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ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 2  |  Page : 405-409

Effect of clomiphene citrate, tamoxifen, and letrozole on endometrial thickness in cycles of ovulation induction: a randomized controlled trial


1 Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Obstetrics and Gynecology, General Administration of Medical Affairs, Mansoura University, Mansoura, Egypt

Date of Submission24-Dec-2018
Date of Decision12-Feb-2019
Date of Acceptance16-Feb-2018
Date of Web Publication25-Jun-2020

Correspondence Address:
Sally Nagah Taha
Street 100, New Damietta
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_427_18

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  Abstract 


Objectives
To compare the effect of clomiphene citrate, tamoxifen, and letrozole on endometrial thickness in anovulatory cycles.
Background
Infertility is frequently caused by anovulation. The affected women were presented with irregular menstrual cycles and the most common diagnosis was polycystic ovary syndrome. Ovulation induction is commonly used to treat these women. We compare between the three drugs to conclude their efficacy on endometrial thickness, number of follicles, and clinical pregnancy rate.
Patients and methods
This prospective study was done in Talkha Hospital. One hundred infertile cases meeting the selection criteria especially patients with polycystic ovarian syndrome were included. They were randomized into three groups. Group A (n = 34) took 100 mg clomiphene citrate, group B (n = 33) took 5 mg letrozole, and group C (n = 33) took 40 mg tamoxifen from day 2 to day 6 of the cycle, once after breakfast for three cycles. The outcome measure was endometrial thickness, number of follicles, and clinical pregnancy rate.
Results
Endometrial thickness was higher in groups B and C than group A, higher number of follicles in group A with no difference regarding the clinical pregnancy rate between the three groups.
Conclusion
Groups B and C had better effect on endometrial thickness than group A although it had higher number of follicles, clinical pregnancy rate increased with group B than groups A and C.

Keywords: clomiphene citrate, endometrial thickness, letrozole, ovulation induction, tamoxifen


How to cite this article:
Sattar MM, El-Halaby AE, El-Shamy ESA, Taha SN. Effect of clomiphene citrate, tamoxifen, and letrozole on endometrial thickness in cycles of ovulation induction: a randomized controlled trial. Menoufia Med J 2020;33:405-9

How to cite this URL:
Sattar MM, El-Halaby AE, El-Shamy ESA, Taha SN. Effect of clomiphene citrate, tamoxifen, and letrozole on endometrial thickness in cycles of ovulation induction: a randomized controlled trial. Menoufia Med J [serial online] 2020 [cited 2020 Jul 14];33:405-9. Available from: http://www.mmj.eg.net/text.asp?2020/33/2/405/287804




  Introduction Top


Infertility is frequently caused by anovulation. The affected women present with irregular menstrual cycles and the most common diagnosis is polycystic ovary syndrome (PCOS). Ovulation induction is commonly used to treat these women[1].

Clomiphene citrate (CC) remains the most used medication for treating these condition. Other alternative drugs could be used such as tamoxifen (TMX), aromatase inhibitors, insulin-sensitizing agents, and ovarian drilling[2].

CC is a nonsteroidal selective estrogen receptor modulator[3].

CC has a long half-life (2 weeks), and this may have a negative effect on the cervical mucus and endometrium, leading to discrepancy between ovulation and conception rates[4].

Letrozole is a triazole (antifungal) derivative that is potent, reversible, competitive, nonsteroidal, and highly selective aromatase inhibitor for oral administration[5].

Letrozole is devoid of any antiestrogenic peripheral actions on the endometrium or cervical mucus, as it is cleared from circulation more rapidly due to a shorter half-life (48 h)[6].

TMX is a selective estrogen receptor modulator.

TMX acts as an agonist on estrogen receptor of the endometrium and vaginal mucosa; its half-life is short (5–7 days) leading to favorable cervical mucus and better endometrial thickness[7].

The aim of this study was endometrial thickness, number of follicles, and clinical pregnancy rate.


  Patients and Methods Top


This prospective study included 100 infertile women who are already diagnosed as anovulatory infertility by ultrasound and progesterone on day 21 in the midluteal phase and met the inclusion criteria. This study followed the Ethics Committee rules of Obstetrics and Gynecology in Talkha Hospital and was approved by the study ethics committee of Menoufia University Hospital. The sample size is 100 participants who were divided randomly by the computer allocation method into three groups.

