Are Caucasian-European men delaying fatherhood? Results of a 7 year observational study of infertile couples with male factor infertility.

This study was aimed at assessing presence and predictors of a trend towards more advanced paternal age at presentation in a cohort of 1283 Caucasian-European infertile couples with male factor infertility (MFI) over a short time frame. Multivariate linear regression analysis tested the association between predictors [namely, partners' age, length of infertility at first presentation, patients' comorbidities as scored with the Charlson Comorbidity Index (CCI) and educational status] and patient's age at presentation. Using anova, patient's age at presentation (F ratio: 2.43; p = 0.024) and patients' educational status (χ(2) trend: 142.38; p < 0.001) significantly increased over time. In contrast, length of infertility at first presentation, CCI and partners' age did not significantly change over time (all p ≥ 0.05). Linear regression analyses showed that CCI, educational status and year of presentation were not correlated with patients' age at presentation (all p ≥ 0.05), whereas partners' age (ß = 0.170; p < 0.001) and length of infertility (ß = 0.123; p = 0.004) were independent predictors of delayed fatherhood. These results showed a significant shift towards advanced paternal age, but a non-significant increase of maternal age at first presentation among Caucasian-European infertile couples with MFI over a short time frame.

Nutrients and infertility: an alternative perspective.

BACKGROUND: Different gonadotrophin preparations or different protocols of ovulation induction are powerless to determine a significantly increase in oocyte quality in the majority of aged patients or in patients with repeated failed in vitro fertilization-embryo transfer (IVF-ET) cycles. INFORMATION SOURCES: Papers published on journal focused on nutraceutical and human reproduction. EVIDENCES: It is questionable if various molecules that are positively associated with higher oocyte competence, higher fertilization rate and embryo development could be supplemented to infertile patients with the aim to partly reduce the frequency of unsuccessful IVF. PERSPECTIVES: Aim of this short review is mainly to focus the attention on potentially positive effects in female fertility of few, well established substances, that could be suggested as a dietary supplement.

Reducing clinical trial risk in multiple sclerosis.

OBJECTIVE: To determine the risk of clinical trial failure for new drugs in multiple sclerosis (MS) and to identify factors that could improve outcomes. METHODS: We collected data on compounds that were tested in MS from Phase I to Phase III clinical trials between 1998 and January 2015. Clinical trials success rates were calculated and compared to industry standards. The exclusion criteria for the drugs in this study were: drugs that commenced Phase I in MS prior to 1998, non-industry conducted trials, trials testing non-disease modifying drug treatment, and trials testing combinations of drugs already approved by the FDA. RESULTS: Fifty-three distinct drugs met our inclusion criteria. The cumulative success rate for MS drugs was 27%, almost triple the 10% industry rate. Clinical trial success rates in MS surpass that of industry across all phases. Phase II clinical trials completed in a "Relapsing MS" population were most successful in predicting Phase III clinical trial success. Small molecules were found to have a higher overall success rate compared to biologics; however, both drug technologies largely pursue different molecular targets. Drugs that were previously FDA approved for another indication and were subsequently tested in MS had lower success rates than drugs that had no previous FDA approval history. CONCLUSIONS: Overall, MS enjoys almost triple the clinical trial success rates of other disease areas. In addition, small molecules are superior to biologics in MS and novel drugs are superior to drugs with a previous FDA approval history outside MS.

Use of growth hormone-releasing factor in ovulation induction in poor responders.

