In vivo fertilization procedures in infertile women with patent fallopian tubes: A comparison of gamete intrafallopian transfer,combined intrauterine and intraperitoneal insemination,and controlled ovarian hyperstimulation alone

This prospective study was undertaken to evaluate the relative efficacy of three in vivo methods of assisted fertilization in 150 infertile women with patent fallopian tubes: gamete intrafallopian transfer (GIFT), combined intrauterine and direct intraperitoneal insemination (IUI + DIPI), and controlled hyperstimulation (COHS) alone. The clinical pregnancy rate was highest in the IUI/DIPI and GIFT groups: IUI/DIPI, 29.3%; GIFT, 28.6%; and COHS, 8.9%. We believe that controlled ovarian hyperstimulation combined with IUI and DIPI is a good alternative to GIFT.     

Adjunctive leuprolide therapy does not improve cycle fecundity in controlled ovarian hyperstimulation and intrauterine insemination of subfertile women

Problems arising from controlled ovarian hyperstimulation for intrauterine insemination, such as premature luteinization and asynchronous ovarian follicular development, are identical to those encountered with controlled ovarian hyperstimulation for in vitro fertilization (IVF) and gamete intrafallopian transfer (GIFT). It has been suggested that the adjunctive use of GnRH agonists for controlled ovarian hyperstimulation improves the efficiency of GIFT and IVF cycles. We hypothesized that adjunctive use of leuprolide acetate, a GnRH agonist, would have a similarly beneficial effect on cycle quality and cycle fecundity in subfertile women treated with controlled ovarian hyperstimulation and intrauterine insemination. We randomly assigned the first cycle of controlled ovarian hyperstimulation and intrauterine insemination for each of 97 subfertile women to include either human menopausal gonadotropins (hMGs) alone or hMGs following midluteal pre-treatment with leuprolide. If a pregnancy did not occur in the first cycle, the woman was given the other treatment in the second cycle. Although the cycles that included leuprolide required a larger amount of hMGs and more days of stimulation per cycle, the mean estradiol concentrations and numbers of follicles were not different. Despite prevention of premature luteinization with leuprolide, the cycle fecundity was not different between groups (0.11 with adjunctive leuprolide treatment and 0.22 with hMGs alone). We conclude that in unselected subfertile patients, the adjunctive use of leuprolide for controlled ovarian hyperstimulation and intrauterine insemination does not improve cycle fecundity compared with treatment cycles that do not include adjunctive leuprolide therapy.     

Gamete intrafallopian transfer (GIFT) compared with intrauterine insemination in the treatment of unexplained infertility.

OBJECTIVE--To compare GIFT, intrauterine insemination (IUI) with, and without, ovarian hyperstimulation in the treatment of unexplained infertility. DESIGN--Women randomly allocated to one of three treatment protocols. SETTING--Northern Regional Fertility Centre. SUBJECTS--59 couples with unexplained infertility of more than 3 years duration. INTERVENTIONS--Three cycles of either GIFT, IUI after ovarian hyperstimulation or IUI in a spontaneous cycle. MAIN OUTCOME MEASURES--Pregnancy resulting in a live birth. RESULTS--Fecundabilities were 0.12 after GIFT, 0.018 after ovarian hyperstimulation and IUI, and 0.018 after IUI in a spontaneous cycle. The fecundability after IUI was no different from that which would be expected without treatment in these couples but fecundability was significantly better (P greater than 0.02) after GIFT. CONCLUSIONS--This trial does not support the use of IUI in the treatment of unexplained infertility but confirms the value of GIFT.     