  • Group A: this group included 34 patients using who are under ovulation induction with CC. Patients took 100 mg of CC daily for 5 days starting from day 2 to day 6 of the cycle. Each tablet of the drug is 50 mg. So, the patients took the dose in the form of two tablets all together after breakfast for three cycles[8]
  • Group B: this group included 33 patients who are under ovulation induction with letrozole. Patients took 5 mg of the drug daily for 5 days, starting from day 2 to day 6 of the cycle, each tablet of the drug is 2.5 mg. So, the patients took the dose in the form of two tablets all together after breakfast for three cycles[8]
  • Group C: this group included 33 patients who are under ovulation induction with TMX. The patients took 40 mg of the drug daily for 5 days starting from day 2 to day 6 of the cycle. Each tablet of the drug is 20 mg. So, the patients took the dose in the form of two tablets all together after breakfast for three cycles[8].


Inclusion criteria

Women selected for this study had all of the following criteria:

  1. Age from 18 to 35 years
  2. BMI from 18 to 30 kg/m2
  3. Patients with anovulatory PCOS chosen by Rotterdam consensus 2003
  4. Normal uterus and patent fallopian tubes proved by hysterosalpingography
  5. Normal semen analysis of the husband
  6. Normal serum prolactin
  7. Women with documented anovulation by measuring progesterone on day 21 and by performing ultrasound in the midluteal phase.


Exclusion criteria

  1. Hyperprolactinemia, thyroid dysfunction, active liver diseases, etc.
  2. Local diseases such as endometriosis, ovarian tumors, hydrosalpinx, or pyosalpinx etc.
  3. Patients with previous history of ovarian drilling.


Methods

All women selected for this study were subjected to explanation of the procedure and consent was obtained from every women participating in this study. All women had the following.

Detailed history taking

Detailed history was taken. It includes: age, duration of infertility, menstrual history, symptoms and signs suggestive of endocrine disorders, history of chronic diseases including diabetes mellitus and hypertension and surgical history including laparoscopy and laparotomy. Data were collected in a special form for each patient.

Physical examination

  1. General examination was done to all cases for determination of acne, obesity, and acanthosis nigricans
  2. Abdominal examination was done to all cases for determination of enlarged uterus and enlarged ovaries
  3. Vaginal examination was done to all cases for determination of congenital anomalies such as vaginal septum or atresia by doing P/v examination.


Investigations

  1. Hormonal profile on days 2–5 of the cycle: FSH, LH, E2, free testosterone, estradiol, TSH, free T3 and T4, and prolactin
  2. Hysterosalpingography to confirm tubal patency
  3. Semen analysis to rule out male factor.


Vaginal ultrasound at ninth day of menstrual cycle, then follow up every other day until the mean diameter of the largest follicle reaches 18 mm, then the endometrial thickness (mm) was measured in the sagittal view as the maximum thickness between the highly reflective interface of the endometrial–myometrial junction if no dominant follicle appeared at day 14 or 15 of the cycle; transvaginal ultrasound was continued till day 20 and the endometrial thickness was measured.

Statistical analysis

The statistical analysis of data was done by using excel program for figures and the SPSS (for IBM) Program Statistical Package for Social Sciences, version 22 (IBM Corp., Armonk, New York, USA). Kruskal–Wallis h test, analysis of variance f test, and χ2 test were used in the study. Bonferroni test is used to compare between each two groups. Mann–Whitney U test is used to compare between each two groups.

Size calculation: sample

The sample size was calculated by www.stat.ubc.ca/~rollin/stats/ssize/n2.html. The estimated difference is due to the intervention in endometrial thickness which is the primary outcome. It is hypothesized to increase by 25%. At the level of confidence 95% and power 80, the sample size is 22 patients. We decide to increase each group by 30% to avoid dropouts and defaulters www.stat.ubc.ca/~rollin/stats/ssize/n2.html.


  Results Top


The mean ± SE for endometrial thickness in the three cycles for the three groups: the first cycle was in group A (n = 34) 6.62 ± 1.07 mm, group B (n = 33) 10.07 ± 1.14 mm, and group C (n = 33) 9.57 ± 1.04 mm.

The second cycle was in group A (n = 33) 7.16 ± 0.76 mm, group B (n = 30) 9.8 ± 1.31 mm, and group C (n = 29) 9.56 ± 0.88 mm.

