Background: Polycystic ovary syndrome ( PCOS ) is associated with about 75 % of adult females who suffer from sterility due to anovulation. Additionally, around 20- 25 % of an ovulatory adult females with PCOS do non react at all to clomiphene citrate and are considered to be ‘clomiphene- immune ‘ . Aromatase inhibitors have been suggested as an alternate intervention to clomiphene as the disagreement between ovulation and gestation rates with Clomid citrate has been attributed to its anti-estrogenic action and estrogen receptor depletion.
Aim: The Present survey is designed to compare Metformin – letrozole with Metformin – Clomid citrate in Clomid opposition PCO patients undergoing IUI.
Materials and Methods: In this individual blind randomised test, ovarian rhythms were studied in 100 clomiphene- immune patients with PCOS.The Inclusion standards concerned PCOS patients who had failed to go pregnant after having 150 mg Clomid citrate per twenty-four hours in3 months. The Patients were matched for their age, organic structure mass index ( BMI ) , and sterility period. They were indiscriminately allocated to a metformin-letrozole group ( n = 50 ) and a metformin- Clomid citrate group ( n = 50 ) . Chemical and clinical gestations were assessed after IUI. Abortion rates were determined in both groups.
Consequences: Sing gestation rate, there is no important difference between the two groups. One abortion ( 2 % ) occurred in the metformin-clomiphene citrate group, whereas none was seen in the metformin- letrozole group.
Decision: There is no important difference in gestation rate between Clomid citrate and letrozole groups although it has been 2 % in the former and 5 % in the latter.
Keywords: Letrozole, Clomiphene Citrate, Ovarian stimulation, PCO, IUI, Metformin.
Polycystic ovary syndrome ( PCOS ) is associated with about 75 % of adult females who suffer from sterility due to anovulation ( 1,2 ) . The debut of little sums of FSH indirectly with Clomid citrate
into the circulation is capable of bring oning ovulation and gestation in a big figure of anovulatory adult females with PCOS. ( 3 ) . Ovulation is restored in about 80 % but consequences in gestation in lone about 35-40 % of patients who are given Clomid ( 3,4,5 ) . Additionally, around 20- 25 % of anovulatory adult females with PCOS do non react at all to clomiphene citrate and are considered to be ‘clomiphene immune ‘ ( 6,7 ) . Patients who do non react to clomiphene are likely to be more corpulent, insulin- resistant, and hyperandrogenic than those who do react ( 7 ) .
Numerous surveies in adult females who were treated with Clomiphene Citrate and in assorted theoretical account systems have reported inauspicious effects on the quality or measure of cervical mucous secretion, endometrial growing, and ripening ( 8,9,10,11,12,13 ) . It is by and large believed that these effects are most evident at higher doses or after longer continuances of intervention with Clomiphene Citrate ( 9,10,11 ) .
The endometrium is believed to be one of the most of import marks of the antiestrogenic consequence of Clomiphene Citrate and may explicate a big portion of the lower gestation rate and the possible higher abortion rate with Clomiphene Citrate. A decrease in endometrial thickness below the degree thought to be needed to prolong nidation was found in up to 30 % of adult females having Clomiphene Citrate ( 10 ) . This observation has been confirmed by other surveies such as Nelson et Al, 1990 and Li et Al, 1992. ( 12,13 ) .
Aromatase inhibitors have been suggested as an alternate intervention to clomiphene as the disagreement between ovulation and gestation rates with Clomid citrate has been attributed to its anti-estrogenic action and estrogen receptor depletion. The aromatase inhibitors do non possess the inauspicious anti-estrogenic effects of Clomid but, by stamp downing estrogen production, mime the cardinal decrease of negative feedback through which Clomid plants.
Letrozole, the most prevalently used antiaromatase for this indicant, has been shown to be effectual, in early tests, in bring oning ovulation and gestation in adult females with anovulatory PCOS and unequal Clomid response ( 14 ) and bettering ovarian response to FSH in hapless respondents ( 15 ) . Evidence from larger tests is still awaited, but some encouragement may be taken from the solidness of the on the job hypothesis and the success of the preliminary consequences. The Present survey is designed to compare Metformin – letrozole with Metformin – Clomid citrate in Clomid opposition PCO patients undergoing IUI.
