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Aromatase inhibitors in women with clomiphene citrate resistance: a randomized, double-blind, placebo-controlled trial
Aromatase inhibitors in women with clomiphene citrate resistance: a randomized, double-blind, placebo-controlled trial In 36 women with polycystic ovary syndrome and clomiphene citrate resistance, letrozole, an aromatase inhibitor, statistically significantly increased the ovulation rate by 33.3% in the treatment group, indicating that letrozole can be used as an effective and simple alternate ovulation-inducing agent in these women. (Fertil Steril 2010;94: 2857–9. 2010 by American Society for Reproductive Medicine.) Key Words: Aromatase inhibitor, letrozole, clomiphene resistance
Disorders of ovulation are a frequent cause of infertility, with polycystic ovary syndrome (PCOS) being the most common cause (1). Clomiphene citrate remains the standard first-line drug for inducing ovulation in these women. However, 20% to 25% of women with PCOS do not respond to increasing doses of clomiphene, and they are labeled as clomiphene resistant (2). Treatment options available for these women are either surgical (laparoscopic ovarian drilling) or medical (gonadotropins or insulin sensitizers). Surgical measures have a temporary effect and may be associated with complications such as pelvic adhesions or extensive ovarian destruction (3, 4). Gonadotropins are expensive and can cause multifollicular development, resulting in high-order pregnancies or ovarian hyperstimulation syndrome (5). The actual benefit of insulin sensitizers is currently debated (6). Aromatase inhibitors have been advocated as an inexpensive, effective treatment option for anovulatory women with clomiphene resistance (7). The enzyme aromatase catalyses the conversion of androgens to estrogens; inhibition of this enzyme results in low estrogen levels, thus releasing the higher centers from a negative feedback effect. Rising follicle-stimulating hormone (FSH) levels cause follicular stimulation and subsequent ovulation. Elevated androgen levels in the ovary are believed to be beneficial because they increase sensitivity to FSH (8). Mohan S. Kamath, M.S., D.N.B. T. K. Aleyamma, M.D., D.N.B. Achamma Chandy, D.G.O. Korula George, M.D., M.R.A.C.O.G. Reproductive Medicine Unit, Christian Medical College, Vellore, Tamil Nadu, India Received February 23, 2010; revised June 4, 2010; accepted June 5, 2010; published online July 17, 2010. M.S.K. has nothing to disclose. T.K.A. has nothing to disclose. A.C. has nothing to disclose. K.G. has nothing to disclose. Drug and placebo tablets provided by Sun Pharmaceuticals Pvt. Ltd., Mumbai, India. Reprint requests: Korula George, M.D., M.R.A.C.O.G., Reproductive Medicine Unit, Christian Medical College, Ida Scudder Road, Vellore, Tamil Nadu, India 632004 (FAX: 91-04162232103; E-mail: gkorula@ gmail.com).
0015-0282/$36.00 doi:10.1016/j.fertnstert.2010.06.008
Letrozole, an aromatase inhibitor that is highly potent, selective, competitive, and reversible in action, does not have a negative effect on the endometrium or cervical mucus (9). We evaluated the efficacy of letrozole as an ovulation-inducing agent in women with PCOS and clomiphene resistance. All consecutive women with PCOS and clomiphene resistance who were being treated in our unit with ovulation induction were invited to participate. The diagnosis of PCOS was made in accordance with the revised 2003 Rotterdam criteria (10). All of the women were found to have PCOS based on chronic anovulation and the ultrasound appearance of their ovaries. They were not tested for hyperandrogenism. Clomiphene resistance was defined as failure to ovulate in response to a dose of 200 mg of clomiphene citrate per day (2). Women with a normal hormone profile and a male partner with normal semen parameters by World Health Organization criteria (11) were recruited. The normal hormone profile was defined as a FSH level of <12 IU/L, serum prolactin level of <25 ng/mL, and a thyroid-stimulating hormone (TSH) value between 0.3 and 4.5 mIU/mL. Women with other endocrine disorders such as Cushing syndrome and congenital adrenal hyperplasia were excluded. All of the women entering the trial underwent a 2-month clomiphene washout period, and they were then randomly distributed, using a computer-generated randomization sequence in blocks of six, into two groups. Allocation concealment was done by using consecutively numbered sealed opaque envelopes containing the treatment packets. Treatment packets prepared by the pharmacy department contained either five tablets of letrozole, 2.5 mg (Letoval; Sun Pharmaceutical Industries Ltd., Mumbai, India), or an identically packed placebo that was similar to the treatment drug in size, shape, weight, color, and number. Women were instructed to take one tablet daily on days 2 to 6 of the menstrual cycle and to present for transvaginal ultrasound evaluation on day 12 of the cycle. Each cycle was monitored for follicle development and ovulation by transvaginal ultrasound and measuring day-21 serum progesterone levels. A serum progesterone value >25 nmol/L was taken as indicative of ovulation (12). Endometrial thickness, defined as the maximum distance between the echogenic
Fertility and Sterility Vol. 94, No. 7, December 2010 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.