The third cycle was in group A (n = 30) 6.44 ± 0.95 mm, group B (n = 24) 9.95 ± 0.95 mm, and group C (n = 25) 9.23 ± 0.99 mm, which was a statistically highly significant difference between the three studied groups [Table 1].
Table 1: Endometrial thickness of the studied groups according to the treatment type

Click here to view


In the current study the clinical pregnancy rate in the first cycle was in group A, 2.9%, group B, 9%, and group C, 6%. In second cycle was in group A, 9%, group B, 16.6%, and group C, 13.7%. In the third cycle was in group A, 13.3%, group B, 25%, and group C, 20%. With the total clinical pregnancy rate of group A, 23.5%, group B, 43.4%, and group C, 33.3%, which was a statistically nonsignificant difference between the three groups [Table 2].
Table 2: Clinical pregnancy rate of the studied groups according to the treatment type

Click here to view


The number of follicles per ovulation in the three groups was as follows: first cycle, group A median 2 (range, 0–4 follicle), group B median range 1 (range, 0–2 follicle), and group C median 1 (range, 0–2 follicle). Second cycle; group A median 2 (range, 0–4 follicle), group B median 1 (range, 0–2 follicle), and group C median 1 (range, 0–2 follicle). Third cycle; group A median 2 (range, 0–3 follicle), group B median 1 (range, 0–2 follicle), and group C median 1 (range, 0–2 follicle), which were statistically significant differences between the three studied groups [Table 3].
Table 3: Number of follicles of the studied groups according to the treatment type

Click here to view


The number of patients were different in each cycle as the missing patients referred to women who had got clinical pregnancy (pregnant women), so they were rolled out of the following cycles.


  Discussion Top


Endometrial thickness was significantly thinner in group A (CC) than the other two groups, group B (letrozole) and group C (TMX).

The study done by El Kateeb and Mahran[8] show agreement with our study, this trial included 200 infertile women with PCOS who were defined according to the Revised Rotterdam criteria and were divided into two groups letrozole and CC; endometrial thickness was highly significant in the letrozole group 10.1 ± 022 mm than the CC group 8. 2 ± 0.69 mm (P = 0.01).

The study done by Anwar et al.[9] agree with our study, this study is based on 150 PCOS patient between three groups CC, CC, TMX, and letrozole showing significantly thinner endometrium in the CC group 6.9 ± 1.2 mm compared with other two groups. Letrozole 9.6 ± 1.6 mm and TMX 9.8 ± 1.7 mm.

Also, the study done by El-Gharib et al.[10] show agreement with our study, this study is based on 60 infertile women with CC-resistant PCOS, on two groups letrozole and TMX, showing endometrial thickness was higher in the letrozole group (10.2 ± 0.7 mm) than in the TMX group (9.1 ± 0.2 mm).

On the other hand, our results disagree with the study done by Kar[11], as this study included 103 anovulatory patients, who were divided into two groups CC and letrozole; the mean endometrial thickness was almost the same between the two groups CC 7.6 mm and letrozole 7.65 mm.

Added to that the mean endometrial thickness was almost the same between CC and letrozole groups in the study done by Dehbashi[12].

This study shows a statistically significant difference between the three groups regarding the number of follicles; it was higher in group A than group B and group C in the three cycles.

The study done by Anwar et al.[9] agree with our study. This study is based on 50 PCOS patients between the three groups. CC, letrozole, and TMX as the clomiphene group shows development of more number of follicles, median range 2 (0–4) to letrozole median range 1 (0–2) and TMX with median range 1 (0–2).

The study done by Badawy and Gibreal[13] agrees with our study which included 371 anovulatory PCOS patients who were divided into two groups CC and TMX where there was a higher significant number of follicle in the CC group.

On the other hand, El Kateeb and Mahran[8] show disagreement with our study as there was no significant difference between the two groups as regards the number of follicles. The study is based on 200 infertile women with PCOS according to the Revised Rotterdam criteria who were divided into two groups: letrozole and CC.

Also, El-Gharib et al.[10] disagree with our study in the number of follicles between the letrozole group and TMX, as the number of follicles, 7.18 mm, in the letrozole group was more than the TMX group. The study was based on 60 infertile women with CC-resistant PCOS who were divided into two groups: letrozole and TMX.

Our study shows statistically difference between the three groups as regards clinical pregnancy rate which was higher in the letrozole group (14/33) TMX group (11/33), and CC group (8/34) which is nonsignificant in the three cycles.

The study done by El Kateeb and Mahran[8], agrees with our study result. This trial included 200 infertile women with PCOS who were defined according to the Revised Rotterdam criteria and were divided into two groups letrozole and CC; clinical pregnancy rate was higher in the letrozole group 14.8% than the CC group (10.4%).

