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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 31  |  Issue : 1  |  Page : 38-45

Letrozole withdexamethasone versus clomiphene citrate with dexamethasone for induction of ovulation in polycystic ovary


1 Department of Obstetrics and Gynecology, Faculty of Medicine-Menoufiya University, El-Shohadaa, Egypt
2 Resident of Obstetrics and Gynecology in General El-Shohadaa Hospital, El-Shohadaa, Egypt

Date of Submission21-Dec-2016
Date of Acceptance27-Feb-2017
Date of Web Publication14-Jun-2018

Correspondence Address:
Ahmed M El-Naggar
Kfar El-Sheikh Khalil, Shebin El-Kom, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_703_16

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  Abstract 


Objective
The objective of this study was to compare the effect of letrozole with dexamethasone(DEX) versus clomiphene citrate(CC) with DEX in ovulation induction in polycystic ovarian syndrome(PCOS).
Background
PCOS is a common endocrinologic disorder in women characterized by chronic anovulation, hyperandrogenemia, and infertility.
Patients and methods
Sixty women with PCOS were included in this study and subdivided randomly into two groups. GroupI included 30 women who took letrozole 2.5mg tablet times daily starting from day 2 to day 6 of menstrual cycle and DEX2mg/day orally in two divided doses starting from day 3 to day 12 of the cycle. GroupII includes 30 women who took the same protocol of DEX combined with CC 50mg two times daily starting from day 2 to day 6 of the menstrual cycle. Treatment was continued for three consecutive cycles. Main outcome measures are number and diameter of follicles, endometrial thickness, ovulation rate, and pregnancy outcome.
Results
In groupI, the number of mature follicles was less than three follicles/cycle with monofollicular stimulation, whereas in groupII it was more than three follicles/cycle with multifollicular stimulation. The mean diameter of follicles was 18.73 in groupI and 16.23 in groupII. Difference in endometrial thickness was highly statistically significant(P<0.001), where the mean endometrial thickness was 10.60 in groupI and 6.97 in groupII. Ovulation was more significantly detected after using letrozole than CC–in 20(62.5%) women in groupI and 12(37.5%) women in groupII(P<0.05). Pregnancy was achieved in 11(68.8%) women in groupI, which is significantly higher than that in groupII–five(31.2%) women(P=0.05).
Conclusion
Letrozole and DEX have more success rates in ovulation induction and pregnancy outcome than CC and DEX.

Keywords: clomiphene citrate, letrozole, polycystic ovary


How to cite this article:
Shabana AA, F. Al-Halby AE, E. Shaheen AH, El-Naggar AM. Letrozole withdexamethasone versus clomiphene citrate with dexamethasone for induction of ovulation in polycystic ovary. Menoufia Med J 2018;31:38-45

How to cite this URL:
Shabana AA, F. Al-Halby AE, E. Shaheen AH, El-Naggar AM. Letrozole withdexamethasone versus clomiphene citrate with dexamethasone for induction of ovulation in polycystic ovary. Menoufia Med J [serial online] 2018 [cited 2018 Aug 18];31:38-45. Available from: http://www.mmj.eg.net/text.asp?2018/31/1/38/234251




  Introduction Top


Infertility is defined as 1year of unprotected coitus without conception. It affects~10–15% of couples in the reproductive age. It has been attributed to various factors, among which is anovulation [1]. Polycystic ovary syndrome(PCOS) is the most common cause of anovulatory infertility [2].

PCOS is a common endocrinologic disorder in women characterized by chronic anovulation, hyperandrogenemia, and infertility [3]. PCOS affects ~4% of women of reproductive age [4]. PCOS is associated with insulin resistance and obesity, and abnormal hair growth on the face or body [5].

In 75% of patients with PCOS, ovulation induction occurs with clomiphene citrate(CC) treatment; however, 25% of patients are CC resistant and require alternative treatment [6].

CC is routinely used by many gynecologists to treat infertile anovulatory PCOS because of the low costs and the simplicity of administration and management [7]. CC resistance refers to persistence of anovulation after standard CC therapy [8].

For those CC nonresponders, there are adjunctive therapies that can be tried before gonadotropin therapy or laparoscopic ovarian drilling, including bromocriptine in the presence of hyperprolactinemia, and dexamethasone(DEX) [9].

