• Users Online: 877
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Archives Submit article Instructions Referee Resource Subscribe


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 2  |  Page : 93-97

A prospective, randomized trial comparing the effects of letrozole versus clomiphene citrate for induction of ovulation and pregnancy rate in women with polycystic ovary syndrome


Department of Gynecology and Infertility, MAGS Medical and Research Center, West Bengal, Kolkata, India

Date of Web Publication16-Nov-2017

Correspondence Address:
Dipanshu Sur
Department of Gynecology & Infertility, MAGS Medical & Research Center, West Bengal, Kolkata-700091
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/fsr.fsr_10_17

Rights and Permissions
  Abstract 

Objective: To compare the effects of letrozole and clomiphene citrate (CC) for ovulation induction in women with polycystic ovary syndrome (PCOS).
Design: Prospective, randomized, not blinded, controlled trial.
Materials and Methods: This prospective, randomized clinical trial included 127 patients of infertile women with PCOS. The first group comprised 66 patients who received letrozole (2.5–5 mg) daily and the second group 61 patients who received (50–100 mg) CC daily for 5 days starting on day 3 of menses. Both the groups were followed by ultrasound until the dominant follicle reached a diameter ≥18 mm, human chorionic gonadotropin (hCG) 10,000 IU was given, and timed intercourse was advised. The treatment continued for three cycles in both the groups.
Main Outcome Measures: Occurrence of ovulation, endometrial thickness, and pregnancy rate.
Results: The mean age, duration of infertility, body weight, body mass index, and endocrine status in both the groups were similar at baseline. The total number of follicles during stimulation was statistically significantly greater in the letrozole group (6.81 ± 1.0 vs. 6.1 ± 1.5; P = 0.002). The number of follicles ≥18 mm was statistically significantly higher in the letrozole group compared with the CC group. There was no statistically significant difference in pretreatment endometrial thickness between the two groups, but endometrial thickness at the time of hCG administration was statistically significantly greater in the letrozole group (9.82 ± 0.7 vs. 8.13 ± 0.56; <0.0001). Ovulation occurred in 25 subjects (37.87%) in the letrozole group and 13 (19.67%) in the CC group, with a statistically significant difference between the two groups (P = 0.024). Serum E2 concentrations were statistically significantly lower in the letrozole group (P = 0.001).
Conclusion: The effect of letrozole showed a better endometrial response and ovulation rate compared with CC. Letrozole may have a role as a first-line treatment for anovulatory patients with PCOS.

Keywords: Clomiphene citrate, letrozole, PCOS, pregnancy


How to cite this article:
Chakravorty R, Athwal A, Sur D, Saha R. A prospective, randomized trial comparing the effects of letrozole versus clomiphene citrate for induction of ovulation and pregnancy rate in women with polycystic ovary syndrome. Fertil Sci Res 2016;3:93-7

How to cite this URL:
Chakravorty R, Athwal A, Sur D, Saha R. A prospective, randomized trial comparing the effects of letrozole versus clomiphene citrate for induction of ovulation and pregnancy rate in women with polycystic ovary syndrome. Fertil Sci Res [serial online] 2016 [cited 2020 Feb 19];3:93-7. Available from: http://www.fertilityscienceresearch.org/text.asp?2016/3/2/93/218542




  Introduction Top


It is now well known that polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in women of reproductive age and has a strong genetic component. It is characterized by ovarian dysfunction, and its clinical manifestations may include obesity, increased insulin resistance and compensatory hyperinsulinemia, oligo-/anovulation, and infertility.[1] It has been recognized that PCOS has an extremely heterogeneous clinical picture and is multifactorial in etiology. PCOS may represent the largest under-appreciated segment of the female population at risk of infertility. The pathophysiology is complex involving the hypothalamo–pituitary–ovarian axis, ovarian theca cell hyperplasia, hyperinsulinemia, and a multitude of other cytokine and adipocyte-driven factors. The diagnosis of PCOS is based on the Rotterdam criteria for the presence of any two of the following conditions: (i) chronic anovulation, (ii) clinical/biochemical parameters for hyperandrogenism, and (iii) polycystic ovaries on ultrasonography.[2] Infertility is a unique medical condition, in that it is a disorder that often involves a couple, not an individual. An infertile couple is one that has been unable to conceive in one year of unprotected intercourse. It is subdivided into primary and secondary.[3] Primary infertility applies to those who have never conceived while secondary infertility is designated to those who have conceived at some time in the past. Clomiphene citrate (CC) is still the standard drug for inducing or augmenting ovulation. It is not, however, equally successful in all situations. Clomiphene resistance, which refers to the persistence of anovulation after standard CC therapy, occurs in 15–20% of the patients.[4] In addition, CC may have a negative effect on the cervical mucus and endometrium. Treatment with CC is associated with a discrepancy between ovulation and conception rates, and the incidence of miscarriage has been claimed to be higher than in the general population.[4],[5] Alternative treatments to CC with insulin-sensitizing drugs such as letrozole have attracted attention. Letrozole is an aromatase inhibitor that has been widely used in women with breast cancer.[6] It works by suppressing estrogen production, and has been used to induce ovulation. But does letrozole add anything to the art of ovulation induction and represent a real alternative to CC?