The study done by Anwar et al.[9] agree with our study. This study is based on 150 PCOS patients between three groups CC, TMX, and letrozole showing a statistically nonsignificant difference with clinical pregnancy rate.

Also, the study done by El-Gharib et al.[10] agrees with our study as letrozole was superior to TMX in achieving higher clinical pregnancy rate as the letrozole group (5.56%) and the TMX group (2.22%). The study was based on 60 infertile women with CC-resistant PCOS who were divided into two groups: letrozole and TMX.

On the other hand, the study done by Diamond[14], disagrees with our study which was done in 746 women with unexplained infertility between three groups, gonadotrop, CC, and letrozole for ovarian stimulation showing a higher clinical pregnancy rate with CC than letrozole.


  Conclusion Top


Endometrial thickness was significantly higher in both letrozole and TMX than CC.

Clinical pregnancy rate was higher with letrozole group than CC and TMX groups but with no significant difference.

The number of follicles was higher with CC than other TMX and letrozole groups which is significantly different.

So letrozole and TMX can induce and even offer better results than CC and each one can be used as first line for treatment of anovulatory infertility.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Legro RS, Barnhart HX, Schalff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for infertility in PCOS. N ENgl J Med 2007; 356 :551–566.  Back to cited text no. 1
    
2.
Bhagavath B, Carson SA. Ovulation induction in women with polycystic ovary syndrome: an update. Am J Obstet Gynecol 2012; 206 :195–198.  Back to cited text no. 2
    
3.
Blank SK, McCartney CR, Marshall JC. The origins and sequelae of abnormo tieurodoenne function in PCOS. Hum Reprod Update 2006; 12 :351–361.  Back to cited text no. 3
    
4.
Roy KK, Baruah J, Singla S, Sharma JB, Singh N, Jain SK, Goyal M. Efficacy of clomiphene citrate or letrozole in ovulation induction in women with polycystic ovarian syndrome. J Hum Reprod 2012; 5 :20–25.  Back to cited text no. 4
    
5.
Badawy A, Abdel Aal I, Abulatta M. Clomiphene citrate or letrozole in women with polycystic ovarian syndrome: a prospective randomized trial. Fertil Steril 2009; 92 :849.  Back to cited text no. 5
    
6.
Casper RF. Letrozole versus clomiphene citrate: which is better for ovulation induction? Fertil Steril 2007; 92 :858–859.  Back to cited text no. 6
    
7.
Dhaliwal LK, Suri V, Gupta KR, Sahdev S. Tamoxifen an alternative to clomiphene in women with polycystic ovary syndrome J Hum Reprod 2011; 4 :76–79.  Back to cited text no. 7
    
8.
El Kateeb RR, Mahran A. Optimized letrozole dose versus traditional use of clomiphene citrate for ovulation induction in patients with POCS: a prospective randomized controlled trial. Gynecol Obstet Res Open J 2016; 3 :7–12.  Back to cited text no. 8
    
9.
Anwar A, Torky H, Dief O, El Wahed AA, Senna HA. The effect of clomiphene citrate versus tamoxifen versus letrozole on endometrial thickness and blood flow in ovulation induction in women with polycystic ovaries. Acta Med Int 2016; 3 :88–92.  Back to cited text no. 9
    
10.
El-Gharib MN, Mahfouz AE, Farahat MA. Comparison of letrozole versus tamoxifen effects in clomiphene critrate resistant women with polycystic ovarian syndrome. J Reprod Infertile 2015; 16 :30–35.  Back to cited text no. 10
    
11.
Kar S. Clomiphene citrate or letrozole as first line ovulation induction drug in infertile polycystic ovary syndrome women. J Hum Reprod 2012; 5 :262–265.  Back to cited text no. 11
    
12.
Dehbashi SK. Comparison of the effects of letrozole and clomiphene citrate on ovulation and pregnancy rate in patients with pcos. Iran J Med Sci 2009; 34 :23–28.  Back to cited text no. 12
    
13.
Badawy A, Gibreal A. Clomiphene citrate versus tamoxifen for ovulation induction in women with polycystic ovarian syndrome. Eur J obset Gynecol Reprod Biol 2011; 159 :151–154.  Back to cited text no. 13
    
14.
Diamond MP, Legro RS, Coutifaris C, Alvero R, Robinson R, Casson P, et al. Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility. N Engl J Med 2015;373:1230-40. doi: 10.1056/NEJMoa1414827.  Back to cited text no. 14
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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