Clomiphene Citrate Cycles Research Articles

Ovulation induction in women with polycystic ovary syndrome: randomized trial of clomiphene citrate versus low-dose recombinant FSH as first line therapy

This single centre randomized controlled trial was undertaken to compare the efficacy and safety of clomiphene citrate and lowdose recombinant FSH as first line pharmacological therapy for anovulatory infertility associated with polycystic ovary syndrome (PCOS). Seventy-six infertile patients with PCOS were randomized to receive clomiphene citrate (50–150 mg/day for 5 days) (clomiphene citrate group, n = 38) or recombinant human FSH (FSH group, n = 38) in a chronic, low-dose, step-up protocol (daily starting dose 75 IU) for up to three consecutive cycles. Ovarian response was monitored by transvaginal ultrasonography and human chorionic gonadotrophin (HCG) was given to trigger ovulation in all cycles with appropriate follicular development. The primary outcome measure was cumulative pregnancy after undergoing up to three treatment cycles. Secondary outcomes were cycle cancellation rate, ovulation rate per cycle, cumulative ovulation rate, pregnancy rate per cycle, incidence of OHSS, cumulative live birth rate, and multiple birth rate. One hundred and four clomiphene citrate cycles and 91 FSH cycles were evaluable. The relative risk and its 95% confidence interval were 1.17 (0.97–1.46) for HCG cycles with ovulation, 1.78 (0.92–3.54) for the pregnancy rate per woman, and 1.83 (0.79–4.40) for live births per woman in favour of FSH. The cumulative pregnancy rate after three treatment cycles was 43% with FSH and 24% with clomiphene citrate (P = 0.06). By logistic regression analysis, the factors predicting ovulation included female age, serum androstenedione and use of FSH. Predictors of pregnancy were duration of infertility and use of FSH. This randomized controlled trial suggests that low-dose recombinant FSH may be an effective alternative to clomiphene citrate in first-line treatment for anovulatory PCOS patients. Thus, further studies, possibly multi-centre, in order to avoid problems with patient recruitment, are warranted to confirm these results.

Laparoscopic evaluation following failure to achieve pregnancy after ovulation induction with clomiphene citrate

Objective To assess the value of laparoscopic evaluation of the pelvis after failure to achieve pregnancy with clomiphene citrate–induced ovulation and to determine whether predictors for significant pelvic pathology can be isolated. Design Retrospective study. Setting Tertiary care academic medical center. Patient(s) Ninety-two patients failing to conceive after four ovulatory cycles with clomiphene citrate with a normal hysterosalpingogram who underwent laparoscopic evaluation of the pelvis. Intervention(s) Laparoscopy. Main outcome measure(s) Presence of pelvic pathology and predictors of pelvic disease. Result(s) Of the 92 patients studied, 32 patients (34.8%) had a “positive” laparoscopy (i.e., stages III and IV endometriosis, an endometrioma, pelvic adhesions, and/or tubal disease), 27 patients (29.3%) had stage I or II endometriosis, and 30 patients (32.6%) had a normal pelvis. The predictors for intrapelvic disease were a history of dyspareunia, no prior use of oral contraceptive pills, and no prior use of any form of contraception. Almost 40% of women with predictors had a “positive” laparoscopy, compared with only 12.5% of patients without predictors; however, the majority of patients (91.3%) had at least one predictor. Conclusion(s) More than one third of the patients failing to conceive after four ovulatory cycles of clomiphene citrate had significant intrapelvic pathology. Although predictors for intrapelvic disease were isolated, their high prevalence reduced their predictive value.

Ovarian Cancer in a Woman Who Had Undergone Multiple Ovarian Stimulation Cycles and Its Subsequent Spread after Laparoscopic Surgery

Objective: To report on a woman with a history of multiple ovarian stimulation cycles using clomiphene citrate who developed ovarian cancer and its subsequent spread after laparoscopic surgery. Case Report(s): A 29-year-old woman suffered from secondary infertility. She failed to conceive after 6 consecutive cycles of clomiphene citrate. A laparoscopic operation was arranged due to a persistent echolucent cystic mass found during ovulation induction. This mass turned out to be a well-differentiated endometrioid adenocarcinoma. Subsequent exploratory laparotomy found cancer progression with implants at the trocar site and on the ovarian and peritoneum surface. Conclusion(s): Although a possible link between ovulation induction drugs and the risk of ovarian carcinoma is inconclusive, one should be very cautious when prescribing ovulation induction agents. Any persistent adnexal mass should be carefully evaluated. Immediate conversion to surgical staging is necessary once a malignancy is found during a laparoscopic examination.

