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Letrozole induction of ovulation in women with clomiphene citrate–resistant polycystic ovary syndrome may not depend on the period of infertility, the body mass index, or the luteinizing hormone/follicle-stimulating hormone ratio

2006; Elsevier BV; Volume: 85; Issue: 2 Linguagem: Inglês

10.1016/j.fertnstert.2005.08.016

1556-5653

Aboubakr Elnashar, Hassan Fouad, Magy Eldosoky, Naser Saeid,

Ovarian cancer diagnosis and treatment

Letrozole induction of ovulation in clomiphene citrate–resistant women with polycystic ovary syndrome is associated with an ovulation rate of 54.6% and pregnancy rate of 25%. There was no significant difference between letrozole responders and nonresponders in age, period of infertility, body mass index, waist circumference, LH, FSH, or LH/FSH ratio. Letrozole induction of ovulation in clomiphene citrate–resistant women with polycystic ovary syndrome is associated with an ovulation rate of 54.6% and pregnancy rate of 25%. There was no significant difference between letrozole responders and nonresponders in age, period of infertility, body mass index, waist circumference, LH, FSH, or LH/FSH ratio. Clomiphene citrate (CC) is the traditional first-line treatment for chronic anovulation that characterizes polycystic ovary syndrome (PCOS) (1Lidor A.L. Goldenberg M. Cohen S.B. Seidman D.S. Mashiach S. Rabinovici J. Management of women with polycystic ovary syndrome who experienced premature luteinization during clomiphene citrate treatment.Fertil Steril. 2000; 74: 749-752Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). Clomiphene citrate is accumulated in the body with low clearance rate and long half-life (5 days). Significant plasma concentrations of the active zu-isomer of CC can be detected up to 6 weeks after administration. However, 20%–25% of PCOS women fail to ovulate with incremental doses of CC. In addition, clinical data revealed a discrepancy between ovulation rates (75%–80%) and conception rates (30%–40%) during CC treatment (2Yen S.S. Chronic anovulation caused by peripheral endocrine disorders.in: Yen S.S. Jaffe R.B. Reproductive endocrinology physiology, pathophysiology, and clinical management. 3rd ed. Saunders, Philadelphia1991: 576-630Google Scholar). For these patients who do not respond to CC, there are a few limited adjunctive therapies that can be tried before moving on to gonadotropin therapy or laparoscopic ovarian drilling, including bromocriptine (in the presence of hyperpolactinemia or galactorrhea), dexamethasone (to reduce adrenal androgen production), insulin sensitizers (to treat hyperinsulinemia), oral contraceptives (for pretreatment suppression of LH), pulsatile GnRH (to preserve physiologic interactive feedback), and extended doses of CC (3Speroff L. Glass R.H. Kase N.G. Hormone biosynthesis, metabolism, and mechanism of action.in: Clinical gynecologic endocrinology and infertility. 6th ed. Lippincott, Williams & Wilkins, Baltimore1999: 31-105Google Scholar). However, their usefulness is limited to specific abnormalities, because many women with CC failure do not present with any overt signs of a treatable disorder (4Branigan M.E. Estes A. Using oral contraceptives as a treatment for clomid-resistant patients.Fertil Steril. 1999; 71: 544-546Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar).Mitwally and Casper (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar) reported the novel use of the aromatase inhibitor letrozole for inducing ovulation in anovulatory women with PCOS and for augmenting ovulation in ovulatory infertile women. Letrozole belongs to a new group of very potent nonsteroidal aromatase inhibitors that are rapidly absorbed from the gastrointestinal tract and excreted by the kidney. The elimination half-life of letrozole is about 2 days (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar). Our objective was to evaluate the efficacy of letrozole in induction of ovulation in cases of CC-resistant PCOS and to compare letrozole responders and nonresponders.Forty-four infertile women were included from the patients attending the outpatient clinic of Benha University Hospital. We obtained approval from the institutional research board to use an aromatase inhibitor for ovarian stimulation. All patients were diagnosed as having PCOS according to the Rotterdam criteria (6Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop GroupRevised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.Fertil Steril. 