has been observed in 40–50xa0% of patients within the first 5xa0years. A variety of regimens such as combined oral contraceptives, GnRH agonists, danazol, and progestins have been used postoperatively to reduce recurrence rates. Oral contraceptives (oCP) have been used either in a cyclic or in a continuous (no pill-free interval) fashion. The purpose of this article was to summarize the existing evidence on the efficacy and patient compliance for the use of oCP in a continuous versus cyclic fashion following conservative surgery for endometriosis.MethodsA systematic search of Medline identified four eligible studies. Studies were considered eligible, if they have evaluated oCP therapy, either in a cyclic or continuous regimen, after conservative surgery for endometriosis. Specifically, studies (1) reporting on women with endometriosis who were treated postoperatively with both continuous oCP and cyclic oCP, (2) written in English, (3) with minimum 6xa0months duration of medical treatment, and (4) with minimum 12xa0months duration of follow-up were considered eligible for our systematic review. Outcome measures of these eligible studies were tabulated and then analyzed cumulatively. A purely descriptive approach was adopted concerning all variables.ResultsPostoperative use of continuous oCP was associated with a reduction in the recurrence rate of dysmenorrhea, delay in the presentation of dysmenorrhea, reduction in nonspecific pelvic pain, and reduction in the recurrence rate for endometrioma.ConclusionsUse of oCP in a continuous fashion following conservative surgery for endometriosis is more beneficial to cyclic use.

Continuous versus cyclic use of oral contraceptives after surgery for symptomatic endometriosis: a prospective cohort study

OBJECTIVEnTo evaluate the efficacy of continuous oral contraceptive (OC) use versus the usual cyclic fashion in the recurrence of endometriosis-related symptoms after surgery.nnnDESIGNnProspective cohort trial involving patients in two tertiary care units.nnnSETTINGnAcademic institution in collaboration with a private hospital.nnnPATIENT(S)n356 patients underwent surgical treatment by laparoscopy for symptomatic endometriosis.nnnINTERVENTION(S)nAfter surgical treatment for endometriosis, patients offered 6-month course of cyclic OC (including a 7-day pill-free period) or continuous OC.nnnMAIN OUTCOME MEASURE(S)nRecurrence rate of endometriosis-related symptoms and endometriomas after fertility-sparing surgery.nnnRESULT(S)nOut of 356 patients, 167 were placed on the usual cyclic OC course and 85 on continuous OC for a minimum of 6 months. The continuous OC group experienced a statistically significant reduction in recurrence rates for endometrioma, dysmenorrhea, and non-menstrual pelvic pain as compared with the cyclic OC group. There was no reduction in the recurrence of dyspareunia between the two groups.nnnCONCLUSION(S)nAfter surgical treatment of endometriosis, the use of both cyclic and continuous OC improves pain symptoms when compared with preoperative scores. Continuous OC appears to be associated with a reduced recurrence rate for dysmenorrhea, non-menstrual pelvic pain, and endometrioma but not for dyspareunia as compared with cyclic OC.

Intraoperative gross assessment of myometrial invasion and cervical involvement in endometrial cancer: Role of tumor grade and size

