Document Detail

The impact of letrozole versus clomiphene citrate on uterine blood flow in patients with unexplained infertility.
Jump to Full Text
MedLine Citation:
PMID:  24971126     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: To compare the effectiveness of letrozole and clomiphene citrate (CC) on uterine blood flow rate in patients with unexplained infertility.
MATERIALS AND METHODS: In this randomized clinical trial 90 women with unexplained infertility referred to a university clinic from January 2011- December 2013 were enrolled. Thirty patients were randomized for letrozole, 30 patients for CC and 3o patients for control group. On the day 3 of cycle the patients were given letrozole 2.5mg/day or CC 100 mg /day orally or did not receive any treatment. Resistance index (RI) and pulsatility index (PI) of uterine artery were calculated and chemical pregnancy rate was evaluated.
RESULTS: Mean age was 26.4±3.2 (20-33) and mean BMI was 26.3± 3.2. After treatment using ultrasonography the Resistance index (RI) and Pulsatility index (PI) showed no significant difference among three groups (P > 0.05). Pregnancy rate in letrozole group (58%) was more in comparison to CC (53.6%) and control groups (46%) but the difference was not significant (P > 0.05).
CONCLUSION: Our study showed that letrozole and clomiphene citrate have comparable impact on uterine blood flow and pregnancy rate in women with unexplained infertility.
Authors:
Nahid Sakhavar; Mania Kaveh; Kambiz Sadegi
Related Documents :
24170246 - Importance of uterine cervical cerclage to maintain a successful pregnancy for patients...
23378556 - Acute gastric incarceration from thoracic herniation in pregnancy following laparoscopi...
20126256 - Quantifying the number of pregnancies at risk of malaria in 2007: a demographic study.
23442536 - Antenatal care visit attendance, intermittent preventive treatment and bed net use duri...
11573116 - A comparison of spontaneous labor with induced vaginal tablets prostaglandin e2 in gran...
17302226 - Extensive sensory block caused by accidental subdural catheterization during epidural l...
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of family & reproductive health     Volume:  8     ISSN:  1735-8949     ISO Abbreviation:  J Family Reprod Health     Publication Date:  2014 Mar 
Date Detail:
Created Date:  2014-06-27     Completed Date:  2014-06-27     Revised Date:  2014-06-30    
Medline Journal Info:
Nlm Unique ID:  101496684     Medline TA:  J Family Reprod Health     Country:  Iran    
Other Details:
Languages:  eng     Pagination:  1-5     Citation Subset:  -    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): J Family Reprod Health
Journal ID (iso-abbrev): J Family Reprod Health
Journal ID (publisher-id): JFRH
ISSN: 1735-8949
ISSN: 1735-9392
Publisher: Tehran University of Medical Sciences
Article Information
Download PDF
Copyright © Vali-e-Asr Reproductive Health Research Center, Tehran University of Medical Sciences
open-access:
Received Month: 4 Year: 2013
Revision Received Month: 5 Year: 2013
Accepted Month: 5 Year: 2013
Print publication date: Month: 3 Year: 2014
Volume: 8 Issue: 1
First Page: 1 Last Page: 5
PubMed Id: 24971126
ID: 4064759
Publisher Id: JFRH-8-001

The Impact of Letrozole Versus Clomiphene Citrate on Uterine Blood Flow in Patients with Unexplained Infertility
Nahid Sakhavar, M.D.1
Mania Kaveh, M.D.1
Kambiz Sadegi, M.D.2
1Obstetrics & Gynecologist Department, Zahedan University of Medical Science, Zahedan, Iran
2Anesthesiology Department, Zabol University of Medical Science, Zabol, Iran
Correspondence: Correspondence: Dr. Mania Kaveh, Obstetrics & Gynecologist Department, Zahedan University of Medical Science, Zahedan, Iran. Email: maniakaveh@gmail.com

Introduction

Unexplained infertility (UI) is the frequent infertility diagnosis given to women and encompassing up to approximately15- 30% of all cases (1). Unexplained infertility diagnosis is made after testing fails to detect any abnormality. Therefore, the treatment for unexplained infertility is empiric because it does not address a preciseimpairment or functional defect (1). Clomiphene citrate and intrauterine insemination (IUI), controlled ovarian hyperstimulation (COH) with IUI, IVF expectant observation with timed intercourse and lifestyle changesare the most frequent treatments for unexplained infertility (2, 3). It has been proposed that the uterine blood flow affects the uterine receptivity (4) and it has been believed that the pulsatility index (blood flow impedance in the uterine arteries) is valuable in measuring endometrial receptivity (5, 6).

Clomiphene citrate (CC) has been presented in 1960 and widely used in infertility treatment (7). Now it is used in the anovulatory treatment and unexplained infertility either alone or in combination with HMG or recombinant FSH (8).

