Hum. Reprod. Advance Access originally published online on November 16, 2006
Human Reproduction 2007 22(3):792-797; doi:10.1093/humrep/del441
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A randomized clinical trial of clomiphene citrate versus low dose recombinant FSH for ovarian hyperstimulation in intrauterine insemination cycles for unexplained and male subfertility
Department of Obstetrics and Gynecology 1 Radboud University Nijmegen Medical Center, Nijmegen 2 Isala Clinics, Zwolle 3 Jeroen Bosch Hospital, ‘s-Hertogenbosch 5 Catharina Hospital Eindhoven and 4 Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
6 To whom should be addressed at: Department of Obstetrics and Gynecology, Radboud University Medical Center, Postbus 9101, 6500 HB Nijmegen, The Netherlands. E-mail: t.dankert{at}obgyn.umcn.nl
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Abstract |
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BACKGROUND: Controlled ovarian hyperstimulation with intrauterine insemination (IUI) is a widely accepted treatment for unexplained and male subfertility. No consensus exists about the drug of first choice to be used as hyperstimulation. This randomized multicentre trial using a parallel design compares the efficacy of clomiphene citrate (CC) with that of recombinant FSH (rFSH). METHODS: Couples with primary unexplained or male subfertility were randomized to receive CC or rFSH for ovarian hyperstimulation. The treatment was continued for up to four cycles unless pregnancy occurred. Cycles with more than three follicles were cancelled. Cumulative pregnancy rates and live birth rates were primary outcomes. Cancellation during treatment and multiple birth rates are secondary outcomes. Results were analysed following the intention-to-treat principle. RESULTS: Seventy couples with male subfertility and 68 couples with unexplained subfertility were included. Seventy-one women received CC, and 67 received rFSH. Twenty-seven pregnancies were observed in the CC group (38%) and 23 in the rFSH group (34.3%) relative risk (RR) 1.11 [95% confidence interval (95% CI) 0.71–1.73]. The live birth rate was 28.2% (20/71) and 26.9% (18/67) for CC and rFSH, respectively, RR 1.05 (95% CI 0.61–1.80). Overall, the live birth rates per cycle were 10% for CC-stimulated and 8.7% for rFSH stimulated cycles. The total multiple pregnancy rate was 6.0%. Thirty-five cycles (8.6%) were cancelled because of four or more follicles (CC, n = 17; rFSH, n = 18). CONCLUSIONS: In couples with primary unexplained or male subfertility participating in an IUI program, ovarian hyperstimulation can be achieved by CC or rFSH. No significant difference in live birth rates between CC and rFSH was observed. Being less expensive, CC seems the more cost-effective drug and therefore, can be offered as drug of first choice.
Key words: intrauterine insemination/clomiphene citrate/recombinant FSH/subfertility/randomized
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionConclusionAcknowledgementsReferences |
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Intrauterine insemination (IUI) with or without ovarian hyperstimulation is regarded as the first treatment option for couples with unexplained or moderate-to-mild male subfertility (Hughes, 1997
; Cohlen, 2005). To achieve mild ovarian hyperstimulation, various drugs have been used: HMG, purified and recombinant FSH (rFSH), anti-estrogens [clomiphene citrate (CC)] and aromatase inhibitors. Our hypothesis was that rFSH would benefit over CC.
Compared with natural cycle IUI, ovarian hyperstimulation improves treatment outcome in couples with unexplained and mild male subfertility (Arici et al., 1994; Cohlen et al., 1999; Guzick et al., 1999). However, there remains a discussion about which drug should be the drug of first choice. Conflicting results have been published comparing the efficacy of CC with different types of gonadotrophins in IUI programs (Karlström et al., 1993; Balasch et al., 1994; Hannoun et al., 1998; Guzich et al., 1999; Ecochard et al., 2000; Matorras et al., 2002). IUI cycles with hMG stimulation showed slightly higher but not significant pregnancy rates than cycles stimulated with CC (Karlström et al., 1993; Hannoun et al., 1998). Guzick et al. concluded that purified FSH stimulation in IUI cycles is an effective treatment for couples with unexplained subfertility. Balasch et al. described a higher pregnancy rate in IUI cycles with late low dose purified FSH compared to stimulation by CC, in couples with male or unexplained subfertility. In IUI cycles with donor sperm, highly purified FSH stimulated cycles showed significant higher pregnancy rates than CC stimulated cycles (Matorras et al., 2002). Matorras et al. (2000) also compared purified FSH to rFSH in IUI cycles; there was no difference in pregnancy rates.