2004; 81: 19-25Scopus (0) Google Scholar). All patients had previously received CC and were diagnosed as having CC resistance (failure of ovulation after 6 cycles of CC reaching a dosage of 150 mg daily) (3Speroff L. Glass R.H. Kase N.G. Hormone biosynthesis, metabolism, and mechanism of action.in: Clinical gynecologic endocrinology and infertility. 6th ed. Lippincott, Williams & Wilkins, Baltimore1999: 31-105Google Scholar). Our inclusion criteria were age 18–39 years, period of infertility >2 years, serum level of FSH 8 (3Speroff L. Glass R.H. Kase N.G. Hormone biosynthesis, metabolism, and mechanism of action.in: Clinical gynecologic endocrinology and infertility. 6th ed. Lippincott, Williams & Wilkins, Baltimore1999: 31-105Google Scholar). Letrozole was started after two months of CC to allow for washout of the latter. Patients underwent physical examination. Weight, height, and waist and hip circumferences were measured.A transvaginal ultrasound examination was performed to exclude any pelvic pathology before treatment with letrozole. Ultrasonography was performed using a Sonoace 5500 with transvaginal transducer 6.5 MHz (Medison, Korea). In all patients, a dose of 2.5 mg of letrozole (Femara; Novartis, East Hanover, NJ) was given orally for 5 days starting from the third day of a spontaneous or progesterone-induced withdrawal bleeding (7Femara (letrozole) package insert. Novartis Pharmaceuticals, East Hanover (NJ)1999Google Scholar). Ovarian follicular response was monitored with transvaginal sonography starting one day after the last tablet of letrozole and thereafter according to the growth of the follicles (usually every other day). When at least one follicle reached >18 mm in diameter, 10,000 U hCG (Pregnyl; N.V. Organon, Oss, The Netherlands) was given intramuscularly, and timed intercourse was advised (3Speroff L. Glass R.H. Kase N.G. Hormone biosynthesis, metabolism, and mechanism of action.in: Clinical gynecologic endocrinology and infertility. 6th ed. Lippincott, Williams & Wilkins, Baltimore1999: 31-105Google Scholar). On the day of hCG administration, endometrial thickness was assessed according to Gonen and Casper (8Gonen Y. Casper R.F. Sonographic determination of an adverse effect of clomiphene citrate on endometrial growth.Hum Reprod. 1990; 5: 670-674Crossref PubMed Scopus (149) Google Scholar) and cervical mucus score was evaluated according to Moghissi (9Moghissi K.S. Postcoital test, physiologic basis, technique and interpretation.Fertil Steril. 1976; 27: 117-129Crossref PubMed Scopus (75) Google Scholar). Cervical mucus score was considered good if >10. Two days after giving hCG, the patients were assessed for ultrasonographic signs of ovulation. Clinical pregnancy was diagnosed when a gestational sac was detected on transvaginal ultrasound examination one week after the missed period. Every patient received one letrozole treatment cycle.During letrozole treatment, ovulation occurred in 24 cases (54.6%) and clinical pregnancy in 6 cases (25%). These pregnancies were singleton. There were no abortions. Table 1 shows the clinical characteristics of letrozole responders and nonresponders. There was no significant difference between the groups regarding age, period of infertility, body mass index (BMI), waist or hip circumference, waist/hip ratio, LH, FSH, or LH/FSH ratio. The mean cycle day of hCG administration was 13.2 ± 1.76, which agrees with the results of Mitwally and Casper (14.2 ± 2.1) (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar). The mean number of days between completion of treatment with letrozole and the day of hCG administration was 6.2 ± 1.8 days. Letrozole has a short half-life (around 2 days), leading to lower negligible levels in the body around the time of ovulation and early embryogenesis period (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar).TABLE 1Clinical characteristics of letrozole responders and letrozole nonresponders.VariableResponders (n = 24)Nonresponders (n = 20)SignificanceAge (years)26.7 ± 4.2128.35 ± 4.36NSat test.Period of infertility (y)4.56 ± 3.295.05 ± 2.29NSat test.BMI (kg/m2)30.07 ± 3.2329.06 ± 3.59NSat test.Waist (cm)99 ± 9.5101 ± 8.41NSat test.Waist/hip ratio0.89 ± 0.040.90 ± 0.04NSat test.Menstrual pattern: Oligomenorrhea: no. (%)16 (66.66%)14 (70%)NSbχ2 tests. Amenorrhea: no. (%)8 (33.33%)6 (30%)NSbχ2 tests.Hirsutism: no. (%)15 (62.5%)13 (65%)NSbχ2 tests.LH (IU/mL)16.7 ± 3.2117.9 ± 3.65NSat test.FSH (IU/mL)6.5 ± 1.626.8 ± 1.81NSat test.LH/FSH ratio2.68 ± 0.482.66 ± 0.45NSat test.Note: NS = not significant; BMI = body mass index.Variables are given as mean ± SD.P = .05.Elnashar. Letrozole