Paul W. Zarutskie

A meta-analysis of the route of administration of luteal phase support in assisted reproductive technology: vaginal versus intramuscular progesterone.

OBJECTIVE To perform an analysis of data with consideration for the current clinically accepted vaginal progesterone (P) or intramuscular (IM) P dosing regimens and the clinically relevant randomized clinical trials published during the time frame 1992 to 2008. DESIGN Meta-analysis of progesterone luteal support in IVF cycles using odds ratios (OR) and 95% confidence intervals (CI). SETTING Previously conducted randomized clinical trials meeting acceptance criteria. PATIENT(S) Infertility patients. INTERVENTION(S) Progesterone (50 mg) IM daily or 200 mg P-in-oil capsules three times a day vaginally or 90 mg P in bioadhesive gel daily vaginally. MAIN OUTCOME MEASURE(S) Clinical pregnancy, ongoing pregnancy, miscarriage. RESULT(S) This analysis showed a comparable effect between vaginal progesterone as an oil-in-capsule or as a bioadhesive gel and IM P administration on the endpoints of clinical pregnancy (OR = 0.91, 95% [CI 0.74, 1.13]) and ongoing pregnancy (OR = 0.94, 95% [CI 0.71, 1.26]). A nominally significantly lower rate of miscarriage was observed with vaginal P compared with IM P (OR = 0.54, 95% [CI 0.29, 1.02]). CONCLUSION(S) Administration of vaginal P is comparable to administration of IM P for luteal phase support in assisted reproductive technology.

Starfish oocyte maturation: 1-Methyladenine triggers a drop of cAMP concentration related to the hormone-dependent period

Oocyte maturation (meiosis reinitiation) in starfish is induced by the natural hormone 1-methyladenine (1-MeAde). Oocytes of Evasterias troschelii contain 0.43 pmole cyclic AMP/mg protein and 0.47 pmole cyclic GMP/mg protein. Upon stimulation by 1-MeAde the oocytes undergo a moderate (10-30%) decrease in their cAMP concentration. The concentration of cGMP remains unaltered. Oocytes treated with forskolin, an activator of adenylate cyclase, increase their cAMP concentration over 35-fold, up to 16 pmole cAMP/mg protein. When stimulated by 1-MeAde these forskolin-pretreated oocytes undergo a major (50-70%) decrease in their cAMP concentration. A similar decrease is triggered by mimetics of 1-MeAde, such as dithiothreitol, arachidonic acid (AA), and 8-hydroxyeicosatetraenoic acid (8-HETE), but not by adenine which is inactive. 1-MeAde-stimulated oocytes of Pisaster ochraceus also undergo a decrease in cAMP content, the size of which is increased by forskolin. Although a decrease in cAMP begins at sub-threshold 1-MeAde concentrations, the maximal decrease occurs at the same concentration of 1-MeAde needed for maturation induction and a further 1000-fold increase of the 1-MeAde concentration has no further effect. Upon removal of 1-MeAde, the cAMP concentration immediately increases to its original level. Sequential addition and removal of 1-MeAde triggers a sequential decrease and increase of the cAMP concentration, illustrating the continuous requirement for 1-MeAde for eliciting the decrease. Successive additions of 1-MeAde, however, do not trigger further decreases of the cAMP concentration. The temperature dependences of the cAMP concentration decrease and of the hormone-dependent period (HDP; the time of contact with 1-MeAde required for induction of maturation) are closely related. Forskolin, which increases the cAMP concentration, also increases the duration of the HDP (2.5-fold), delays the time course of protein phosphorylation burst and germinal vesicle breakdown, and inhibits AA- and 8-HETE-induced maturation. We conclude that 1-MeAde triggers a drop in cAMP concentration, which is tightly associated with the hormone-dependent period of oocyte maturation.

The clinical relevance of sex selection techniques

Clinical and laboratory attempts to alter the sex ratio require more complete and thorough study. Improved identification of Y-bearing sperm through chromosome evaluation rather than by F-body identification is critical to provide a more precise definition. The tentative conclusions stated below are based on an assessment of literature from which it is generally difficult to draw conclusions: 1. The timing of intercourse in relation to ovulation and subsequent fertilization appears to influence the sex ratio. More females are conceived when coitus occurs relatively close to ovulation, and more males are conceived when the sperm or egg is in the reproductive tract for a relatively longer time before conception. The influence of coital timing on the sex ratio is overall quite subtle and is not a practical method to alter the sex ratio for individual couples. 2. The use of ovulation-inducing medications slightly favors female offspring. A decrease in sex ratio of 5% to 10% has been shown in multiple studies. 3. Artificial insemination with fresh donor or homologous spermatozoa results in more male births with a reported 7% to 10% increase in the sex ratio. It appears that ovulation induction combined with artificial insemination cancels the respective influences of each on the sex ratio. 4. Sperm separation techniques using albumin (for selection of Y-bearing sperm) or Sephadex column filtration (for selection of X-bearing sperm) are the only techniques that have been reported to alter the sex ratio to a degree that is clinically relevant. Although clinical birth data are just beginning to accumulate, these methods appear to have a 70% to 80% success for selection of assumed Y-bearing sperm and a 75% to 80% success for selection of assumed X-bearing sperm. The validity of these results will remain questionable until fully detailed accounts are published and successfully repeated. Free-flow electrophoresis appears to achieve significant separation; however, the depressed postprocedure spermatozoa motility presently limits the usefulness of this procedure. 5. There is a potential to combine clinical and laboratory methods to maximize the efficiency of sex selection for interested couples. Modern methods to identify ovulation (e.g., urinary LH kits, ultrasonography) may help the timing of coitus for sex selection. Clomiphene citrate may enhance female sex preselection when Sephadex column filtration is also employed. 6. The priority of sex preselection in terms of medical, social, and demographic consideration remains to be determined. The avoidance of sex-linked genetic disorders is a reasonable and desirable goal.(ABSTRACT TRUNCATED AT 400 WORDS)

