A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women

OBJECTIVE: To evaluate the ovarian follicular dynamics of cycle modification with the aromatase inhibitor letrozole compared with clomiphene citrate in normal ovulatory women. DESIGN: Randomized double-blind controlled trial. SETTING: Tertiary care hospital. PATIENT(S): Nineteen ovulatory female volunteers, ages 18-35 years. INTERVENTION(S): Subjects were monitored in one control cycle. Subjects then received either letrozole 2.5 mg daily or clomiphene citrate 50 mg daily on days 5-9 after menses. MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness and endometrial pattern at ovulation, and follicular profiles of LH, FSH, and E(2). RESULT(S): The number of mature follicles at the LH surge in natural cycles was 1.0 with an exaggerated response seen for treatment both with clomiphene and letrozole. There was no difference in the endometrial thickness at midcycle during either the natural cycles or the medicated cycles. LH surges and spontaneous ovulation were documented in all natural and medicated cycles. When measured daily, follicular profiles of LH and FSH are similar between the groups in both the natural and medicated cycles. In the medicated cycles, clomiphene results in a significant increase in E(2) levels, while E(2) levels in letrozole-stimulated cycles appeared lower than in natural cycles. CONCLUSION(S): Transient inhibition of aromatase activity in the early follicular phase with the aromatase inhibitor letrozole results in stimulation of ovarian folliculogenesis similar to that seen with clomiphene citrate with no apparent adverse effect on endometrial thickness or pattern at midcycle.     

A comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on superovulation in Asian women with normal ovulatory cycles

OBJECTIVE: To compare the effect of the aromatase inhibitor letrozole and clomiphene citrate (CC) on superovulation in women with normal ovulation. METHODS: A cross-over randomized study of 22 women with normal ovulation, divided randomly into two equal cohorts, was carried out. Each group of 11 women was randomly allocated to take letrozole or CC for one cycle. After washing out for one cycle, the alternative drug was administered in the subsequent cycle. The number and size of mature follicles, endometrial thickness, and estradiol and progesterone levels were monitored. RESULTS: The number of mature follicles and estradiol levels on ovulation day were significantly lower in the letrozole group than the CC group (p < 0.05 for both). However, no differences between the two groups in endometrial thickness and pattern were observed. Progesterone levels showed ovulation in all cycles. CONCLUSIONS: The administration of 50 mg CC on days 3-5 was superior to 2.5 mg letrozole for superovulation induction in women with normal ovulation.     

A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation

OBJECTIVE: To compare the effects of the aromatase inhibitor letrozole (7.5 mg) and clomiphene citrate (CC; 100 mg) in women undergoing superovulation and IUI. DESIGN: Prospective randomized trial. SETTING: University teaching hospital. PATIENT(S): We studied a total of 238 cycles of superovulation and IUI in women with idiopathic infertility. INTERVENTIONS: Patients were randomized into treatment with 7.5 mg of letrozole daily (74 patients, 115 cycles) or 100 mg of CC daily (80 patients, 123 cycles). MAIN OUTCOME MEASURE(S): Number of follicles, endometrial thickness, pregnancy rate, and miscarriage rate. RESULT(S): The mean age, parity, and duration of infertility in both groups of patients were similar. There was no significant difference between the total number of developing follicles in the letrozole (5.7 +/- 3.7) and in the CC groups (4.8 +/- 2.5). The number of follicles of > or =14 mm and of >18 mm were 2.1 +/- 1.2 and 1.4 +/- 0.7 in the letrozole group, and 1.7 +/- 0.9 and 1.1 +/- 0.5 in the CC group, respectively. No difference was found in the endometrial thickness between the two groups (7.1 +/- 0.2 mm in the letrozole group, 8.2 +/- 5.9 mm in the CC group). The pregnancy rate per cycle was 11.5% in the letrozole group and 8.9% in the CC group. Four of the 11 pregnancies in the CC group resulted in a miscarriage (36.6%). CONCLUSION(S): Superovulation and IUI with letrozole and CC are associated with similar pregnancy rates, but the miscarriage rate is higher with CC. The ideal dose of letrozole remains unknown and further study is needed.     

A randomized comparison of ovulation induction and hormone profile between the aromatase inhibitor anastrozole and clomiphene citrate in women with infertility

Background. In the present study we evaluated and compared the effects of ovulation and hormonal dynamics induced by anastrozole and clomiphene citrate in women with infertility.

