• Users Online: 146
  • Print this page
  • Email this page


 
 
Table of Contents
ORIGINAL ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 2  |  Page : 88-92

The effect of clomiphene citrate versus tamoxifen versus letrozol on endometrial thickness and blood flow in ovulation induction in women with polycystic ovaries


1 Department of Obstetrics & Gynecology, Alazhar University, Egypt
2 Department of Obstetrics & Gynecology, 6th October University, Egypt

Date of Web Publication6-Jul-2017

Correspondence Address:
Asem Anwar
Professor of Obstetrics & Gynecology, Alazhar School of Medicine, 123 Mostafa Elnahas Street, Nasr City-Madient Nasr-Cairo
Egypt
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.5530/ami.2016.2.19

Rights and Permissions
  Abstract 


Aim of Work: To compare between the effects of clomiphene citrate, tamoxifen and letrozol as ovulation induction agents on endometrial thickness and blood flow as non-invasive parameters of endometrial receptivity in women with polycystic ovaries.
Patients and Methods: One hundred and fifty cases meeting the selection criteria were prospectively randomized into three groups 1st Group took 100 mg clomiphene citrate, 2nd Group took 5 mg letrozol and 3rd group took 40 mg tamoxifen. Transvaginal ultrasound and Doppler were done to measure endometrial thickness and endometrial blood flow both pulsatility index (PI) and resistance index (RI) at the day of the maximum follicular growth or at day 20 in the absence of the dominant follicle in the three groups.
Results: Significantly thinner endometrium in the clomiphene citrate group as compared to the other two groups and lower impedance in the spiral arteries in both letrozol and tamoxifen groups (P value less than 0.001).
Conclusion: Endometrium was thicker with lower impedance in the spiral arteries in both letrozol and tamoxifen groups as compared to clomiphene citrate group. Ovulation and pregnancy rates were not significantly different. Other studies are needed to measure the cumulative results of six cycles, increasing the dose in non-responders and the incidence of miscarriage.

Keywords: Polycystic ovaries, Ovulation-induction, Endometrium


How to cite this article:
Anwar A, Torky H, Dief O, Elwahed AA, Senna HA. The effect of clomiphene citrate versus tamoxifen versus letrozol on endometrial thickness and blood flow in ovulation induction in women with polycystic ovaries. Acta Med Int 2016;3:88-92

How to cite this URL:
Anwar A, Torky H, Dief O, Elwahed AA, Senna HA. The effect of clomiphene citrate versus tamoxifen versus letrozol on endometrial thickness and blood flow in ovulation induction in women with polycystic ovaries. Acta Med Int [serial online] 2016 [cited 2020 Sep 18];3:88-92. Available from: http://www.actamedicainternational.com/text.asp?2016/3/2/88/209805






  Introduction Top


Polycystic ovary syndrome (PCOS) is the commonest form of ovarian causes of infertility representing between 90% and 95% of women with ovarian causes presenting to infertility clinics. PCOS women have normal count of primordial follicles while, there is a significant increase in primary and secondary follicles. However, due to a disturbance in the factors affecting normal follicular development, follicular growth stops when follicles reach a diameter between 4 and 8 mm. Anovulation is due to the lack of development of a dominant follicle.[1],[2]

Clomiphene citrate acts as a partially selective modulator of estrogen receptors. It acts on the level of the hypothalamus by inducing changes in gonadotropin releasing hormone (GnRH) frequency of pulses leading to increased in the release of follicle stimulating hormone (FSH) from the pituitary gland, it's ovulation rate ranges between 70% and 85% in each cycle while, it's cumulative live birth rate is lower ranging between 50% and 60% in treatment for six cycles.[3]

Aromatase inhibitors inhibit the conversion of testosterone to estradiol and of androstenedione to estrone which decreases the estrogenic activity releasing the hypothalamus from its negative feedback leading to an increase in FSH release.[4]