Human sperm penetration assay as an indicator of sperm function in human in vitro fertilization

Performance of spermatozoa in a hamster oocyte/human sperm penetration assay (SPA) was correlated with the results of in vitro fertilization (IVF). Forty-two patients underwent 50 IVF cycles. SPA scores were obtained before IVF cycles (screening SPA, n = 30) and, where practical, on the semen sample used for IVF (IVF SPA, n = 26). Screening SPA score did not correlate to IVF result, fertilization and cleavage rates were similar between normal (n = 17) and low (n = 13) SPA groups, pregnancy rates were 35 and 46%, respectively. In addition, SPA score at the time of IVF did not correlate with IVF result. Pregnancy rates were 33% for the normal group (n = 16) and 30% for the low SPA group (n = 10). Overall, the low SPA group (n = 16) exhibited a 78% fertilization rate and a 38% pregnancy rate, which was not different from the normal SPA group: 76 and 29%, respectively. The results of this study indicate that SPA score is a poor indicator of sperm function in IVF.

Endocrine changes in the late-follicular and postovulatory intervals as determinants of the in vitro fertilization pregnancy rate

This investigation examines the hormone pattern in in vitro fertilization (IVF) cycles from the time of human chorionic gonadotropin (hCG) administration through embryo transfer to ascertain whether the absolute levels or secretory patterns of the major reproductive hormones affect the IVF pregnancy rate. Thirty-one women who underwent IVF treatment were enrolled in the study. All patients received clomiphene citrate/human menopausal gonadotropin for ovulation induction. Significant elevations in serum estradiol (E2) levels in the pregnant group were found throughout the cycle interval studied. After hCG administration the serum hCG levels were not different between the groups. Significant elevations in serum progesterone (P) concentrations were found in the pregnant group from the day after laparoscopy through embryo transfer. Embryos obtained from the pregnant group appeared to be different in that the mean number of blastomeres per embryo transferred was significantly greater. Therefore for achievement of an IVF pregnancy the optimal hormone pattern employing combination ovulation induction in the ovulation to transfer interval is a relatively high E2 level in ovulation followed by a high P level at transfer and into the luteal phase. These elevated hormone levels do not depend on the response to exogenous hCG.

Hormonal and Clinical Predictors for Post-egg Retrieval Pain in Women Undergoing Assisted Reproductive Technology Procedures.

Objectives:The intensity of post–egg retrieval pain is underestimated, with few studies examining postprocedural pain and predictors to identify women at risk for severe pain. We evaluated the influence of preprocedural hormonal levels, ovarian factors, and mechanical temporal summation (mTS) as predictors for post–egg retrieval pain in women undergoing in vitro fertilization. Methods:Eighteen women scheduled for ultrasound-guided egg retrieval under standardized anesthesia and postprocedural analgesia were enrolled. Preprocedural mTS, questionnaires, clinical data related to anesthesia and the procedure itself, postprocedural pain scores, and pain medication for breakthrough pain were recorded. Statistical analysis included Pearson product-moment correlations, Mann-Whitney U tests, and multiple linear regressions. Results:Average peak post–egg retrieval pain during the first 24 hours was 5.0±1.6 on a numerical response scale (0=no pain, 10=worst pain imaginable). Peak post–egg retrieval pain was correlated with basal antimullerian hormone (AMH) (r=0.549, P=0.018), preprocedural peak estradiol (r=0.582, P=0.011), total number of follicles (r=0.517, P=0.028), and number of retrieved eggs (r=0.510, P=0.031). Ovarian hyperstimulation syndrome (n=4) was associated with higher basal AMH (P=0.004), higher peak pain scores (P=0.049), but not with peak estradiol (P=0.13). The mTS did not correlate with peak postprocedural pain (r=0.266, P=0.286), or peak estradiol level (r=0.090, P=0.899). Discussion:Peak post–egg retrieval pain intensity was higher than anticipated. Our results suggest that post–egg retrieval pain can be predicted by baseline AMH, high peak estradiol, and ovarian hyperstimulation syndrome. Further studies to evaluate intraprocedural and postprocedural pain in this population are needed, as well as clinical trials to assess postprocedural analgesia in women presenting with high hormonal levels.