Induction of ovulation by adding DEX(high dose, short course) to CC in CC-resistant PCOS is associated with no antiestrogenic effect on the endometrium and higher ovulation and pregnancy rates [10].

The aromatase inhibitor letrozole was reported to be effective in inducing ovulation with better pregnancy rate, endometrial development, and favorable cervical mucus as compared with CC. Letrozole is a potent aromatase inhibitor that peripherally decreases the production of estrogen from androgen [11].

Advantages of letrozole include reduced multiple pregnancies, absence of antiestrogenic adverse effects [12], and rare occurrence of ovarian hyperstimulation syndrome(OHSS) [13].

Our study aimed to compare the effect of letrozole with DEX versus CC with DEX in ovulation induction in PCOS.


  Patients and Methods Top


This randomized controlled clinical trial was performed at the Department of Obstetrics and Gynecology in El-Menoufia University Hospital(outpatient clinic) and General El-Shohadaa Hospital during the period from October 2014 to July 2015. After obtaining approval from Faculty of Medicine Ethics Committee for Human Research, all enrolled women provided informed consent for participation in the study. The patients included in this study were randomly allocated by an independent statistician with concealment of treatment allocation by use of sealed opaque envelopes that were given to a third personnel(nurse) who assigned patients to the study arms. This study included 60 infertile women with PCOS who were divided into two groups –30 in each group.

In our inclusion criteria, women selected for this study had all of the following criteria: age 20–35years and polycystic ovary disease that can be diagnosed according to the criteria of American Society for Reproductive Medicine and European Society for Human Reproduction and Embriology consensus meeting on PCO held in Rotterdam [14] by the presence of two from the following three criteria: menstrual disturbances such as amenorrhea or oligomenorrhea; hyperandrogenism either clinically presented by hirsutism or biochemically measured of total or free testosterone and ultrasound(U/S) criteria of PCOS (12 or more follicles measuring 2–9mm in diameter, increased ovarian volume>10cm, increase stromal volume, and echogenicity); and anovulation, which is documented by midluteal level of serum progesterone on cycle day 21 less than 3ng/ml. (Normal level of serum progesterone during luteal phase is 10–20ng/ml.) Husbands of all women were available with timed intercourse at proposed ovulation period and proved to have spermiograms within normal, as documented by a recent semen analysis(within 1month before starting treatment). Criteriafor normal semen analysis were considered according to the WHO(2005) standards that consider the 'normal' semen sample which contains; volume 1.5–5ml, concentration at least 20×106 spermatozoa/ml, motility more than 60% motile exhibiting good to excellent forward progressive movement within 60min after ejaculation, morphology more than 30% normal forms, and white blood cell count less than 5/HPF.

Exclusion criteria included patients who had hyperprolactinemia, thyroid disease, male factor infertility, known or suspicious tubal factor infertility(endometriosis), and unexplained infertility.

Methods

All women selected for this study were subjected to full history taking including detailed personal, obstetric, menstrual, and medical history; examination(breast, abdominal, and bimanual pelvic examination); hormonal profile [follicle-stimulating hormone(FSH), lutenizing hormone (LH), free testosterone, estradiol(E2), thyroid-stimulating hormone(TSH), and prolactin]; and baseline U/S on the first day of the menstrual cycle. Then, all 60 participants were subdivided randomly into two groups. GroupI included 30 women who took letrozole(Femara; Novartis) 2.5mg tablet two times daily starting from day 2 to day 6 of the menstrual cycle and DEX2mg/day orally in two divided doses starting from day 3 to day 12 of the cycle (high dose, short course) [10],[15]. GroupII included 30 women who took the same protocol of DEX combined with CC 50mg two times daily starting from day 2 to day 6 of menstrual cycle and the treatment was continued for three consecutive cycles. Ovulation was monitored by transvaginal ultrasonographic folliculometry. Transvaginal U/S was performed by using the transvaginal probe(Model Nemio XG SSA-580 A; Toshiba, Tokyo, Japan). Folliculometry was done starting from day 7 of the menstrual cycle and every other day accordingly on days 9, 11, and 13 of the menstrual cycle but maximally to day 17 of the menstrual cycle with measurement of endometrial thickness, number, and diameter of the growing follicle(s). Human chorionic gonadotropin(hCG)(10000IU) was given intramusculary to trigger ovulation when at least one mature follicle of 18mm or more was detected or endometrial thickness more than 6mm. Every patient was advised to have sexual intercourse 24–36h after hCG injection. Luteal phase support in the form of micronized progesterone 100mg/day orally for 14days was given to every patient. Evidence of failure to respond to induction was documented by failure of oocyte maturation or those with endometrial thickness less than 6mm. Serum hCG was measured after 2weeks of hCG injection in the absence of menstruation for diagnosis of pregnancy. Earlydetection of OHSS, multiple pregnancies, and any other complications by U/S was performed.

