Use of recombinant human follicle-stimulating hormone in the treatment of male factor infertility

OBJECTIVE: To evaluate the effects of treatment with recombinant human FSH (r-hFSH) on seminal parameters and seminiferous epithelium in idiopathic patients with oligozoospermia with normal FSH plasma levels. DESIGN: Randomized single-blind study. SETTING: Academic setting. PATIENT(S): Forty-five subjects with idiopathic oligozoospermia (sperm count <10 x 10(6)/mL) and normal FSH and inhibin B plasma levels. INTERVENTION(S): Three months of treatment with r-hFSH 50 IU (15 patients) or with r-hFSH 100 IU on alternate days (15 patients) or no treatment (15 patients); bilateral testicular fine-needle aspiration (FNA) performed before and after therapy; FSH and inhibin B plasma levels evaluated during treatment. MAIN OUTCOME MEASURE(S): Seminal parameters; testicular cytological features evaluated by FNA; plasma levels of FSH, LH, T, and inhibin B. RESULT(S): Treatment with r-hFSH at a dose of 50 IU induced no increase in sperm concentration, while treatment with r-hFSH at a dose of 100 IU induced a significant increase in sperm concentration. In particular, in 11/15 patients a doubling of the pretreatment sperm concentration was observed. No significant increase in sperm parameters was observed in the control group. In both groups of patients treated with r-hFSH, the cytological analysis before treatment showed hypospermatogenesis. An increase in the percentage of spermatogonia and spermatocytes was observed only after the treatment with r-hFSH at a dose of 100 IU. CONCLUSION(S): The findings of this study demonstrate that r-hFSH at a dose of 100 IU, as previously seen with highly purified FSH, increases the spermatogonial population and sperm production in idiopathic patients with oligozoospermia with normal FSH and inhibin B plasma levels and a cytological picture of hypospermatogenesis.     

Economic evaluation of highly purified menotropin compared with recombinant follicle-stimulating hormone in assisted reproduction

OBJECTIVE: To determine the cost of achieving pregnancy with different gonadotropin preparations. DESIGN: Cost-minimization analysis of a prospective randomized clinical trial. SETTING: Twenty-two centers in six countries. PATIENT(S): Women 18 to 36 years of age with infertility for more than 1 year who were undergoing IVF or ICSI. INTERVENTION(S): Highly purified hMG or recombinant FSH. RESULT(S): Mean cost of achieving an ongoing pregnancy.The mean cost per patient treatment cycle was estimated to be pound 2423 with highly purified hMG (95% CI, pound 2356 to pound 2495) and pound 2745 with recombinant FSH (95% CI, pound 2658 to pound 2830). The ongoing pregnancy rate was 22% with highly purified hMG and 19% with recombinant FSH. The cost per ongoing pregnancy was pound 10781 with highly purified hMG (95% CI, pound 9056 to pound 12919) and pound 14284 with recombinant FSH (95% CI, pound 11883 to pound 17891). CONCLUSION(S): Highly purified hMG and recombinant FSH are equally effective, but highly purified hMG is less expensive per cycle. Using highly purified hMG instead of recombinant FSH would translate into a 13% increase in the number of cycles that could be offered.     

Epigenetic consequences of assisted reproduction and infertility on the human preimplantation embryo

Epigenetic information, which is essential for normal mammalian development, is acquired during gametogenesis and further regulated during preimplantation development. The epigenetic consequences of assisted reproductive technologies (ARTs) and infertility on the health and quality of the human preimplantation embryo are considered in this review. In the zygote, the epigenetic information that is inherited from the sperm and the oocyte intersects and must be appropriately recognized, regulated and then propagated during preimplantation development so as to regulate gene expression in an appropriate manner. A growing body of evidence suggests that ARTs and/or infertility itself may affect these complex processes leading to epigenetic diseases that include disorders of genomic imprinting. The epigenetic safety of human gametes and embryos is of paramount importance. Unfortunately, morphological methods of assessing embryo quality are incapable of detecting epigenetic errors. Further research is therefore critical to resolve these issues.     