2857
TABLE 1 Patient characteristics and clinical outcomes in the letrozole and placebo groups.
Age (y)a Infertility duration (y)a BMI (kg/m2)a FSH (mIU/mL)a Ovulation rate (%)b Endometrial thickness (mm)a Day-21 serum progesterone (nmol/L)a No. of patients with mature follicle (%) Clinical pregnancy rate (%) Live-birth rate (%)
Letrozole group n [ 18
Placebo group n [ 18
P value
25.61 3.583 5.17 3.167 26.06 3.733 6.05 1.925 6/18 (33.33) 7.81 1.187 24.42 32.17 5/18 (27.77) 1/18 (5.55) 1/18 (5.55)
25.72 3.723 3.56 2.148 24.67 4.144 7.01 1.639 0 7.40 2.014 1.66 0.925 0 0 0
.928 .083 .298 .119 .006 .467 .014 .015 .324 .324
Notes: BMI ¼ body mass index; FSH ¼ follicle-stimulating hormone. a Values are mean standard deviation (SD). b Ovulation: D21 progesterone >25 nmol/L. Kamath. Correspondence. Fertil Steril 2010.
interfaces of the myometrium, was measured through the central longitudinal axis plane of the uterus. Frequent intercourse was advised for the couple when at least one dominant follicle (>17 mm) was detected on ultrasound. Serum b-human chorionic gonadotropin (b-hCG) was estimated 2 weeks later in the absence of menses. Women with a positive b-hCG (>25 IU/mL) concentration were advised to undergo a transvaginal ultrasound 2 weeks later to confirm clinical pregnancy (intrauterine gestational sac) and fetal viability (presence of cardiac activity). All women who entered the study underwent a single cycle of stimulation only. The primary outcome was the ovulation rate, and secondary outcome measures included the clinical pregnancy, live-birth, and miscarriage rates. Our literature review pointed to a 75% ovulation rate when 2.5 mg of letrozole was used in women with PCOS who had clomiphene resistance (7).We hypothesized an ovulation rate of 60% with letrozole and 10% with placebo. On this basis, a sample size of 17 women in each arm (80% power and alpha .05 for a two-sided test) was calculated. The data were analyzed using SPSS 11.5 (SPSS, Inc., Chicago, IL). Student’s t-test was used for continuous data and the chisquare test for categorical data. P<.05 was considered statistically significant. Analysis was performed on an intention-to-treat basis. The protocol of the study was approved by the institutional review board, and written informed consent was obtained from each patient. The trial was registered with the clinical trial registry of India. This trial was conducted in a university teaching hospital between 2007 and 2009. The randomization code was maintained by the pharmacy department, which revealed the group assignments at the end of the trial. The code was revealed after the statistical analysis had been performed. Of the 42 women found to be eligible for the trial, six women declined to participate. Thirty-six women were enrolled and randomized, with 18 in each arm. After randomization, two women (one from each group) did not return for follicular monitoring and were lost to follow-up evaluation. Data from the remaining 34 women were available for analysis.
