JRI Journal of Reproduction and Infertility 2228-5482 2251-676X Avicenna Research Institute JRI-13-158 Original Article Pregnancy Predictors after Intrauterine Insemination: Analysis of 3012 Cycles in 1201 Couples Soria Macizo 1 * Pradillo Gálvez 1 García Jorquera 1 Ramón Peinado 1 Castillo Alvarez 1 Jordana Canteras 2 Paricio Parrilla 1 Department of Obstetrics and Gynecology, Human Reproduction Unit, Virgen de la Arrixaca University Hospital, Murcia, Spain Department of Biostatistics, School of Medicine, University of Murcia, Murcia, Spain Corresponding Author: Macizo Soria, Department of Obstetrics and Gynecology, Human Reproduction Unit, Virgen de la Arrixaca University Hospital, Murcia, Spain. E-mail: maribelmacizosoria@gmail.com Jul-Sep 2012 13 3 158 166 21 02 2012 29 05 2012 Copyright © 2012 Avicenna Research Institute 2012

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Background

Intrauterine insemination (IUI) is the first therapeutic step in assisted reproductive techniques and many factors, including male and female infertility and technique-dependent factors, have been reported to influence pregnancy rates after IUI.

Methods

We carried out this retrospective study on 1201 couples undergoing 3012 intrauterine insemination cycles during 2002 to 2009. Pregnancy rate per cycle in terms of female infertility factors, male infertility factors, and technique-dependent factors were evaluated. The χ 2 , t-test, Kaplan-meier method, and multiple logistics regression model, were used for data analysis. The p < 0.05 was considered statistically significant.

Results

The highest pregnancy rates were obtained in cases whose infertility duration was shorter (p < 0.05), Body Mass Index (BMI) was ≥25 (p < 0.05), FSH < 9 IU/L (p < 0.05), anovulation due to polycystic ovary syndrome (p < 0.05), donor sperm was used due to azoospermia (p < 0.01), three IUI cycles (p < 0.01), at least two follicles were recruited through controlled ovarian hyperstimulation (p < 0.01), and where higher total doses of FSH were administered as necessary (p < 0.05).

Conclusion

This study characterizes predictors of pregnancy following IUI, for cases with shorter periods of infertility, BMI of 25 or more, FSH value below 9 IU/L, anovulation, donor sperm and performance of three intrauterine insemination cycles.

Gonadotropin Intrauterine insemination Ovarian hyperstimulation Pregnancy rate Semen analysis

To cite this article: Macizo Soria MI, Gálvez Pradillo J, Jorquera García A, Peinado Ram༾n I, Alvarez Castillo J, Canteras Jordana M, et al. Pregnancy Predictors after Intrauterine Insemination: Analysis of 3012 Cycles in 1201 Couples. J Reprod Infertil. 2012;13(3):158-166.

Introduction

Intrauterine insemination (IUI) is the first therapeutic step in assisted reproductive techniques, and is especially appropriate for cases with mild male factor infertility, anovulation, endometriosis with at least one patent tube, and unexplained infertility (1). Among the assisted reproductive techniques, IUI is considered a first-line procedure due to its simplicity, easy management, low cost, and absence of potentially serious complications. Although the literature reports several factors affecting the likelihood of pregnancy after IUI, among them, age, body mass index (BMI), female etiology, and semen quality, there is little consensus regarding the extent to which these factors affect the likelihood of pregnancy (24).

Epidemiological studies report varying rates of infertility in developed countries, ranging between 8% and 32% of couples of reproductive age (510). Recent data for Spain indicate that approximately 15% of couples of childbearing age have problems conceiving (11).

The objective of this study was to identify factors that predict pregnancy in terms of 3 categories: female infertility factors (duration of infertility, age, weight, hormones on the 3rd day of the cycle, and etiology), male infertility factors (semen analysis according to the strict morphology criteria), and technique-dependent factors (type of insemination, number of cycles, number of inseminations per cycle, follicle development, type of stimulation received, and total dose administered).

Methods

This is a retrospective study performed between 2002 and 2009 on 1201 couples with infertility problems, who consulted the reproduction department of Virgen de la Arrixaca University Hospital in Murcia, Spain. Overall, we analyzed 3012 IUI cycles. A basic infertility study was performed before starting controlled ovarian hyperstimulation (COH). The study consisted of medical history, physical examination, transvaginal ultra-sonography, hormone study, hysterosalpingogram, and semen analysis. The hormones studied were follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and estradiol on the third day and estradiol, progesterone, and PRL on the 22nd day of menstrual cycle. PRL was analyzed twice in the same cycle, since the value of this hormone can be affected by punction stress.