An evaluation of the effect of pentoxifylline on sperm function and treatment outcome of male-factor infertility: A preliminary study

Objective Our objective was to study the effect of pentoxifylline (PF) on fertilization rates in couples with previous failure of fertilization and male-factor infertility and to determine the predictive value of conventional semen analysis parameters in selecting the couples who would benefit from the elective use of PF in IVF.Design This prospective controlled study was conducted in an assisted conception unit.Methods Sixty-nine couples with previous failed IVF cycle, who had a low fertilization rate and/or male-factor infertility, were recruited to the study. Multiple follicular development was induced using the same protocol of human menopausal gonadotropin and gonadotropin releasing hormone analogue in both cycles. The oocytes were inseminated with spermatozoa treated with PF. The fertilization rates in the PF cycle were compared to the reference cycle based on semen analysis parameters and previous fertilization rates.Results In couples with male infertility, the fertilization rate improved significantly, from 17 to 50% in PF cycles (P<0.001). A significant improvement in fertilization rate was also demonstrated in couples with previous poor fertilization. <30% (P<0.01). particularly in those with a very low fertilization rate, <20% (P<0.001). Although there was an overall improvement in fertilization rates in couples with male-factor infertility, there was no cutoff value in sperm motility that would make a significant difference in the impact of PF on fertilization rates.Conclusion Couples with poor fertilization rates in vitro benefit with a significant improvement in fertilization by the elective use of PF. The improvement is most significant in couples with previous complete failure of fertilization and poor fertilization rates, <30%.     

Cost-effectiveness of recombinant versus urinary follicle-stimulating hormone in assisted reproduction techniques in the Spanish public health care system

Purpose : To evaluate the relative cost-effectiveness of recombinant and urinary follicle-stimulating hormone (FSH) in assisted reproduction techniques in the Spanish National Health Service. Methods : Markov modelling was used to compare costs and outcomes of three complete treatment cycles using recombinant or urinary FSH for controlled ovarian stimulation. Cost and effectiveness estimates were obtained from the literature and from Spanish clinicians. A Monte Carlo technique was used to randomise the distribution of outcomes at each stage. The analysis was performed by passing a virtual population of 100,000 patients through the computer simulation in each of 5000 Monte Carlo simulations. Results : The cost per pregnancy was €12,791 ± 1202 ($11,346 ± 1066) with recombinant and €13,007 ± 1319 ($11,537 ± 1170) with urinary FSH (p < 0.0001). The mean number of cycles per pregnancy was 4.69 and 5.21, respectively. Conclusions : Recombinant FSH is more cost-effective than urinary FSH in the Spanish public health care system.     

Effects of high doses of recombinant human follicle-stimulating hormone in the treatment of male factor infertility: results of a pilot study

We performed a randomized double-blind placebo-controlled study on seminal parameters and endocrine profile of 30 normogonadotropic patients with male factor infertility to assess the efficacy of treatment with recombinant human FSH (rhFSH) at high doses (300 IU on alternate days) for a period of >or=4 months. The treatment induced a marked increase in sperm count, a slight increase in sperm motility, no change in sperm morphology, and an evident increase only in FSH serum levels, showing that a prolonged treatment with rhFSH at high doses led to an evident improvement of sperm count in normogonadotropic infertile patients with idiopathic oligoasthenozoospermia.     

Efficiency of follicle-stimulating hormone, commenced in the luteal phase, for overcoming a poor response in assisted reproduction

Aim:  The efficacy of commencement of recombinant follicle-stimulating hormone (recFSH) during the luteal phase in the long-protocol gonadotropin-releasing hormone (GnRH) agonist regimen in poor responders was compared with the conventional protocol in a prospective, randomized, controlled study.
Methods:  Forty-two women who responded poorly to previous conventional controlled ovarian hyperstimulation were included in the study. Recombinant FSH (150 IU) was started simultaneously with the GnRH agonist long protocol in the study group. The control group was started recFSH on Day 2 of menstruation in the long-protocol GnRH agonist regimen. The number of metaphase (M) II oocytes, the number of embryos transferred, and the pregnancy rate were analyzed as main outcome measures.
Results:  Patients in the study group had a higher number of MII oocytes compared with the control group (6.8 vs 3.2, respectively; P  < 0.005), received a higher number of embryos (2.7 vs 1.2, respectively; P  < 0.05), and had higher pregnancy rates (38% vs 15%, respectively; P  < 0.005).
Conclusions:  Commencement of recFSH during the luteal phase simultaneously with the long-protocol GnRH agonist regiment in poor responder women produces better results compared with the conventional long-protocol GnRH agonist plus high-dose recFSH regimen.     