2858
Kamath et al.
Correspondence
Table 1 shows the patient characteristics as well as the outcome parameters. The baseline clinical and endocrine characteristics of both the groups were similar, with no statistically significant differences being observed between the two groups. There was a statistically significant difference in the ovulation rate between the two groups: six women in the letrozole group ovulated as compared with none in the placebo group (P¼.006). There was one clinical pregnancy in the letrozole group, which went to term; a healthy girl baby weighing 3.1 kg was delivered, giving a live-birth rate of 5.55%. No other pregnancies were recorded. Clomiphene is ineffective in 20% to 25% of women with PCOS being treated for anovulatory infertility. In these women, letrozole has been reported to be of benefit, with an ovulation rate of 75% and a comparatively better endometrial thickness and pattern (7). Although the suspected association of aromatase inhibitors with fetal malformations has been assuaged by subsequent studies, it resulted in letrozole being inadequately studied (13, 14). Clomiphene resistance is an important management issue, and it requires proper evaluation of simple and inexpensive treatment options. Our study design was chosen because letrozole has not been adequately evaluated and we felt that comparison with other intensive therapeutic options such as ovarian drilling or gonadotropins would not establish its role in clomiphene-resistant women. Our sample size was calculated based on a conservative estimate of the ovulation rate in the initial reports (15, 16). The physician, participants, and outcome assessor were all blinded, with the drugs code being revealed only after study completion and statistical analysis. Confounding variables, both clinical and endocrinologic, were evenly distributed among the two groups (Table 1). There was a statistically significant difference between the two groups in the follicular development rate, in favor of the letrozole group (5 out of 18 vs. 0 out of 18; P¼.015). One of the patients in the treatment group had an ovulatory range of serum progesterone even though a mature follicle was not documented on day 12 by transvaginal ultrasound. Early rupture of the follicle could explain the disparity in the radiologic and biochemical findings.
Vol. 94, No. 7, December 2010
The midluteal serum progesterone levels were also statistically significantly higher in the letrozole group (24.42 32.17 vs. 1.66 0.925 nmol/L; P¼.014). We obtained an ovulation rate of 33.33% in the letrozole group, which was lower than the rates that had been reported by other studies: 54% to 87% (7, 15, 16). This may be explained by either their use of a higher drug dose (5 mg) or repetitive cycles. There was no statistically significant difference between the two groups when endometrial thickness was evaluated, and all women in the letrozole group had an endometrial thickness of more than 5 mm, indicating that letrozole is not associated with endometrial thinning. (7.81 1.187 vs. 7.40 2.014 mm; P¼.467). Monofollicular development was observed in the letrozole group, which is consistent with other reports (15). In all of the studies, including ours, singleton pregnancies were observed (7, 15). This is consistent with the mechanism of action of letrozole, which allows the negative feedback of rising estrogen, favoring a monofollicular development. No side effects such as cyst formation were noticed in our study.
The limitations of our study include the small sample size and the observed response. Although the estimated 50% difference in the ovulatory rate between the two groups was not observed in our study, we were able to demonstrate a statistically significant difference in the ovulatory rate. Although it is unlikely, it is possible that the women in whom ovulation was not detected by our methods could have ovulated at a later date. If this were true, it would influence the primary outcome of our study. No difference was observed in the endometrial thickness between the two groups, which may reflect the continued estrogenic activity seen in women with PCOS. To the best of our knowledge, ours is the first randomized, controlled trial comparing letrozole as an ovulation induction agent with a placebo in clomiphene-resistant women with PCOS. Using 2.5 mg of letrozole we achieved an ovulation rate of 33.33%. We feel there is a need for a larger study, perhaps using a higher drug dose that could result in better ovulation and pregnancy rates. Although it is small, this study provides information for future planning, as aromatase inhibitors could possibly play an important role as an effective alternative in clomiphene-resistant women.