Material and methods
In this individual blind randomised test, 148 ovarian rhythms were studied in 100 clomiphene- opposition patients with PCOS who were chosen among 250 PCOS patients go toing the sterility research centre of Shahid Sadoughi medical university in Yazd, Iran during the old ages 2007-2008.The Study was approved by Yazd Medical University Ethical Board and was to the full supported and funded by Yazd Medical University.
In this survey, 50 people are needed in each group so as to derive a important difference of 22 % in gestation rate at a important degree of 5 % and a power 80 % . Randomization is conducted on the footing of random Numberss table right after metformin disposal. The major standards for diagnosing of PCOS were oligo and /or anovulation, clinical or biochemical marks of hyperandrogenism, and polycystic ovaries, viz. 10 or more follicles with 2 – 9 millimeters size ) which are in conformity with the revised 2003 Rotterdom standards of PCOS. Thyroid, liver, kidneys function, and prolactin degree were checked for normal values. Samples without any of them were excluded from the survey. Datas were collected from the samples via questionnaires along with conversation and physical scrutiny done by a medical research worker. Hysterosalpingo graphy and sperm analysis of our samples were normal.
Inclusion standards covered PCOS patients who had failed to go pregnant after having 150 mg Clomid citrate per twenty-four hours in 3 months that considered as clomiphene failure. In this survey, nevertheless, the selected instances took the drug in merely one intervention rhythm Exclusion standards concerned patients with a history of liver and kidney failure, cardiovascular disease, diabetes ( based on the standards set by the American Diabetic Association ) , or patients who had taken Glucophage or drugs impacting insulin secernment or Clomid citrate in the old 2 months.
The Patients were indiscriminately allocated to a metformin-letrozole group ( n=50 ) and a metformin Clomid citrate group ( n = 50 ) .
All the patients of both groups received 1500 mg/day Glucophage for 6-8 hebdomads. After metformin disposal, two patients in the letrozole group had drug side effects and were excluded from the survey. If gestation occurred, the patient was excluded from the survey. In instance of gestation failure after the terminal of this period, the patients in the metformin- Clomid group were given 100 mg Clomid citrate for 5 yearss get downing from the 3rd twenty-four hours of their catamenial rhythm, and those in the metformin-letrozole group received 5 milligrams letrozole for 5 yearss from the 3rd twenty-four hours of their catamenial rhythm. The drug disposal continued in three rhythms for all the included patients. Monitoring of follicular development was done by transvaginal echography every other twenty-four hours from twenty-four hours 12 of the rhythm by a individual sonographist. A sum of 10 000 IU of HCG was administered to those in whom at least one ovarian follicle was ?18 millimeter in size. Endometrial thickness, figure of mature follicles & A ; gt ; 18mm, estradiol degree, and the ratio of chemical and clinical gestations were determined.
Chemical gestations were assessed 2 hebdomads after IUI by serum degree of ? HCG measuring. Being of at least one gestational pouch in echography was confirmed as a clinical gestation. Ongoing gestation was defined as the observation of at least one foetus with bosom activity in echography after the first trimester of gestation. Abortion rates were determined in both groups.
The sample is divided into two groups utilizing the random allotment package. SPSS version 12.0 package was used for the statistical analysis. T-test, chi-square and Fisher exact trials were used when appropriate. P-values less than 0.05 were considered as statistically important.
On the whole, 148 ovarian rhythms were studied in 98 patients ( 70 rhythms in 48 patients in the Glucophage – letrozole group and 78 rhythms in 50 patients in the Glucophage – Clomid citrate group ) .
Ninty eight PCO patients who were allocated to the two groups were included in the survey. All the patients had at least 2 out of 3 Rotterdom standards. No important statistical difference was observed between the two groups with regard to the mean of demographic variables, including age, BMI, continuance of sterility.