induction of ovulation. Fertil Steril 2006.a t test.b χ2 tests. Open table in a new tab Letrozole was well tolerated with no reported side effects. The mean number of mature follicles ≥18 mm on the day of hCG administration was 1.21 (range 1–2; 19 patients (79%) developed one mature follicle and 5 patients (21%) developed two mature follicles). This limited number of mature follicles with letrozole decreases the risk of multiple pregnancy and ovarian hyperstimulation syndrome. These results are in agreement with the results of Al-Omari et al. (10Al-Omari W. Al-Hadithi N. Izat B. Sulaiman W. The effect of an aromatase inhibitor on ovulation induction and endometrial receptivity in clomiphene resistant women with polycystic ovary syndrome.Mid East Fertil Soc J. 2001; 6: S2-S5Google Scholar) and Mitwally and Casper (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar). Therefore, letrozole treatment does not need intensive monitoring compared to CC and gonadotropins. The mean endometrial thickness on the day of hCG administration was adequate for implantation (10.2 ± 1.31 mm). Letrozole induces ovulation without down-regulation of estrogen receptors. This adverse endometrial effect seen with CC and prolonged by the relatively long half-life of CC (5 days) is not seen with letrozole. The mean cervical mucus score was 11.42 ± 2.48, indicating that letrozole, unlike CC, has no adverse antiestrogenic effect on the cervical mucus. These results are consistent with that of Metawie (11Metawie M.H. Comparative study of aromatase inhibitor, letrozole, with clomiphene citrate for induction of ovulation.Mid East Fertil Soc J. 2001; 6: S7-S9Google Scholar). Poor mucus at midcycle can be a physical barrier that decreases sperm penetration.Administration of letrozole in the early part of the menstrual cycle would release the pituitary/hypothalamic axis from the estrogenic negative feedback, similar to the effect of CC but without down-regulation of estrogen receptors, and the resulting increase in gonadotropin secretion could stimulate ovarian follicle development (1Lidor A.L. Goldenberg M. Cohen S.B. Seidman D.S. Mashiach S. Rabinovici J. Management of women with polycystic ovary syndrome who experienced premature luteinization during clomiphene citrate treatment.Fertil Steril. 2000; 74: 749-752Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). Also, letrozole may act locally on the ovary to increase the follicular sensitivity to FSH by blocking conversion of androgen substrate to estrogen, increasing the local androgen. The ovulation rate in this study is lower than that obtained by other studies using letrozole in ovulation induction. Mitwally and Casper (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar) had ovulatory rates of 75%, Al-Omari et al. (10Al-Omari W. Al-Hadithi N. Izat B. Sulaiman W. The effect of an aromatase inhibitor on ovulation induction and endometrial receptivity in clomiphene resistant women with polycystic ovary syndrome.Mid East Fertil Soc J. 2001; 6: S2-S5Google Scholar) had an ovulatory rate of 87.5%, and Metawie (11Metawie M.H. Comparative study of aromatase inhibitor, letrozole, with clomiphene citrate for induction of ovulation.Mid East Fertil Soc J. 2001; 6: S7-S9Google Scholar) had a rate of 92.5%. This may be explained by the small sample size, higher dose (5 mg daily), or repeated cycles of letrozole in the same patient in other studies.Pregnancy occurred in 6 patients; thus the percent of pregnancies per induced ovulatory cycle is 25%. This result is comparable with the results of Mitwally and Casper (25%), Al-Omari et al. (27.27%), and Metawie >17.5%) (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar, 10Al-Omari W. Al-Hadithi N. Izat B. Sulaiman W. The effect of an aromatase inhibitor on ovulation induction and endometrial receptivity in clomiphene resistant women with polycystic ovary syndrome.Mid East Fertil Soc J. 2001; 6: S2-S5Google Scholar, 11Metawie M.H. Comparative study of aromatase inhibitor, letrozole, with clomiphene citrate for induction of ovulation.Mid East Fertil Soc J. 2001; 6: S7-S9Google Scholar). All these pregnancies were singleton, which is consistent with the results of other studies. This may be due to the limited number of mature follicles compared to other methods of ovulation induction. The multiple pregnancy rate is approximately 10% with CC, almost entirely twins (12Kousta E. White D.M. Franks S. Modern use of clomiphene citrate in induction of ovulation.Hum Reprod Update. 