Treatment of severe male-factor infertility with high concentrations of motile sperm by microinsemination in embryo cryopreservation straws

A microinsemination technique was evaluated for treating our program's most severe cases of male-factor infertility. Oocytes were inseminated with high concentrations of motile sperm (1 to 9×10⁶/ml) in 10 to 150 l within embryo cryopreservation straws. Fertilization was obtained in 20 of 29 (69%) couples treated by this technique. In the 15 patients in which only embryos generated from the straw technique were transferred, 7 clinical pregnancies resulted (46.7% per transfer). The implantation rate for couples receiving embryos from the straw technique only (12/58; 20.7%) compared favorably to that observed for other cases treated during this same time period with regular insemination techniques (111/766; 14.5%). Clinical pregnancy rates per transfer for IVF-ET, TET, and PROST were 33.0% (1/3), 0% (0/2), and 60.0% (6/10), respectively. The percentage of polyploidic embryos was significantly lower (P<0.0001) for male-factor patients treated by the straw technique with high sperm concentrations that for non-male-factor patients treated during this same time period with standard sperm concentrations. Normal births have resulted from straw inseminations with 3.4×10⁶ and ongoing pregnancies with 5.0×10⁶ motile sperm/ml. The results of this study suggest that some cases of male-factor infertility can be successfully treated by insemination with high concentrations of motile sperm in embryo cryopreservation straws. A technique of centrifuging sperm in straws was also developed to concentrate the entire fraction of washed sperm into 10 l. Further development of this technique may allow treatment of more severe cases of oligo/asthenospermia by microinsemination with high concentrations of motile sperm than is presently possible with standard washing techniques.     

The role of DEFB126 variation in male infertility and medically assisted reproduction technique outcome

Research questionHuman DEFB126 is an important component of the glycocalyx of human spermatozoa. Beta-defensins play a primary role in male infertility due to their involvement in maturation and capacitation of spermatozoa. A 2-nt deletion of DEFB126 affects sperm function and so this study investigated the possible association between DEFB126 variants and its protein expression on medically assisted reproduction (MAR) technique outcome in Iranian infertile males.DesignThe presence of a 2-nt deletion of DEFB126, and its protein expression in spermatozoa, were investigated by standard polymerase chain reaction (PCR) sequencing and immunocytochemistry, respectively. MAR technique outcome according to clinical pregnancy rates was assessed in 277 Iranian males with unexplained infertility, including 139 patients who underwent intrauterine insemination (IUI) and 103 patients who underwent IVF/intracytoplasmic sperm injection (ICSI), as well as 35 infertile males who declined to use any MAR treatment. As the control group, 100 fertile males with a normal spermiogram were enrolled.ResultsThe 2-nt deletion of DEFB126 was significantly higher in infertile patients than controls (P ≤ 0.05). The presence of this deletion resulted in significantly lower clinical pregnancy rates following IUI (P ≤ 0.05); however, there were no differences in IVF/ICSI outcomes according to genotype. The protein expression in del/del males was also remarkably lower than that of the other genotypes.ConclusionsThis sequence variation of DEFB126 may impair male reproductive function and can be related to male infertility. Interestingly, males with the del/del genotype have a normal spermiogram; however, their spermatozoa are evidently functionally impaired, which can affect IUI treatment outcome, but not treatment by IVF/ICSI.     