The rate of ovulation in previous experiences usingclomiphene has been about 60%–85% and 10%–20% pregnancy rate per cycle (9, 10). However resistance to CCoccurs on 15-20%, moreover it may negatively affect cervical mucus and endometrium and it is related with difference between ovulation and conception rates (11, 12).

Letrozole is an alternative treatment for unexplained infertility and it is an aromatase inhibitor that suppresses intratumoral systemic production of estrone from androstenedione (13, 14). An experience with letrozole on rats divulged more than 80% ovarian E2 levels suppression and remarkable increasing in LH and FSH, furthermore it increased ovarian weights about 35% within 1 week of treatment (15). Although the effect of letrozole and CC in patients with infertility are studied in many different ways the impact of these agents on endometrial blood flow on Iranian women with unexplained infertility are not evaluate. This controlled clinical trial was steered to compare the effectiveness of letrozole and CC on blood flow in patients with unexplained infertility.


Materials and methods

In this randomized clinical trial 90 women with unexplained fertility referred to Ali –ibn-e- Abitaleb clinic affiliated to Zahedan University of medical sciences in from January to December 2011 were enrolled. Including criteria were: women with unexplained infertilitylasting more than 1 year, age more than 25 and less than 35years, BMI >19 kg/m2 and <30 kg/m2, normal cycles, at least one open tube in hysterosalpingography (HSG), normal male factor, documentation of ovulation with midluteal serum progesterone levels exceeding 5 ng/mL, normal hormonal profile (TSH, PRL, T, and DHEAS), and day 3 FSH ≤12 IU/L. Unexplained infertility was diagnosed based on a normal semen analysis according to World Health Organization criteria (16). On the other hand the patients were excluded if they have experienced ART (assistant reproductive technology), cervicitis, age more than 35 and BMI >30. There was no history of underlying disease and surgery, moreover hysterosalpingography (HSG) did not detect any abnormality. Additionally to rule out the male factor the semen of husband of all patients were analyzed and did not show any abnormality.

The study procedure was explained for all women and informed written consents were given. The study protocol was approved by ethical committee of Zahedan Universityof medical sciences.

To randomization, the blocks of six were used and two patients of each block were selected for each group. In this regard 30 patients were selected for letrozole, 30 patients CC and 3o patients were selected as a control group.

Initially the demographic and clinical data of patients were record and patients were visited by obstetrics and gynecologist specialist. Then on the day 3 of cycle the patients were given letrozole 2.5mg/day and CC 100 mg /day orally in letrozole and CC groups respectively,but patients in control group did not receive any treatment to ovulation induction.

To measurement of uterine blood flow, resistance index (RI) and pulsatility index (PI) of uterine were calculated moreover to evaluate the pregnancy rate βHCG was measured.

Data were analyzed using SPSS version 20. Categorical data are presented as numbers (%), and continuous data as mean ± SD. We used the Chai_2 or Fisher's exact test to compare categorical variables and the Student's t test to compare continuous variables.


Results

Totally we evaluated 90 patients in three groups with Mean age 26.4±3.(20-33) and mean BMI 26.3± 3.2. The demographic and clinical data in three groups are detailed in Table 1.

After treatment the Resistance index (RI) and Pulsatility index (PI) uterine artery were measured using ultrasonography. The difference between three groups was not significant (P > 0.05) (Table 2).

The pregnancy rate in letrozole group (58%) was more than CC (53.6%) and control groups (46%) but the difference was not significant (P > 0.05) (Table 3).


Discussion

Previous studies have been examined some ultrasonographic indicators as endometrium blood flow, uterine artery, endometrial thickness and endometrial pattern for evaluation of receptivity of endometrium. The most of these surveys have reported that sufficient uterine perfusion increased the endometrial receptivity and pregnancy rate (1618). Another study by kupesic et al specified that endometrial perfusion performs the implantation success rate and exposes the problem of unexplained infertility (17). Additionally another study by Chien et al. signified mean PI and RI value in pregnant women was lower than nonpregnant (18).