Effect of diagnosis, age, sperm quality, and number of preovulatory follicles on the outcome of multiple cycles of clomiphene citrate-intrauterine insemination

Objective: To determine how diagnosis, age, sperm quality, and number of preovulatory follicles affect pregnancy rates when multiple cycles of clomiphene citrate (CC)-IUI are performed. Design: Fifteen-year prospective observational study. Setting: Private infertility clinic. Patient(s): Three thousand, three hundred eighty-one cycles of husband or donor IUI. Intervention(s): Ovulation induction with CC and IUI. Main Outcome Measure(s): Per-cycle pregnancy rate (PR), cumulative pregnancy rate (CPR). Result(s): Pregnancy rates remained constant through four cycles, then fell significantly for diagnoses other than ovulatory dysfunction. Mean PRs for cycles 1–4 were significantly lower for patients with the following characteristics: age ≥43 years, poor semen quality, single preovulatory follicles, and diagnoses other than ovulatory dysfunction. Additional cycles of CC-IUI compensated for low PRs because of age, semen quality, or number of follicles. After four cycles, CPRs were 46% for ovulatory dysfunction; 38% for cervical factor, male factor, and unexplained infertility; 34% for endometriosis; and 26% for tubal factor. After six cycles, CPRs were 65% for ovulation dysfunction, 35% for endometriosis, and unchanged for other diagnoses. Conclusion(s): Clomiphene citrate-intrauterine insemination should be performed for a minimum of four cycles. Additional cycles of CC-IUI can compensate for low pregnancy rates due to age, semen quality, or follicle number in patients with ovulation dysfunction.

Double intrauterine inseminations (IUI) in clomiphene citrate (CC) cycles do not provide any advantage over single IUI: a randomized controlled trial

Objective: We have shown the benefit of double IUI in controlled ovarian hyperstimulation in a recent meta-analysis of prospective randomized studies presented in ASRM Annual Meeting 2001. However, due to the cost of gonadotropins, evidence based medicine suggests that trial of CC with IUI in mild male infertility and unexplained infertility may be an option for the initial step. In addition, a recent report suggested the application of misoprostol just after IUI increased pregnancy chance. Therefore we aimed to compare the efficiencies of double IUI and IUI + misoprostol versus single IUI in CC cycles using husband’s sperm to have a better cost-benefit analysis.

Sequential hormonal supplementation with vaginal estradiol and progesterone gel corrects the effect of clomiphene on the endometrium in oligo-ovulatory women

We investigated the possibility of correcting the endometrial alterations induced with clomiphene citrate (CC) by vaginal hormonal supplementation (HS) with estradiol (E2) and progesterone gel. Oligo-ovulatory women were prospectively randomized into four groups receiving either 50 mg (groups 1 and 2) or 100 mg (groups 3 and 4) of CC from cycle day 3-8. Groups 2 and 4 also received vaginal E2 cream 0.1 mg twice daily from day 8 until the LH surge and vaginal progesterone gel, starting 3 days after ovulation. All participants had an endometrial biopsy performed 10 +/- 1 days after ovulation. All biopsies in the HS groups (2 and 4) showed complete predecidual changes, and were 'in-phase' with findings normally made 10 days post-ovulation (+/- 2 days of clinical dating). However, without HS (groups 1 and 3), only 4/6 and 3/6 biopsies showed predecidual changes in women receiving 50 and 100 mg of CC. The addition of vaginal E2 and progesterone to CC ovulation induction regimens normalizes the alterations in endometrial morphology. Hormonal treatment combining vaginal E2 and progesterone may improve endometrial receptivity in CC cycles and ultimately yield higher pregnancy rates.