The swim-up technique was used to prepare the semen and the total motile spermatozoa (TMS) count was done by multiplying the total sperm count by the prewash percentage of motile sperm. Based on semen analysis, oligo/astheno/ teratospermia (OAT) were classified: mild OAT (TMS >5 million); moderate OAT (TMS 3–5 million); and severe OAT (<3 million sperm). Sperm morphology was rated according to Kruger cri-teria (teratospermia < 5% normal sperm shapes).

All IUI cycles were stimulated by gonadotropins. Treatment was started between the second and fifth day of the cycle, using pure urinary FSH (pFSH; Fostipur), recombinant FSH (rFSH; Gonal-F or Puregon), or human menopausal gonadotropin (hMG; Menopur). The most frequent starting dose of gonadotropins was 75–150 IU/24 hr. Hormone administration was adjusted accord-ing to each patient's characteristics, especially age, hormones on the third day of the cycle, and BMI. The first ultrasound scan to assess the number and size of follicles and endometrial thickness was performed five days after starting the treatment, and subsequent scans were performed on individual patients depending on ovarian response. Ovulation was induced by 250 µg of sub-cutaneously administered recombinant human chorionic gonadotropin (hCG; Ovitrelle), and insemination was performed 36 hr later. The criterion used to trigger ovulation was to obtain at least a single 18 mm follicle.

Following 48–72 hr of abstinence, semen was collected three hours before insemination for laboratory processing. After determining motility (TMS), sperm were washed free of seminal fluid and prepared for insemination. A soft catheter (Laboratoire CCD, Paris, France) was used for insemination. The proximal end of the catheter was located in the center of the uterine cavity, and 0.5 ml of sperm preparation was slowly injected over about 15 s. A hard catheter (Laboratoire CCD) was used if it was not possible to pass the soft catheter through the cervix. Luteal phase support was provided by 200 mg/24 hr of natural micronized progesterone (Utrogestan), administered vaginally starting on the night of insemination and continuing until the pregnancy test; if pregnancy occurred, administration continued until the 12th week of gestation.

Statistical analysis was carried out using SPSS version 15. Results were expressed as means. Categorical variables were compared using the chi-square test (χ 2 ) and quantitative variables were analyzed using the Student's t-test. A value of p < 0.05 was considered statistically significant. The Kaplan-Meier method was used to measure the time elapsing until pregnancy as a function of baseline FSH levels. Multivariate logistic regression analysis was performed to identify correlations between the study variables and pregnancy. Only statistically significant co-variables were selected.

Results

We studied a total of 3012 IUI cycles corresponding to 1201 couples between 2002 and 2009, for which the outcome was 306 pregnancies (10.2% per cycle), representing a pregnancy rate per couple of 25.5%. Infertility was primary and secondary in 87.8% and 12.2% of the cases, respectively. Female and male infertility factors were detected in 21.9% and 26.3% of the cases, respectively. Infertility was due to combined factors in 35.3% of the cases, and was unexplained in the remaining 16.5%. The mean duration of infertility was 3.04 years (range, 1 to 10). The pregnancy rate decreased significantly (p< 0.05), in line with years of infertility: 1 year (12.3%), 2 years (10.3%), 3 years (9.8%), and 4 or more years (8.9%).

Female infertility factors

The mean age of the participants was 32.2 years (range, 23 to 41 years), and mean BMI was 26 (range, 18 to 38). Age was not a strong predictor of success: the pregnancy rates per cycle for age brackets below 30 years, 30 to 35 years, and 35 to 40 years, were 11.4%, 10.6%, and 9.6%, respectively. Women older than 40 years only underwent 20 cycles, and none became pregnant. The participant's weight, however, did affect the pregnancy rate. The proportion of pregnancies increased with BMI, with a significant difference between a BMI (kg/m 2 ) under 25 (18.5 to <25), and a BMI of 25 or more (≥25 to 35.0) (8.9% vs. 12.1%; p < 0.05).