1997; 3: 359-362Crossref PubMed Scopus (255) Google Scholar), 15%–25% with gonadotropins (13March C.M. Human menopausal gonadotropins.Infertil Reprod Med Clin North Am. 1990; 1: 59-78Google Scholar), and about 2% with laparoscopic ovarian drilling (14Felemban A. Tan S.L. Tulandi T. Laparoscopic treatment of polycystic ovary syndrome with insulated needle cautery, a reappraisal.Fertil Steril. 2000; 73: 266-269Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). Letrozole, as compared to laparoscopic ovarian drilling, has no risk of operative interference, such as anesthetic risk, adhesion formation, and possibility of ovarian destruction and premature ovarian failure (15Balen A.H. Jacobs H.S. A prospective study comparing unilateral and bilateral laparoscopic ovarian diathermy in women with the polycystic ovary syndrome.Fertil Steril. 1994; 62: 921-925Abstract Full Text PDF PubMed Scopus (121) Google Scholar).Comparing letrozole responders and nonresponders with regard to clinical and laboratory characteristics, there were no significant differences in BMI, waist or hip circumference, waist/hip ratio, hirsutism, LH, FSH, or LH/FSH ratio. Thus, letrozole can be given to all patients with CC resistance, because its efficacy is not limited to a specific abnormality. Achieving weight reduction is difficult, particularly as the metabolic status of patients with PCOS conspires against weight loss (16Kim L.H. Taylor A.E. Barbieri R.L. Insulin sensitizers and polycystic ovary syndrome can a diabetes medication treat infertility?.Fertil Steril. 2000; 73: 1097-1098Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Letrozole can be used in patients with hirsutism, and there is no need to add dexamethasone to reduce adrenal androgen production. Dexamethasone can worsen diabetic tendencies and as a result it may not be a suitable treatment for patients with diabetes, insulin resistance, or glucose intolerance, conditions present in many PCOS patients (3Speroff L. Glass R.H. Kase N.G. Hormone biosynthesis, metabolism, and mechanism of action.in: Clinical gynecologic endocrinology and infertility. 6th ed. Lippincott, Williams & Wilkins, Baltimore1999: 31-105Google Scholar). Letrozole can be used in case of high LH without the need to add oral contraceptives for pretreatment suppression of LH. Oral contraceptive pills exacerbate insulin resistance. Many PCOS patients are overweight, and obesity is a relative contraindication to oral contraceptive pills (17Sheu W.H. Hsu C.H. Chen Y.S. Jeng C.Y. Fuh M.M. Prospective evaluation of insulin resistance and lipid metabolism in women receiving the oral contraceptive.Clin Endocrinol. 1994; 40: 249-255Crossref PubMed Scopus (16) Google Scholar).In conclusion; induction of ovulation with letrozole in CC-resistant PCOS patients is associated with limited number of mature follicles, no adverse effect on endometrial thickness or cervical mucous, and ovulation and pregnancy in a significant number of patients. Induction with letrozole does not seem to depend on age, period of infertility, BMI, waist circumference, LH, FSH or LH/FSH ratio. The small sample size could be the reason for the failure to detect a significant difference between responders and nonresponders. Further larger studies are necessary to confirm our results. Clomiphene citrate (CC) is the traditional first-line treatment for chronic anovulation that characterizes polycystic ovary syndrome (PCOS) (1Lidor A.L. Goldenberg M. Cohen S.B. Seidman D.S. Mashiach S. Rabinovici J. Management of women with polycystic ovary syndrome who experienced premature luteinization during clomiphene citrate treatment.Fertil Steril. 2000; 74: 749-752Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). Clomiphene citrate is accumulated in the body with low clearance rate and long half-life (5 days). Significant plasma concentrations of the active zu-isomer of CC can be detected up to 6 weeks after administration. However, 20%–25% of PCOS women fail to ovulate with incremental doses of CC. In addition, clinical data revealed a discrepancy between ovulation rates (75%–80%) and conception rates (30%–40%) during CC treatment (2Yen S.S. Chronic anovulation caused by peripheral endocrine disorders.in: Yen S.S. Jaffe R.B. Reproductive endocrinology physiology, pathophysiology, and clinical management. 