OBJECTIVESnTo evaluate the accuracy of visual examination of myometrial invasion and the involvement of the cervix in the hysterectomy specimen and to explore the role of tumor grade and size in the accuracy of gross estimation of myometrial invasion.nnnMETHODSnIn 142 patients with apparent early endometrial cancer the uterus was opened after its removal and inspected. The size of the tumor (<or= or >2 cm), the depth of myometrial invasion (less or greater than 50%) and the involvement of the cervix (as positive or negative) were visually estimated and recorded. All patients underwent surgical staging. The gross findings were compared with the final histological results. Estimations of myometrial invasiveness were analyzed according to the tumor grade and size. Accuracy, specificity, sensitivity, positive and negative predictive values were calculated.nnnRESULTSnThe overall accuracy rate for myometrial invasion was 81.7% (116/142). False positive and false negative results noted in 17/101 (17%) and 9/41 (21.9%) of patients. Sensitivity, specificity, positive and negative predictive values were 78%, 83.2%, 65.3% and 90.3% respectively. Gross estimation of invasion was more often successful in patients with smaller (<or=2 cm) than in those with grater tumors (accuracy 88.9% vs. 79.2%). Increasing tumor grade found to diminish the rate of correct prediction. The accuracy for grade I tumors was 93.5%, for grade II 80.4% and only 58.6% for grade III lesions. Cervical involvement was correctly evaluated in 138/142 patients with one false positive and 3 false negative results.nnnCONCLUSIONnThese data show that gross estimation of myometrial invasion is highly accurate in small (<or=2 cm) and grade I tumors. Visual evaluation of cervical involvement is also reliable. However, prediction of myometrial invasion is lower in tumors with higher grade, being poor in grade III lesions. Inaccuracies of preoperative histology may decrease the sensitivity of intraoperative assessment based on final grade.

Dehydroepiandrosterone administration before IVF in poor responders: a prospective cohort study

The use of dehydroepiandrosterone (DHEA) may improve ovarian stimulation outcomes in women of advanced reproductive age and could reduce embryo aneuploidy. In this prospective study, 48 women diagnosed with poor ovarian response received DHEA supplementation for at least 12 weeks. These women were compared with a group of poor responders (n = 113) who did not receive supplementation. During the study period, patients taking day 2 FSH and oestradiol were measured monthly before and after treatment. Stimulation characteristics, stimulation outcome and clinical outcome (clinical pregnancy and live birth rates) were reported. Evaluation of anti-Müllerian hormone (AMH) was carried out before initiation of treatment and immediately before the subsequent stimulation. Supplementation with DHEA for at least 12 weeks resulted in a modest, but statistically significant, increase in AMH levels and decrease in baseline FSH (P < 0.001 and P = 0.007, respectively). Administration of DHEA had no effect on any of the stimulation parameters nor was there any difference in clinical pregnancy rates and live birth rates between the two groups. Supplementation with DHEA significantly affects women with poor prognosis undergoing ovarian stimulation for IVF. Patients should be counselled about the uncertain effectiveness, potential side-effects and cost of this treatment.

Effect of luteal-phase support on endometrial microRNA expression following controlled ovarian stimulation

BackgroundStudies suggested that microRNAs influence cellular activities in the uterus including cell differentiation and embryo implantation. In assisted reproduction cycles, luteal phase support, given to improve endometrial characteristics and to facilitate the implantation process, has been a standard practice. The effect of different types of luteal phase support using steroid hormones in relation to endometrial miRNA profiles during the peri-implantation period has not seen described. This study was designed to evaluate the expression of miRNAs during the luteal phase following controlled ovarian stimulation for IVF and the influence of different luteal phase support protocols on miRNA profiles.MethodsThe study was approved by the Johns Hopkins Hospital Institutional Review Board. Endometrial biopsies were obtained on the day of oocyte retrieval from 9 oocyte donors (group I). An additional endometrial biopsy was obtained 3–5u2009days later (Group II) after the donors were randomized into three groups. Group IIa had no luteal-phase support, group IIb had luteal support with micronized progesterone (P), and Group IIc had luteal support with progesterone plus 17-beta-estradiol (Pu2009+u2009E). Total RNA was isolated and microarray analysis was performed using an Illumina miRNA expression panel.ResultsA total of 526 miRNAs were identified. Out of those, 216 miRNAs were differentially regulated (pu2009<u20090.05) between the comparison groups. As compared to the day of retrieval, 19, 11 and 6 miRNAs were differentially regulated more than 2 fold in the groups of no support, in the P support only, and in the Pu2009+u2009E support respectively, 3–5u2009days after retrieval. During the peri-implantation period (3–5u2009days after retrieval) the expression of 33 and 6 miRNAs increased, while the expression of 3 and 0 miRNAs decreased, in the P alone and in the Pu2009+u2009E group respectively as compared to the no steroid supplementation group.ConclusionLuteal support following COS has a profound influence on miRNA profiles. Up or down regulation of miRNAs after P or Pu2009+u2009E support suggest a role(s) of luteal support in the peri-implantation uterus in IVF cycles through the regulation of associated target genes.