The aim of the study is to compare between the use of letrozole and CC in women with polycystic ovaries undergoing ovarian stimulation and to evaluate the pregnancy rate (PR) between the two groups.


  Materials and methods Top


This prospective clinical trial was conducted at the infertility center of MAGS Medical & Research Center, Kolkata, India. A written informed consent was obtained from all the participants. One hundred and twenty-seven infertile women were selected from those who were attending the infertility center with primary infertility.

All patients were diagnosed as having anovulation due to PCOS. PCOS were diagnosed when the ultrasonography findings of the ovaries were more than 10 follicles 2–8 mm in diameter scattered either around or through an echo-dense thickened central stroma were present plus one or more of the following: oligomenorrhea, positive progesterone, withdrawal bleeding, hirsutism/acne, obesity, and raised luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratio more than two or raised circulating androgen. All patients have documented at least one patent  Fallopian tube More Details by either hysterosalpingogram or laparoscopy, and history of pelvic surgery with tubal blockage was excluded from the study. The male partners had to have a normal seminal analysis by World Health Organization (WHO) (2010) criteria. The patients were examined clinically. Their weight, height, and body mass index (BMI) were estimated. Transvaginal ultrasonography (U/S) examination was performed to exclude any pelvic pathology before treatment.

On the basis of previous studies to achieve a statistically valid comparison of PRs in the two groups, with a type I error of 0.05 and a power of 80%, a sample size of at least 40 women in each arm was required.

The randomization of recruited women was performed using online software (www.randomization.com) to generate a random number table. The patients were randomly divided into two groups. Sixty-six patients received letrozole with a starting dose of 2.5 mg, increasing up to 5 mg daily for 5 days starting from the third day of a menstrual bleeding. Sixty-one patients had received CC with a starting dose of 50 mg, increasing up to 100 mg daily for 5 days beginning on day 3 of the menstrual cycle. All women continued to receive 500 mg metformin t.i.d. Follicular development was monitored using transvaginal U/S from day 10 onward. When at least one mature follicle (with a mean diameter ≥18 mm) was observed, 10,000 IU of human chorionic gonadotropin (hCG) were given subcutaneously to trigger ovulation. The second transvaginal U/S was performed after 48 h of injection of (hCG) to observe the release of ova. Ovulation was ascertained by observing the rupture of the follicle by transvaginal U/S and elevated serum progesterone level. Each woman was asked to have timed intercourse/intrauterine insemination 24–36 h after the ovulatory dose of hCG. Women in both the groups without the evidence of ovulation and with negative pregnancy tests were asked to follow the respective schedule of treatment in subsequent cycles. Chemical pregnancy was assessed by the serum level of beta-hCG measurement once the patient missed her period. The work was approved by the local ethical committee.

Statistical analysis

The analysis was performed using the Statistical Package for the Social Sciences version 20.0 software (SPSS Inc., Chicago, IL, USA) statistical software. Data were expressed as the mean ± standard deviation (SD). A Student’s t-test was performed. Proportions were analyzed using the chi-square test. P < 0.05 was considered a statistically significant difference.


  Results Top


During the study period, a total of 162 patients were analyzed for recruitment. Twenty-one patients did not meet inclusion criteria and 14 patients were lost to follow-up in between the study, and therefore, 127 patients entered and completed the study. The flow of participants is shown in [Figure 1]. There were no statistically significant differences between the two groups in age, duration of infertility, body weight, BMI, and endocrine status at baseline level [Table 1]. The total number of follicles during stimulation was statistically significantly greater in the letrozole group (6.81 ± 1.0 vs. 6.1 ± 1.5; P = 0.002). The number of follicles ≥18 mm was statistically significantly higher in the letrozole group compared with the CC group. There was no statistically significant difference in pretreatment endometrial thickness between the two groups, but endometrial thickness at the time of hCG administration was statistically significantly greater in the letrozole group (9.82 ± 0.7 vs. 8.13 ± 0.56; <0.0001). Ovulation occurred in 25 subjects (37.87%) in the letrozole group and 13 subjects (19.67%) in the CC group, with a statistically significant difference between the two groups (P = 0.024). Serum E2 concentrations were statistically significantly lowered in the letrozole group (P = 0.001). There is no significant difference in PR between the two groups [Table 2]. There was no occurrence of ovarian hyperstimulation syndrome in the letrozole group compared with the CC group.
Figure 1: Flow of participants through the study