Ovarian function was calculated in terms of serum concentrations of FSH and estradiol before cycle commencement. A strongly significant relationship was observed between the FSH value on the third day of the cycle and the probability of pregnancy (p < 0.01), (Table 1).

Results for female- and male-dependent factors

Pregnancy predictors Rate/Cycle (%)
Female factors
    Irregular ovulation 8.9
    Occult ovarian failure 7.7
    Anovulation (PCOS) 13.3
    Tuboperitoneal 7.7
    Endometriosis
        I-II 7.0
        III-IV 6.4
Male factors
    Asthenospermia 8.1
    OAT 9.4
        Mild 8.5
        Moderate 6.4
        Severe
   Teratospermia 10.8
    Azoospermia 16.7

In terms of baseline FSH, we observed that the probability of pregnancy during IUI cycles fell significantly for baseline FSH values of 9 IU/L or more (p < 0.05) (Figure 1).

Accumulated probability over time of no pregnancy (Kaplan-Meier test) for participants with baseline FSH ≥ 9 IU/L and <9 IU/L

The estradiol value on the third day of the cycle (over 80 pg/ml) was not a relevant pregnancy predictor.

Female infertility factors were classified as follows, in order of frequency: irregular ovulation due to short or unsuitable luteal phases (41.2%); tuboperitoneal factors (16.5%); anovulation associated with polycystic ovary syndrome (PCOS) (10.4%); occult ovarian failure (10.2%); stage I-II endometriosis (7.8%); stage III-IV endometriosis (2.8%); uterine factors (2.6%); cervical factors (1.7%); and other causes (6.8%).

Female etiology was a powerful predictor of success in achieving pregnancy. Couples treated for anovulation associated with PCOS had the highest pregnancy rate per cycle (13.3%; p < 0.05). The lowest pregnancy rates were obtained for moderate to severe cases of endometriosis (6.4%), (Table 1).

Male infertility factors

Based on semen analysis, male infertility factors were classified as follows, in order of frequency: asthenospermia (29.4%); mild oligo/astheno/teratospermia (OAT) (24%); moderate OAT (18.9%); severe OAT (6%); oligospermia (0.7%); teratospermia (4.1%); azoospermia (12.5%); and causes unrelated to semen quality, such as erectile dysfunction, positive serology results, etc (4.4%).

Male factor etiology was a powerful predictor of success in achieving pregnancy when donor sperm was used due to azoospermia in the partner. Couples treated for azoospermia had the highest pregnancy rates per cycle (16.7%; p < 0.01), (Table 1).

Multivariate analysis was used to determine whether there was an association between pregnancy and the predictors that were found to be significant. The results are shown in Table 2.

Factors associated with the probability of pregnancy (Multivariate analysis)

Factors Odds Ratio 95% Confidence Interval p-value
Anovulation (due to PCOS) 1.47 0.93-2.31 0.09
Infertility duration (less than 4 years) 0.56 0.26-1.18 0.13
BMI (25 and over) 0.82 0.54-1.25 0.35
FSH (below 9 IU/L ) 3.17 1.36-7.41 0.008

Women with a baseline FSH below 9 IU/L were 3.17 times more likely to become pregnant than women with a baseline FSH of 9 IU/L or more (95% CI: 1.3–;7.4 times).

Technique-dependent factors

The type of semen used (partner or donor) was a strong predictor of success, with a pregnancy rate per cycle of 18.1% for donor sperm (p < 0.01) Results for the technique-dependent factors are summarized in Table 3.

Results for technique-dependent factors

Cycles (n) Pregnancies Rate/Cycle (%)
Insemination type
IUI–Partner 2708 251 9.3
IUI–Donor 304 55 18.1
Cycle
1st 1202 129 10.7
2nd 884 94 10.6
3rd 571 59 10.3
4th 300 22 7.3
≥5th 55 2 3.6
Follicles ( n )
1 1535 124 8.1
≥2 1477 182 12.3
Stimulation
rFSH 2549 259 10.2
hMG 347 33 9.5
pFSH 67 7 10.4
Total dose
<300 IU/L 152 14 9.2
300-499 IU/L 1139 104 9.1
500-699 IU/L 1294 121 9.4
700-899 IU/L 320 53 12.6
900-1100 IU/L 107 14 13.1

In terms of the number of IUI cycles performed, the couples underwent an average 2.1 cycles each (range, 1 to 6). In 98.2% of the cases, between one to four inseminations were performed. A maintained pregnancy rate was observed until the third cycle, after which the pregnancy rate decreased noticeably (p < 0.01), (Table 3).