3rd ed. Saunders, Philadelphia1991: 576-630Google Scholar). For these patients who do not respond to CC, there are a few limited adjunctive therapies that can be tried before moving on to gonadotropin therapy or laparoscopic ovarian drilling, including bromocriptine (in the presence of hyperpolactinemia or galactorrhea), dexamethasone (to reduce adrenal androgen production), insulin sensitizers (to treat hyperinsulinemia), oral contraceptives (for pretreatment suppression of LH), pulsatile GnRH (to preserve physiologic interactive feedback), and extended doses of CC (3Speroff L. Glass R.H. Kase N.G. Hormone biosynthesis, metabolism, and mechanism of action.in: Clinical gynecologic endocrinology and infertility. 6th ed. Lippincott, Williams & Wilkins, Baltimore1999: 31-105Google Scholar). However, their usefulness is limited to specific abnormalities, because many women with CC failure do not present with any overt signs of a treatable disorder (4Branigan M.E. Estes A. Using oral contraceptives as a treatment for clomid-resistant patients.Fertil Steril. 1999; 71: 544-546Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). Mitwally and Casper (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar) reported the novel use of the aromatase inhibitor letrozole for inducing ovulation in anovulatory women with PCOS and for augmenting ovulation in ovulatory infertile women. Letrozole belongs to a new group of very potent nonsteroidal aromatase inhibitors that are rapidly absorbed from the gastrointestinal tract and excreted by the kidney. The elimination half-life of letrozole is about 2 days (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar). Our objective was to evaluate the efficacy of letrozole in induction of ovulation in cases of CC-resistant PCOS and to compare letrozole responders and nonresponders. Forty-four infertile women were included from the patients attending the outpatient clinic of Benha University Hospital. We obtained approval from the institutional research board to use an aromatase inhibitor for ovarian stimulation. All patients were diagnosed as having PCOS according to the Rotterdam criteria (6Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop GroupRevised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.Fertil Steril. 2004; 81: 19-25Scopus (0) Google Scholar). All patients had previously received CC and were diagnosed as having CC resistance (failure of ovulation after 6 cycles of CC reaching a dosage of 150 mg daily) (3Speroff L. Glass R.H. Kase N.G. Hormone biosynthesis, metabolism, and mechanism of action.in: Clinical gynecologic endocrinology and infertility. 6th ed. Lippincott, Williams & Wilkins, Baltimore1999: 31-105Google Scholar). Our inclusion criteria were age 18–39 years, period of infertility >2 years, serum level of FSH 8 (3Speroff L. Glass R.H. Kase N.G. Hormone biosynthesis, metabolism, and mechanism of action.in: Clinical gynecologic endocrinology and infertility. 6th ed. Lippincott, Williams & Wilkins, Baltimore1999: 31-105Google Scholar). Letrozole was started after two months of CC to allow for washout of the latter. Patients underwent physical examination. Weight, height, and waist and hip circumferences were measured. A transvaginal ultrasound examination was performed to exclude any pelvic pathology before treatment with letrozole. Ultrasonography was performed using a Sonoace 5500 with transvaginal transducer 6.5 MHz (Medison, Korea). In all patients, a dose of 2.5 mg of letrozole (Femara; Novartis, East Hanover, NJ) was given orally for 5 days starting from the third day of a spontaneous or progesterone-induced withdrawal bleeding (7Femara (letrozole) package insert. Novartis Pharmaceuticals, East Hanover (NJ)1999Google Scholar). Ovarian follicular response was monitored with transvaginal sonography starting one day after the last tablet of letrozole and thereafter according to the growth of the follicles (usually every other day). When at least one follicle reached >18 mm in diameter, 10,000 U hCG (Pregnyl; N.V. Organon, Oss, The Netherlands) was given intramuscularly, and timed intercourse was advised (3Speroff L. Glass R.H. Kase N.G. Hormone biosynthesis, metabolism, and mechanism of action.in: Clinical gynecologic endocrinology and infertility. 6th ed. Lippincott, Williams & Wilkins, Baltimore1999: 31-105Google Scholar). On the day of hCG administration, endometrial thickness was assessed according to Gonen and Casper (8Gonen Y. Casper R.F. Sonographic determination of an adverse effect of clomiphene citrate on endometrial growth.Hum Reprod. 1990; 5: 670-674Crossref PubMed Scopus (149) Google Scholar) and cervical mucus score was evaluated according to Moghissi (9Moghissi K.S. Postcoital test, physiologic basis, technique and interpretation.Fertil Steril. 