The entire Mean estradiol on the twenty-four hours of HCG disposal was significantly higher among the patients in the metformin- Clomid group as compared with those in the metformin-letrozole group ( 175.01 ± 168.93 Vs 70.24 ± 138.32 pg /ml ; P & A ; lt ; 0.05 ) ( Table I ) . Average endometrial thickness was besides significantly lower in the metformin- Clomid group as compared to those in the metformin-letrozole group ( 0.9 ± 9.3 centimeters versus 1.03 ± 10.2 centimeter ; P & A ; lt ; 0.05 ) ( Table I ) .
One abortion ( 2 % ) occurred in the metformin-clomiphene citrate group, whereas none were seen in the metformin- letrozole group. The clinical gestation rate was non significantly different between the two groups ( 4 patients ( 8.3 % ) in metformin-letrozole group as compared to 1 patient ( 2 % ) in metformin- Clomid group ; P & A ; gt ; 0.05 ) ( Table II ) . The rate of gestation in the rhythms was 1 % ( 1of 78 rhythms ) in the clomiphene-citrate group but 5 % ( 4 of 70 rhythms ) in the letrozole group, which was non statistically important.
Table I. Comparison of baseline parametric quantities and different variables in the metformin-clomiphene citrate group and the metformin-letrozole group based on average ± SD
Metformin Clomid group
Metformin letrozole group
29.55 ± 3.47
28.54 ± 3.13
Body mass index
29.21 ± 2.92
28.98 ± 3.83
Endometrial thickness on twenty-four hours of hcg disposal ( mm ) *
9.3 ± 0.9
10.2 ± 1.03
& A ; lt ; 0.05
Duration of sterility
LevelE2Mean sum ( pg/ml ) on twenty-four hours of HCG disposal
168.93 ± 175.01
138.32 ± 70.24
& A ; lt ; 0.05
Number of follicles & A ; gt ; 18 millimeter in diameter
1.85 ± 0.27
1.80 ± 0.32
P-value: No difference was found between the two groups for the above parametric quantities ( by t-Test as appropriate ) .
Table II. Comparison of Pregnancy and abortion rate in the metformin-clomiphene citrate group and the metformin-letrozole group based on average ± SD
Metformin Clomid group
Metformin letrozole group
0.95 CI ( 0.5-34.5 )
Regular menstruations after Glucophage
36 ( 75 % )
36 ( 72 % )
0 ( 0 % )
2 ( 4 % )
Chemical gestation rate
Clinical gestation rate
Intension to handle Analysis
1 ( 2 % )
4 ( 8 % )
P-value* : No difference was found between the two groups for the above parametric quantities ( by exact t-Test as appropriate ) .
The consequences of this survey indicate that clomiphene-failure adult females with PCOS experience higher gestation rates and fewer abortions when they receive combined metformin-letrozole in comparing with metformin-clomiphene. No important relationship was observed between age, BMI, and continuance of sterility in the Clomid citrate and the letrozole groups was observed. Mean of endometrial thickness on the twenty-four hours of HCG disposal was significantly less in patients that received Clomid citrate than those who received letrozole. ( Our consequences were similar with consequences that were presented by Mitwally et Al ( 16,17 ) . But in survey that was done by Al-Fozan et al a important relationship was non reported between these two groups. Fisher et Al in their survey believed that the cause of endometrial thickener in patients having letrozole is because of improved vascularisation as compared with Clomid citrate ( 18 ) . Some surveies showed that Clomid citrate can do unequal endometrial thickness in 15-50 % of patients ( 19 ) and the quality or measure of the cervical and endometrial mucous membrane can impact ( 14 ) . These side effects may be attributed to the anti-estrogenic consequence and the comparatively longer half life of Clomid citrate, therefore diminishing endometrial thickness by its long-run consequence in diminishing the figure of estrogen receptors ( 14 ) .