The role of superovulation with menotropins in ovulatory infertility: a review

The risks of menotropin therapy (ovarian hyperstimulation syndrome, multiple gestation, adnexal torsion) are well known and have been previously described. Superovulation should not be considered for the indications described herein until more traditional therapies for infertility have been tried and found unsuccessful and sufficient time has elapsed for conception to occur. The cost of superovulation is high: the medications are expensive, frequent E2 monitoring and US studies are costly, and pregnancy complications relating to the higher rate of pregnancy loss and multiple gestation may add substantially to the overall cost. Yet, compared with IVF and GIFT, superovulation cycles combined with IUI cost between one third to one sixth that of an IVF cycle. Protocols involving combined CC/hMG/hCG, which reduce the total number of ampules of Pergonal needed per cycle and still provide multiple follicular development, may further reduce costs. There is a growing consensus that superovulation-IUI protocols should be attempted before GIFT and IVF in couples with normal pelvic viscera. There is little doubt that IVF and GIFT cycles are more costly, stressful, and complex. No comparative data have clearly shown IVF and GIFT to be superior to superovulation protocols in ovulatory women with normal pelvic anatomy. In the only study examining this issue published to date, Kaplan et al. retrospectively analyzed all GIFT and superovulation/IUI cycles at a single university center and found GIFT to be three times more efficient. However, the inherent limitations of a nonrandomized, nonprospective study of this kind are obvious as these authors have suggested. Therefore, it may be wise to consider the use of superovulation before assisted reproductive technologies until this issue is settled. It would be interesting to determine if the high PRs reported for couples with unexplained infertility or mild endometriosis in IVF and GIFT cycles in some centers not incorporating superovulation/IUI protocols would hold up if such an approach was routinely followed. Despite the increasing acceptance of superovulation protocols, we must be aware that many of the studies suggesting a role of hMG in treating ovulatory infertile women with normal pelvic anatomy suffer from deficiencies in experimental design. In a payor-driven system, such as in the United States, the difficulties in designing and carrying out scientifically sound clinical studies examining infertility therapies are obvious. The lack of federal or outside funding for the study of infertility issues contributes to the problem. It is our hope that better designed studies examining the role of superovulation in the treatment of ovulatory infertile women with normal pelvic anatomy will be forthcoming.     

Intrauterine insemination after ovarian stimulation as a treatment for subfertility because of subnormal semen: a prospective randomized controlled trial.

OBJECTIVE: To determine whether intrauterine insemination (IUI) after ovarian stimulation with human menopausal gonadotropin (hMG) gives a better pregnancy rate (PR) than natural intercourse in couples with subfertility because of subnormal semen. DESIGN: Prospective randomized controlled trial. SETTING: University based subfertility clinic. PATIENTS: Couples with subnormal semen as the only identifiable cause of subfertility. INTERVENTIONS: In control cycles, the couples had natural intercourse. In IUI cycles, IUI was performed after ovarian stimulation with hMG and human chorionic gonadotropin. MAIN OUTCOME MEASURE: The clinical PRs and complications of IUI cycles and control cycles were compared. RESULTS: There were six clinical pregnancies in the 42 IUI cycles, whereas there was no clinical pregnancy in the 42 control cycles. The clinical PR in IUI cycles (14.3% per cycle) was significantly higher than that in control cycles (0%). Six patients (14.3%) developed moderate degree of ovarian hyperstimulation syndrome in IUI cycles. CONCLUSION: Intrauterine insemination after ovarian stimulation with hMG is useful in treatment of subfertile couples with subnormal semen.     

Optimal treatment for poor responders to ovarian stimulation: does in vitro insemination offer any advantages to intrauterine insemination?

A retrospective study was performed of 1832 consecutive in vitro insemination (IVF)/intracytoplasmic sperm injection (ICSI) cycles over 18 months, to analyse the benefits or otherwise to the patient of continuing with in vitro treatment or converting the assisted conception cycle to intrauterine insemination (IUI). Two hundred and seventy cycles were identified in which three follicles or fewer were obtained after controlled ovarian hyperstimulation; in 143 of these cycles, the clinicians or patients elected to abandon all treatment, whereas treatment was continued in 127 patients. In 79 cycles, the patients proceeded with IVF/ICSI and in 48 patients, the cycles were converted to IUI. Data were analysed with regard to the clinical pregnancy rate. In addition, the data for IUI were compared with eight cycles of supraovulation IUI (S/IUI) performed over the same period. There were no significant differences in clinical pregnancy rates among any treatment modality 6/48 (12.5%), 6/79 (7.7%) and 1/8 (12.5%) for IUI, IVF and S/IUI, respectively (P = 0.64). The lowest total number of motile spermatozoa required to achieve pregnancy using IUI was 2.0 x 10(6). In conclusion, it appears that, if the treatment is suitable, patients who respond poorly to controlled hyperstimulation for IVF would not be disadvantaged in achieving a pregnancy by offering them conversion to the medically and financially less interventional IUI.     