In terms of the number of inseminations per cycle, in 95.6% of the cases a single insemination was performed. The pregnancy rate was not found to increase when two inseminations were performed in the same cycle.

The number of pre-ovulatory follicles recruited was observed to be a significant factor (p < 0.01). Recruitment of at least two follicles increased the pregnancy rate in cases of COH combined with IUI (Table 3).

Regarding the type of gonadotropin used, rFSH was administered in most cycles (86.3%), followed by hMG (11.5%), and pFSH (2.2%). The type of stimulation used did not affect the probability of pregnancy (Table 3). The mean dose of administered gonadotropin was 600 IU/L. The units of FSH used for COH were a marker of success (p< 0.05).

Discussion

IUI is frequently offered to couples with problems conceiving, provided the woman has at least one patent ovarian tube and her partner has only mildly altered semen quality. An important factor to assess as a predictor of pregnancy in response to IUI is the duration of infertility. A number of studies have reported higher pregnancy rates corresponding to shorter periods of infertility (12, 13) but our study revealed significant differences (p < 0.05) in this regard. Nuojua-Huttunen et al. (14), unlike Goverde et al. (15), reported significant differences that depended on whether the infertility period was more or less than six years (14.2% vs. 6.1%). We observed that pregnancy rate fell as the duration of infertility increased, suggesting that other more complex assisted reproduction techniques should be used after four years of infertility.

Female infertility factors

In our study, the woman's age did not significantly affect the pregnancy rate. Nuojua-Huttunen et al. (14) reported a pregnancy rate of 13.7% per cycle for a total of 811 IUI cycles in women up to the age of 40, and a rate of 4.1% thereafter. Like Brzechffa et al. (15), we found that, after COH, age did not affect the pregnancy rate provided the woman was under 40 years. Other researchers, however, such as Goverde et al. (16), and Bronte et al. (17) consider age to be an important factor in achieving pregnancy.

Souter et al. (10) described the impact of BMI on IUI cycles. In our analysis, BMI significantly affected the pregnancy rate; however, women with a BMI of 25 or more achieved a higher pregnancy rate (12.1% per cycle) than women with a BMI below 25 (8.9%). Our results would indicate that in women with overweight that undergo treatment for anovulation, the likelihood of achieving pregnancy increases significantly. Dodson and Legros (18) found no differences for weight, although they did observe that higher gonadotropin doses were necessary for ovarian stimulation in obese women. Another study (19) pointed to the impact of lifestyle factors such as excess weight on the time elapsing before becoming pregnant; the annual probability of pregnancy for couples not exposed to risk factors was 83%, compared to 38% when they were present. Undoubtedly, lifestyle changes, exercise and weight loss are key factors in successfully treating infertility in such patients (20, 21).

A hormone analysis (estradiol and FSH) on the third day of the cycle is the main method for evaluating ovarian reserve. In our study we found a significant difference in pregnancy rates according to FSH levels, with values above 9 IU/L reducing the probability of pregnancy. In contrast, there was no clear difference regarding estradiol concentrations. A number of authors agree that higher FSH concentrations reduce the overall number of follicles produced, affect oocyte quality, and indicate a less favorable prognosis for treatment (22, 23), even though the cycle may appear to be regular (24). However, Mullin et al. (25), who evaluated threshold FSH and estradiol values of 15 IU/L and 80 pg/ml, respectively, found no significant differences in the pregnancy rate per couple. We agree with the opinion that women for whom ovulation induction prior to IUI is likely to be effective–that is, those with functioning ovaries–should be selected for this procedure (26).

In our study, the pregnancy rate per cycle for patients with anovulation due to PCOS was 13.3%, confirming the significant relationship between this etiology and IUI outcomes. It seems clear that COH corrects ovulation and, therefore, results in a high IUI success rate. Endometriosis, on the other hand, which is among the disorders that are the most difficult to treat (27), decreased the IUI success rate in our study to 7% per cycle for mild cases and to 6.4% for severe ones. Similar results were obtained by Vlahos et al. (28), who reported a pregnancy rate per cycle of 19.1% for cases with anovulation, compared to 9.1% for cases with endometriosis, and by Dickey et al. (29), who also reported better results for cases with anovulation. Toma and Hammond (30) reported a pregnancy rate of 6.5% per IUI cycle for donor sperm in women with stage I-II endometriosis compared to 14% in the control group. Some other authors (14) reported similar results.