Clomiphene is a non-steroidal agent and blocks estrogenic hypothalamic receptors, moreover it has peripheral anti estrogenic activity on endometrium and cervical mucus (19). Letrozole, is a selective aromatase inhibitor and increases FSH secretion from the anterior pituitary (20). However letrozole has not anti-estrogenic peripheral activity, furthermore it is cleared from the circulation more rapidly than clomiphene citrate (half-life 48 hours for letrozole vs. 2 weeks for CC) (21). Based on our knowledge the impact of CC and letrozole on endometrium blood flow in Iranian women with unexplained infertility did not study before. So in this controlled clinical trial we evaluated the effect of letrozole and clomiphene citrate on endometrium blood flow. We measured the pulsatility index, resistance index and pregnancy rate in 90 women. The results did not indicate significant difference between three groups regarding pulsatility index, resistance index and pregnancy rate. In line with our study Bayar et al in a randomized controlled trial (RCT) compared letrozole with clomiphene citrate and indicated no significant difference in either the ovulation rate or the clinical pregnancy rate between the two groups (22). Furthermore another largest RCT by Badawy et al compared letrozole versus clomiphene on women with PCOS (poly cystic ovary syndrome) and specified that the ovulation and pregnancy rates between the two groups was comparable, however the endometrial thickness in clomiphene group was meaningfully higher than letrozole group (23). Additionally, in agreement to our results Jee et al compared the clinical outcomes between letrozole and clomiphene citrate (CC) in gonadotropin combined intrauterine insemination (IUI) cycles in 93 infertile women and implied that letrozole produce a comparable pregnancy rate vs. CC in gonadotropin combined IUI cycles (24).

In contrast to our findings Atay et al compared letrozole (2.5 mgs) with clomiphene citrate (100 mgs/day) in 106 women with PCOS and designated that the ovulation rate and the clinical pregnancy rate were significantly higher in the letrozole than clomiphene group. Moreover the authors advised letrozole as a better first line treatment in these patients (25). Consistently another study by Jirge et al compared endocrine and follicular dynamics in 30 ovulatory volunteer women in natural cycles and cyclesstimulated with clomiphene or letrozole and pointed out that the shorter follicular phase and less multiple follicular development in letrozole than CC group, however the ovulation profiles were similar in all cycles (26).

The most of studies that we reviewed in this article were consistent with our experience and emphasized that two agents have relatively equal effect on ovulation and pregnancy rate in unexplained infertile women. However mono follicular cycles in letrozole group was more than CC in some studies (27). Moreover some of these studies indicated that endometrial thickening in letrozole group was higher than CC (28). Additionally another study showed letrozole increase the endometrial thickening more than CC without any adverse effect (29). These findings confirm the hypotheses that declare lack of peripheral anti estrogenic effect of letrozole.

The main limitation of our study is the relatively small sample size so further investigations are recommended with larger series to validate the findings reported here.

In conclusion our study confirmed the previous reports and showed that letrozole and clomiphene citrate have comparable impact on uterine blood flow and pregnancy rate in women with unexplained infertility.


Acknowledgements

We would like to thank the nursing, administrative and secretarial staff of the obstetrics and gynecology department and clinic at our hospital for their contribution to the maintenance of our patient record without which this project would have been impossible. There is no conflict of interest in this article.


