Amir Weiss

GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data

BACKGROUND Cancer survival rates in young women are improving due to progress in treatment. This includes aggressive chemotherapy, a treatment that often poses a threat to fertility. GnRH agonists were proposed as ovarian protectors during gonadotoxic therapies. This study was undertaken in order to determine the clinical evidence concerning this issue. METHODS The medical literature was searched for studies that reported on ovarian function after the administration of GnRH agonists concomitant with chemotherapy. Twelve studies met the predetermined selection criteria. RESULTS Data on ovarian function were obtained for 579 women who received chemotherapy. Among 345 women who received GnRH agonist co-treatment, ovarian function was preserved in 91% and 9% had premature ovarian failure. In 234 women who did not receive GnRH agonist co-treatment, ovarian function was preserved in 41% and failed in 59%. Only two of the studies were randomized. The control and the GnRH agonist groups differed in several important characteristics: the follow-up times were not equal, different treatment protocols were utilized and end-points were poorly defined and inconsistent between the studies. CONCLUSIONS The effectiveness of GnRH agonists as fertility-preserving agents is debatable. A thorough literature search has found insufficient evidence to show that GnRH agonist co-treatment is effective in protecting the ovary from the damage of chemotherapy. A large randomized controlled trial with adequate follow-up is needed.

The matrix metalloproteinases (MMPS) in the decidua and fetal membranes

The role of the matrix metalloproteinases (MMPs) in the decidua, fetal membranes and amniotic fluid (AF) has been receiving more and more attention. The MMPs are not only important intermediaries in pathological processes leading to preterm labor but it seems that they also play a crucial role in the activation of labor at term. During normal gestation MMP-1, -2, -3, -7 and -9 are found in the amniotic fluid and fetal membranes. MMP-2 and MMP-3 are expressed constitutively while MMP-9 is barely detectable until labor. At labor, while MMP-9 is the major MMP responsible for gelatinolytic activity in the membranes, MMP-2 is dominant in the decidua. MMP-7 (AF) increases with gestation but does not appear to play a major role in labor. The expression of MMPs is attenuated through the expression of relaxins, integrins and extracellular matrix metalloproteinase inducer (EMMPRIN). Spontaneous preterm delivery (PTD) may be a product of preterm labor (PTL), preterm premature rupture of membranes (P-PROM) or placental abruption. Each of these processes may have differing pathways but the presence of an intrinsic inflammatory response with or without infection seems to involve all etiologies. The inflammatory response is mediated with cytokines such as interleukins -1, -6 and -8 and tumor necrosis factor alpha. MMP-3, MMP-7 and MMP-8 appear to be important in these processes. MMP-9, which is the major MMP involved in normal labor, plays an important role in pathological labor as well. Finally, apoptosis seems to play a role in pathological labor, particularly deliveries involving P-PROM. African-American are at greater risk of PTD than white or Hispanic Americans. Environmental differences may not suffice to explain this phenomenon. Genetic polymorphisms of the MMP genes may help explain the greater risk among this population. Finally, manipulating MMPs may have a role in the prevention of PTD. Agents suggested include indomethacin, N-acetylcysteine, progesterone and specific inhibitors of phosphodiesterase 4.

Empty follicle syndrome: successful treatment in a recurrent case and review of the literature

Empty follicle syndrome is a condition in which no oocytes are retrieved after an apparently adequate ovarian response to stimulation and meticulous follicular aspiration. It is a rare condition of obscure etiology. A patient with primary infertility who underwent seven assisted reproductive technique cycles is described. In spite of a satisfactory ovarian response, aspiration yielded no oocytes in four cycles and 1-4 low quality oocytes in three cycles. In the index treatment cycle, ovulation was triggered using GnRH agonist 40 h prior to ovum pickup and hCG was added 6 h after the first trigger. Eighteen oocytes were recovered, of which 16 were mature and were inseminated by ICSI. Two embryos were transferred 48 h after aspiration and nine embryos were cryopreserved. The patient conceived and delivered a healthy boy at 38 weeks of gestation. The literature is reviewed and possible etiologies and treatment options of this enigmatic syndrome are suggested.