Efficacy of recombinant human follicle-stimulating hormone in improving oocyte quality in assisted reproductive techniques

OBJECTIVE: To estimate the efficacy of recombinant human follicle-stimulating hormone (rFSH) versus highly purified urinary human FSH (uFSH) in women undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization and embryo transfer (IVF-ET). STUDY DESIGN: This prospective, randomized, quality of retrieved double-blind study compared uFSH with rFSH in IVF-ET rFSh cycles. A total of 254 cycles from 241 patients who attended the infertility clinic at Samsung Cheil Hospital from January to August 2001 were included in the study. With pituitary desensitization using gonadotropin-releasing hormone agonist and a short protocol, rFSH was administered in 131 cycles; uFSH was administered in 123 cycles. We analyzed ovarian response, oocyte quality, fertilization rate, embryo quality, pregnancy rate and live birth rate in the uFSH and rFSH groups. RESULTS: Total FSH dosage (1322.3 +/- 526.2 vs. 2124.4 +/- 881.9 i.u.) and dosage per retrieved oocyte (90.6 +/- 36.0 vs. 138.0 +/- 57.2 i.u.) were significantly lower in the rFSH group than those in the uFSH group (P < .001). The proportion of good-quality oocytes (grade 1 and 2) was higher in the rFSH group (68.2% vs. 64.8%, P = .024). Moreover, the proportion of atretic oocytes (grade 5) was lower in the rFSH group (7.5% vs. 10.3%, P = .002). The fertilization rate, quality of transferred embryos, clinical pregnancy rate and live birth rate were not significantly differ between the 2 groups. CONCLUSION: In women undergoing COH, rFSH revealed more efficient ovarian response and better quality of oocytes than did uFSH.     

Blastocyst transfer for patients with multiple assisted reproduction treatment failures: preliminary experience

This preliminary study reports the results obtained from a patient group in which blastocyst culture and transfer were performed, and discusses the advantages and disadvantages of introducing blastocyst transfer in a clinic. Twenty-six patients who had failed to achieve a pregnancy in previous in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatments were offered the choice of a fresh cycle with culture to the blastocyst stage. Of the 26 patients who elected to attempt blastocyst culture, 11 opted to have transfer on day 2 or day 3 due to low numbers of embryos. Of the 15 patients who proceeded to blastocyst culture, 46.2% of the embryos cultured reached the blastocyst stage or later and eight of the patients achieved a clinical pregnancy. More oocytes were collected in this patient group, hence the chances of obtaining blastocysts were higher. Offering blastocyst culture to patients with a reasonable chance of success who have had previous multiple assisted reproduction failures is an acceptable way of introducing blastocyst culture into practice.     

The influence of infertility treatment and assisted reproduction techniques on multiple pregnancy rates

It has to be remembered that pregnancies resulting from assisted reproductive technologies are more complicated that spontaneous pregnancies. There are higher rates of spontaneous abortions, ectopic, and multiple pregnancies. This work summarizes the latest year's experiences from the best world's clinics with multifetal pregnancy incidence in assisted reproductive technologies programs.     

Updated meta-analysis of recombinant follicle-stimulating hormone (FSH) versus urinary FSH for ovarian stimulation in assisted reproduction

OBJECTIVE: To determine the relative efficacy of recombinant FSH (rFSH) and urinary FSH (uFSH) for ovarian stimulation in assisted reproductive techniques (ART). DESIGN: Systematic review and meta-analysis of randomized, controlled trials comparing rFSH and uFSH. SETTING: Infertility centers providing treatment with ART. PATIENT(S): Patients undergoing IVF with or without ICSI. INTERVENTION(S): Controlled ovarian stimulation using uFSH or rFSH (follitropin alpha or follitropin beta). MAIN OUTCOME MEASURE(S): Primary: rate of clinical pregnancy per cycle. Secondary: rates of spontaneous abortion, multiple pregnancy, and severe ovarian hyperstimulation syndrome (OHSS); total gonadotropin dose; serum E(2) level and number of follicles at hCG administration; number of oocytes retrieved. RESULT(S): Eighteen trials were included in the meta-analysis. Subgroup analyses demonstrated higher pregnancy rates with both follitropins compared with uFSH. However, statistical significance was reached only in the follitropin alpha versus uFSH comparison in IVF cycles, with an additional pregnancy for every 19 patients treated. Fewer units of rFSH than uFSH achieved the same E(2) level and oocyte yield. No differences were found between treatments in rates of spontaneous abortion, OHSS, and multiple gestation. CONCLUSION(S): rFSH produced higher pregnancy rates per cycle than uFSH when follitropin alpha was used in IVF, and the total gonadotropin dose required was lower.     