No studies comparing rFSH and CC for ovarian hyperstimulation in an IUI program for couples with unexplained or male subfertility were found in an intensive Pubmed search. We therefore started a prospective multicentre randomized trial to compare in a parallel design the efficacy of CC with rFSH for ovarian hyperstimulation in an IUI program for couples with unexplained or male subfertility of at least 24 months. The cumulative live births rates were the primary outcome. Multiple birth rates, ovarian hyperstimulation and number of follicles were secondary outcomes.
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Materials and methods |
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Patients
Between January 2001 and September 2004, a total of 138 couples with unexplained or male subfertility in four clinics signed a written informed consent to take part in this study. All couples had suffered from primary subfertility for at least 24 months. They had undergone fertility investigation by a medical history, physical examination, confirmation of ovulation by basal body temperature, ultrasound and/or mid-luteal serum progesterone, post-coital testing, semen analysis, chlamydia antibody titre and laparoscopy and/or hysterosalpingography to confirm at least unilateral tubal patency. All women had regular spontaneous menstrual cycles of 21–35 days. If serum chlamydia antibodies were detectable, a laparoscopy was carried out. Semen analysis was performed according to standardized methods by trained technicians at each centre. Smoking habits of both men and women and the body mass index (BMI) of the women were determined.
Unexplained subfertility was defined if no abnormality was found during these infertility investigations.
Male infertility was defined if no abnormality was found, but semen analyses were subnormal in respect to the World Health Organization criteria (WHO, 1992), that is, sperm count less than 20 x 106/ml and/or type A+ type B motility <50% and/or normal morphology <30%.
Exclusion criteria were women younger than 18 years and over 38 years of age, those with anovulation, previous assisted reproduction attempts, endometriosis classification stage III or IV of the American Fertility Society, contraindications for one of the investigated drugs, resisting ovarian cyst (>19 mm and >1 months), total motile sperm count <1 million after semen preparation, malignancies of ovaries, breast and/or uterus.
The ethical committees of the four clinics had approved the protocol.
Design
Couples in each diagnostic subgroup were randomized using a computer-generated list prepared at another institution, contacted by a central phone number, to receive CC or rFSH for ovarian stimulation. Couples received up to four cycles in a parallel design unless pregnancy occurred (positive urine pregnancy test). Cycles of rest could intervene between treatment cycles for personal or clinical reasons (ovarian cysts). Intercourse was not restricted in the rest cycles. The starting dose in the CC group was 100 mg/day on days 3–7 of the menstrual cycle. If the patient showed mono-follicular or excessive multiple follicular (
3 follicles of >14 mm) development, the dose was increased or decreased, respectively, by 50 mg in the next cycle. Women in the rFSH group received 75 IU/day s.c. (Gonal-F, Serono Benelux) from cycle day 3 until follicular maturation was reached. If follicular development (one follicle >10 mm) was not seen on day 11, the dose was increased to 112.5 IU/day. If the patient showed mono-follicular development or excessive multiple follicular development (3 follicles >14 mm), the starting dose was increased or decreased, respectively, by 37.5 IU in the next cycle.
Ovarian response and endometrial thickness was monitored by transvaginal ultrasonography. Monitoring was carried out every other day from day 9 onwards, until a dominant follicle >14 mm was identified; from that point daily monitoring was performed. The aim was to obtain two follicles with a maximum of three follicles >14 mm. When the dominant follicle reached a mean diameter of at least 18 mm, 5000 IU HCG (Profasi, Serono Benelux) was given. Single insemination with homologous semen was performed 38–40 h after the administration of HCG. Semen specimens were produced by masturbation and collected for insemination within 1 h after production. The semen specimen was diluted with 5 ml of human tubal fluid (HTF) medium, BioWhittaker, Cambrex Bio Science, Verviers, Belgium) containing 10% gepasteuriseerde plasma oplossing (GPO) (pasteurized plasma solution, Sanquin, Amsterdam, the Netherlands). A gradient technique with Pure Sperm 100 (NidaCon International AB, Mölndal, Sweden) was used. After centrifugation at 600–900 g for 20 min, the pellet was resuspended and washed twice with HTF/10% GPO. The sperm suspension was kept at room temperature until transfer into the uterine cavity. Time between production and transfer did not exceed 2.5 h in the clinics in Nijmegen, Zwolle and ‘s Hertogenbosch. In Eindhoven, this time did not exceed 5.5 h.