Rescue intracytoplasmic sperm injection: a systematic review

OBJECTIVE To assess the feasibility, efficacy, and safety of rescue intracytoplasmic sperm injection (ICSI) in cases of fertilization failure, using a scientific literature search. DESIGN Systematic review. SETTING Centers for reproductive care. PATIENT(S) Infertility patients with total or partial fertilization failure during an IVF cycle. INTERVENTION(S) An electronic literature search was performed in PubMed from 1992 through May 2013. The search was then expanded by using listed references from selected articles. MAIN OUTCOME MEASURE(S) Pregnancy rate. The secondary outcome measures were fertilization rate, normal fertilization rate, cleavage rate, birth rate, and malformation rate. RESULT(S) Thirty-eight studies including 1,863 patients were included. The pooled pregnancy rate was 14.4%; 194 babies were delivered. CONCLUSION(S) Rescue ICSI can result in the delivery of a healthy newborn, although the pregnancy rates are low. The clinical evidence did not indicate an elevated rate of malformations, although the data are limited and incomplete.

Clinical benefit using sperm hyaluronic acid binding technique in ICSI cycles: a systematic review and meta-analysis

The human oocyte is surrounded by hyaluronic acid, which acts as a natural selector of spermatozoa. Human sperm that express hyaluronic acid receptors and bind to hyaluronic acid have normal shape, minimal DNA fragmentation and low frequency of chromosomal aneuploidies. Use of hyaluronic acid binding assays in intracytoplasmic sperm injection (ICSI) cycles to improve clinical outcomes has been studied, although none of these studies had sufficient statistical power. In this systematic review and meta-analysis, electronic databases were searched up to June 2015 to identify studies of ICSI cycles in which spermatozoa able to bind hyaluronic acid was selected. The main outcomes were fertilization rate and clinical pregnancy rate. Secondary outcomes included cleavage rate, embryo quality, implantation rate, spontaneous abortion and live birth rate. Seven studies and 1437 cycles were included. Use of hyaluronic acid binding sperm selection technique yielded no improvement in fertilization and pregnancy rates. A meta-analysis of all available studies showed an improvement in embryo quality and implantation rate; an analysis of prospective studies only showed an improvement in embryo quality. Evidence does not support routine use of hyaluronic acid binding assays in all ICSI cycles. Identification of patients that might benefit from this technique needs further study.

Thrombophilia and stillbirth: possible connection by intrauterine growth restriction

Objective  To define the association between thrombophilia and unexplained stillbirth.

Ultrasound Assessment of the Bladder Volume after Anterior Colporrhaphy

In 40 gynecological patients 44 different determinations of the bladder volume were made using ultrasonic methods. The product of bladder depth, height, and width, as determined from transverse and sagittal scans, showed the best correlation with the bladder volume measured by urethral catheter (r = 0.981). For 73% of the measurements the error was under 20% when the true bladder volume was greater than 100 cm3. This method gives a reasonable assessment of the bladder residual volume. It is quick, safe, and repeatable and, therefore, useful in postoperative clinical practice.

Mechanisms of matrix metalloproteinase-9 and matrix metalloproteinase-2 inhibition by N-acetylcysteine in the human term decidua and fetal membranes