One abortion was happened in the metformin-clomiphene-citrate group whereas none were seen in the metformin- letrozol group. The clinical gestation rate between the two groups did non demo important difference. In survey was performed by Mitwally and Casper consequence of letrozol disposal in 10 adult females with PCOS was assessed. They found that gestation occurred in 20 % of adult females ( 14 ) . Sammour et Al in their survey on efficaciousness of letrozole and clomiphen citrate in 49 adult females with idiopathic sterility showed that gestation rate was higher in patients having letrozole than clomiphene citrate group ( 16.7 versus 5.6 % ) ( 20 ) . Harmonizing to consequences of those surveies ; gestation rate is higher in patients having letrozole than clomiphene citrate group but is lower when compared with the current survey. Moll et Al in their survey showed that in clomiphene citrate-resistant adult females, the combination of clomiphene plus Glucophage was the preferable intervention. Some surveies reported that rate of abortion was higher than expected in Clomid group. ( In this survey ) , There is one instance of abortion in Clomid group. This addition may be due to alterations in peripheral estrogen degree in the cervical and endometrial mucous membrane. Some grounds exists that assess the risky effects of Clomid citrate accretion during gestation and the initial phases of development in mouse and coney but has non been proved ( 21 ) . We Hypothesize that Clomid may hold direct inauspicious effects on oocytes. Some surveies reported that unequal uterine blood flow during the early luteal stage was one of the likely causes of low gestation rate in patients who received clomiphen citrate. ( 21 ) Womans with oligomenorrhea and PCOS had some ovulatory upset because of insulin opposition and its related factors ( 22 ) . Serum insulin degree was chief function in PCOS pathogenesis. Metformin can increase tissue sensitiveness to insulin every bit good as lessening plasma insulin degree and hepatic glucose production. In PCOS, Glucophage can diminish the degree of L.H. and ovarian androgen degree every bit good as right hyperinsulinemia ( 23 ) . Some clinical tests presented the consequence of Glucophage on the activity of ovaries ( 22 ) . These surveies showed that Glucophage can rectify catamenial abnormality by bring oning ovulation ( 16,17 ) . Harmonizing to Nestler survey, ovarian response to clomiphen was higher in corpulent adult females with PCOS ( 24 ) .
Aromatase is the enzyme necessary for change overing androstenedione to estrone and eventually to E2 in peripheral tissues and Aromatase inhibitors can forestall peripheral estrogen production in patients that have higher peripheral estrogen production ( 25 ) . Harmonizing to noted mechanism, some of selective aromatase inhibitors such as letrozole are used to bring on ovulation particularly in sterile adult females with PCOS ( 21 ) . They may besides hold direct action on the ovaries and increase follicular sensitiveness to FSH. Women with PCOS may besides hold comparatively low degrees of ovarian aromatase. High androgen degrees result in the formation of multiple little ovarian follicles. In add-on, androgens increase the figure of FSH receptors in the ovaries, which consequences in increasing FSH sensitiveness. High exogenic FSH or low estrogen production because of aromatase inhibitors will take to growing of one or more ovarian follicles ( 25,26 ) .
Our Consequences show that letrozole is a suited option to clomiphene citrate, particularly in instances, who are ( clomiphene failure ) , or it can be a first-line drug in ovarian stimulation and intervention of anovulation. It seems that letrozole and is a safe, dependable and inexpensive drug with curative value ( 16,17 ) . Serum clearance of letrozole is faster than clomiphene citrate ( 50h versus 4 hebdomads ) and because letrozole does non diminish estrogen receptors, has no hurtful effects similar to that found with clomiphene citrate on the endometrium, and lead to higher gestation rates ( 4,12 ) . Because we did n’t hold one optimal dose for curative effects of letrozole, Further surveies are necessary for accomplishing that ( 16,17 ) .Moreover I.U.I. had no favourable success and because I.U.I. wasnot considered as a curative mode in recent mentions ( Textbook of Assisted Reproductive Technologies, David K Gardner, etal 2009. ) , it should be better to make I.V.F. or ICSI in patients who donot react to medical therapy.