Associations between Doppler ultrasound-derived luteal blood flow indices and functional hormonal profile in spontaneous and stimulated cycles

The associations between Doppler ultrasound-derived luteal blood flow indices and luteal hormonal profile in the midluteal phase were assessed in both spontaneous and stimulated cycles. Transvaginal color Doppler ultrasound evaluation and blood sampling were carried out prospectively on 61 infertility patients in 43 spontaneous cycles, 31 clomiphene citrate (CC) cycles, and 16 controlled ovarian hyperstimulation (COH) cycles in the midluteal phase. Luteal blood flow Doppler indices included peak systolic veloicty (PSV), time-averaged maximum velocity (TAMXV), pulsatile index (PI), and resistance index (RI). Hormonal profile indices included serum levels of 17 β-estradiol (E2), progesterone (P) and P/E2 ratio. The correlation between each end-point in each treatment group was assessed by regression analysis. PSV and TAMXV in the COH group were significantly higher than in the spontaneous group (P=0.0435 vsP=0.0359, respectively). Serum E2 and P were significantly higher than in the spontaneous group (P=0.0435 vsP=0.0359, respectively). Serum E2 and P levels were significantly higher in the COH group than in the CC (P<0.0001 vsP<0.0001, respectively) and spontaneous groups (P<0.0001 vsP<0.0001, respectively). PSV and TAMXV correlated positively with P level in spontaneous cycles (P=0.0131 vsP=0.0142, respectively) and CC (P=0.0120 vsP=0.0066, respectively) but correlated negatively P level in COH cycles (P=0.0348 vsP=0.0383, respectively). PI and RI correlated with P only in CC cycles (P=0.0357 vsP=0.0369, respectively). Doppler ultrasound-derived indices all correlated with P/E2 ratio in spontaneous and CC cycles but not in COH cycles. These results indicate that velocity indices should be considered as complementary parameters of luteal function for infertility but that the relationship of these indices to P level in COH cycles differs from that in spontaneous and CC cycles. The correlation of luteal blood flow indices with P/E2 ratio suggests that Doppler ultrasound indices may be useful in predicting reproductive outcome in spontaneous and CC cycles.

Electroejaculation and assisted reproductive technologies in the treatment of anejaculatory infertility

Objective: To determine the efficacy of electroejaculation in combination with assisted reproductive technology (ART). Design: Case series. Setting: University fertility program. Patient(s): One hundred twenty-one consecutive couples seeking treatment of anejaculatory infertility. Intervention(s): Electroejaculation with IUI, or gamete intrafallopian transfer or IVF. Main Outcome Measure(s): Pregnancy and pregnancy outcome. Result(s): Fifty-two couples became pregnant (43%), 39 by IUI alone (32.2%). Cycle fecundity for IUI was 8.7%. No difference in cycle fecundity was seen among ovarian stimulation protocols (clomiphene citrate, 7.6%, hMG, 13.2%, and natural cycle, 11.2%). Pregnancy was unlikely when the inseminated motile sperm count was <4 million. Female management protocol and etiology of anejaculation did not affect results. Patients undergoing IVF had higher cycle fecundity (37.2%) than did those undergoing IUI. The rates of spontaneous abortion and multiple gestations were 23% and 12%, respectively. Conclusion(s): Electroejaculation with stepwise application of ART is effective in treating anejaculatory infertility. Intrauterine insemination with the least expensive monitoring protocol should be used for most couples, because use of more expensive monitoring did not improve results. It is cost-effective to bypass IUI and proceed directly to IVF in men who require anesthesia for electroejaculation and in those with a total inseminated motile sperm count < 4 million.

A study of infertility treatment and melanoma.

This study examined the possible association between melanoma and exposure to fertility drugs, specifically clomiphene citrate, human menopausal gonadotrophin (HMG) and human chorionic gonadotrophin (HCG). A cohort of 3186 women who attended a fertility clinic between 1 January 1980 and 31 December 1990 was studied; by January 1996, 14 women had been diagnosed with primary melanoma. Details of fertility treatment were extracted from the clinical records. The incidence of melanoma in the cohort resembled that of the female Queensland population (standardized incidence ratio = 0.89, 95% confidence interval [CI] = 0.54-1.48). Exposure to clomiphene citrate, HMG or HCG did not affect the incidence of melanoma. Women with infertile partners who were treated with fertility drugs were at increased risk of melanoma (odds ratio [OR] = 3.17, 95% CI = 1.01-9.98). Compared with women exposed only to clomiphene citrate and HMG, a lower incidence of melanoma was observed among those who received HCG as well (OR = 0.10, 95% CI = 0.02-0.42). Women exposed to two or more cycles of either clomiphene citrate (OR = 0.27, 95% CI = 0.08-0.94) or HMG (OR = 0.23, 95% CI = 0.07-0.84) had a significant reduction in melanoma risk compared with women exposed to no or one cycle. In summary, a woman's infertility per se was not found to be associated with melanoma, while exposure to fertility drugs was positively associated with melanoma in women with infertile partners and negatively associated in women with low doses of fertility drugs.