REFERENCES 1. Kovacs G, Wood C. The current status of polycystic ovary syndrome. Aust NZ J Obstet Gynecol 2001;41:65–8. 2. Mitwally MF, Kuscu NK, Yalcinkaya TM. High ovulatory rates in case of troglitazone in clomiphene-resistant women with polycystic ovary syndrome. Hum Reprod 1999;14:2700–3. 3. Greenblatt EM, Casper RF. Adhesion formation after laparoscopic ovarian cautery for polycystic ovarian syndrome: lack of correlation with pregnancy rates. Fertil Steril 1993;60:766–70. 4. Felemban A, Tan SL, Tulandi T. Laparoscopic treatment of polycystic ovaries with insulated needle cautery: a reappraisal. Fertil Steril 2000;73:266–9. 5. Homburg R, Howles CM. Low dose FSH therapy for anovulatory infertility associated polycystic ovary syndrome: rationale, results, reflection and refinements. Hum Reprod Update 1999;5:493–9. 6. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitizing drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhea and subfertility. Cochrane Database Syst Rev 2009;4: CD003053.
Fertility and Sterility
7. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001;75:305–9. 8. Mitwally M, Casper R. Aromatase inhibitors in ovulation induction. Semin Reprod Med 2004;22: 61–78. 9. Young SL, Opsahl MS, Fritz MA. Serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile women. Fertil Steril 1999;71:639–44. 10. Rotterdam ESHRE/ASRM Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19–25. 11. World Health Organization. Laboratory manual for the examination of human semen and semencervical mucus interaction. 3rd ed. New York: Cambridge University Press, 1992: 3–4. 12. Amer SA, Li TC, Metwally M, Emarh M, Ledger WL. Randomized controlled trial comparing laparoscopic ovarian diathermy with
13.
14.
15.
16.
clomiphene citrate as a first-line method of ovulation induction in women with polycystic ovary syndrome. Hum Reprod 2009;24:219–25. Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;85:1761–5. Biljan MM, Hemming R, Brassard N. The outcome of 150 babies following treatment with letrozole or letrozole with gonadotrophins. Fertil Steril 2005;84(Suppl 1):O-231, Abstract-1033. Elnashar A, Fouad H, Eldosky M, Saeid N. 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. Fertil Steril 2006;85:511–3. Al-Omari WR, Sulaiman W, Al-Hadithi N. Comparison of two aromatase inhibitors in women with clomiphene-resistant polycystic ovary syndrome. Intern J Gynecol Obstet 2004;85: 289–91.
2859
Disorders of ovulation are a frequent cause of infertility, with polycystic ovary syndrome (PCOS) being the most common cause (1). Clomiphene citrate remains the standard first-line drug for inducing ovulation in these women. However, 20% to 25% of women with PCOS do not respond to increasing doses of clomiphene, and they are labeled as clomiphene resistant (2). Treatment options available for these women are either surgical (laparoscopic ovarian drilling) or medical (gonadotropins or insulin sensitizers). Surgical measures have a temporary effect and may be associated with complications such as pelvic adhesions or extensive ovarian destruction (3, 4). Gonadotropins are expensive and can cause multifollicular development, resulting in high-order pregnancies or ovarian hyperstimulation syndrome (5). The actual benefit of insulin sensitizers is currently debated (6). Aromatase inhibitors have been advocated as an inexpensive, effective treatment option for anovulatory women with clomiphene resistance (7). The enzyme aromatase catalyses the conversion of androgens to estrogens; inhibition of this enzyme results in low estrogen levels, thus releasing the higher centers from a negative feedback effect. Rising follicle-stimulating hormone (FSH) levels cause follicular stimulation and subsequent ovulation. Elevated androgen levels in the ovary are believed to be beneficial because they increase sensitivity to FSH (8). Mohan S. Kamath, M.S., D.N.B. T. K. Aleyamma, M.D., D.N.B. Achamma Chandy, D.G.O. Korula George, M.D., M.R.A.C.O.G. Reproductive Medicine Unit, Christian Medical College, Vellore, Tamil Nadu, India Received February 23, 2010; revised June 4, 2010; accepted June 5, 2010; published online July 17, 2010. M.S.K. has nothing to disclose. T.K.A. has nothing to disclose. A.C. has nothing to disclose. K.G. has nothing to disclose. Drug and placebo tablets provided by Sun Pharmaceuticals Pvt. Ltd., Mumbai, India. Reprint requests: Korula George, M.D., M.R.A.C.O.G., Reproductive Medicine Unit, Christian Medical College, Ida Scudder Road, Vellore, Tamil Nadu, India 632004 (FAX: 91-04162232103; E-mail: gkorula@ gmail.com).