OBJECTIVE: To evaluate the effect of growth hormone-releasing factor (GRF), given in addition to follicle-stimulating hormone (FSH), after pituitary down-regulation, on follicular development in poor responders. GRF was added in a prospective, randomized manner to an existing stimulation protocol. STUDY DESIGN: Forty-two women, demonstrated to be poor responders in previous attempts at induction of ovulation, were included in the study. Follicular stimulation with FSH was started after pituitary downregulation obtained using gonadotropin-releasing hormone agonist (GnRH-a). GRF, 1,000 mg/day, was given in addition to FSH to 22 patients randomly chosen until human chorionic gonadotropin administration. RESULTS: The number of ampules of FSH needed to obtain follicular growth was significantly reduced in the group of women who received GRF. Also, the number of follicles obtained was higher and the days of treatment generally reduced. However, a greatly beneficial effect for some women was observed, while a second subgroup did not have any. No differences were observed in follicular steroid and insulin growth factor 1 (IGF-1) between GRF patients and controls or in serum IGF-1 between the two subgroups of patients who received GRF. CONCLUSION: In vivo administration of GRF with FSH after pituitary down-regulation may be beneficial for some poor responders, although prognostic criteria could not be established. However, the use of GRF does not seem to influence the chance of obtaining pregnancy; it remains low in these patients.

Tumor-associated trypsin inhibitor as a possible marker in male infertility.

The concentrations of tumor-associated trypsin inhibitor (TATI) in the seminal plasma of infertile males was studied. The TATI levels in seminal plasma were not correlated with either sperm count or ejaculate volume. High levels were observed in some men with unexplained infertility and high or normal sperm counts, whereas normal levels were observed in males with antisperm antibodies. The concentrations in seminal plasma were stable in the same subjects. These results suggest that TATI may be an important marker of reproductive pathology in men.

Oocyte cryopreservation: clinical outcome of slow-cooling protocols differing in sucrose concentration.

Oocyte cryopreservation represents an important option for management of female fertility, avoiding the ethical concerns associated with embryo storage. This retrospective study evaluated the clinical outcome of two alternative slow freezing protocols involving different sucrose concentrations. From January 2004 to March 2006, spare oocytes from selected couples undergoing IVF or intracytoplasmic sperm injection were frozen using a slow-cooling protocol and thawed at a later stage. Patients were divided into two groups: group A (n = 65), whose oocytes were frozen with propane-1,2-diol (PrOH) and 0.1 mol/l sucrose; and group B (n = 66) whose oocytes were frozen with 0.3 mol/l sucrose. A total of 543 oocytes were thawed in group A and 601 in group B, achieving a survival rate of 24.3 and 71.2% respectively. Whilst fertilization rate (53.5 and 80.4% respectively) was higher in group B, enhanced results for group A were achieved over all (implantation rate per transferred embryos 12.2 versus 5.7%; pregnancy rate per transfer 16.7 versus 9.5%). Normal births and ongoing pregnancies have occurred in both groups. Although in slow-cooling methods higher sucrose concentration in the freezing mixture allows higher post-thaw survival and fertilization rates, overall this did not coincide with an improved clinical outcome.

Objective evaluation of the viability of cryopreserved oocytes.

Recent studies of fundamental cryobiology, empirical observations and more systematic clinical experiences have generated a renewed interest in oocyte cryopreservation. Poor survival rate has long been the limiting factor which has prevented widespread adoption of oocyte storage. Slow-cooling and vitrification protocols developed in the last few years have apparently solved this problem, ensuring high recovery of viable oocytes from liquid nitrogen storage. However, the definition of oocyte viability appears rather vague. In fact, post-storage survival as assessed on morphological criteria, indicated by the absence of overt cell degeneration, is not necessarily synonymous with viability. Despite its sensitivity to low temperatures, the meiotic spindle can be preserved after cryopreservation and its constitution after thawing can be monitored non-invasively through polarized light microscopy. Assessment of oocyte cryopreservation via clinical parameters is a daunting task. Most studies are small and difficult to interpret because of confounding factors, such as age, patient selection and quality and strategy of use of the cryopreserved material. Some progress has been made, however, as suggested by recent experiences in which the implantation efficiency of embryos produced from thawed oocytes approaches that reported using cryopreserved embryos directly.

Comparison of GnRH agonists and antagonists in assisted reproduction cycles of patients at high risk of ovarian hyperstimulation syndrome.

