Martha Dirnfeld

Cessation of gonadotropin-releasing hormone analogue (GnRH-a) upon down-regulation versus conventional long GnRH-a protocol in poor responders undergoing in vitro fertilization

OBJECTIVE To determine whether a controlled ovarian hyperstimulation (COH) regimen that involves GnRH agonist (GnRH-a) discontinuation before administration of gonadotropins would benefit poor responders. DESIGN A prospective, randomized controlled trial. SETTING Hospital-based IVF Unit. PATIENT(S) Sixty-three patients with previous poor response to COH and/or high basal FSH level (> or =9 mIU/mL) undergoing 78 IVF-ET cycles. INTERVENTION(S) In both groups, administration of GnRH-a was started in the midluteal phase. Whereas in the study group (40 cycles), it ended before administration of gonadotropins, in controls (38 cycles) GnRH-a treatment was continued throughout the follicular phase. MAIN OUTCOME MEASURE(S) Ovarian stimulation patterns and IVF outcome. RESULT(S) A significantly higher cancellation rate was noted in the study group than in the controls (22.5% versus 5%, respectively). The new and control regimens resulted in similar stimulation characteristics and clinical pregnancy rates (11% versus 10.3%, respectively). In 13 patients with a basal FSH level that was not persistently high, the new regimen resulted in a significantly higher number of retrieved oocytes compared with the standard protocol (7.6+/-1.03 versus 4.0+/-0.68, respectively). CONCLUSION(S) Whereas for most low responders, the new COH regimen offers no further advantage, future prospective studies may demonstrate whether it can confer a benefit for a subset of patients with a basal FSH level that is not persistently high.

Advanced paternal age and reproductive outcome

Women have been increasingly delaying the start of motherhood in recent decades. The same trend is seen also for men. The influence of maternal age on fertility, chromosomal anomalies, pregnancy complications, and impaired perinatal and post-natal outcome of offspring, has been thoroughly investigated, and these aspects are clinically applied during fertility and pregestational counseling. Male aging and reproductive outcome has gained relatively less attention. The purpose of this review is to evaluate updated and relevant literature on the effect of paternal age on reproductive outcome.

Spontaneous fetal reduction in multiple gestations assessed by transvaginal ultrasound

Objective To assess the occurrence of disappearance of one or more of the fetuses in pregnancies which start as multiple gestation.

A simplified coculture system with luteinized granulosa cells improves embryo quality and implantation rates: a controlled study.

OBJECTIVE To investigate the use of a simplified short-term coculture system with luteinized granulosa cells (GCs) in patients with failed IVF-ET. DESIGN Controlled clinical study. SETTING IVF unit, Department of Obstetrics and Gynecology, Carmel Medical Center. PATIENT(S) Patients with poor embryo quality in their previous IVF-ET cycles. INTERVENTION(S) Embryos from 40 patients, in which > 50% of the embryos were classified as poor quality in their previous IVF attempts, were grown on autologue GC culture system for a short period (24-48 hours) before being replaced in the uterine cavity. MAIN OUTCOME MEASURE(S) Embryo quality. RESULT(S) Significant decrease in poor quality embryos and increase in the proportion of good quality embryos were observed using a coculture system with autologue human GCs. Pregnancy rates in this groups of patients reached our standard IVF results during the same period. CONCLUSION(S) This study describes a simplified short-term coculture system with human autologue GCs. Poor quality embryos may be rescued to cleave regularly.

Growth rate of follicular estrogen secretion in relation to the outcome of in vitro fertilization and embryo replacement

Estradiol growth rate (EGR) during active follicular development was calculated for 89 stimulated in vitro fertilization cycles by exponential curve fit (r = 0.83). Cycles could be divided into four groups with very low, low, moderate, and high EGR values. Cases without oocyte fertilization and/or embryo replacement did not occur in the moderate EGR range, which also corresponded to a significantly better ratio of replaceable embryos versus oocytes recovered. This group was also endowed with a pregnancy rate amounting to 28.5% per laparoscopy and per replacement, i.e., about three times higher than in the three other groups. Very low or high EGR entailed significantly higher percentages of missed oocyte recovery and/or fertilization failure. The frequency of occurrence of a spontaneous luteinizing hormone peak was negatively correlated with EGR. The data indicate that a better outcome of in vitro fertilization may be expected when the estrogen rise starts early in the cycle and adopts a moderate growth rate (0.3 to 0.4).

Morphometrical quantification of spermatogonial germ cells with the 57B anti-MAGE-A4 antibody in the evaluation of testicular biopsies for azoospermia.

The melanoma-associated antigen (MAGE) gene family of cancer–testis antigens is expressed in certain malignant neoplasms and the testis, but not in other healthy tissues. The aim of this study was to determine the usefulness of immunohistochemical staining with the 57B anti-MAGE-A4 mouse monoclonal antibody (MAb) in testicular biopsy specimens from patients with nonobstructive azoospermia and obstructive azoospermia (OA). Fifty-four cases of Sertoli cell only (SCO), 30 cases of spermatocytic arrest, 15 cases of hypospermatogenesis, and 10 testicular biopsy specimens with OA (normal spermatogenesis) were evaluated. Immunohistochemistry was performed using the 57B MAb, which primarily recognizes the MAGE-A4 antigen in paraffinized tissues. The cells were quantitated by a computerized image analysis system. Testicular biopsy specimens with normal spermatogenesis exhibited strong nuclear and cytoplasmic MAGE-A4 staining of spermatogonia and weak staining of spermatocytes, but not spermatids or Sertoli or Leydig cells. No staining was detected in SCO cases. In five cases of SCO with focal spermatogenesis, spermatogonial cells that were initially missed by hematoxylin and eosin staining were detected by MAGE-A4 immunohistochemistry. Immunostaining with the 57B MAb greatly enhanced identification of spermatogonia in cases of spermatocytic arrest and hypospermatogenesis. The number of MAGE-A4-positive spermatogonia was significantly decreased in hypospermatogenesis, as opposed to the OA group (12.1 ± 4.3 and 30.3 ± 10.0, respectively). The number of MAGE-A4-positive primary spermatocytes was significantly increased in early maturation arrest, as compared with the OA group (48.2 ± 10.8 and 16.9 ± 9.8, respectively). The 57B anti-MAGE-A4 MAb is a useful marker for the detection and quantitation of spermatogonial germ cells. It also facilitates automated image analysis and provides greater accuracy in the histopathologic evaluation of testicular biopsy specimens.