How do laboratory embryo transfer techniques affect IVF outcomes? A review of current literature

Abstract Over the last few years, many studies have focused on embryo selection methods, whereas little attention has been given to the standardization of the procedure of embryo transfer. In this review, several parameters of the embryo transfer procedure are examined, such as the: (i) culture medium volume and loading technique; (ii) syringe and catheters used for embryo transfer; (iii) viscosity and composition of the embryo transfer medium; (iv) environment of embryo culture; (v) timing of embryo transfer; (vi) and standardization of the embryo transfer techniques. The aim of this manuscript is to review these factors and compare the existing embryo transfer techniques and highlight the need for better embryo transfer standardization.

Continuous versus cyclic oral contraceptives for endometriosis: any conclusive evidence?

We would like to thank Dr Muzii et al. [1] for their constructive comments regarding our recent systematic review [2]. Indeed, usage of a wider variety of keywords in our search strategy would have resulted to inclusion of one additional eligible multicenter, prospective, randomized trial performed by the same group of authors [3]. Although we used a set of keywords including the most common terms relevant to the subject and we performed our search according to the PRISMA guidelines, we were not successful in identifying all the published studies on the field. However, ‘‘estroprogestins’’ (which was the main term used in the title of the article by Muzii et al. [1] ) is apparently an extremely rare term as it appears in only 15 articles in the Medline database to date (date of search: 3.11.15). Fortunately, the results and conclusions by Muzii et al. [3] are in line with the rest of the evidence in the existing literature and inclusion of this study does not significantly alter the conclusions of our systematic review [2]. Regarding the inclusion of a self-controlled study [4], although we agree that these studies have major limitations, the cross-over design per se is not a reason to exclude the study especially when you do not perform a quantitative synthesis of the data (i.e., meta-analysis). Moreover, this study reaches the same conclusions as the other included studies in our review. Rather expectedly, the systematic review reflects the limitations of the existing literature. Finally, we did not perform any assessment of bias as Muzii et al. [1] denote in their letter. Methodological quality assessment regarding the two studies of Seracchioli et al. [5, 6] was properly performed. In both articles, the authors clearly state that: ‘‘Treatment allocation was performed in accordance with a computer-generated randomization sequence with use of numbered, opaque, sealed envelopes.’’ In any case, we acknowledge the need for additional randomized studies with adequate power to evaluate the preferred type of progestin that should be used in the future combined with oCPs. We also would like to express our pleasure to receive the letter byMuzii et al. [1], as we believe that it portrays the contribution of our systematic review to the ongoing debate between continuous versus cyclic oral contraceptives for the treatment of endometriosis.

Preimplantation Genetic Diagnosis in Marfan Syndrome

Marfan syndrome (MFS) is a systemic hereditable disorder of the connective tissue with mainly cardiovascular manifestations, such as aortic dilatation and dissection. We describe a case of a 32-year-old Caucasian woman, clinically asymptomatic with MFS who presented for genetic consultation to prevent the transmission of disease to her offspring. She underwent controlled ovarian stimulation (COH), in vitro fertilization (IVF) combined with preimplantation genetic diagnosis (PGD), and a singleton pregnancy with positive fetal heart rate was revealed. At 34 weeks gestation she delivered vaginally a healthy premature male infant weighting 2440 gr. The patient remained asymptomatic during pregnancy, delivery, and 3 months postpartum. It is has to be mentioned that the availability of PGD is essential to prevent the transmission of disease to the next generation.