Tamoxifen is a pro-drug converted in the liver to its active metabolites as 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen. These active metabolites compete with estrogen for its receptors.[5]

Tamoxifen is used in the treatment of anovulatory infertility with a favorable action on cervical mucus and acting as an estrogen receptor agonist on the endometrium leading to better endometrial thickness and better endometrial blood flow, thus, improving endometrial receptivity and fertility.[6]

Endometrial receptivity is a unique and temporary sequence of factors making the endometrium receptive to embryo implantation.[7] Ultrasonic parameters of endometrial receptivity are endometrial thickness, endometrial volume, endometrial pattern and Doppler study of uterine arteries and the endometrium.[8]

Endometrium thickness of less than 7 mm is a sign of suboptimal implantation potential.[9] Pregnant women had significantly higher mean endometrial thickness than non- pregnant women as shown in a meta-analysis done by.[10]

A good blood supply to the endometrium is an essential factor for normal implantation. Color and power Doppler ultrasound are non-invasive methods to evaluate endometrial blood flow,[11] which is a more important parameter for embryo transplantation than total uterine blood flow.[12]

The aim of our work was to compare between the effects of clomiphene citrate, tamoxifen and letrozol as ovulation induction agents on endometrial thickness and blood flow as non-invasive parameters of endometrial receptivity in women with polycystic ovaries.


  Patients and Methods Top


Three hundred and thirty seven infertile women with anovulatory (PCOS) were recruited from the outpatient clinics of both 6th October and Bab Elshaaria University Hospitals from August 2014 and January 2015, of which one hundred and fifty met the inclusion criteria of the study which are: age between 20 and 35 years, body mass index (BMI) between 18 and 30 kg/m2, normal uterus and patent tubes by hysterosalpingography (H.S.G.), normal semen analysis and normal serum prolactin, while, exclusion criteria included women with endocrinal disturbance, active liver disease, local disease as hydro- or pyosalpinx, and history of previous ovarian surgery. The study was approved by the ethical committee of Al Azhar University.

All patients were subjected to the following: detailed history and physical examination, hormonal profile on day 2-4 (FSH, LH, E2, Prolaction, TSH, free T3 and T4), HSG and semen analysis.

The patients were prospectively randomized into three groups each containing fifty patients by computer allocation method. Each of the three groups received 2 tablets for 5 days sarting from day 3 to day 7 of the cycle. Group 1 received 100 mg (50 mg/tablet) clomiphene citrate, Group 2 5 mg (2.5 mg/tablet) letrozole and Group 3 40 mg (20 mg/tablet) tamoxifen.

Transvaginal ultrasound was done on day 3 then on day 10 of the cycle then every other day until a single follicle of at least 18 mm. in diameter was detected, if no follicle by this size was detected by day 20 it is considered as failure. Endometrial thickness and endometrial blood flow both pulsatility index (PI) and resistance index (RI) were measured at the day of the maximum follicular growth (18 mm. or more) or at day 20 in the absence of the dominant follicle.

The primary outcomes of the study were endometrial thickness and endometrial blood flow (PI and RI), while the secondary outcomes were the development and number of follicles, and the pregnancy rate.

Statistical Methods

Statistical analysis was done using IBM© SPSS © Statistics version 21 (IBM© Corp., Armonk, NY) and MedCalc© version 12.5 13 (MedCalc© software bvba, Ostend, Belgium).


  Results Top


As regards the type of infertility in the three groups it was as follows: group 1 38 (76%) had primary infertility and 12 (24%) had secondary infertility, group 2 36 (72%) had primary infertility and 14 (28%) had secondary infertility, and group 3 37 (74%) had primary infertility and 13 (26%) had secondary infertility. This was statistically insignificant as the P-value was 0.785.

As regards the mean duration of infertility in the three groups it was as follows: Group 1 1.9 with an SD of +/- 0.7, group 2 1.9 +/- an SD of +/- 0.7, and group 3 2.2 with an SD of +/- 0.7. This was statistically insignificant as the P-value was 0.146.