Materials and methods. Thirty-three infertile patients, aged 25–41 years, were enrolled. Patients received either anastrozole 1 mg daily (AI group) or clomiphene citrate 100 mg daily (CC group) from cycle day 3 to day 7. Number of mature follicles (≥18 mm), endometrial thickness, pregnancy rate and serial hormone profiles (follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E₂), testosterone and progesterone) were measured on cycle day 3, day 8, day 10, the day of intrauterine insemination (IUI), day 7 after IUI and day 14 after IUI.

Results. Baseline parameters were similar in the two groups, including age, body mass index, infertility duration and day-3 serum hormones except FSH. The mean FSH value on day 3 was significantly different (4.3 mIU/ml in the AI group vs. 6.3 mIU/ml in the CC group; p < 0.05). The women receiving anastrozole had fewer ovulatory follicles (1.2 in the AI group vs. 1.8 in the CC group; p < 0.05) and a thicker endometrium (10.6 mm in the AI group vs. 7.8 mm in the CC group; p < 0.05). The levels of progesterone and testosterone were similar during ovulation stimulation cycles in both groups. On the other hand, the AI group had a significantly higher LH level but a significantly lower E₂ level in the stimulation cycle.

Conclusion. Anastrozole has a high pregnancy rate, although it induces fewer ovulatory follicles compared with clomiphene citrate. The two drugs gave different responses of FSH, LH and E₂ during stimulation cycles.     

Comparison of endometrial receptivity of clomiphene citrate versus letrozole in women with polycystic ovary syndrome: a randomized controlled study

Abstract

The aim of the study was to compare the effect of clomiphene citrate (CC) and letrozole on endometrial receptivity for ovulation induction in women with polycystic ovary syndrome (PCOS). A randomized controlled study included 160 patients diagnosed with PCOS, out of which 80 patients received 50?mg of CC and 80 patients received 2.5?mg of letrozole for successful ovulation induction. Endometrial thickness and pattern, the blood flow of uterine artery and subendometrial region, endometrial volume and vascularization index were measured. The ratio of multilayered endometrial pattern in letrozole group was significantly increased on the day of human chorionic gonadotropin (hCG) administration compared with CC group (77.5% vs. 55.0%). The volume, vascularization index (VI), flow index (FI), and vascularization flow index (VFI) of endometrium on the day of hCG administration and 7–9?days after ovulation in letrozole group were significantly increased. The biochemical pregnancy rate, clinical pregnancy rate, and ongoing pregnancy rate in letrozole group were significantly increased compared with CC group (36.3%, 30.0%, 22.5% vs. 21.3%, 13.8%, 10.0%, respectively). Letrozole increased pregnancy rates by improving endometrial receptivity compared with CC in patients with PCOS.     

Comparison of clomiphene citrate and letrozole for ovulation induction in women with polycystic ovary syndrome: a prospective randomized trial

To compare the therapeutic efficacy of clomiphene citrate (CC) and letrozole (LE) on ovulation, pregnancy, and live birth in women with polycystic ovary syndrome (PCOS); and to ensure if LE can replace CC as the first-line therapy for ovulation induction in these women. This is a prospectively, randomized, controlled trial in the tertiary hospital. Two-hundred and sixty-eight anovulatory PCOS patients were treated by CC or CC plus metformin and LE or LE plus metformin for three continuous cycles or conception; their ovulation rates, pregnancy rates, and live birth rates were calculated and compared. No significant difference was noted among the four groups regarding to the baseline data of clinical manifestations, serum sex hormone levels, and serum insulin levels. A total of 240 patients completed the therapies. The ovulation rate was significantly higher in the group LE than the group CC; however, no significant difference was noted between the groups LE and CC, CC, and CC?+?MET, or LE and LE?+?MET in the pregnancy rate, abortion rate, and live birth rate. No birth defect was found in the total of 63 newborns. CC regimen was still recommended to be the first-line therapy of ovulation induction for PCOS.     

The effects of letrozole and clomiphene citrate on ligands expression of Wnt3, Wnt7a,and Wnt8b in proliferative endometrium of women with Polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS) is a common endocrinologic disorder in women of reproductive age characterized by polycystic ovaries, oligo/anovulation, and hyperandrogenism. Not only anovulation but also endometrial dysfunction can reduce fertility in PCOS patients. Wnt pathway is responsible for endometrial proliferation which be strongly regulated by estradiol. To determine the effects of clomiphene citrate (CC) and letrozole, we measured the expression of some main ligands of Wnt/β-catenin signaling including Wnt7a, Wnt3, and Wnt8b in the endometrial samples taken from PCOS women on day 12 of the menses who received 100?mg CC or 5?mg letrozole as well as from women without treatment. Significantly, the mean estrogen and progesterone concentration were lower and higher, respectively, in letrozole than CC. The mean endometrial thickness (ET) was significantly greater in letrozole compared to CC. Assessment of the mRNA and protein expression of Wnt7a, Wnt3, and Wnt8b showed significantly lower expression in CC than the letrozole and control groups. Collectively, letrozole provided a better molecular response in the endometrium of PCOS patients during the proliferative phase, similar to natural cycles, compared to CC. CC decreased the ligands expression of Wnt3, Wnt7a, and Wnt8b, resulting in endometrial dysfunction.     