The main outcome measures were number of follicles in each group, diameter of follicles in each group, endometrial thickness, ovulation rate, pregnancy outcome, and occurrence of complications such as OHSS and multiple pregnancies[Figure1].
Figure 1: Flow chart of the study. E2, estradiol; FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; LH, lutenizing hormone; TSH, thyroid-stimulating hormone.

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Statistical analysis

Data entry, coding, and analysis were performed using statistical package for social science [16](released 2011, IBM SPSS Statistics for Windows, version20.0; IBM Corp., Armonk, NewYork, USA). Data of this study were of both qualitative and quantitative types. Qualitative data were expressed in number(frequency) and percentage. Quantitative data were expressed in mean, standard deviation of the mean(SD), and SEM. Tests of significance used were Student's t-test to assess the difference in mean between two groups and c2-test to assess the relation between two or more qualitative variables. Level of significance used was 95%. Therefore, P value more than 0.05 was considered a nonstatistical significant outcome, P value less than or equal to 0.05 was considered a statistically significant outcome, and that P value less than or equal to 0.01 was considered a highly statistically significant outcome.


  Results Top


The present study includes a total of 60 women with the diagnosis of PCOS. The participants were divided into two groups: groupI included 30 women who took letrozole and DEX and GroupII included 30 women who took CC and DEX.

There was a nonsignificant difference between the studied groups regarding age of patients(P>0.05), where the mean age of patients in groupI was 25.97 and the mean age of patients in groupII was 24.97[Table1].
Table 1: Comparison between groups of the study as regards age of patients (years)

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There was a nonsignificant difference between the studied groups regarding parity(P>0.05), where the number of nullipara(P0+0) was 20 in groupI and 20 in groupII, and number of P1+0 women was 6 in groupI and 6 in groupII. In P2+0 women, the number is 4 in groupI and 4 in groupII[Table2].
Table 2: Comparison between groups of the study as regards parity

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There was a nonsignificant difference between the studied groups regarding hormonal profile(P>0.05). The mean values of the following hormones among the studied groups are as follows: TSH is 2.39 in groupI and 2.58 in groupII, prolactin is 16.43 in groupI and 17.90 in groupII, E2 is 42.84 in groupI and 45.10 in groupII, free testosterone is 0.30 in groupI and 0.33 in groupII, LH is 10.97 in groupI and 9.85 in groupII, and, finally, FSH is 6.25 in groupI and 6.37 in groupII[Table3].
Table 3: Comparison between groups of the study as regards hormonal profile

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There was a statistically significant difference between the studied groups regarding number of follicles (P<0.01), where the combination of letrozole and DEX shows stimulation of one or more follicles, whereas the combination of clomiphene and DEX shows stimulation of 2, 3, and 4 follicles[Table4].
Table 4: Comparison between groups of the study as regards number of follicles

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There was a statistically significant difference between the studied groups regarding diameter of follicles (P<0.01), where the mean diameter of follicles is 18.73 in groupI and 16.23 in groupII[Table5].
Table 5: Comparison between groups of the study as regards diameter of follicles

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There was a high statistically significant difference between the studied groups regarding endometrial thickness (P<0.001), where the mean endometrial thickness was 10.60 in groupI and 6.97 in groupII [Table6].
Table 6: Comparison between groups of the study as regards endometrial thickness

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Regarding the duration to reach follicular maturity and giving hCG injection in both groups of the study, follicular maturity was achieved in a relatively shorter period among women in the letrozole group (day 13–day 17 of the menstrual cycle) than those of the clomiphene group(day 14–day 17 of the menstrual cycle).