0015-0282/$36.00 doi:10.1016/j.fertnstert.2010.06.008
Letrozole, an aromatase inhibitor that is highly potent, selective, competitive, and reversible in action, does not have a negative effect on the endometrium or cervical mucus (9). We evaluated the efficacy of letrozole as an ovulation-inducing agent in women with PCOS and clomiphene resistance. All consecutive women with PCOS and clomiphene resistance who were being treated in our unit with ovulation induction were invited to participate. The diagnosis of PCOS was made in accordance with the revised 2003 Rotterdam criteria (10). All of the women were found to have PCOS based on chronic anovulation and the ultrasound appearance of their ovaries. They were not tested for hyperandrogenism. Clomiphene resistance was defined as failure to ovulate in response to a dose of 200 mg of clomiphene citrate per day (2). Women with a normal hormone profile and a male partner with normal semen parameters by World Health Organization criteria (11) were recruited. The normal hormone profile was defined as a FSH level of <12 IU/L, serum prolactin level of <25 ng/mL, and a thyroid-stimulating hormone (TSH) value between 0.3 and 4.5 mIU/mL. Women with other endocrine disorders such as Cushing syndrome and congenital adrenal hyperplasia were excluded. All of the women entering the trial underwent a 2-month clomiphene washout period, and they were then randomly distributed, using a computer-generated randomization sequence in blocks of six, into two groups. Allocation concealment was done by using consecutively numbered sealed opaque envelopes containing the treatment packets. Treatment packets prepared by the pharmacy department contained either five tablets of letrozole, 2.5 mg (Letoval; Sun Pharmaceutical Industries Ltd., Mumbai, India), or an identically packed placebo that was similar to the treatment drug in size, shape, weight, color, and number. Women were instructed to take one tablet daily on days 2 to 6 of the menstrual cycle and to present for transvaginal ultrasound evaluation on day 12 of the cycle. Each cycle was monitored for follicle development and ovulation by transvaginal ultrasound and measuring day-21 serum progesterone levels. A serum progesterone value >25 nmol/L was taken as indicative of ovulation (12). Endometrial thickness, defined as the maximum distance between the echogenic
Fertility and Sterility Vol. 94, No. 7, December 2010 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.
2857
TABLE 1 Patient characteristics and clinical outcomes in the letrozole and placebo groups.
Age (y)a Infertility duration (y)a BMI (kg/m2)a FSH (mIU/mL)a Ovulation rate (%)b Endometrial thickness (mm)a Day-21 serum progesterone (nmol/L)a No. of patients with mature follicle (%) Clinical pregnancy rate (%) Live-birth rate (%)
Letrozole group n [ 18
Placebo group n [ 18
P value
25.61 3.583 5.17 3.167 26.06 3.733 6.05 1.925 6/18 (33.33) 7.81 1.187 24.42 32.17 5/18 (27.77) 1/18 (5.55) 1/18 (5.55)
25.72 3.723 3.56 2.148 24.67 4.144 7.01 1.639 0 7.40 2.014 1.66 0.925 0 0 0
.928 .083 .298 .119 .006 .467 .014 .015 .324 .324
Notes: BMI ¼ body mass index; FSH ¼ follicle-stimulating hormone. a Values are mean standard deviation (SD). b Ovulation: D21 progesterone >25 nmol/L. Kamath. Correspondence. Fertil Steril 2010.