The effects of clomiphene citrate on normally ovulatory women

Objective: To investigate the efficacy of clomiphene citrate (CC) on normally ovulatory women who complained of infertility.

Design: A randomized study.

Setting: University Hospital.

Patient(s): Thirty-three normally ovulatory women with unexplained infertility.

Intervention(s): Eighteen women received CC at a 50-mg dosage. Fifteen women received no ovulation-induction drugs.

Main Outcome Measures: The pregnancy rate (PR) per patient, the PR per cycle, and the cumulative pregnancy rate.

Result(s): Seven patients in the CC group stopped taking CC, and observations were terminated because of antiestrogenic effects. The pregnancy rate (PR) per patient and the PR per cycle were significantly decreased (P < 0.005) in the CC group (4 of 18 [22.2%] and 4 of 66 [6.1%], respectively) than in the spontaneous group (11 of 15 [73.3%] and 11 of 52 [21.2%], respectively). Kaplan-Meier tests showed that the cumulative pregnancy rate in the CC group was significantly lower than in the spontaneous group (P <0.05). Five of seven patients who had stopped taking CC became pregnant in spontaneous cycles.

Conclusion(s): Administration of CC to normally ovulatory women is not efficacious in terms of increasing the pregnancy rate.     

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Objective?To investigate the clinical effect of letrozole (LE) combined with clomiphene (CC) in the treatment of polycystic ovary syndrome (PCOS). Methods?A total of 120 patients with PCOS were selected as the research objects, of which 60 patients who received single CC treatment were the control group, while the combined group (60 patients) was given LE+CC treatment. Menstrual conditions and sex hormone levels [luteinizing hormone (LH), estradiol (E2), and progesterone (P)] were compared between the two groups, and ovulation and pregnancy were recorded in the two groups. Results?The number of mature follicles, endometrial thickness, menstrual cycle, menstrual volume and early abortion rate in the combined group were lower than those in the control group (P<0.05). After treatment, E2, LH, P secretion levels, ovulation rate, pregnancy rate and twin rate in the combined group were higher than those in the control group (P<0.05). Conclusion? LE combined with CC in the treatment of PCOS patients can achieve better efficacy in ovulation induction and pregnancy.     

Differential expression of endometrial integrins and progesterone receptor during the window of implantation in normo-ovulatory women treated with clomiphene citrate

OBJECTIVE: To assess the effect of clomiphene citrate (CC) on endometrial epithelial integrins and P receptors (PR) during the window of implantation. DESIGN: Controlled, prospective, clinical study. SETTING: Teaching hospital and university research laboratory. PATIENT(S): Thirty-one fertile, normo-ovulatory women participated in this trial. Thirteen women exhibited a CC-stimulated cycle with 50 mg on days 5-9, and 18 women with spontaneous menstrual cycles served as controls. INTERVENTION(S): Endometrial biopsies in the midluteal phase. MAIN OUTCOME MEASURE(S): Immunohistochemical determination and endometrial cellular localization of alpha1, alpha v, beta3, and alpha4 epithelial integrins and PR during the window of implantation. The staining intensity was assessed by a semiquantitative index (HSCORE) and compared by nonparametric Mann-Whitney test. RESULT(S): Higher plasma levels of P and E2 and delayed histologic dating of the endometrium (38%) were features of CC-treated women. In addition, a low epithelial beta3 integrin expression and persistent PR were observed in glandular epithelial cells of "out-of-phase" endometrial biopsies from CC-treated women. In contrast, in "in-phase" biopsies, neither epithelial PR nor beta3 integrin were different from spontaneous control cycles. There was no difference in the expression of alpha1, alpha v, and alpha4 between the groups studied. CONCLUSION(S): The administration of clomiphene produces aberrant endometrial beta3 integrin expression in conjunction with a failure in the down-regulation of PR during the window of implantation in a significant number of normo-ovulatory women, notwithstanding the higher plasma P levels. Therefore, CC might affect the expression of endometrial receptivity markers.