Thin endometrium in donor oocyte recipients: enigma or obstacle for implantation?

OBJECTIVE To evaluate the combined effect of endometrial thickness and anatomic uterine factors on clinical outcome in oocyte donation recipients. DESIGN Retrospective analysis of oocyte donation cycles conducted between 2005 and 2010. SETTING Two private IVF centers. PATIENT(S) A total of 737 donor oocyte cycles. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Clinical pregnancy and live birth rates. RESULT(S) No statistically significant difference was found in clinical pregnancy rates and live birth rates in cycles with endometrial thickness <6 mm compared with those with endometrial thickness >10 mm. However, a relatively high rate of live births was found within a medium range of endometrial thickness (8.2-10 mm). All intrauterine adhesion cases occurred in cycles with thinner endometrium. CONCLUSION(S) No statistically significant difference was found in clinical pregnancy rates and live birth rates in cycles with endometrial thickness <6 mm compared with those with thickness >6 mm. A relatively high rate of live births was found within a medium range of endometrial thickness (9.1-10 mm).

Decreased expression of tissue inhibitor of matrix metalloproteinases in follicular fluid from women with polycystic ovaries compared with normally ovulating patients undergoing in vitro fertilization

OBJECTIVE To compare activity of matrix metalloproteinases (MMP) and expression of their tissue-specific inhibitor (TIMP) in the follicular fluid of normally ovulating women and women with the polycystic ovary syndrome (PCOS). DESIGN Prospective study. SETTING IVF unit and endocrine research unit. PATIENT(S) Fourteen patients undergoing IVF treatment (seven with normal ovulation and seven with PCOS). MAIN OUTCOME MEASURE(S) Activity of MMP-2 and MMP-9 and expression of MMP-1, TIMP-1, and TIMP-2 was measured in follicular fluid of the leading follicles by using gel zymography and immunoblot analysis. RESULT(S) The activity of MMP-2 and MMP-9 and expression of MMP-1 was similar in follicular fluid of normally ovulating patients and patients with PCOS. Significantly lower expression of TIMP-1 was found in follicular fluid of patients with PCOS women compared with normally ovulating patients. CONCLUSION(S) Because MMPs and TIMPs play a role in the physical and chemical structure of the follicular compartment, the decreased expression of TIMP in patients with PCOS may be part of a compensatory process to overcome the physical properties of the thick ovarian capsule.

The use of long-acting gonadotropin-releasing hormone agonist (GnRH-a;decapeptyl) and gonadotropins versus short-acting GnRH-a (buserelin) and gonadotropins before and during ovarian stimulation for in vitro fertilization (IVF)

The efficiency of two ovarian stimulation protocols using different gonadotropin-releasing hormone agonists (GnRH-a) for in vitro fertilization (IVF) was examined and compared with human menopausal gonadotropin (hMG)-only stimulation. Fifty-four patients who had 57 aspiration cycles were treated with protocol 1, which consisted of long-acting GnRH-a D-Trp6 (Decapeptyl Depot) and hMG. Protocol 2 entailed intranasal administration of short-acting GnRH-a (Buserelin) and human menopausal gonadotropin (hMG) in 66 women, who underwent 70 aspiration cycles. Fifty-five patients who had 59 ovum pickups (OPU) treated with hMG only served as a control. No differences were observed in cycle parameters and hormonal concentrations among the three groups. The total clinical pregnancy rates per OPU for patients receiving protocols 1 and 2 were 12.3 and 27.1%, respectively (P<0.05). The pregnancy loss was significantly lower in protocol 2 than in protocol 1 (26.3 versus 71.4%;P<0.05). Our data show superiority of short-acting GnRH-a over the long-acting agents in achievement of pregnancy and its outcome, though neither was significantly different from the hMG-only protocol.

A randomized prospective study on the effect of short and long Buserelin treatment in women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response

Fifty four women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response to stimulation with human menopausal gonadotropins (hMG) participated in this study. They were randomized to receive either gonadotropin releasing hormone agonist (GNRHa), Buserelin, prior to and during induction of ovulation by hMG (Group I—long protocol), or GnRHa starting on the first day of the cycle together with induction of ovulation by hMG (Group II—short protocol). Mean follicular phase serum luteinizing hormone (LH) and progesterone (P) levels were significantly lower in Group I than in Group II (P<0.01). Cancellation rate was significantly lower in Group I than in Group II (P<0.01). The long GNRHa protocol resulted in statistically significant lower cancellation rates, more oocytes per pickup (OPU), more embryos trans-ferred per patient, and a higher pregnancy rate. Significantly more hMG ampoules and more treatments days were required in the long GNRHa protocol. Our data demonstrate that the use of GNRHa prior to and during ovarian stimulation with hMG offers a very good alternative for patients with repetitive unsuccessful IVF cycles due to inadequate response.