interfaces of the myometrium, was measured through the central longitudinal axis plane of the uterus. Frequent intercourse was advised for the couple when at least one dominant follicle (>17 mm) was detected on ultrasound. Serum b-human chorionic gonadotropin (b-hCG) was estimated 2 weeks later in the absence of menses. Women with a positive b-hCG (>25 IU/mL) concentration were advised to undergo a transvaginal ultrasound 2 weeks later to confirm clinical pregnancy (intrauterine gestational sac) and fetal viability (presence of cardiac activity). All women who entered the study underwent a single cycle of stimulation only. The primary outcome was the ovulation rate, and secondary outcome measures included the clinical pregnancy, live-birth, and miscarriage rates. Our literature review pointed to a 75% ovulation rate when 2.5 mg of letrozole was used in women with PCOS who had clomiphene resistance (7).We hypothesized an ovulation rate of 60% with letrozole and 10% with placebo. On this basis, a sample size of 17 women in each arm (80% power and alpha .05 for a two-sided test) was calculated. The data were analyzed using SPSS 11.5 (SPSS, Inc., Chicago, IL). Student’s t-test was used for continuous data and the chisquare test for categorical data. P<.05 was considered statistically significant. Analysis was performed on an intention-to-treat basis. The protocol of the study was approved by the institutional review board, and written informed consent was obtained from each patient. The trial was registered with the clinical trial registry of India. This trial was conducted in a university teaching hospital between 2007 and 2009. The randomization code was maintained by the pharmacy department, which revealed the group assignments at the end of the trial. The code was revealed after the statistical analysis had been performed. Of the 42 women found to be eligible for the trial, six women declined to participate. Thirty-six women were enrolled and randomized, with 18 in each arm. After randomization, two women (one from each group) did not return for follicular monitoring and were lost to follow-up evaluation. Data from the remaining 34 women were available for analysis.
2858
Kamath et al.
Correspondence
Table 1 shows the patient characteristics as well as the outcome parameters. The baseline clinical and endocrine characteristics of both the groups were similar, with no statistically significant differences being observed between the two groups. There was a statistically significant difference in the ovulation rate between the two groups: six women in the letrozole group ovulated as compared with none in the placebo group (P¼.006). There was one clinical pregnancy in the letrozole group, which went to term; a healthy girl baby weighing 3.1 kg was delivered, giving a live-birth rate of 5.55%. No other pregnancies were recorded. Clomiphene is ineffective in 20% to 25% of women with PCOS being treated for anovulatory infertility. In these women, letrozole has been reported to be of benefit, with an ovulation rate of 75% and a comparatively better endometrial thickness and pattern (7). Although the suspected association of aromatase inhibitors with fetal malformations has been assuaged by subsequent studies, it resulted in letrozole being inadequately studied (13, 14). Clomiphene resistance is an important management issue, and it requires proper evaluation of simple and inexpensive treatment options. Our study design was chosen because letrozole has not been adequately evaluated and we felt that comparison with other intensive therapeutic options such as ovarian drilling or gonadotropins would not establish its role in clomiphene-resistant women. Our sample size was calculated based on a conservative estimate of the ovulation rate in the initial reports (15, 16). The physician, participants, and outcome assessor were all blinded, with the drugs code being revealed only after study completion and statistical analysis. Confounding variables, both clinical and endocrinologic, were evenly distributed among the two groups (Table 1). There was a statistically significant difference between the two groups in the follicular development rate, in favor of the letrozole group (5 out of 18 vs. 0 out of 18; P¼.015). One of the patients in the treatment group had an ovulatory range of serum progesterone even though a mature follicle was not documented on day 12 by transvaginal ultrasound. Early rupture of the follicle could explain the disparity in the radiologic and biochemical findings.