BACKGROUND: During IVF or ICSI cycles, ovarian hyperstimulation syndrome (OHSS) is a major problem. The aim of this prospective, multicentre, comparative study (using historical controls) was to assess the efficacy of a GnRH antagonist protocol in preventing OHSS in selected patients who had experienced OHSS or had been at risk of OHSS in their previous IVF/ICSI attempt. METHODS AND RESULTS: Patients underwent a new cycle where the same gonadotrophin protocol was used [same dose of recombinant FSH (rFSH)] but a different protocol was used for pituitary desensitization: cetrorelix 0.25 mg multiple-dose antagonist instead of GnRH agonist long protocol. Cetrorelix 0.25 mg was administered daily, starting when the leading follicle reached a diameter of 14 mm. In other words, rFSH was administered in the new cycle according to the dosage and the step-up or step-down modalities used during the previous cycle, independently of ultrasound findings and serum estradiol (E(2)) levels. Eighty-seven patients entered the study. Out of the 87 cycles involving GnRH agonists, 49 (56.3%) were cancelled and out of the 87 involving GnRH antagonists 28 (32.2%) were cancelled [McNemar's test; 95% confidence interval (CI) -35.8% to -11.2%; P < 0.001]. After GnRH agonist cycles, we recorded 24 cases of OHSS (18 moderate and six severe; 27.6%), whereas after the GnRH antagonist cycles there were 10 cases of OHSS (nine moderate and one severe; 11.5%) (95% CI-26.4% to -5.7%; P = 0.006). There was a statistically significant reduction in the total number of follicles with a diameter >10 mm (Wilcoxon's test; Z = 6.1; P < 0.001) and of E(2) levels on the day of HCG administration (2538 versus 4322.4 pg/ml; P < 0.001) in the GnRH antagonist cycles versus GnRH agonist cycles. Twenty-nine patients had an embryo transfer in the first cycle (76.3% of oocyte retrievals) and 57 in the cycle using GnRH antagonist (96.6%). This 20.3% difference was also significant (Z-test; 95% CI 6.8-36.0%; P = 0.003). After the antagonist cycles, 18 pregnancies (20.7 per initiated cycle; 31.6% per embryo transfer) were obtained. CONCLUSIONS: Although this study presents some limitations owing to the use of historical controls, our data show a favourable effect of GnRH antagonists in reducing the incidence of OHSS and the number of assisted fertilization cycles cancelled because of the risk of OHSS in high responder patients. As a consequence, GnRH antagonist plus gonadotrophin administration could also increase the percentage of oocyte retrievals and embryo transfers in this high risk group of patients.

Immunomagnetic separation of antibody-labelled from antibody-free human spermatozoa as a treatment for immunologic infertility. A preliminary report.

A method is described where superparamagnetic polymer microspheres coated with monoclonal antibodies are used to isolate antibody-labelled from antibody-free spermatozoa in male autoimmune infertility. Autoimmune sperm samples or antibody-free spermatozoa adsorbed with antisperm-antibodies from sera were incubated with microspheres coated with a specific monoclonal antibody to murine immunoglobulins, after their preincubation with mouse anti-human IgG and IgA. Using a magnet, the microsphere-labelled spermatozoa were separated from the samples. Immunobead binding was performed before and after the treatment in order to detect changes in the percentage of antibody-bound spermatozoa. After the immunomagnetic separation, approximately 50% of the IgA-labelled spermatozoa was isolated while no difference was demonstrated when antisperm antibodies of IgG class were involved. The evaluation of sperm motility and membrane integrity after treatment seemed to indicate that the technique did not have any relevant effect on sperm characteristics. The fact that only a partial success in separation of IgA-bound spermatozoa and no success for IgG-labelled sperm was obtained indicates that the method needs to be improved before its clinical utilization might be postulated.

Comparison between immunobead test, indirect immunofluorescence and a quantitive ELISA for the diagnosis of antisperm antibodies.

Immunobead Test, Indirect Immunofluorescence and ELISA, have been used to research antisperm antibodies in serum of 105 fertile male patients and in serum of 109 infertile male patients. Antisperm antibodies were present among 12.8% of infertile patients and 0.9% of infertile patients. The immunological factor is certainly an important factor in the aetiology of male hypofertility.