Male infertility factors

Dorjpurev et al. (31) described the influence of semen characteristics on the pregnancy rate following IUI. In our case, using donor sperm for cases of azoospermia resulted in a pregnancy rate per cycle of 16.7%. When only mobility and altered morphology were considered, our study showed no significant differences; however, when OAT was included, the pregnancy rate decreased in line with severity (9.4%, 8.5%, and 6.4% for mild, moderate, and severe OAT, respectively). Sakhel et al. (32) reported a direct relationship between sperm count and poor sperm mobility with the pregnancy rate.

Unexplained infertility

We were unable to determine the cause of infertility in 16.5% of the couples. In these cases, the pregnancy rate per couple was 10.5%. Hughes (33) achieved a pregnancy rate of 15% for this indication after stimulition by gonadotropins. This author strongly recommends IUI as a first-line treatment for such couples, provided the woman's age and the duration of infertility are acceptably low. Aboulghar et al. (34) proposed performing three cycles of IUI, and if pregnancy did not result, using a more complex assisted reproduction technique.

Technique-dependent factors

Most studies are based on artificial insemination using partner sperm. When we compared our study with studies that also included donor sperm insemination, we found that the proportion of cycles in which donor sperm was used were similar (35, 36). The fact that donor sperm is of higher quality explains why the percentage of pregnancies per cycle was significantly higher (18.1%) than when partner sperm was used (9.3%).

In our study, the mean number of IUIs per couple was 2.1. Over 90% of pregnancies occurred in the initial three cycles, with the pregnancy rate dropping noticeably from the fourth cycle (p <0.01). Plosker and Amato (37) advise considering in vitro fertilization after three failed inseminations. For 811 cycles, Nuoja-Huttunen et al. (14) observed that the highest pregnancy rate occurred in the first cycle, and that 97% of all pregnancies occurred within four cycles.

The number of inseminations per cycle did not affect the pregnancy rate. In a prospective study of 226 cycles in 169 patients, Ransom et al. (38) found no difference in results for one or two inseminations per cycle. In contrast, for 449 cycles in 273 patients, Ragni et al. (39) concluded that results improved in response to two inseminations per cycle. From the literature, we could not conclude which approach was more appropriate. With ultrasound-controlled ovulation, a single insemination per cycle is probably sufficient and is certainly less costly (40).

In our study, the number of pre-ovulatory follicles recruited was a significant predictor of pregnancy (p < 0.01). Plosker and Amato (37) showed that recruitment of at least two follicles increased success rates in COH in combination with IUI-by 2% for one follicle, and by 15% for two or more follicles (p < 0.01). In their study of 9963 cycles, Bronte et al. (17) reported similar results, with pregnancy rates of 7.6% for one follicle, 10.1% for two follicles, 8.6% for three follicles, and 14% for four follicles (p < 0.01). Similar analyses by some other authors (14) confirm these results.

It is not clear which of the drugs available on the market is preferably used for COH (4145). It seems that higher pregnancy rates result when gonadotropins are primarily used (46, 47). Several studies have compared different types of gonadotropins (4850), with some authors pointing to the greater potency of rFSH (51, 52). However, recent studies have reported higher pregnancy rates for the ‘older’ hMG, rather than the more recent FSH and rFSH products (53, 54). In our hospital we mainly use rFSH, as it has been reported to reduce the possibility of developing ovarian cysts associated with LH contamination, and also to increase the probability of a more consistent, effective, and efficient response (51, 52). In our study, no differences in pregnancy rates were found for the different protocols used.

The probability of success increases with higher total gonadotropin doses. This occurs in cases of PCOS, where ovarian stimulation represents a real challenge, first, because of the range of endocrine factors to consider, including chronic anovulation and obesity, and second, because of the variability in ovarian response (55, 56). To obtain a single mature follicle, FSH should reach but not exceed the threshold FSH, as otherwise the response will be multifollicular, resulting in a higher rate of cycle cancellation, an increased risk of multiple pregnancy, and ovarian hyperstimulation (57). In our setting, we applied a protocol based on low doses administered over time, sometimes over 10 to 15 days. This induction protocol, although lengthy and expensive for the amount of gonadotropin administered, aimed to avoid excessive recruitment of follicles.