1976; 27: 117-129Crossref PubMed Scopus (75) Google Scholar). Cervical mucus score was considered good if >10. Two days after giving hCG, the patients were assessed for ultrasonographic signs of ovulation. Clinical pregnancy was diagnosed when a gestational sac was detected on transvaginal ultrasound examination one week after the missed period. Every patient received one letrozole treatment cycle. During letrozole treatment, ovulation occurred in 24 cases (54.6%) and clinical pregnancy in 6 cases (25%). These pregnancies were singleton. There were no abortions. Table 1 shows the clinical characteristics of letrozole responders and nonresponders. There was no significant difference between the groups regarding age, period of infertility, body mass index (BMI), waist or hip circumference, waist/hip ratio, LH, FSH, or LH/FSH ratio. The mean cycle day of hCG administration was 13.2 ± 1.76, which agrees with the results of Mitwally and Casper (14.2 ± 2.1) (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar). The mean number of days between completion of treatment with letrozole and the day of hCG administration was 6.2 ± 1.8 days. Letrozole has a short half-life (around 2 days), leading to lower negligible levels in the body around the time of ovulation and early embryogenesis period (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar). Note: NS = not significant; BMI = body mass index. Variables are given as mean ± SD. P = .05. Elnashar. Letrozole induction of ovulation. Fertil Steril 2006. Letrozole was well tolerated with no reported side effects. The mean number of mature follicles ≥18 mm on the day of hCG administration was 1.21 (range 1–2; 19 patients (79%) developed one mature follicle and 5 patients (21%) developed two mature follicles). This limited number of mature follicles with letrozole decreases the risk of multiple pregnancy and ovarian hyperstimulation syndrome. These results are in agreement with the results of Al-Omari et al. (10Al-Omari W. Al-Hadithi N. Izat B. Sulaiman W. The effect of an aromatase inhibitor on ovulation induction and endometrial receptivity in clomiphene resistant women with polycystic ovary syndrome.Mid East Fertil Soc J. 2001; 6: S2-S5Google Scholar) and Mitwally and Casper (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar). Therefore, letrozole treatment does not need intensive monitoring compared to CC and gonadotropins. The mean endometrial thickness on the day of hCG administration was adequate for implantation (10.2 ± 1.31 mm). Letrozole induces ovulation without down-regulation of estrogen receptors. This adverse endometrial effect seen with CC and prolonged by the relatively long half-life of CC (5 days) is not seen with letrozole. The mean cervical mucus score was 11.42 ± 2.48, indicating that letrozole, unlike CC, has no adverse antiestrogenic effect on the cervical mucus. These results are consistent with that of Metawie (11Metawie M.H. Comparative study of aromatase inhibitor, letrozole, with clomiphene citrate for induction of ovulation.Mid East Fertil Soc J. 2001; 6: S7-S9Google Scholar). Poor mucus at midcycle can be a physical barrier that decreases sperm penetration. Administration of letrozole in the early part of the menstrual cycle would release the pituitary/hypothalamic axis from the estrogenic negative feedback, similar to the effect of CC but without down-regulation of estrogen receptors, and the resulting increase in gonadotropin secretion could stimulate ovarian follicle development (1Lidor A.L. Goldenberg M. Cohen S.B. Seidman D.S. Mashiach S. Rabinovici J. Management of women with polycystic ovary syndrome who experienced premature luteinization during clomiphene citrate treatment.Fertil Steril. 2000; 74: 749-752Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). Also, letrozole may act locally on the ovary to increase the follicular sensitivity to FSH by blocking conversion of androgen substrate to estrogen, increasing the local androgen. The ovulation rate in this study is lower than that obtained by other studies using letrozole in ovulation induction. Mitwally and Casper (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar) had ovulatory rates of 75%, Al-Omari et al. (10Al-Omari W. Al-Hadithi N. Izat B. Sulaiman W. The effect of an aromatase inhibitor on ovulation induction and endometrial receptivity in clomiphene resistant women with polycystic ovary syndrome.Mid East Fertil Soc J. 2001; 6: S2-S5Google Scholar) had an ovulatory rate of 87.5%, and Metawie (11Metawie M.H. Comparative study of aromatase inhibitor, letrozole, with clomiphene citrate for induction of ovulation.Mid East Fertil Soc J. 2001; 6: S7-S9Google Scholar) had a rate of 92.5%. This may be explained by the small sample size, higher dose (5 mg daily), or repeated cycles of letrozole in the same patient in other studies. Pregnancy occurred in 6 patients; thus the percent of pregnancies per induced ovulatory cycle is 25%. This result is comparable with the results of Mitwally and Casper (25%), Al-Omari et al. (27.27%), and Metawie >17.5%) (5Mitwally F.M. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar, 10Al-Omari W. Al-Hadithi N. Izat B. Sulaiman W. The effect of an aromatase inhibitor on ovulation induction and endometrial receptivity in clomiphene resistant women with polycystic ovary syndrome.Mid East Fertil Soc J. 2001; 6: S2-S5Google Scholar, 11Metawie M.H. Comparative study of aromatase inhibitor, letrozole, with clomiphene citrate for induction of ovulation.Mid East Fertil Soc J. 2001; 6: S7-S9Google Scholar). All these pregnancies were singleton, which is consistent with the results of other studies. This may be due to the limited number of mature follicles compared to other methods of ovulation induction. The multiple pregnancy rate is approximately 10% with CC, almost entirely twins (12Kousta E. White D.M. Franks S. Modern use of clomiphene citrate in induction of ovulation.Hum Reprod Update. 1997; 3: 359-362Crossref PubMed Scopus (255) Google Scholar), 15%–25% with gonadotropins (13March C.M. Human menopausal gonadotropins.Infertil Reprod Med Clin North Am. 1990; 1: 59-78Google Scholar), and about 2% with laparoscopic ovarian drilling (14Felemban A. Tan S.L. Tulandi T. Laparoscopic treatment of polycystic ovary syndrome with insulated needle cautery, a reappraisal.Fertil Steril. 2000; 73: 266-269Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). Letrozole, as compared to laparoscopic ovarian drilling, has no risk of operative interference, such as anesthetic risk, adhesion formation, and possibility of ovarian destruction and premature ovarian failure (15Balen A.H. Jacobs H.S. A prospective study comparing unilateral and bilateral laparoscopic ovarian diathermy in women with the polycystic ovary syndrome.Fertil Steril. 1994; 62: 921-925Abstract Full Text PDF PubMed Scopus (121) Google Scholar). Comparing letrozole responders and nonresponders with regard to clinical and laboratory characteristics, there were no significant differences in BMI, waist or hip circumference, waist/hip ratio, hirsutism, LH, FSH, or LH/FSH ratio. Thus, letrozole can be given to all patients with CC resistance, because its efficacy is not limited to a specific abnormality. Achieving weight reduction is difficult, particularly as the metabolic status of patients with PCOS conspires against weight loss (16Kim L.H. Taylor A.E. Barbieri R.L. Insulin sensitizers and polycystic ovary syndrome can a diabetes medication treat infertility?.Fertil Steril. 2000; 73: 1097-1098Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Letrozole can be used in patients with hirsutism, and there is no need to add dexamethasone to reduce adrenal androgen production. Dexamethasone can worsen diabetic tendencies and as a result it may not be a suitable treatment for patients with diabetes, insulin resistance, or glucose intolerance, conditions present in many PCOS patients (3Speroff L. Glass R.H. Kase N.G. Hormone biosynthesis, metabolism, and mechanism of action.in: Clinical gynecologic endocrinology and infertility. 6th ed. Lippincott, Williams & Wilkins, Baltimore1999: 31-105Google Scholar). Letrozole can be used in case of high LH without the need to add oral contraceptives for pretreatment suppression of LH. Oral contraceptive pills exacerbate insulin resistance. Many PCOS patients are overweight, and obesity is a relative contraindication to oral contraceptive pills (17Sheu W.H. Hsu C.H. Chen Y.S. Jeng C.Y. Fuh M.M. Prospective evaluation of insulin resistance and lipid metabolism in women receiving the oral contraceptive.Clin Endocrinol. 1994; 40: 249-255Crossref PubMed Scopus (16) Google Scholar). In conclusion; induction of ovulation with letrozole in CC-resistant PCOS patients is associated with limited number of mature follicles, no adverse effect on endometrial thickness or cervical mucous, and ovulation and pregnancy in a significant number of patients. Induction with letrozole does not seem to depend on age, period of infertility, BMI, waist circumference, LH, FSH or LH/FSH ratio. The small sample size could be the reason for the failure to detect a significant difference between responders and nonresponders. Further larger studies are necessary to confirm our results.