To minimize the risk of a multiple pregnancy, HCG was withheld if more than three follicles with a diameter of >14 mm were seen. In this case, the couple was strictly advised not to have unprotected intercourse. In one clinic, blood for LH determination was drawn on the day of HCG administration and 1 week later for progesterone (Cantineau and Cohlen, in press).
Outcome parameters
Pregnancy was confirmed by a urine pregnancy test. Ultrasonography was performed at the 7th and 12th week of gestation. Multiple pregnancies were documented. Patients with singletons and uneventful medical history were referred to their midwife as is usual in the Netherlands. The pregnancy and live birth rates were evaluated 2 months post-partum by reviewing patients charts or by telephone calls to the patients.
Statistical methods
A power analysis was done. With statistical power of 80%, a two-sided significance level of 0.05 and expected pregnancy rates per cycle of 7 and 13% for CC-stimulated and rFSH-stimulated cycles, respectively, the calculated number of necessary cycles to be included was 400 (sample size for two-sided comparison) for each group. Based on the observation in one of the clinics (Eindhoven) that one pregnancy required about three cycles, the number of patients to be included is 
1/3 of the estimated number of cycles (130 couples each group).
In this study, we defined two primary outcomes: ongoing pregnancy rates and live birth rates. It is obvious from a clinical point of view that these two outcomes are not unrelated but express more or less the same outcome in two different ways. Loss of pregnancy beyond 12 weeks of gestation seems unrelated to the variables of this comparison: either the use of CC or rFSH. Therefore, the formal adjustment of the alpha of 0.05, as should be the case when the two outcomes would be independent, is not necessary.
Analysis was done in accordance with intention to treat.
In contingency tables, the chi-square test or the two-sided Fisher’s exact test (in sparse tables) was used. The difference in means for two groups for continuous variables was tested by the Student’s t-test for two independent groups. For assessing the difference of duration of subfertility and sperm count, prior to washing, the non-parametric Wilcoxon sum rank test was used. Relative risk (RR) with a 95% confidence interval (95% CI) was used to compare probability of pregnancy and live birth between stimulation with CC and stimulation with rFSH. A two sided P-value <0.05 was considered significant.
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Results |
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After randomization, 68 couples with unexplained subfertility and 70 couples with male subfertility were included. Seventy-one couples were included in the CC group (199 started cycles) and 67 in the rFSH group (207 started cycles) (Figure 1 ).
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During the study, the Dutch government decided to stop the general reimbursement of fertility medication. Because the personal costs for patients in the two treatment groups were different, we thought it was not ethically correct to include patients without additional reimbursement. We were not able to include many couples since this decision. Therefore, the number of 130 couples each group calculated by the power analysis was not reached.
The treatment groups were similar with respect to baseline characteristics (Table I ). As expected, the semen analysis during the investigation period had a significant lower sperm count in couples with male compared to unexplained subfertility. Although the inclusion criterion of subfertility was for more than 24 months, 16 couples have been included despite subfertility for only 13.1–23.9 months (CC, n = 9; rFSH n = 7): seven couples had been subfertile for 23–23.9 months (two pregnancies), six between 18.3 and 20 months (two pregnancies) and three couples between 13.1 and 17.2 months (one pregnancy). These 16 couples are included in the further analyses. After randomization and before starting the treatment program, six women became spontaneously pregnant (CC, n = 4; rFSH, n = 2; unexplained, n = 5; male, n = 1). These six couples were included in the intention to treat analyses.
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During the treatment, 24 patients (18%) dropped out for various reasons (CC, n = 16; rFSH n = 8, not significant). Five couples dropped out for too poor semen quality, five for insufficient endometrial response, one woman had a persistent ovarian cyst, three women dropped out because of hyperstimulation in a previous cycle and eight couples had personal reasons for drop out. Two of the women randomized for CC wanted to change to rFSH stimulation after three unsuccessful cycles (Table II ). Thirty-five cycles (8.6%) were cancelled because of ovarian hyperstimulation (CC, n = 17/199; rFSH, n = 18/207) and another 10 cycles because of ovulation prior to HCG administration (CC, n = 4; rFSH, n = 6). Four times personal reasons caused cancellation of the cycle (CC, n = 3; rFSH, n = 1); in one rFSH-stimulated cycle, there was no follicle development and no insemination.