OBJECTIVE The purpose of this study was to evaluate the effect of N-acetylcysteine on the activity and secretion of the matrix metalloproteinases in the decidua, amnion, and chorion and the secretion of the tissue inhibitor of matrix metalloproteinase-1. STUDY DESIGN Samples from eight nonlaboring women were taken at elective cesarean section and incubated in an in vitro organ culture in the absence or presence of N-acetylcysteine. Matrix metalloproteinase-2 and matrix metalloproteinase-9 activity was measured with the use of gel zymography. Western blot analysis was used to measure matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase-1 secretion. Data were analyzed with the paired Student t test. RESULTS N-acetylcysteine had a direct inhibitory effect on matrix metalloproteinase-2 and matrix metalloproteinase-9 activity, regardless of tissue origin, starting at 1.0 mmol/L. In cultured media, 20 mmol/L N-acetylcysteine inhibited matrix metalloproteinase-2 and matrix metalloproteinase-9 activity in all three tissues. A differential response was demonstrated for matrix metalloproteinase-2 secretion, depending on the tissue that was studied. Its secretion was decreased in decidua at 10 mmol/L and 20 mmol/L; in amnion, the secretion was inhibited at 0.1 mmol/L and not affected at all in chorion. Matrix metalloproteinase-9 secretion was not affected in a statistically significant manner in any tissue. In the chorion, matrix metalloproteinase-9 showed a trend toward increased secretion. Tissue inhibitor of matrix metalloproteinase-1 secretion significantly decreased in the decidua at 20 mmol/L. CONCLUSION N-acetylcysteine, at higher concentrations, has an inhibitory effect on matrix metalloproteinase-2 and matrix metalloproteinase-9 activity, regardless of the tissue origin and the differential effect on secretion depending on the tissue and N-acetylcysteine concentration.

Ectopic pregnancy risk factors for ART patients undergoing the GnRH antagonist protocol: a retrospective study

BackgroundIn-vitro fertilization is a known risk factor for ectopic pregnancies. We sought to establish the risk factors for ectopic pregnancy in GnRH antagonist cycles examining patient and stimulation parameters with an emphasis on ovulation trigger.MethodsWe conducted a retrospective, cohort study of 343 patients undergoing 380 assisted reproductive technology (ART) cycles with the GnRH antagonist protocol and achieving a clinical pregnancy from November 2010 through December 2015.ResultsSignificant risk factors for ectopic pregnancy in the univariate analysis included prior Cesarean section (CS), endometriosis, mechanical factor infertility, longer stimulation, elevated estradiol and progesterone levels, GnRH agonist trigger, higher number of oocytes aspirated, and insemination technique. Independent risk factors for ectopic pregnancy in the multivariate analysis included GnRH agonist trigger, higher number of oocytes aspirated, insemination technique, and prior Cesarean section.ConclusionExcessive ovarian response, IVF (as opposed to ICSI), prior Cesarean section and GnRH agonist trigger were found to be independent risk factors for ectopic pregnancy. Caution should be exercised before incorporating the GnRH agonist trigger for indications other than preventing OHSS. When excessive ovarian response leads to utilization of GnRH agonist trigger, strategies for preventing ectopic pregnancy, such as a freeze all policy or blastocyst transfer, should be considered. Further studies should elucidate whether adjusting the luteal support can reduce the ectopic pregnancy risk.

Lag time from ovulation trigger to oocyte aspiration and oocyte maturity in assisted reproductive technology cycles: a retrospective study

OBJECTIVE To study the correlation between the lag time from ovulation trigger to oocyte aspiration and the proportion of metaphase II (MII) mature oocytes aspirated. DESIGN Retrospective study. SETTING Fertility and IVF center in an academic regional hospital. PATIENT(S) A total of 511 women undergoing IVF-intracytoplasmic sperm injection at our center, with at least one oocyte available for maturity determination. INTERVENTION(S) Data were retrieved from patient electronic databases and files. Demographic data, hormone treatments and ovarian response, and the time of ovulation trigger and oocyte aspiration were recorded. MAIN OUTCOME MEASURE(S) The primary outcome was the proportion of MII mature oocytes relative to the total number of oocytes aspirated and allocated to intracytoplasmic sperm injection. Pregnancy rates and clinical pregnancy rates were secondary outcomes. RESULT(S) There were fewer MII mature oocytes when the lag time between oocyte trigger and aspiration was between 33.45 hours and 34.45 hours. The proportion of MII oocytes seems to increase up to a 35-hour lag time and then stabilizes up to 38 hours. Pregnancy and clinical pregnancy rates did not differ among the different time groups studied. CONCLUSION(S) Oocyte aspiration should be scheduled at least 35 hours after ovulation trigger. Oocytes can be aspirated in a 3-hour window of time between 35 and 38 hours without compromising results. Further research should elucidate whether even longer lag times will improve the proportion of MII mature oocytes.