References
1. The Practice Committee of the American Society for Reproductive MedicineEffectiveness and treatment for unexplained infertilityFertil SterilYear: 2006861114
2. Stephen EH,Chandra A. Updated projections of infertility in the United States: 1995–2025Fertil SterilYear: 1998703049660416
3. The Practice Committee of the American Society for Reproductive Medicine, Optimal evaluation of the infertile femaleFertil SterilYear: 2006862647
4. Noyes N,Liu HC,Sultan K,Schattman G,Rosenwaks Z. Endometrial thickness appears to be a significant factor in embryoimplantation in in-vitro fertilizationHum ReprodYear: 199510919227650143
5. Tekay A,Martikainen H,Jouppila P. Blood flow changes in uterine and ovarian vasculature, and predictive value of transvaginal pulsed colour Doppler ultrasonography in an in-vitro fertilization programmeHumReprodYear: 19951068893
6. Coulam CB,Stem JJ,Soenksen DM,Britten S,Bustillo M. Comparison of pulsatility indices on the day of oocyte retrieval and embryo transferHum ReprodYear: 1995108247745076
7. Badawy A,State O,Abdelgawad S. N-Acetyl cysteine and clomiphene citrate for induction of ovulation in polycystic ovary syndrome: a cross-over trialActaObstet et GynecolYear: 20078621822
8. Badawy A,El Nashar A,El Totongy M. Clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for augmenting ovulation in the management of unexplained infertility: a randomized double-blind controlled trialFertil SterilYear: 2006866477016831439
9. Dickey RP,Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrateHum Reprod UpdateYear: 199624835069111183
10. Dickey RP,Taylor SN,Curole DN,Rye PH,Pyrzak R. Incidence of spontaneous abortion in clomiphene pregnanciesHum ReprodYear: 199611262389021363
11. Acharya U,Irvine DS,Hamilton MP,Templeton AA. The effects of three anti-oestrogen drugs on cervical mucus quality and in-vitro sperm–cervical mucus interaction in ovulatory womenHum ReprodYear: 19938437418473463
12. Homburg R. Clomiphene citrate—end of an era? A mini-reviewHum ReprodYear: 2005820435115878925
13. Lamb HM,Adkins JC. Letrozole: a review of its use in postmenopausal women with advanced breast cancerDrugsYear: 1998561125409878997
14. Dowsett M,Jones A,Johnston SR,Jacobs S,Trunet P,Smith IE. In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal women with breast cancerClin Cancer ResYear: 19951151159815951
15. Sinha S,Kaseta J,Santner SJ,Demers LM,Bremmer WJ,Santen RJ. Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the ratBreast Cancer Res TreatYear: 19984845519541188
16. World Health OrganizationWHO laboratory manual for the examination of human semen and sperm cervical mucus interactionYear: 19994th edCambridgeCambridge University Press
17. Kupesic S,Kurjak A. Uterine and ovarian perfusion during the preovulatory period assessed bytransvaginal color DopplerFertil SterilYear: 199360439438375523
18. Chien LW,Lee WS,Au HK,Tzeng CR. Assessment of changes in utero- ovarian arterial impedance during the peri implantation priod by Doppler sonography in women undergoing assisted reproductionUltra sound obstetgynecoleYear: 200423496500
19. Homburg R. Clomiphene citrate - end of an era? A mini reviewHum ReprodYear: 20052020435115878925
20. Holzer H,Casper R,Tulandi T. A new era in ovulation inductionFertil SterilYear: 2006852778416595197
21. Young SL,Opashi MS,Fritz MA. Serum concentration of euclomiphene andzuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile womenFertil SterilYear: 1999716394410202872
22. Bayar U,Basavan M,Coskun A,Gezer S. Use of an aromatase inhibitors in Patient with polycystic ovary syndrome: a prospective randomized trialFertil SterilYear: 20068614475117070196
23. Badawy A,Abdul Aal I,Abulatta M. Clomiphene citrate or Letrozole in women polycystic ovarian syndrome: a prospective randomized trialFertil SterilYear: 2009928495217582406
24. Jee BC,Ku SY,Suh CS,Kim KC,Lee WD,Kim SH. Use of letrozole versus clomiphene citrate combined with gonadotropins in intrauterine insemination cycles: a pilot studyFertil SterilYear: 2006851774716677640
25. Atay V,Cam C,Muhcu M,Cam M,Karateke A. Comparision of Letrozole and Clomiphene citrate in women with polycystic ovaries undergoing ovarian stimulationJ Int Med ResYear: 20063473616604826
26. Jirge PR,Patil RS. Comparison of endocrine and ultrasound profilesduring ovulation induction with clomiphene citrate andletrozole in ovulatory volunteer womenFertil SterilYear: 2010931748319028384
27. Requena A,Herrero J,Landeras J,Navarro E,Neyro JL,Salvador C,et al. Use of letrozole in assistedreproduction: a systematic review and meta-analysisHum Reprod UpdateYear: 2008145718218812422
28. Badawy A,Abdel Aal I,Abulatta M. Clomiphene citrate or letrozole for ovulation induction in women withpolycystic ovarian syndrome: a prospective randomized trialFertil SterilYear: 200992860318166179
29. Mitwally M,Casper RF. Aromatase inhibition reduces gonadotrpin does required for controlled ovarian stimulationin women with unexplained infertilityHum ReprodYear: 2003815889712871867

Tables
[TableWrap ID: T0001] Table 1 

The demographic and clinical data in three groups


Groups Letrezole CC Control P value
Age 23.1 ± 2.3 23.07 ± 1.5 22.9 ± 1.3 NS
BMI 26.8 ± 3.6 26.6 ± 3.51 25.8 ± 2.7 NS
Cycle days 5.3 ± 1 5.2 ± 0.7 4.9 ± 0.5 0.006
Interval between cycles 29.4 ± 3.5 31.4 ± 2.9 30 ± 3.3 NS
Infertility time (years) 4.2 ± 1.8 3.4 ± 3 3 ± 0.8 0.07
Nulipar 86.6% 80% 73.3% NS
Multipar 13.4% 20% 26.7% NS

[TableWrap ID: T0002] Table 2 

Resistance index (RI) Pulsatility index (PI)


Groups letrozole CC Control p value
Resistance index (RI) 0.85 ± 0.2 0.85 ± 0.03 1.01± 0.02 NS
Pulsatility index (PI) 2.8 ± 0.04 2.4 ± 0.04 2.6 ± 0.02 NS

[TableWrap ID: T0003] Table 3 

The pregnancy rate on three groups


Groups letrozole CC Control p value
β-HCG positive 58% 53.6% 46% NS
β-HCG negative 39% 46.7% 53.3% NS
β-HCG intermediate 3% - - -


Article Categories:
  • Original Article

Keywords: Uterine Blood Flow, Letrozole, Clomiphene Citrate, Ovulation Induction, Unexplained Infertility.

Previous Document:  Parkinsonism in a recurrent cervical cancer patient: case report and review of the literature.
Next Document:  Obstetric and Neonatal Outcome in PCOS with Gestational Diabetes Mellitus.