The rate of ovulation (at least one follicle with a diameter 18 m or more) in the three groups was as follows: Group 1 33 (66%), group 2 36 (72%) and group 3 34 (68%). The P-value was not statistically significant P-value more than 0.05.

The number of follicles per ovulating patient in the three groups are as follows: Group 1 median 2 (ranging between 0 and 4 follicles) and mean 2* +/- SD 0.9, group 2 median 1 (ranging between 0 and 2 follicles) and mean 1.2 +/- SD 0.4, and group 3 median 1 (ranging between 0 and 2 follicles) and mean 1.2 +/- SD 0.4. The P-value was statistically significant with a value of less than 0.001. Clomiphene citrate group showed development of more number of follicles as compared to letrozol and tamoxifen.

The current study revealed a highly significant negative correlation coefficient between endometrial thickness and Doppler indices i.e. as endometrial thickness decreases Doppler indices (PI and RI) increase [Table 3] this was evident in the clomiphene citrate group as compared to the other two groups. This result was similar to the result found by[19] who concluded that endometrial thickness and pattern were impaired in PCO women taking clomiphene citrate. These results suggest that endometrial receptivity parameters might have been worse in patients taking clomiphene citrate with consequently lower implantation and pregnancy rates.
Table 3: Highly statistically significant negative correlation coefficient between endometrial thickness and Doppler indices in the studied groups

Click here to view



  Discussion Top


Ovulation induction drugs are one of the main lines of treatment of anovulation due to polycystic ovaries. Clomiphene citrate (CC) has been used as the first line for ovulation induction since 1961. Although clomiphene citrate has higher ovulation rates ranging between 50 and 90% pregnancy rates are much lower ranging between 20 and 40%,[13] such difference may be due to the peripheral anti-estrogenic effect on the cervical mucus and the endometrium.[14] Clomiphene citrate is believed to slow down the uterine blood flow in early luteal phase and around the time of implantation. Some authors stated that clomiphene citrate may have a direct effect on both ovarian and uterine blood flow.[15] The above mentioned actions of clomiphene citrate have a negative impact on endometrial receptivity which is a possible explanation for the big discrepancy between ovulation and pregnancy rates with this medication, furthermore, the development of clomiphene citrate resistant patients led several authors to investigate alternative medications as the study done by[16] who reported a thirty percent pregnancy rate in those patients after using 40 mg tamoxifen per day for 5 successive days starting from day 3 of the cycle and suggested that tamoxifen may be a proper alternative in those patients before starting treatment with gonadotrophins.

There was neither a significant difference as regards age and BMI [Table 1] and [Figure 1] nor a significant difference as regards the type and duration of infertility in the studied groups.
Table 1: The patients' characteristics in the three group (no statistically significant difference)

Click here to view
Figure 1: Shows the patients' characteristics in the three group

Click here to view


The current study investigated the effect of clomiphene citrate, letrozol and tamoxifen on both endometrial thickness and endometrial blood flow as non-invasive parameters in the assessment of endometrial receptivity and showed a significantly thinner endometrium in the clomiphene citrate group as compared to the other two groups (P value less than 0.001) [Table 2] and the same high significance for Doppler indices measuring endometrial blood flow [Table 2] and [Figure 2]. Pregnancy rate was slightly lower in the clomiphene citrate group compared to the other two groups, however, this result was statistically insignificant (P value = 0.413) [Table 4]. Selim and Borg[17] studied 200 anovulatory women and reached the same conclusion as regards endometrial thickness and endometrial blood flow when comparing clomiphene citrate to letrozol with higher pregnancy rate in the letrozol group. However, Badawy and co-workers[18] reached different results when comparing clomiphene citrate to letrozol as they had higher endometrial thickness, ovulation and pregnancy rates and in the clomiphene citrate group.
Table 2: A highly statistically significant difference as regards endometrial thickness and Doppler indices (PI and RI) in the studied groups as the P value was less than 0.001