There was a statistically significant difference between the studied groups regarding ovulation(P<0.05), where in groupI the number of women who had ovulation is 20 and the ovulation rate is 62.5%, whereas in groupII the number of ovulating women is 12 and ovulation rate is 37.5%[Table7].
Table 7: Ovulation results among the study group

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There was a statistically significant difference between the studied groups regarding pregnancy outcome(P=0.05), where in groupI the number of pregnant women is 11 and pregnancy outcome is 68.8% and in groupII the number of pregnant women is 5 and pregnancy outcome is 31.2%[Table8].
Table 8: Comparison between groups of the study as regards pregnancy outcome

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  Discussion Top


PCOS has multiple reproductive, metabolic, and cardiovascular components, with health implications across a woman's life span. Approximately 75% of these women suffer from infertility due to anovulation [17]. The first line of treatment to induce ovulation is CC, but about 20% of CC-treated women who fail to ovulate are considered to be CC-resistant. On induction of ovulation by CC, if anovulation persists or pregnancy does not occur at a dosage level of 150mg per day other medications may be added to the regime to induce ovulation [18]. Addition of oral DEX to clomiphene therapy has been advocated to improve the chances of ovulation and pregnancy without any described side effects or serious sequelae [19].

In a study by Parsanezhad etal. [15] on 230patients, the ovulation rate was significantly higher in the DEX+CC group when compared with the CC alone group. The pregnancy rate was also higher. Both groups were treated for up to six cycles.

In addition, Elnashar etal.[10] evaluated the efficacy of adding DEX(high dose, short course) to CC in CC-resistant PCOS with normal DHEAS in induction of ovulation in 80patients divided into two groups and matched for age, duration of infertility, and BMI. The ovulation and pregnancy rates in their DEX group showed significant results, which were comparable to those of Parsanezhad etal. [15].

Elnashar etal.[10] concluded that induction of ovulation by adding DEX(high dose, short course) to CC in CC-resistant PCOS with normal DHEAS is associated with no adverse antiestrogenic effect on the endometrium and higher ovulation and pregnancy rates in a significant number of patients. Induction with DEX appears to be independent of age, period of infertility, BMI, or WHR. Addition of DEX to CC is an effective, inexpensive, and safe method for stimulating follicular development in CC-resistant PCOS and may be tried before gonadotropins and laparoscopic ovarian drilling.

Begum etal. [20] explored the efficacy of letrozole in folliculogenesis by reducing androgen to some extent in PCOS. They concluded that use of letrozole as an adjuvant of ovulation-inducing agent is safe, economic, and effective for PCOS patients. It can eliminate the use of invasive LOD and risky gonadotropins in most of the PCOS cases.

El Bigawy etal.[16] have demonstrated in their prospective randomized study the advantages of the use of letrozole in patients with PCOS, which is mono-ovulation and absence of antiestrogenic effect on endometrium, and higher pregnancy rate per cycle. These properties make letrozole a viable alternative to CC in patients with PCOS.

The present study aimed to compare the role of CC with DEX versus letrozole with DEX in improving induction of ovulation in PCOS in 60 women with the diagnosis of PCOS, who were divided into two groups: groupI included 30 women who took letrozole and DEX and groupII included 30 women who took CC and DEX.

In the present study, the two studied groups were equal in number and there were no statistically significant differences between the studied groups regarding patients' characteristics: age, parity and hormonal profile(basal hormone levels) of FSH, LH, E2, free testosterone, TSH, and prolactin(P>0.05).

Women's response of the following parameters was compared in both groups as regards the number of follicles, diameter of follicles, endometrial thickness, ovulation rate, pregnancy outcome, and occurrence of complications such as OHSS and multiple pregnancies.

In our study, there were statistically significant differences between the studied groups regarding number and diameter of follicles, day of hCG administration, ovulation rate, and pregnancy outcome. In addition, there was a high statistically significant difference between the studied groups regarding endometrial thickness.

These statistical data are consistent with the results of other several studies, which have assessed the efficacy of aromatase inhibitors such as letrozole for ovulation induction compared with CC. Findings of these studies deserve to be commented on.

As regards number of follicles, the current study detected a statistically significant difference between the two studied groups(P<0.01). In groupI the total number of mature follicles was less than three follicles/cycle with tendency to mono-oocyte stimulation, whereas in groupII the total number of mature follicles was more than three follicles/cycle with tendency to multi-oocyte stimulation.

The number of stimulated mature follicles was one follicle in 11(73.3%) women in groupI compared with four(26.7%) women in groupII; two stimulated mature follicles were detected in 16(57.1%) women in groupI compared with 12(42.9%) women in groupII; three stimulated mature follicles were detected in three(25%) women in groupI compared with nine(75%) women in groupII; and four stimulated mature follicles were detected in no women in groupI compared with five(100%) women in groupII.