Incidence of baseline ovarian cysts in clomiphene citrate ovulation induction cycles.

Objective: In contrast to COH and IVF cycles, the literature provides no conclusive results concerning the incidence and effect of pretreatment ovarian cysts during Clomiphene Citrate ovulation induction cycles. Our objectives were to evaluate the incidence of ovarian cysts ≥ 10.0 mm in patients undergoing infertility treatment with clomiphene citrate and to evaluate the factors associated with ovarian cysts in clomiphene citrate cycles.

A research based practice change: outcome evaluation after altering the start date of clomiphene citrate (CC) in controlled ovulation induction (COI) cycles.

Objective: Research utilization is an important tool to improve clinical Nursing practice. Outcome evaluation of practice changes based on research utilization generates empirical knowledge for nursing decisions. A recent study1 reported that in COI cycles, initiating CC on the traditional cycle day (cd) 5 had a lower pregnancy rate (PR) outcome than CC cycles initiated on cd 1. Persuasive arguments citing the negative antiestrogenic effects on endometrial receptivity and cervical mucous, along with the long half-life of CC, suggested that initiation of CC earlier in the cycle might minimize these adverse effects during the periimplantation time. Therefore the purpose of this study was to implement and then evaluate the effect on PRs when the initiation of CC was changed from cd 5 to cd 1 or 2.

Metformin improves ovulation and pregnancy rates in patients with polycystic ovary syndrome.

We evaluated the fertility promoting effect of metformin in infertile patients with polycystic ovary syndrome. Twenty-nine infertile patients with polycystic ovary syndrome (PCOS) are included in our prospectively designed study and 15 normal menstruating women served as controls for reproductive hormones and ovarian volumes. All PCOS patients received a total of 78 cycles of clomiphene citrate (CC) in the beginning, then patients who could not get pregnant were switched to metformin plus clomiphene citrate. PCOS patients served as their own controls for the ovulation and pregnancy rates. At the end of the CC cycles 4.2% of patients got pregnant and 65.2% of the remaining group got pregnant with metformin plus CC cycles (p=0.0001). We have not observed any serious side effects of metformin. The high pregnancy rate of our study population is consistent with the hypothesis that insulin resistance plays an important role in the pathogenesis of anovulation in patients with PCOS.

Use of an Aromatase Inhibitor for Induction of Ovulation in Patients With an Inadequate Response to Clomiphene Citrate

Abstract Objective: To use aromatase inhibition for induction of ovulation in women in whom clomiphene citrate (CC) treatment was unsuccessful. Design: Prospective trial in infertility patients treated with CC. Setting: Two tertiary-referral infertility clinics associated with the Division of Reproductive Sciences, University of Toronto. Patient(s): Twelve patients with anovulatory polycystic ovary syndrome (PCOS) and 10 patients with ovulatory infertility, all of whom had previously received CC with an inadequate outcome (no ovulation and/or endometrial thickness of ≤0.5 cm). Intervention(s): The aromatase inhibitor letrozole was given orally in a dose of 2.5 mg on days 3–7 after menses. Main Outcome Measure(s): Occurrence of ovulation, endometrial thickness, and pregnancy rates. Result(s): With CC treatment in patients with PCOS, ovulation occurred in 8 of 18 cycles (44.4%), and all ovulatory cycles for the women included in this study had endometrial thickness of ≤0.5 cm. In 10 ovulatory patients, 15 CC cycles resulted in a mean number of 2.5 mature follicles, but all cycles had endometrial thickness of ≤0.5 cm on the day of hCG administration. With letrozole treatment in the same patients with PCOS, ovulation occurred in 9 of 12 cycles (75%) and pregnancy was achieved in 3 patients (25%). In the 10 patients with ovulatory infertility, letrozole treatment resulted in a mean number of 2.3 mature follicles and mean endometrial thickness of 0.8 cm. Pregnancy was achieved in 1 patient (10%). Conclusion(s): Oral administration of the aromatase inhibitor letrozole is effective for ovulation induction in anovulatory infertility and for increased follicle recruitment in ovulatory infertility. Letrozole appears to avoid the unfavorable effects on the endometrium frequently seen with antiestrogen use for ovulation induction.

Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate

Objective: To use aromatase inhibition for induction of ovulation in women in whom clomiphene citrate (CC) treatment was unsuccessful. Design: Prospective trial in infertility patients treated with CC. Setting: Two tertiary-referral infertility clinics associated with the Division of Reproductive Sciences, University of Toronto. Patient(s): Twelve patients with anovulatory polycystic ovary syndrome (PCOS) and 10 patients with ovulatory infertility, all of whom had previously received CC with an inadequate outcome (no ovulation and/or endometrial thickness of ≤0.5 cm). Intervention(s): The aromatase inhibitor letrozole was given orally in a dose of 2.5 mg on days 3–7 after menses. Main Outcome Measure(s): Occurrence of ovulation, endometrial thickness, and pregnancy rates. Result(s): With CC treatment in patients with PCOS, ovulation occurred in 8 of 18 cycles (44.4%), and all ovulatory cycles for the women included in this study had endometrial thickness of ≤0.5 cm. In 10 ovulatory patients, 15 CC cycles resulted in a mean number of 2.5 mature follicles, but all cycles had endometrial thickness of ≤0.5 cm on the day of hCG administration. With letrozole treatment in the same patients with PCOS, ovulation occurred in 9 of 12 cycles (75%) and pregnancy was achieved in 3 patients (25%). In the 10 patients with ovulatory infertility, letrozole treatment resulted in a mean number of 2.3 mature follicles and mean endometrial thickness of 0.8 cm. Pregnancy was achieved in 1 patient (10%). Conclusion(s): Oral administration of the aromatase inhibitor letrozole is effective for ovulation induction in anovulatory infertility and for increased follicle recruitment in ovulatory infertility. Letrozole appears to avoid the unfavorable effects on the endometrium frequently seen with antiestrogen use for ovulation induction.

Relationship of follicle numbers and estradiol levels to multiple implantation in 3,608 intrauterine insemination cycles

Objective: To determine the relationship of follicle numbers and estradiol (E 2) levels to multiple implantations in human menopausal gonadotropin (hMG) and clomiphene citrate (CC) cycles. Design: Fifteen-year prospective study. Setting: Private infertility clinic. Patient(s): Women who underwent 3608 cycles of husband or donor intrauterine insemination (IUI). Intervention(s): Ovulation induction (OI) with CC, hMG, or CC+hMG. Main Outcome Measure(s): Pregnancy and multiple implantations. Result(s): Triplet and higher-order implantations—but not twin implantations—were related to age, E 2 levels, and number of follicles ≥12 mm and ≥15 mm, but not number of follicles ≥18 mm, in hMG and CC+hMG cycles. For patients less than 35 years old, three or more implantations tripled when six or more follicles were ≥12 mm, in CC, hMG, and CC+hMG cycles, and when E 2 was ≥1000 pg mL in hMG and CC+hMG cycles. For patients 35 or older, pregnancy rates in hMG and CC+hMG cycles doubled when six or more follicles were ≥12 mm, or E 2 levels were >1000 pg mL, whereas 3 or more implantations were not significantly increased. Conclusions: Withholding hCG or IUI in CC, hMG, and CC+hMG cycles when six or more follicles are ≥12 mm may reduce triplet and higher-order implantations by 67% without significantly reducing pregnancy rates for patients under 35 years of age.

A Prospective Randomized Trial Comparing Clomiphene Citrate with Tamoxifen for Ovulation Induction in Anovulatory Women