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Twenty-seven pregnancies were observed in the CC group (38%) and 23 in the rFSH group (34.3%), resulting in a small non-significant difference in cumulative pregnancy rates, RR 1.11 (95% CI 0.71–1.73) (Table III). The cumulative live birth rate was 28.2% (20/71) and 26.9% (18/67) for CC and rFSH respectively, RR 1.05 (95% CI 0.61–1.80) including one conception during a cycle of rest. One twin pregnancy and one triplet occurred in the CC group. One twin pregnancy occurred in the rFSH group (no significant difference in multiple pregnancy rates between CC and rFSH). The total multiple pregnancy rate was 6% (3/50).
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All ongoing pregnancies resulted in live births (Table III). None of the patients developed ovarian hyperstimulation syndrome (OHSS).
There was a small, but statistically insignificant difference in cumulative pregnancy rates between unexplained and male subfertility: 39.7% (27/68) versus 32.9% (23/70). The cumulative live birth rate was 30.9% (21/68) and 24.3% (17/70) for unexplained and male subfertility, respectively (Tables IV and V).
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Per cycle, the ongoing pregnancy rate was for couples with unexplained subfertility 12.2% when CC was used and 9.8% with rFSH. For male subfertility, these rates were 8.3 and 7.6% for CC versus rFSH, respectively (Table IV and V). Overall, the live birth rates per cycle were 10% for CC-stimulated and 8.7% for rFSH stimulated cycles.
There was a statistically non-significant decrease in live birth rates per cycle with increasing age of the women (age 
35 years of age: 10%, age >35 years: 6.6%) (data not shown). The BMI of the women had no effect on outcomes, with live birth rates per cycle of 7.3 and 8.8% for BMI <20 and >25, respectively, while for women with a normal BMI (20–25), the pregnancy rate was 9.7% per cycle.
There was a slight, but not significant, difference in ongoing pregnancy rates when there was a well-developed endometrium (thickness 5–10 mm: 9%, compared to <5mm: 0% and >10mm: 2.9%). The number of follicles >14 mm did not significantly influence the outcome. In the 174 cycles with mono-follicular development, 13 (7.5%) ongoing pregnancies were seen. When two or three follicles >14 mm developed, this ongoing pregnancy rate was 9.2% (18/195).
Endometrial development, sperm count and number of follicles were not different between treatment groups.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionConclusionAcknowledgementsReferences |
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In subfertile couples with idiopathic and mild male subfertility IUI with or without ovarian hyperstimulation is the first treatment option. Many studies have been done comparing different forms of ovarian stimulation. An intensive Pubmed search did not reveal studies comparing rFSH and CC for ovarian hyperstimulation in a prospective randomized fashion in an IUI program for couples with unexplained or male subfertility. Observational or non-randomized studies were also not found. We therefore started a prospective multicentre randomized trial to compare in a parallel design the efficacy of CC with rFSH for ovarian hyperstimulation in an IUI program for couples with unexplained or male subfertility of at least 24 months. We did not observe a significant difference in live birth rates and multiple pregnancy rates between CC and low dose rFSH stimulation in IUI cycles.
For couples with unexplained subfertility, studies suggest higher pregnancy rates per cycle when treated by CC-stimulated cycles during IUI programs versus no treatment or IUI in natural cycles (Deaton et al., 1990; Arici et al., 1994). Guzick et al. (1999) concluded that purified FSH stimulation in IUI cycles is an effective treatment for couples with unexplained subfertility. In a meta-analysis, Hughes found a greater pregnancy rate in IUI cycles with stimulation using gonadotrophin than in cycles without stimulation (Hughes, 1997). In another meta-analysis, Cohlen et al. (1999) advised mild ovarian stimulation with gonadotrophins in couples with sperm counts between 10–20 million. Karlström et al. (1993) showed for couples with unexplained subfertility a statistically non-significant difference in pregnancy rates in HMG-stimulated IUI cycles (20%) compared with CC-stimulated IUI cycles (6%). This difference was not seen in a study comparing CC stimulation to HMG stimulation in couples with subfertility for various reasons (Hannoun et al., 1998; Ecochard et al., 2000). Matorras et al. compared ovarian stimulation with either CC or highly purified urinary FSH in IUI with donor sperm. They showed a significant difference in pregnancy rates for CC (31%) and FSH (61%) (Matorras et al., 2002). Balasch et al. (1994) described a higher pregnancy rate in IUI cycles with late low dose purified FSH (13%) compared to stimulation by CC (4%), in couples with male or unexplained subfertility.