Conclusion

In this study aimed at identifying factors that predict pregnancy following IUI, we found that the probability was greatest for couples composed as follows: men with mildly altered semen quality, and women aged less than 40 years, with a BMI of 25 or more, with an infertility duration of less than four years, with an FSH value on day three of the cycle below 9 IU/L, who undergo COH, and in whom anovulation due to PCOS can be corrected. According to our results, the ‘ideal’ stimulation is to administer the amount of gonadotropin necessary to induce ovarian response and recruit at least two follicles in a maximum of three cycles.

Conflict of Interest

Authors declare no conflict of interest.

References Katzorke T Kolodziej FB [Significance of insemination in the era of IVF and ICSI] Urologe A. 2010 49 7 842 6 German Kamath MS Bhave P Aleyamma T Nair R Chandy A Mangalaraj AM Predictive factors for pregnancy after intrauterine insemination: A prospective study of factors affecting outcome J Hum Reprod Sci. 2010 3 3 129 34 Souter I Baltagi LM Kuleta D Meeker JD Petrozza JC Women, weight, and fertility: the effect of body mass index on the outcome of superovulation/ intrauterine insemination cycles Fertil Steril. 2011 95 3 1042 7 Akanji Tijani H Bhattacharya S The role of intrauterine insemination in male infertility Hum Fertil (Camb) 2010 13 4 226 32 Abma JC Chandra A Mosher WD Peterson LS Piccinino LJ Fertility, family planning, and women's health: new data from the 1995 National Survey of Family Growth Vital Health Stat 23 1997 19 1 114 World Health Organization Recent advances in medically assisted conception 1992 Geneva, Spanish WHO 111 2 7 Report No.: 820 Gray RH Epidemiology of infertility Curr Opin Obstet Gynecol. 1990 2 2 154 8 Templeton A Fraser C Thompson B The epidemiology of infertility in Aberdeen BMJ. 1990 301 6744 148 52 Vanrell JA Vanrell JA Calaf J [Sterility, subfertility and infertility: definition, frequency and etiology] Human Fertility and sterility 1992 Barcelona, Spanish Masson-Salvat 1 8 Stephen EH Chandra A Updated projections of infertility in the United States: 1995-2025 Fertil Steril. 1998 70 1 30 4 Matorras R [Epidemiology of infertility, Updates of the Spanish Society of Fertility] 2000 Spain, Spanish Spanish Fertility Society 7 9 Collins JA Burrows EA Wilan AR The prognosis for live birth among untreated infertile couples Fertil Steril. 1995 64 1 22 8 Snick HK Snick TS Evers JL Collins JA The spontaneous pregnancy prognosis in untreated sub-fertile couples: the Walcheren primary care study Hum Reprod. 1997 12 7 1582 8 Nuojua-Huttunen S Tomas C Bloigu R Tuomivaara L Martikainen H Intrauterine insemination treatment in subfertility: an analysis of factors affecting outcome Hum Reprod. 1999 14 3 698 703 Brzechffa PR Daneshmand S Buyalos RP Sequential clomiphene citrate and human menopausal gonadotrophin with intrauterine insemination: the effect of patient age on clinical outcome Hum Reprod. 1998 13 8 2110 4 Goverde AJ McDonnell J Vermeiden JP Schats R Rutten FF Schoemaker J Intrauterine insemination or in-vitro fertilisation in idiopathic subfertility and male subfertility: a randomised trial and cost-effectiveness analysis Lancet. 2000 355 9197 13 8 Stone BA Vargyas JM Ringler GE Stein AL Marrs RP Determinants of the outcome of intrauterine insemination: analysis of outcomes of 9963 consecutive cycles Am J Obstet Gynecol 1999 180 6 Pt 1 1522 34 Dodson WC Kunselman AR Legro RS The effect of obesity on treatment outcomes for infertile ovulatory women undergoing superovulation and intrauterine insemination Fertil Steril. 2005 84 Supple1 S72 73 Hassan MA Killick SR Negative lifestyle is associated with a significant reduction in fecundity Fertil Steril. 2004 81 2 384 92 Clark AM Thornley B Tomlinson L Galletley C Norman RJ Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment Hum Reprod. 