Gamete intra-fallopian transfer or intrauterine insemination after controlled ovarian hyperstimulation for treatment of infertility due to endometriosis.

We compared the effectiveness of gamete intra-Fallopian transfer (GIFT) and intrauterine insemination (IUI) after controlled ovarian hyperstimulation (COH) in the treatment of infertility due to endometriosis. This was a retrospective study carried out at a tertiary teaching medical center. A total of 127 consecutive patients with endometriosis were treated with GIFT or IUI after COH between June 1990 and December 1998. Patients were divided into two groups. Group 1 (n = 97) included patients with stages 1 and 2 endometriosis, and group 2 (n = 30) included patients with stages 3 and 4 endometriosis. Laparoscopic conservative surgery for endometriosis was performed prior to IUI for patients in both group 1 and group 2. In group 1, 55 patients underwent 95 cycles of IUI after COH and 42 patients underwent 57 cycles of GIFT. In group 2, 14 patients underwent 16 cycles of IUI after COH, while 16 patients underwent 22 cycles of GIFT. The stimulation protocol for both GIFT and IUI was mid-luteal pituitary down-regulation with a gonadotropin releasing hormone agonist (GnRH-a) followed by gonadotropins. In group 1, the pregnancy rates (GIFT = 50.9%, IUI = 29.4%) and the delivery rates (GIFT = 28.1%, IUI = 14.7%) per cycle were significantly higher in GIFT compared to IUI (p = 0.009 and p = 0.05, respectively). There was no significant differences in the pregnancy rate (GIFT 69%, IUI 50.9%, respectively) or the delivery rate (GIFT 38.1%, IUI 25.5%) per patient. In group 2, there was no significant difference in the pregnancy rate (GIFT 54.5%, IUI 31.3%) or the delivery rate (GIFT 40.9%, IUI 12.5%) per cycle, but the difference in the pregnancy rate (GIFT 75%, IUI 35.7%) and the delivery rate (GIFT 56.3%, IUI 14.3%) per patient was significantly higher in GIFT compared to IUI (p = 0.04 and p = 0.02, respectively). We conclude that, when the same stimulation protocol is used in the early stages of endometriosis, a few cycles of IUI can achieve similar results to GIFT, and therefore should be used first. In advanced stages of endometriosis GIFT appears to be more effective.     

Diagnosis and management of unexplained infertility: an update

Unexplained infertility constitutes around 15% of patients presenting with infertility. A lack of agreement exists among infertility specialists with regard to the diagnostic tests to be performed and their prognostic value as well as criteria of normality. It seems that serum progesterone for detection of ovulation, hysterosalpingography and or laparoscopy for tubal patency and semen analysis are the basic tests for diagnosis of unexplained infertility. Expectant treatment is the option of choice for young patients with short period of infertility. The spontaneous pregnancy rate is very high in this group of patients. The world literature have shown that controlled ovarian hyperstimulation and intrauterine insemination (COH and IUI) is an effective treatment of unexplained infertility. According to the available data, this procedure could be limited to three trials. There is evidence that both COH and IUI are important independent positive factors in achieving better pregnancy rate in unexplained infertility. If the above measures fail to achieve pregnancy, GIFT or IVF/ICSI could be performed as it yields a high pregnancy rate.     

Should we continue performing intrauterine inseminations in the year 2004?