In various studies, the difference between CC and gonadotrophins might be due to different follicular development. In many prospective and retrospective studies, the pregnancy rate increased with increasing number of developing follicles (Plosker et al., 1994; Nuojua-Huttunen et al., 1999; Matorras et al., 2000) as did the multiple birth rate. Different stimulation protocols of the treatment groups might also cause higher pregnancy rates in gonadotrophin-stimulated cycles compared to CC-stimulated cycles (Matorras et al., 2002). In their study, Matorras et al. used a fixed stimulation protocol for CC without ovarian monitoring, the FSH group was monitored.
Althaullah et al. (2002) concluded in their meta-analysis that in many studies the groups did not only differ in stimulating protocol but, for example, also in the HCG trigger of ovulation. They did not show that CC was inferior to gonadotrophins.
Our hypothesis was that rFSH would benefit over CC for pregnancy outcome. But the live birth rates per couple were 28.2% (CC) and 26.9% (rFSH) and per cycle 10% with CC and 8.7% with rFSH. As live births are the main goal of every couple, we analysed the live birth rates and not the total pregnancy rates. Instead of including only completed cycles, we included all started cycles. Prevention of multiple pregnancies is important in controlled ovarian hyperstimulation in IUI. For this reason, the use of a moderate dose (75 IU) of rFSH and a strict cancellation regime was carried out. This might have influenced the present pregnancy outcomes compared with those presented in literature. The multiple birth rate in our study was low (6%) compared to previous trials (Karlström et al., 1993; Nuojua-Huttunen et al., 1999; Guzick et al., 1999; Matorras et al., 2002). There was no significant difference in multiple pregnancy rates between CC and rFSH. Guzick et al. showed pregnancy rates of 33% per couple treated with superovulation with purified FSH and IUI, but they had an overall multiple pregnancy rate of 19.8% per couple including three quadruplets and four triplets. Per insemination cycle with superovulation, the multiple pregnancy rate was even 30% (24/80). In their study, Karlström et al. showed ongoing pregnancy rates of 13% per cycle when ovarian stimulation was done with HMG, the ongoing multiple pregnancy rate was 41%.
Unfortunately, we did not reach the power that was calculated before hand due to the previously mentioned changes in reimbursement. Our power calculation was based on expected pregnancy rates per cycle of 7% (CC) versus 13% (rFSH). Assuming pregnancy rates to remain constant during consecutive cycles, expected cumulative pregnancy rates per couple can be calculated: 20 versus 40%. With alpha set at 0.05 and the statistical power at 80%, we can calculate that we should have included 89 couples in each treatment arm expecting a 10% drop-out rate. This example shows the calculated power of our trial had we not encountered inclusion problems due to governmental reimbursement changes. Nevertheless, after inclusion of 138 couples in this trial, the differences in ongoing pregnancy rates per couple observed were much smaller than expected and we should have included much higher number of couples to reach statistical significance based upon the observed differences. We therefore argue, based on the results we have shown, that even with a sufficient number of couples included, a significant difference would still not have been found. To test this assumption, larger studies are necessary.
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Conclusion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionConclusionAcknowledgementsReferences |
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We did not observe a difference in ongoing pregnancy rates between CC and rFSH stimulation in IUI cycles in couples with unexplained or male primary subfertility. When rFSH is used in a low dose with a strict cancellation regime, the multiple pregnancy rate in rFSH-stimulated cycles does not differ from CC-stimulated cycles. Unless larger studies demonstrate otherwise, for economic reasons, CC seems still the drug of choice for ovarian stimulation in IUI cycles.
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Acknowledgements |
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The authors thank Serono Benelux for their support of this project. Parts of this study were presented by a poster presentation at the annual ASRM meeting, Montreal, 2005.
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References |
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Submitted on August 19, 2006; resubmitted on October 6, 2006; accepted on October 12, 2006.
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