Click here to view
Figure 2: Showed a statistically difference as regards endometrial thickness and Doppler indices (PI and RI) in the studied groups

Click here to view
Table 4: Statistically insignificant difference as regards pregnancy rate in the three groups, however, the highest pregnancy rate was in group 2 (letrozol group)

Click here to view


The current study showed a statistically significant mean number of follicles in the clomiphene citrate group as compared to the other two groups (P value less than 0.001), however, both ovulation and pregnancy rates were higher in the other two groups although those differences were statistically insignificant. Roy and co-workers,[20] reached the same results when they compared between clomiphene citrate and letrozol, however, pregnancy rate was significantly higher in the letrozol group in their study. Pant[21] had no significant difference as regards ovulation and pregnancy rate when comparing clomiphene citrate with tamoxifen, however, a significant difference was detected as regards endometrial thickness in favor of the tamoxifen group.


  Conclusion Top


The current study concluded that endometrium was thicker with lower impedance in the spiral arteries in both letrozol and tamoxifen groups as compared to clomiphene citrate group. Ovulation and pregnancy rates were not significantly different among the three groups, however, certain issues were not addressed in this study which, need to be addressed in other studies as the cumulative results of six cycles, increasing the dose in non-responders and the incidence of miscarriage.


  Acknowledgment Top


Authors declare that they have neither conflict of interest nor received financial support.



 
  References Top

1.
Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med. 2010;8:41  Back to cited text no. 1
    
2.
Brassard M, AinMelk Y, Baillargeon JP. Basic infertility including polycystic ovary syndrome. Med Clin North Am. 2008; 92:1163–1192.  Back to cited text no. 2
    
3.
Balen AH. Ovulation induction in the management of anovulatory polycystic ovary syndrome. Mol Cell Endocrinol. 2013; 373(1–2):77–82.  Back to cited text no. 3
    
4.
Casper RF, Mitwally MF. Use of the aromatase inhibitor letrozole for ovulation induction in women with polycystic ovarian syndrome. Clin Obstet Gynecol. 2011; 54(4):685–695.  Back to cited text no. 4
    
5.
Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M. Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell. 2000:103(6); 843–852.  Back to cited text no. 5
    
6.
Steiner A.Z., Terplan M., Paulson R.J. Comparison of clomiphene citrate and tamoxifen for ovulation induction. Hum Reprod. 2005; 20:1511–1515.  Back to cited text no. 6
    
7.
Bergh PA, Navot D. The impact of embryonic development and endometrial maturity on the timing of implantation. Fertil Steril 1992; 58:537–42.  Back to cited text no. 7
    
8.
Yu NG E.H., Ho P.C. Ultrasound assessment of endometrial receptivity in in vitro fertilization treatment. DSJUOG. 2010; 4(2):179–188.  Back to cited text no. 8
    
9.
Elnashar A, Afifi A, Donia O. Endometrial thickness and pregnancy rates in infertile couples undergoing AIH. Benha M J 1995; 12:1–9.  Back to cited text no. 9
    
10.
Richard JP, Steiner AZ, Terplan M. Comparison of tamoxifen and clomiphene citrate for ovulation induction: a meta-analysis. Hum Reprod. 2005:20; 1511–1515.  Back to cited text no. 10
    
11.
Chwalisz K, Garfield RE. Role of nitric oxide in implantation and menstruation. Hum Reprod 2000; 3:96–111.  Back to cited text no. 11
    
12.
Jinno M, Ozaki T, Iwashita M, Nakamura Y, Kudo A, Hirano H. Measurement of endometrial tissue blood flow: a novel way to assess uterine receptivity for implantation. Fertil Steril. 2001:76; 1168–1174.  Back to cited text no. 12
    
13.
Momeni M, Rahbar MH, Kovanci E. A meta-analysis of the relationship between endometrial thickness and outcome of in vitro fertilization cycles. J Hum Reprod Sci. 2011; 4(3): 130–137.  Back to cited text no. 13
    