This review summarizes the existing evidence regarding intrauterine insemination (IUI) as a treatment for cervical hostility, male and unexplained subfertility. IUI in natural cycles has been proven effective in patients with cervical hostility and moderate male subfertility. IUI in cycles with mild ovarian hyperstimulation (MOH) should be the treatment of choice in couples with mild male subfertilty (average total motile sperm count above 10 million) and unexplained subfertilty. When MOH is applied, gonadotropins have been proven more effective compared with clomiphene citrate. Further large trials comparing clomiphene citrate with gonadotropins are mandatory. Prevention of multiple pregnancies in MOH/IUI programs is of paramount importance. A strategy with a low-dose step-up protocol and strict cancellation criteria is proposed. When multiple pregnancies are kept to a minimum, MOH/IUI is more cost-effective compared with in vitro fertilization and embryo transfer. Future research should focus on prediction models to predict the outcome of MOH/IUI treatment for individual couples before starting treatment.     

Status and perspectives of in vitro fertilization and gamete transfer in the treatment of sterility

The treatment of human infertility has changed enormously since the introduction of IVF and GIFT. GIFT can be offered as a reduced-cost technique compared with IVF, but the same methods of ovarian stimulation, oocyte retrieval and sperm preparation have to be used as for IVF. Recently even more simplified methods have been suggested.     

Converting an IVF cycle to IUI in low responders with at least 2 follicles

OBJECTIVE: To assess the utility of transforming an in vitro fertilization (IVF) cycle with low ovarian response to an intrauterine insemination (IUI) cycle. STUDY DESIGN: The inclusion criteria were women undergoing IVF because of idiopathic infertility, a mild to moderate male factor or IUI failure, with at least 1 normal, patent tube. When ovarian stimulation produced 2-4 follicles > or = 18 mm, the IVF cycle was converted to an IUI cycle. In cases with 4 follicles, estradiol had to be < 800 pg/mL. A total of 57 cycles were analyzed. RESULTS: The clinical pregnancy rate (PR) was 14.0% (8/57) in IVF cycles converted to IUI vs. 17.3% in our general IUI population (240/1,389). Converted cycles were associated with longer ovarian stimulation and with lower estradiol levels and less mature follicles than was IUI in the general population. There was a trend toward higher PR in women starting ovarian stimulation with 225 IU of gonadotropins (18.2%) than in those starting with higher doses (8.6%) (P > .05). CONCLUSION: In IVF low responders with at least 1 normal, patent tube when 2-4 follicles are observed, converting the IVF cycle to an IUI cycle yields a PR of 14.0%. This option should be considered in the management of low responders, especially those not stimulated with high doses of gonadotropins.     

子宫内膜异位症不孕患者辅助生殖技术治疗结局分析

目的:探讨子宫内膜异位症(EMs)不孕患者应用辅助生殖技术(ART)的治疗结局。方法:回顾性分析2006.01-2008.02期间在我中心行ART治疗的EMs患者。比较以下各组的治疗结局:行常规体外受精-胚胎移植/卵胞浆内单精子显微注射(IVF/ICSI-ET)的EMs患者(n=42,48个周期)与单纯输卵管因素患者(n=1060,1211个周期);采用3种超排卵方案的EMs患者(n=42,48个周期);行卵巢囊肿穿刺术后,病理结果确诊为EMs的患者(n=16,16个周期)与非EMs单纯囊肿患者(n=79,79个周期);接受夫精人工授精(AIH)治疗,采用自然周期(51个周期)和诱导排卵周期(31个周期)的EMs患者。结果:EMs患者的临床妊娠率(12.5%)比单纯输卵管因素患者(36.2%)明显降低,P<0.05;3种超排卵方案的临床妊娠率无统计学差异,P>0.05;卵巢囊肿穿刺术后确诊的EMs患者与非EMs单纯囊肿患者的治疗结局无统计学差异,P>0.05;EMs患者采用诱导排卵周期AIH的妊娠率(29.0%)明显高于自然周期(9.8%),P<0.05。结论:由于EMs引起不孕的机制复杂,EMs患者接受IVF/ICSI-ET治疗后的临床妊娠率明显低于单纯输卵管因素患者。EMs患者行AIH治疗时,建议采用诱导排卵方案。     

Controlled ovarian hyperstimulation and intrauterine insemination for treatment of unexplained infertility should be limited to a maximum of three trials