Click here to view
Table 1: Baseline characteristic of the patients with primary infertility in both the groups

Click here to view
Table 2: Response to ovarian stimulation in the patients with letrozole versus clomiphene citrate therapy

Click here to view



  Discussion Top


The first line of ovulation inducing agent CC is not equally effective in all situations for induction of ovulation or superovulation. Clomiphene resistance occurs in 15–20% of the patients. The use of CC may be associated with poor cervical mucous and endometrial thinning in 15–50% of the patients due to prolonged estrogen-receptor depletion in the endometrium and possibly in the cervix.[7],[8],[9],[10],[11] CC, which is the most commonly prescribed medication, initiates ovulation by blocking the negative feedback on endogenous estrogen at the level of hypothalamus–pituitary promoting on the increase in the pulsatile release of LH and FSH in anovulatory patients with POCS.[12] For many years, the first treatment of choice for ovulation induction in POCS was CC,[13] but up to 58% of such patients are resistant to it and do not ovulate.[14] The PR per cycle remains relatively low. It has also been demonstrated that CC has an antagonistic effect on the endometrium and may reduce endometrial thickness.[15] The inappropriate development of endometrium is associated with a low implantation rate and early pregnancy loss caused by luteal phase defect.[16] Some patients (20–28%) do not respond to CC in spite of high dose, because the antiestrogenic effect is dose-dependent, and a daily dose of CC >150 mg is not recommended.[4]

Letrozole (4,40-[1H-1, 2, 4-triazol-1-ylmethylene]-bis-benzonitrile) is a type IIa third-generation aromatase inhibitor. It was postulated that blocking estrogen production by inhibiting aromatization, the conversion of androstenedione and testosterone to estrogen in the ovary would release the hypothalamic/pituitary axis from estrogenic negative feedback. As a result, the FSH secretion increases, stimulating the development of ovarian follicles. Preliminary studies reported that aromatase inhibitors were useful for inducing ovulation and in superovulation. Mitwally and Casper[14] described the use of 2.5 mg of letrozole on days 3–7 of menses in 12 patients with PCOS. Ovulation occurred in nine patients (75%), and pregnancy was achieved in three (25%). Sammour et al.[17] found in their double-blind randomized trial comparing the use of an aromatase inhibitor with CC for stimulation in 49 women with infertility that increased endometrial thickness compared with those receiving CC, because threefold increase in the PR was observed in the patients who received aromatase inhibitor compared with CC treatment (16.7% vs. 5.6%, respectively).

Compared with CC, the use of letrozole led to a statistically significant increase in the number of developing and mature follicles (18 mm follicles). Al-Fozan et al.[18] reported better results in the letrozole group for the number of developing and mature follicles than in the CC group. The endometrium was, astoundingly, statistically significantly thicker in the letrozole group. Information on the teratogenic capacity of letrozole in humans is lacking, but animal studies have shown that the low doses of letrozole are effective in inducing noxious effects on the developing conceptus. CC has been reported to elicit various ocular side effects in 1.5–10.0% of the patients taking CC.[19] Mitwally et al.[20] reported favorable pregnancy outcomes and low multiple gestation rates with aromatase inhibitors for ovarian stimulation. Bedaiwy et al.[21] have suggested that a letrozole-FSH combination could be more cost-effective than FSH alone for ovarian stimulation in intrauterine insemination cycles.


  Conclusion Top


Although there are some limitations to the present study, our study found advantages to using letrozole rather than CC as a first-line treatment for inducing ovulation in women with PCOS. The strength of our study is that we have been able to preliminarily explore the effects of letrozole and CC for ovulation induction in women with PCOS.

Acknowledgements

The authors gratefully thank all the couples who participated in the study and the co-workers of the MAGS Medical and Research Center; this study was impossible without their contribution.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
The 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.  Back to cited text no. 1
    
2.
Saxena P, Prakash A, Nigam A, Mishra A. Polycystic ovary syndrome: Is obesity a sine qua non? A clinical, hormonal, and metabolic assessment in relation to body mass index. Indian J Endocrinol Metab 2012; 16:996–9.  Back to cited text no. 2
    
3.
Dor J, Lerner-Geva L, Rabinovici J, Chetrit A, Levran D, Lunenfeld B et al. Cancer incidence in a cohort of infertile women who underwent in vitro fertilization. Fertil Steril 2002;77:324-7.  Back to cited text no. 3
    