Objective: To evaluate the rates of ovulation and pregnancy in a cohort of anovulatory women with infertility randomized to treatment with either Tamoxifen (TMX) or Clomiphene Citrate (CC). Design: Prospective randomized non-crossover trial. Materials and Methods: From August 1997 through November 1999, 95 anovulatory women were enrolled in the investigation. A total of 86 subjects had appropriate follow up for evaluation, 46 in the TMX arm and 40 in the CC arm. The mean age of the TMX group was 26.6 (±4.2) years and that of the CC group was 26.5 (±4.3) years. The mean years of infertility and Body Mass Index were also similar; 3.5 (±2.9) years and 30.9 (±6.0) kg/m2 for the TMX group and 3.7 (±2.5) years and 30.2 (±6.2) kg/m2 for the CC group (P>.05). Subjects were randomized to receive either 20 mg of TMX or 50 mg of CC cycle days 5–9. Ovulation was defined as a mid-luteal progesterone of 3.0 ng/mL or higher. If ovulation failed to occur, the dose of the medication was sequentially increased in each subsequent treatment cycle. The daily dose of TMX was increased to 40 mg and then 60 mg and the dose of CC to 100 mg and then 150 mg. A total of 113 evaluable TMX cycles and 91 CC cycles were available for interpretation. Results: The overall rate of ovulation in the TMX group was 50/113 cycles (44.2%) and in the CC group 41/91 cycles (45.1%), P>0.05. The ovulatory rate per cycle in subjects who received 20 mg of TMX was 56.5% and in subjects who received 50 mg of CC was 46.0%. Ovulatory rates per cycle with 40 mg of TMX or 100 mg of CC were 27.6% and 39.3% respectively, and with use of 60 mg of TMX or 150 mg of CC were 20.0% and 53.9%. Ten of 13 (76.9%) subjects receiving 60 mg of TMX failed to ovulate and 6 of 11 (54.5%) subjects receiving 150 mg of CC failed to ovulate, P>0.05. There were 10 pregnancies in the TMX group and 6 pregnancies in the CC group. The fecundability with TMX was 20.0% (10/50) per ovulatory cycle and the fecundability with CC was 14.6% (6/41) per ovulatory cycle (P>0.05). Conclusions: In a cohort of anovulatory women, the overall rate of ovulation and pregnancy were similar with TMX and CC. We conclude that TMX is an acceptable alternative ovulation induction agent to CC.

Low-Dose Gonadotropins plus Intrauterine Insemination Treatment in Patients with Clomiphene Resistant Polycystic Ovary Syndrome

Objectives: Ovulation induction (OI) with gonadotropins is widely accepted as the second-line treatment in clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). Low-dose step-up regimen was suggested to have comparable pregnancy rates (PR) with minimal risk of multiple pregnancy and ovarian hyperstimulation syndrome. This study was designed to determine the effect of intrauterine insemination (IUI) added to low-dose gonadotropins in patients with CC-resistant PCOS. Design: A randomized controlled clinical trial. Materials and Methods: Twenty-eight patients with PCOS who previously failed to conceive despite 3 ovulatory cycles of CC were randomized to 3 groups; (i) OI with CC (100 mg/d) and IUI (n:8), (ii) OI with low dose gonadotopins and IUI (n. 10), (iii) OI with low dose gonadotropins (n:10). Fifteen patients with PCOS who previously failed to develop preovulatory follicles in 3 cycles on CC (100–200 mg/d) were randomized to 2 groups; (i) OI with low dose gonadotropins (n:7), (ii) OI with low dose gonadotropins and IUI (n:8). In IUI cycles, two IUI procedures were done and sperm was prepared using a two-step wash procedure. Results: In patients with failure to conceive despite ovulation on CC, ongoing PRs per started cycles were 4/8 (50%) In CC+IUI group, 6/10 (60%) in low dose gonadotropin+IUI group, and 2/10 (20%) in low dose gonadotropin only group (p<0.05). In patients with failure to develop follicles on CC, ongoing PRs per started cycles were 2/19 (10%) in low dose gonadotropin only group, and 4/19 (21%) in low dose gonadotropin+IUI group (p>0.05). Conclusions: In case of anovulatory resistance to CC, we offer combination of low dose gonadotropin regimen with IUI in order to decrease the number of cycles with costly gonadotropins to achieve a pregnancy. In case of non-conceptional resistance either to CC or gonadotropins, IUI should be tried before stepping up to a higher line of treatment.