OBJECTIVE: To investigate the optimum number of cycles of controlled ovarian hyperstimulation and intrauterine insemination in the treatment of unexplained infertility. DESIGN: Observational prospective study. SETTING: In vitro fertilization embryo transfer center. PATIENT(S): Five hundred ninety-four couples with unexplained infertility. INTERVENTION(S): Controlled ovarian hyperstimulation (COH), intrauterine insemination (IUI), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI). MAIN OUTCOME MEASURE(S): Cycle fecundity. RESULT(S): One to 3 cycles of COH/IUI were performed in 594 patients (group A) undergoing 1,112 cycles (mean, 1.9 cycles/patient). Up to 3 further trials (cycles 4-6) of COH/IUI were then performed in 91 of these women (group B), a total of 161 cycles (mean, 1.8 cycles/patient). A historical comparison group C consisted of 131 patients with 3 failed cycles of COH/IUI who underwent 1 cycle of IVF and ICSI at our center. In group A, 182 pregnancies occurred, with a cycle fecundity of 16.4% and a cumulative pregnancy rate (PR) of 39.2% after the first 3 cycles. In group B, 9 pregnancies occurred in cycles 4-6, with a cycle fecundity of 5.6%, significantly lower than that of group A (P<.001). The cumulative PR rose to 48.5% by cycle 6, a further increase of only 9.3%. In the women undergoing IVF and ICSI in group C, 48 pregnancies occurred, with a cycle fecundity of 36.6% per cycle, significantly higher than that of group B (P<.001). CONCLUSION(S): In unexplained infertility, the cycle fecundity in the first three trials of COH and IUI was higher than in cycles 4-6, with a statistically significant difference. Patients should be offered IVF or ICSI if they fail to conceive after three trials of COH and IUI.     

A three step protocol for the treatment of idiopathic subfertility

650 couples with idiopathic subfertility (mean duration: 5.7 year, range 2–21 years) were treated during 2870 cycles by three assisted conception methods (each involving mild ovarian stimulation): I timed intercourse (TI), II intrauterine insemination (IUI), III in vitro fertilization/embryo transfer (IVF/ET). Treatment started with TI in most cases and then changed to IUI after three to six cycles. Couples who failed to conceive were treated after another 3–9 cycles by IVF/ET. An overall cumulative pregnancy rate of 80.2% was reached after 18 treatment months. The pregnancy rates per treatment cycle were: TI 5.3%, IUI 6.9%, IVF/ET 15.8% (per oocyte retrieval)     

Use of gonadotrophin-releasing hormone agonists to trigger ovulation

The introduction of gonadotrophin-releasing hormone (GnRH) agonists combined with gonadotrophins is considered to be one of the most significant advances in the development of in vitro fertilization (IVF) treatment. However, ovarian hyperstimulation syndrome (OHSS) remains a significant complication of controlled ovarian hyperstimulation. One possible strategy to reduce the risk of this complication would be the use of GnRH agonists instead of human chorionic gonadotrophin (hCG) to trigger the final stages of oocyte maturation. GnRH agonists are able to induce an endogenous surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and the effect may be more physiological than that of exogenous hCG. Several uncontrolled and controlled clinical studies have confirmed the efficacy of GnRH agonists for triggering ovulation, and pregnancy rates are comparable to those achieved with hCG. The incidence of OHSS appears to be decreased, but larger controlled studies are required to confirm this observation. The recent introduction of GnRH antagonists has led to renewed interest in the use of GnRH agonists to induce final oocyte maturation. An international multicentre randomized controlled trial has been completed recently comparing the efficacy of GnRH agonist with hCG for triggering ovulation in women undergoing controlled ovarian hyperstimulation using the GnRH antagonist ganirelix for pituitary suppression. The aim of the study was to determine the efficacy of the novel protocol for ovarian stimulation before IVF, in terms of pregnancy outcomes and the prevention of OHSS.     

Which factors play a role in clinical decision-making in subfertility?