Vol. 94, No. 7, December 2010
The midluteal serum progesterone levels were also statistically significantly higher in the letrozole group (24.42 32.17 vs. 1.66 0.925 nmol/L; P¼.014). We obtained an ovulation rate of 33.33% in the letrozole group, which was lower than the rates that had been reported by other studies: 54% to 87% (7, 15, 16). This may be explained by either their use of a higher drug dose (5 mg) or repetitive cycles. There was no statistically significant difference between the two groups when endometrial thickness was evaluated, and all women in the letrozole group had an endometrial thickness of more than 5 mm, indicating that letrozole is not associated with endometrial thinning. (7.81 1.187 vs. 7.40 2.014 mm; P¼.467). Monofollicular development was observed in the letrozole group, which is consistent with other reports (15). In all of the studies, including ours, singleton pregnancies were observed (7, 15). This is consistent with the mechanism of action of letrozole, which allows the negative feedback of rising estrogen, favoring a monofollicular development. No side effects such as cyst formation were noticed in our study.
The limitations of our study include the small sample size and the observed response. Although the estimated 50% difference in the ovulatory rate between the two groups was not observed in our study, we were able to demonstrate a statistically significant difference in the ovulatory rate. Although it is unlikely, it is possible that the women in whom ovulation was not detected by our methods could have ovulated at a later date. If this were true, it would influence the primary outcome of our study. No difference was observed in the endometrial thickness between the two groups, which may reflect the continued estrogenic activity seen in women with PCOS. To the best of our knowledge, ours is the first randomized, controlled trial comparing letrozole as an ovulation induction agent with a placebo in clomiphene-resistant women with PCOS. Using 2.5 mg of letrozole we achieved an ovulation rate of 33.33%. We feel there is a need for a larger study, perhaps using a higher drug dose that could result in better ovulation and pregnancy rates. Although it is small, this study provides information for future planning, as aromatase inhibitors could possibly play an important role as an effective alternative in clomiphene-resistant women.
REFERENCES 1. Kovacs G, Wood C. The current status of polycystic ovary syndrome. Aust NZ J Obstet Gynecol 2001;41:65–8. 2. Mitwally MF, Kuscu NK, Yalcinkaya TM. High ovulatory rates in case of troglitazone in clomiphene-resistant women with polycystic ovary syndrome. Hum Reprod 1999;14:2700–3. 3. Greenblatt EM, Casper RF. Adhesion formation after laparoscopic ovarian cautery for polycystic ovarian syndrome: lack of correlation with pregnancy rates. Fertil Steril 1993;60:766–70. 4. Felemban A, Tan SL, Tulandi T. Laparoscopic treatment of polycystic ovaries with insulated needle cautery: a reappraisal. Fertil Steril 2000;73:266–9. 5. Homburg R, Howles CM. Low dose FSH therapy for anovulatory infertility associated polycystic ovary syndrome: rationale, results, reflection and refinements. Hum Reprod Update 1999;5:493–9. 6. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitizing drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhea and subfertility. Cochrane Database Syst Rev 2009;4: CD003053.
Fertility and Sterility
7. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001;75:305–9. 8. Mitwally M, Casper R. Aromatase inhibitors in ovulation induction. Semin Reprod Med 2004;22: 61–78. 9. Young SL, Opsahl MS, Fritz MA. Serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile women. Fertil Steril 1999;71:639–44. 10. Rotterdam ESHRE/ASRM Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19–25. 11. World Health Organization. Laboratory manual for the examination of human semen and semencervical mucus interaction. 3rd ed. New York: Cambridge University Press, 1992: 3–4. 12. Amer SA, Li TC, Metwally M, Emarh M, Ledger WL. Randomized controlled trial comparing laparoscopic ovarian diathermy with
13.
14.
15.
16.
clomiphene citrate as a first-line method of ovulation induction in women with polycystic ovary syndrome. Hum Reprod 2009;24:219–25. Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;85:1761–5. Biljan MM, Hemming R, Brassard N. The outcome of 150 babies following treatment with letrozole or letrozole with gonadotrophins. Fertil Steril 2005;84(Suppl 1):O-231, Abstract-1033. Elnashar A, Fouad H, Eldosky M, Saeid N. 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. Fertil Steril 2006;85:511–3. Al-Omari WR, Sulaiman W, Al-Hadithi N. Comparison of two aromatase inhibitors in women with clomiphene-resistant polycystic ovary syndrome. Intern J Gynecol Obstet 2004;85: 289–91.
2859