1998 13 6 1502 5 Pasquali R Antenucci D Casimirri F Venturoli S Paradisi R Fabbri R Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss J Clin Endocrinol Metab. 1989 68 1 173 9 Buyalos RP Daneshmand S Brzechffa PR Basal estradiol and follicle-stimulating hormone predict fecundity in women of advanced reproductive age undergoing ovulation induction therapy Fertil Steril. 1997 68 2 272 7 Navot D Bergh PA Williams MA Garrisi GJ Guzman I Sandler B Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility Lancet. 1991 337 8754 1375 7 Ahmed Ebbiary NA Lenton EA Salt C Ward AM Cooke ID The significance of elevated basal follicle stimulating hormone in regularly menstruating infertile women Hum Reprod. 1994 9 2 245 52 Mullin CM Trivax B Baxter M Virji N Saketos M San Roman G Day 3 follicle stimulating hormone (FSH) and estradiol (E2): could these values be used as markers to predict pregnancy outcomes in women undergoing ovulation induction (OI) therapy with intrauterine insemination (IUI) cycles? Fertil Steril. 2005 84 Suppl1 S162 Scott RT Toner JP Muasher SJ Oehninger S Robinson S Rosenwaks Z Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome Fertil Steril. 1989 51 4 651 4 Härkki P Tiitinen A Ylikorkala O Endometriosis and assisted reproduction techniques Ann N Y Acad Sci. 2010 1205 207 13 Vlahos NF Coker L Lawler C Zhao Y Bankowski B Wallach EE Women with ovulatory dysfunction undergoing ovarian stimulation with clomiphene citrate for intrauterine insemination may benefit from administration of human chorionic gonadotropin Fertil Steril. 2005 83 5 1510 6 Dickey RP Taylor SN Lu PY Sartor BM Rye PH Pyrzak R Effect of diagnosis, age, sperm quality, and number of preovulatory follicles on the outcome of multiple cycles of clomiphene citrate-intrauterine insemination Fertil Steril. 2002 78 5 1088 95 Toma SK Stovall DW Hammond MG The effect of laparoscopic ablation or danocrine on pregnancy rates in patients with stage I or II endometriosis undergoing donor insemination Obstet Gynecol. 1992 80 2 253 6 Dorjpurev U Kuwahara A Yano Y Taniguchi T Yamamoto Y Suto A Effect of semen characteristics on pregnancy rate following intrauterine insemination J Med Invest. 2011 58 1-2 127 33 Sakhel K Abozaid T Schwark S Ashraf M Abuzeid M Semen parameters as determinants of success in 1662 cycles of intrauterine insemination after controlled ovarian hyperstimulation Fertil Steril 2005 84 Suppl 1 S248 9 Hughes EG The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis Hum Reprod. 1997 12 9 1865 72 Aboulghar M Mansour R Serour G Abdrazek A Amin Y Rhodes C Controlled ovarian hyper-stimulation and intrauterine insemination for treatment of unexplained infertility should be limited to a maximum of three trials Fertil Steril. 2001 75 1 88 91 Khalil MR Rasmussen PE Erb K Laursen SB Rex S Westergaard LG Intrauterine insemination with donor semen. An evaluation of prognostic factors based on a review of 1131 cycles Acta Obstet Gynecol Scand. 2001 80 4 342 8 Dickey RP Olar TT Taylor SN Curole DN Rye PH Relationship of follicle number and other factors to fecundability and multiple pregnancy in clomiphene citrate-induced intrauterine insemination cycles Fertil Steril. 1992 57 3 613 9 Plosker SM Jacobson W Amato P Predicting and optimizing success in an intra-uterine insemination programme Hum Reprod. 1994 9 11 2014 21 Ransom MX Blotner MB Bohrer M Corsan G Kemmann E Does increasing frequency of intra-uterine insemination improve pregnancy rates significantly during superovulation cycles? Fertil Steril. 1994 61 2 303 7 Ragni G Maggioni P Guermandi E Testa A Ba-roni E Colombo M Efficacy of double intrauterine insemination in controlled ovarian hyper-stimulation cycles Fertil Steril. 1999 72 4 619 22 Bagis T Haydardedeoglu B Kilicdag EB Cok T Simsek E Parlakgumus AH Single versus double intrauterine insemination in multi-follicular ovarian hyperstimulation cycles: a randomized trial Hum Reprod. 