Sixteen vignettes of subfertile couples were constructed by varying fertility history, post-coital test, sperm motility, FSH concentration and Chlamydia antibody titre (CAT). Thirty-five gynaecologists estimated probabilities of treatment-independent pregnancy, intrauterine insemination (IUI) and IVF. Thereafter, they chose IUI, IVF or no treatment. The relative contribution of each factor to probability estimates and to subsequent treatment decisions was calculated. Duration of subfertility and maternal age were the most important contributors for gynaecologists' estimates of treatment-independent pregnancy [relative contribution (RC) 41, 26%]. Maternal age and FSH concentration were the most important contributors in the estimates for IUI (RC: 51, 25%) and for IVF (RC: 64, 31%). The decision to start IVF was mainly determined by maternal age, duration of subfertility, FSH concentration and CAT. The relative contribution of maternal age and duration of subfertility was in concordance with existing prediction models, whereas previous pregnancy and FSH concentration were under- and overestimated respectively. In conclusion, maternal age, duration of subfertility and FSH concentration are the main factors in clinical decision-making in subfertility. Gynaecologists overestimate the importance of FSH concentration, but underestimate that of a previous pregnancy, as compared with their importance reported in prediction models and guidelines.     

Endometriosis-associated infertility

This review summarizes the recent literature examining the relationship between endometriosis and infertility. It is clear that the advanced stage of the disease and the mechanical disruption of the pelvic anatomy may cause infertility. The link between early stage endometriosis and infertility remains a source of controversy. Management plans must be individualized contingent upon the stage of disease, the age of the patient and the duration of infertility. The preponderance of data suggests that ablative therapy at the time of laparoscopy is as good as, or superior to expectant or medical therapy. With the exception of IVF/ET, ovarian suppression with GnRH agonists is not warranted in endometriosis-associated infertility. Controlled ovarian hyperstimulation with IUI is appropriate therapy in women with minimal-to-mild and surgically corrected endometriosis.     

Use of gonadotrophin-releasing hormone agonists to trigger ovulation

The introduction of gonadotrophin-releasing hormone (GnRH) agonists combined with gonadotrophins is considered to be one of the most significant advances in the development of in vitro fertilization (IVF) treatment. However, ovarian hyperstimulation syndrome (OHSS) remains a significant complication of controlled ovarian hyperstimulation. One possible strategy to reduce the risk of this complication would be the use of GnRH agonists instead of human chorionic gonadotrophin (hCG) to trigger the final stages of oocyte maturation. GnRH agonists are able to induce an endogenous surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and the effect may be more physiological than that of exogenous hCG. Several uncontrolled and controlled clinical studies have confirmed the efficacy of GnRH agonists for triggering ovulation, and pregnancy rates are comparable to those achieved with hCG. The incidence of OHSS appears to be decreased, but larger controlled studies are required to confirm this observation. The recent introduction of GnRH antagonists has led to renewed interest in the use of GnRH agonists to induce final oocyte maturation. An international multicentre randomized controlled trial has been completed recently comparing the efficacy of GnRH agonist with hCG for triggering ovulation in women undergoing controlled ovarian hyperstimulation using the GnRH antagonist ganirelix for pituitary suppression. The aim of the study was to determine the efficacy of the novel protocol for ovarian stimulation before IVF, in terms of pregnancy outcomes and the prevention of OHSS.     

Subfertility: causes,treatment and outcome

Common causes of subfertility include ovulatory disorders, tubal disease, peritoneal adhesions, endometriosis, uterine abnormalities, abnormalities of sperm and advancing female age. Infertility is unexplained after thorough evaluation in about 5-10% of cases. Significant caveats must be attached to the interpretation of available data regarding infertility treatments. Successful ovulation induction in anovulatory women is possible for nearly all women except in cases of ovarian failure. Surgery is an option for some patients with tubal damage, adhesions, endometriosis and uterine abnormalities. Male factor infertility may be amenable to treatment of a specific cause, but is often empirical with the use of intra-uterine insemination (IUI) or in vitro fertilization (IVF). Egg donation is currently the most effective treatment available for age-related infertility when other treatments have not been successful. Couples with unexplained infertility may be effectively treated with ovulation induction plus IUI or IVF.