4.
Franks S, Adams J, Mason H, Polson D. Ovulatory disorders in women with polycystic ovary syndrome. Clin Obstet Gynecol 1985;12:605-32.  Back to cited text no. 4
    
5.
Bao SH, Sheng SL, Peng YF, Lin QD. Effects of letrozole and clomiphene citrate on the expression of HOXA10 and integrin αβ in uterine epithelium of rats. Fertil Steril 2009;91:244-8.  Back to cited text no. 5
    
6.
Pfister CU, Martoni A, Zamagni C, Lelli G, De Braud F, Souppart C. Effect of age and single versus multiple doses, pharmacokinetic of letrozole (Femara) in breast cancer patients. Biopharm Drug Dispos 2001;22:191-7.  Back to cited text no. 6
    
7.
Gonen Y, Casper RF. Sonographic determination of a possible adverse effect of clomiphene citrate on endometrial growth. Hum Reprod 1990;5:670-4.  Back to cited text no. 7
    
8.
Yagel S, Ben-Chetrit A, Anteby E, Zacut D, Hochner-Celnikier D, Ron M. The effect of ethinyl estradiol on endometrial thickness and uterine volume during ovulation induction by clomiphene citrate. Fertil Steril 1992;57:33-6.  Back to cited text no. 8
    
9.
Dickey RP, Olar TT, Taylor SN, Curole DN, Matulich EM. Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: Effect of clomiphene citrate alone and with human menopausal gonadotropin. Fertil Steril 1993;59:756-60.  Back to cited text no. 9
    
10.
Opsahl MS, Robins ED, O’Connor DM, Scott RT, Fritz MA. Characteristics of gonadotropin response, follicular development, and endometrial growth and maturation across consecutive cycles of clomiphene citrate treatment. Fertil Steril 1996;66:533-9.  Back to cited text no. 10
    
11.
Eden JA, Place J, Carter GD, Jones J, Alaghband-Zadeh J, Pawson ME. The effect of clomiphene citrate on follicular phase increase in endometrial thickness and uterine volume. Obstet Gynecol 1989;73:187-90.  Back to cited text no. 11
    
12.
Kettel LM, Roseff SJ, Berga SL. Hypothalamus-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome. Fertil Steril 1993;59:532-8.  Back to cited text no. 12
    
13.
Franks S. Polycystic ovary syndrome. N Eng J Med 1995;333:853-61.  Back to cited text no. 13
    
14.
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.  Back to cited text no. 14
    
15.
Nakamura Y, Ono M, Yoshida Y. Effect of clomiphene citrate on the endometrial thickness and echogenic pattern of the endometrium. Fertil Steril 1997;67:256-60.  Back to cited text no. 15
    
16.
Randall JM, Templeto A. Cervical mucus score and in vitro sperm mucus interaction in spontaneous and clomiphene citrate cycles. Fertil Steril 1991;56:465-8.  Back to cited text no. 16
    
17.
Sammour A, Biljan MM, Tan SL, Tulandi T. Prospective randomized trial comparing the effects of letrozole and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing superovulation prior to intrauterine insemination. 57th Annual Meeting of the American Society for Reproductive Medicine. Orlando, FL: 2001. (Abstract O-291). Fertil Steril 2001;76(Suppl 1):S110.  Back to cited text no. 17
    
18.
Al-Fozan H, Al-Khadouri M, Tan SL, Tulandi T. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril 2004;82:1561-3.  Back to cited text no. 18
    
19.
Bishai R, Arbour L, Lyons C, Koren G. Intrauterine exposure to clomiphene and neonatal persistent hyperplastic primary vitreous. Teratology 1999;60:143-5.  Back to cited text no. 19
    
20.
Mitwally M, Biljan M, Casper R. Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation. Am J Obstet Gynecol 2005;192:381-6.  Back to cited text no. 20
    
21.
Bedaiwy MA, Forman R, Mousa NA, Al Inany HG, Casper RF. Cost-effectiveness of aromatase inhibitor co-treatment for controlled ovarian stimulation. Hum Reprod 2006;21:2838-44.  Back to cited text no. 21
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]


This article has been cited by
1 Therapeutic effects of dimethyldiguanide combined with clomifene citrate in the treatment of polycystic ovary syndrome
Jingjing Jiang,Shanshan Gao,Yang Zhang
Revista da Associação Médica Brasileira. 2019; 65(9): 1144
[Pubmed] | [DOI]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Materials and me...
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed1602    
    Printed75    
    Emailed0    
    PDF Downloaded195    
    Comments [Add]    
    Cited by others 1    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]