14.
Banerjee Ray P, Ray A, Chakrborti PS. Comparison of efficacy of letrozole and clomiphene citrate in ovulation induction in women with polycystic ovary syndrome. Arch Gynecol Obstet. 2012;285 873–877.  Back to cited text no. 14
    
15.
Wang L, Qiao J, Li R, Zhen X, Liu Z. Role of endometrial blood flow assessment with Doppler energy in predicting pregnancy outcome of IVF-ET cycles. Reprod Biol Endocrinol. 2010:8; 122.  Back to cited text no. 15
    
16.
Gulekli B, Ozaksit G, Turhan NO, Senoz S, Oral H, Gokmen O. Tamoxifen. An alternative approach in clomiphene resistant polycystic ovarian syndrome patients. J Pak Med Assoc. 1993; 43(5):89–90.  Back to cited text no. 16
    
17.
Selim MF, Borg TF. Clomiphene citrate and letrozole effect on endometrial and sub-endometrial vascularity in women with polycystic ovary syndrome. J Gynecol Surgery. 2012:28; 405–410.  Back to cited text no. 17
    
18.
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. 18
    
19.
Russo SPT, Orio F Jr, Falbo A, Manguso F, Sammartino A, Tolino A, Colao A, Carmina E, Zullo F. Uterine effects of clomiphene citrate in women with polycystic ovary syndrome: a prospective controlled study. Human Reproduction. 2006:21(11); 2823–2829.  Back to cited text no. 19
    
20.
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. 20
    
21.
Pant PR. Comparison of efficacy of tamoxifen and clomiphene citrate for induction of ovulation. Medica Innovatica. 2013:2; 68–71.  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


This article has been cited by
1 To share or not to share data: how valid are trials evaluating first-line ovulation induction for polycystic ovary syndrome?
Esmee M Bordewijk,Rui Wang,Madelon van Wely,Michael F Costello,Robert J Norman,Helena Teede,Lyle C Gurrin,Ben W Mol,Wentao Li
Human Reproduction Update. 2020;
[Pubmed] | [DOI]
2 First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis
Rui Wang,Wentao Li,Esmée M Bordewijk,Richard S Legro,Heping Zhang,Xiaoke Wu,Jingshu Gao,Laure Morin-Papunen,Roy Homburg,Tamar E König,Etelka Moll,Sujata Kar,Wei Huang,Neil P Johnson,Saad A Amer,Walter Vegetti,Stefano Palomba,Angela Falbo,Ülkü Özmen,Hakan Nazik,Christopher D Williams,Grasso Federica,Jonathan Lord,Yilmaz Sahin,Siladitya Bhattacharya,Robert J Norman,Madelon van Wely,Ben Willem Mol
Human Reproduction Update. 2019;
[Pubmed] | [DOI]
3 Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome
Sebastian Franik,Stephanie M Eltrop,Jan AM Kremer,Ludwig Kiesel,Cindy Farquhar
Cochrane Database of Systematic Reviews. 2018;
[Pubmed] | [DOI]
4 Impact of clomiphene citrate, tamoxifen and letrozole to induce ovulation in anovulatory women with polycystic ovary syndrome on endometrial thickness and clinical pregnancy rates, a two center cohort study
Elsayed Elshamy,Mohammed Khalafallah
Obstetrics & Gynecology International Journal. 2018; 9(4)
[Pubmed] | [DOI]
5 Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis
M. A. Gadalla,S. Huang,R. Wang,R. J. Norman,S. A. Abdullah,A. M. El Saman,A. M. Ismail,M. van Wely,B. W. J. Mol
Ultrasound in Obstetrics & Gynecology. 2017;
[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
Patients and Methods
Results
Discussion
Conclusion
Acknowledgment
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed1507    
    Printed159    
    Emailed0    
    PDF Downloaded156    
    Comments [Add]    
    Cited by others 5    

Recommend this journal