Impact of infertility characteristics and treatment modalities on singleton pregnancies after assisted reproduction

Obstetric and neonatal outcomes of assisted reproduction and control singletons were evaluated after taking into account treatment characteristics and infertility background. The elective single embryo transfer (eSET) group (n = 45) was compared with the compulsory single embryo transfer (cSET; n = 52), double embryo transfer (DET; n = 227) and control (n = 304) groups. Infertility-related prognostic factors for neonatal outcomes were also analysed. Data were collected with structured questionnaires at gestational week 20 and 8 weeks after delivery. Spontaneous onset of delivery was more typical of the eSET group than of cSET and DET groups (68.9 versus 52.0%, P = 0.02). Mean (+/-SD) gestation at birth (39.3 +/- 1.6 weeks) and mean birth weight (3,470 +/- 505 g) of eSET singletons were comparable with other assisted reproduction groups, but gestational duration was lower than in the eSET group than in the control group (39.9 +/- 1.4; P < 0.05). However, numbers of preterm births and low birth weight infants were similar between groups. History of induced abortion increased risk of preterm birth (OR 4.5 and 95% CI 1.2-17.1) in assisted reproduction singletons. A small though clinically unimportant difference in gestational age at birth and birth weight between assisted reproduction and control singletons was found regardless of the number of embryos transferred.     

Serum luteinizing hormone,follicle-stimulating hormone and oestradiol pattern in women undergoing pituitary suppression with different gonadotrophin-releasing hormone analogue protocols for assisted reproduction

Gonadotrophin-releasing hormone analogues (GnRH-a) are used widely in controlled ovarian stimulation (COS) cycles for assisted reproduction. At present, there is great debate about the influence of exogenous hormone activity on the hypothalamus–pituitary axis following pituitary desensitization. The objective of this comparative study was to investigate the pattern of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and oestradiol in women undergoing ovarian stimulation with different GnRH-a preparations. We retrospectively analysed 201 women, aged between 27 and 43 years, who were referred consecutively to our infertility clinic between January 2002 and January 2003. All women had no endocrinopathies or occult ovarian failure as assessed by day-3 hormone profile. Women were enrolled in one of the following COS protocols: depot triptorelin long protocol (n?=?38), buserelin long protocol (n?=?101) or buserelin short protocol (n?=?62). Recombinant FSH was used to induce ovulation. Treatment was monitored by transvaginal ultrasound scan and serum measurement of FSH, LH and oestradiol. Among the women initially included, 30 had cancelled cycles due to poor ovarian response. Serum LH levels were significantly higher in the short-protocol group compared with the long-protocol groups (p?<?0.001). The number of follicles, oocyte yield, number of grade-I embryos and fertilization rate were significantly lower in the short-protocol group than in the long-protocol groups. These findings showed that LH concentrations are significantly higher in women undergoing reversible medical hypophysectomy with a GnRH-a short protocol than in women treated with a long protocol. The hypothesis of an LH ceiling is confirmed.     

Fate of sperm components during assisted reproduction: implications for infertility

Studies in non-human primates highlight their suitability as preclinical models for investigating assisted reproduction techniques. The cytoskeletal events of fertilization in non-human primates are similar to those in humans in that they require a paternally derived centrosome. The centrosome, introduced by the sperm at fertilization, organizes a microtubule array that is responsible for bringing the parental genomes together at first mitosis. Incomplete functioning of the sperm centrosome during fertilization has been identified as a novel form of infertility that would not necessarily benefit from intracytoplasmic sperm injection (ICSI). The global use of ICSI to overcome male infertility has been very successful, although concerns remain regarding the long-term effects on children born after ICSI. The cytoskeletal events that occur during ICSI are quite different from the events of in vitro fertilization: a sperm selected for ICSI does not undergo typical oocyte interactions, and abnormal remodelling of the male pronucleus may result. The implications of these findings are discussed in relation to the safety of the ICSI technique.