2010 25 7 1684 90 Cohlen BJ Vandekerckhove P te Velde ER Habbema JD Timed intercourse versus intra-uterine insemination with or without ovarian hyperstimulation for subfertility in men Cochrane Database Syst Rev 2000 2 CD000360 Bry-Gauillard H Coulondre S Cédrin-Durnerin I Hugues JN Benefits and risks of ovarian stimulition before intrauterine insemination] Gynecol Obstet Fertil. 2000 28 11 820 31 French Cantineau AE Cohlen BJ Heineman MJ Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility Cochrane Database Syst Rev 2007 2 CD005356 Casadei L Zamaro V Calcagni M Ticconi C Dorrucci M Piccione E Homologous intrauterine insemination in controlled ovarian hyperstimulation cycles: a comparison among three different regimens Eur J Obstet Gynecol Reprod Biol. 2006 129 2 155 61 Dankert T Kremer JA Cohlen BJ Hamilton CJ Pasker-de Jong PC Straatman H A randomized clinical trial of clomiphene citrate versus low dose recombinant FSH for ovarian hyperstimulation in intrauterine insemination cycles for unexplained and male subfertility Hum Reprod. 2007 22 3 792 7 Gerli S Bini V Di Renzo GC Cost-effectiveness of recombinant follicle-stimulating hormone (FSH) versus human FSH in intrauterine insemination cycles: a statistical model-derived analysis Gynecol Endocrinol. 2008 24 1 18 23 Demirol A Gurgan T Comparison of different gonadotrophin preparations in intrauterine insemination cycles for the treatment of unexplained infertility: a prospective, randomized study Hum Reprod. 2007 22 1 97 100 Kocak M Dilbaz B Demir B Taşci Y Tarcan A Dede S Lyophilised hMG versus rFSH in women with unexplained infertility undergoing a controlled ovarian stimulation with intrauterine insemination: a prospective, randomised study Gynecol Endocrinol. 2010 26 6 429 34 Sagnella F Moro F Lanzone A Tropea A Martinez D Capalbo A A prospective randomized noninferiority study comparing recombinant FSH and highly purified menotropin in intrauterine insemination cycles in couples with unexplained infertility and/or mild-moderate male factor Fertil Steril. 2011 95 2 689 94 Matorras R Osuna C Exposito A Crisol L Pijoan JI Recombinant FSH versus highly purified FSH in intrauterine insemination: systematic review and metaanalysis Fertil Steril. 2011 95 6 1937 42 Balasch J Fábregues F Peñarrubia J Creus M Vidal R Casamitjana R Follicular development and hormonal levels following highly purified or recombinant follicle-stimulating hormone administration in ovulatory women and WHO group II an-ovulatory infertile patients J Assist Reprod Genet. 1998 15 9 552 9 Matorras R Recio V Corcóstegui B Rodríguez-Escudero FJ Recombinant human FSH versus highly purified urinary FSH: a randomized study in intrauterine insemination with husbands’ spermatozoa Hum Reprod. 2000 15 6 1231 4 Balasch J Miró F Burzaco I Casamitjana R Civico S Ballescá JL The role of luteinizing hormone in human follicle development and oocyte fertility: evidence from in-vitro fertilization in a woman with long-standing hypogonadotrophic hypogonadism and using recombinant human follicle stimulating hormone Hum Reprod. 1995 10 7 1678 83 De la Fuente A Evaluation of the effectiveness, safety and cost-effectiveness of highly purified human menopausal gonadotropin. Study of use Menopur ® in Intrauterine Artificial Insemination (IAC/IAD)] Fertil Rev. 2007 24 6 363 7 Spanish Dickey RP Taylor SN Curole DN Rye PH Lu PY Pyrzak R Relationship of clomiphene dose and patient weight to successful treatment Hum Reprod. 1997 12 3 449 53 Mannaerts B Shoham Z Schoot D Bouchard P Harlin J Fauser B Single-dose pharmacokinetics and pharmacodynamics of recombinant human follicle-stimulating hormone (Org 32489*) in gonadotropin-deficient volunteers Fertil Steril. 1993 59 1 108 14 Chung MT Chan TF Loo TC Tang HH Lin LY Tsai YC Comparison of the effect of two different doses of recombinant gonadotropin for ovarian stimulation on the outcome of intrauterine insemination Taiwan J Obstet Gynecol. 2011 50 1 58 61