Fertility Drugs and the Risk of Breast and Ovarian Cancers

Abstract Objective: To investigate a possible linkage between the use of fertility drugs for infertility and the risk of breast and ovarian cancers. Design: Long-term, historic-prospective study. Setting: Fertility clinic in a university hospital. Patient(s): Files of 1,197 infertile women with a mean (± SD) follow-up of 17.9 ± 5 years (21,407 person-years) were reviewed. Diagnoses, number of courses, and dosage of fertility drugs were extracted from the files. Intervention(s): Cancers were identified by record linkage to the National Cancer Registry. Histopathologic reports and data on estrogen and progesterone receptors in breast cancer tissue were also reviewed. Main Outcome Measure(s): Standardized incidence ratio with 95% confidence interval (CI) were used for risk assessment. Result(s): Of 20 breast cancers (standardized incidence ratio, 1.40 [95% CI, 0.83–2.10]), 16 were detected among 780 women who had been exposed to 3,978 cycles of clomiphene citrate (CC) and/or hMG (standardized incidence ratio, 1.65 [95% CI, 0.94–2.68]). The standardized incidence ratio for this cancer was significantly increased only in patients with one or two CC treatments and a dose of ≤1,000 mg (2.6 [1.19–5.0] and 2.52 [1.21–4.64], respectively). Two cases of ovarian cancer (1 patient unexposed) were observed with no evidence of excessive risk. Six of the eight patients with data on estrogen and progesterone receptors were exposed to CC, and all tested positive for these receptors. Conclusion(s): An association between the use of fertility drugs and an increased risk of breast and ovarian cancers has not been confirmed.

Fertility drugs and the risk of breast and ovarian cancers: results of a long-term follow-up study

Objective: To investigate a possible linkage between the use of fertility drugs for infertility and the risk of breast and ovarian cancers. Design: Long-term, historic-prospective study. Setting: Fertility clinic in a university hospital. Patient(s): Files of 1,197 infertile women with a mean (± SD) follow-up of 17.9 ± 5 years (21,407 person-years) were reviewed. Diagnoses, number of courses, and dosage of fertility drugs were extracted from the files. Intervention(s): Cancers were identified by record linkage to the National Cancer Registry. Histopathologic reports and data on estrogen and progesterone receptors in breast cancer tissue were also reviewed. Main Outcome Measure(s): Standardized incidence ratio with 95% confidence interval (CI) were used for risk assessment. Result(s): Of 20 breast cancers (standardized incidence ratio, 1.40 [95% CI, 0.83–2.10]), 16 were detected among 780 women who had been exposed to 3,978 cycles of clomiphene citrate (CC) and/or hMG (standardized incidence ratio, 1.65 [95% CI, 0.94–2.68]). The standardized incidence ratio for this cancer was significantly increased only in patients with one or two CC treatments and a dose of ≤1,000 mg (2.6 [1.19–5.0] and 2.52 [1.21–4.64], respectively). Two cases of ovarian cancer (1 patient unexposed) were observed with no evidence of excessive risk. Six of the eight patients with data on estrogen and progesterone receptors were exposed to CC, and all tested positive for these receptors. Conclusion(s): An association between the use of fertility drugs and an increased risk of breast and ovarian cancers has not been confirmed.

Prospective randomized double-blind trial of the correlation between time of administration and antiestrogenic effects of clomiphene citrate on reproductive end organs

Objective: To investigate whether the timing of administration of clomiphene citrate (CC) affects hormone levels, follicular recruitment, reproductive end organs, and pregnancy rates. Design: Prospective, randomized, double-blind trial. Setting: Academic center. Patient(s): Twenty-three patients with unexplained infertility. Intervention(s): Twenty-three patients with unexplained infertility underwent 45 cycles of CC and IUI. For each cycle, patients were randomized either to receive 100 mg of CC on days 1–5 and placebo on days 5–9 (study group), or placebo on days 1–5 and CC on days 5–9 (control group). Main Outcome Measure(s): The difference in uterine artery PI, number of follicles, endometrial thickness, and pregnancy rates. Result(s): Gonadotropins and E 2 levels, as well as uterine artery pulsatility index, were significantly higher in the study group on day 5. In addition, in the study group, a longer time interval existed between finishing CC and IUI (8 versus 6 days; MD = 2 days; 95% CI = 1–3) and the pregnancy rate was higher than in the control group (6 versus 0; OR = 15.1; 95% CI = 1.1–72.4). Conclusion(s): Clomiphene citrate commenced on day 1 of the menstrual cycle, rather than day 5, results in more rapid follicular growth, a longer CC-free period before IUI, and higher pregnancy rates. Although methodologically sound, our results should be taken with some degree of caution because they are based on a relatively small number of patients.