Success in inducing ovulation in a case of premature ovarian failure using growth hormone-releasing hormone.

Ovulation was obtained in a 29-year-old woman affected by premature ovarian failure who had previously failed to respond to two attempts performed administering human menopausal gonadotropin or follicle-stimulating hormone after the spontaneous gonadotropin production was suppressed using a gonadotropin-releasing hormone analog (buserelin). Induction of ovulation succeeded when 1000 mg/day growth hormone-releasing hormone was added to the induction scheme. Five mature follicles were obtained after 27 days therapy and the serum level of 17 beta-estradiol was 975 pg/ml (195 pg/ml per follicle) at the time of human chorionic gonadotropin administration.

Evaluation of antisperm antibodies in infertile couples with immunobead test: prevalence and prognostic value.

We know that antisperm antibodies can cause infertility. We studied the prevalence of the immune response against spermatozoa in infertile couples using immunobead test. 16.2% of the men were autoimmune and 7.3% of the women isoimmune. Both partners were immune in 1.6% of the couples. We also studied the degree of impairment of sperm penetration into cervical mucus in couples in which one of the partners exhibited immunity and we found that generally it correlates with the proportion of sperm exhibiting surface-bound immunoglobulins. In some cases the sperm penetration into cervical mucus was normal in spite of immunization. So other mechanisms of interference should be explored. We found a significant difference (p less than 0.02) in the conception rate between immune and non immune couples (19.3% vs 42%). The pregnancy outcome of immune couples was favorable only in 50% of the cases.

Abdominal pregnancy as a result of gamete intrafallopian transfer (GIFT) and subsequent treatment with methotrexate: case report.

A patient underwent a minilaparotomy for gamete intrafallopian transfer (GIFT), and subsequently developed an abdominal pregnancy. The patient was treated with methotrexate, and a good resolution was obtained, with total disappearance of beta-hCG titers after 22 days from the beginning of therapy.

Treatment of idiopathic oligozoospermia with tamoxifen.

Eighteen subfertile men, with idiopathic normogonadotropic oligozoospermia were treated with an antiestrogenic compound, tamoxifen (Nolvadex), at the dose of 20 mg/day for four months. Hormonal parameters (LH, FSH, Testosterone, Prolactin) were evaluated before treatment and after 45 and 90 days of therapy. Serum LH, FSH and Testosterone increased significantly after 45 days of tamoxifen treatment. Seminal analyses, performed before and after three months of therapy showed improvements in sperm motility and in sperm density. By our clinical findings, tamoxifen can be considered a useful approach for an empiric treatment of idiopathic oligozoospermia.

GnRH antagonists and mild ovarian stimulation for intrauterine insemination: a randomized study comparing different gonadotrophin dosages.

BACKGROUND: The precise role of GnRH antagonists in the armamentarium of drugs for stimulation of ovulation associated with intrauterine insemination remains to be clarified. In this study, we have compared two different protocols employing GnRH antagonists in order to determine the lower effective dose of gonadotrophins to use. METHODS: Sixty-six couples with unexplained infertility or moderate male subfertility were recruited. Starting on day 3 of the cycle, 32 patients were randomized to receive 50 IU of recombinant FSH per day, whereas 34 were treated with 50 IU of recombinant FSH on alternate days. Women received the GnRH antagonist Ganirelix at a dose of 0.25 mg per day starting on the day in which a leading follicle > or =14 mm in mean diameter was visualized, until HCG administration. Insemination was performed 34 h after HCG injection. RESULTS: The regimen with daily recombinant FSH was associated with a lower rate of mono-ovulation (53.3% versus 78.8%, P=0.06) but also with a higher clinical pregnancy rate per initiated cycle (34.4% versus 5.9%, P=0.005). CONCLUSIONS: A protocol of recombinant FSH 50 IU daily and GnRH antagonist may represent an effective and safe regimen for ovulation induction associated with intrauterine insemination.