These results were in agreement with many other studies, whereAl-Fouzan etal.(2005), Jee etal.(2006), and Badawy etal.(2007) found a significant reduced number of prevoulatory follicles(P=0.03) in letrozole compared with CC. In addition, these agreed with the results of Atay etal.(2009), who found that the number of mature follicles was significantly lower in the letrozole group.

As regards diameter of follicles, there was a statistically significant difference between the studied groups (P<0.01), where the mean diameter of follicles is 18.73 in groupI and 16.23 in groupII. Theseresults were in agreement with those of Begum etal. [21], who found that there is a significant difference in follicular development in both the groups(P<0.05), where average follicular diameter by day 16 of the cycle was 18.84 in the letrozole group and 16.19 in the CC group.

Clomiphene, a nonsteroidal compound, structurally similar to estrogen, blocks estrogenic hypothalamic receptors, resulting in blinding of the hypothalamus–pituitary axis to endogenous circulating estrogen. This in turn triggers release of FSH from the anterior pituitary following alterations in gonadotropin-releasing hormone pulsatility. Clomiphene also has peripheral antiestrogenic action at the level of the endometrium and cervical mucus, partly explaining the discrepancy in ovulation rates and pregnancy rates and thinning of the endometrium [22].

Letrozole, a selective aromatase inhibitor, prevents the conversion of androgens to estrogen, thus releasing the hypothalamopituitary axis from the negative feedback of estrogen, resulting in an increase of FSH secretion from the anterior pituitary. The accumulated androgens in the ovary further increase follicular sensitivity to FSH [23].

Importantly, unlike CC, letrozole is devoid of any antiestrogenic peripheral action leading to higher endometrial thickness. Letrozole is also cleared from the circulation more rapidly because of a shorter half-life(48h) as compared with CC, which may take up to 2months because of its prolonged half-life(2weeks) [24].

As regards endometrial thickness, there was a high statistically significant difference between the studied groups (P<0.001), where the mean endometrial thickness is 10.60 in groupI and 6.97 in groupII. These results are in agreement with the findings of Fisher etal.[25] and Begum etal.(2008), who described thicker endometrium in patients taking letrozole compared with patients who had CC-induced cycles.

As regards day of hCG administration and duration of follicular development, oocyte maturity was achieved in a relatively shorter period among women in the letrozole group(day 13–day 17 of the menstrual cycle) than those of the clomiphene group(day 14–day 17 of the menstrual cycle).

As regards ovulation, it was more significantly detected after using letrozole than CC–in 20(62.5%) women in groupI compared with 12(37.5%) women in groupII(P<0.05).

These results were in agreement with those of Begum etal.(2007) in his study of 64patients who had failed to ovulate using CC in previous cycles. These women were randomized to receive letrozole and CC for 5days; the authors observed a significant higher ovulation rate(63%) in letrozole compared with those receiving CC(37%), and these results agreed with the study of Atay etal. [26], in which 106 women with oligoamenorrhea and PCOS were enrolled(55 received CC and 51 letrozole). Results were more favorable in the letrozole group than in the CC group regarding ovulation rate(82.4vs. 63.6%).

As regards pregnancy outcome, pregnancy was achieved in 11 women(68.8%) in groupI, which is significantly higher than that achieved in groupII–five(31.2%) women(P=0.05).

These results were in agreement with the findings of Mitwally and Casper [11], who reported that 50–90% of women who took letrozole showed evidence of ovulation with the lowest dose of 2.5mg/day for 5days and ~50% of women who ovulated became pregnant within first three to six cycles.

In addition, these results were in agreement with a recent study by Kallol etal. [27], who reported that letrozole is as good as CC in terms of ovulation rate. The endometrial thickness was significantly better in the letrozole group. Letrozole was also found to be superior in terms of pregnancy outcome than CC.

As regards the side effects, both groups showed that all drugs were generally tolerated as no patients complained of any side effect. No cases of ovarian hyperstimulation during induction with either letrozole and DEX or CC and DEX were detected. All pregnant cases were single pregnancies.


  Conclusion Top


According to the results of this study, it was found that letrozole and DEX are an orally effective method for stimulating follicular development.

Letrozole is effective for ovulation induction in anovulatory infertility. It has the benefit of predominantly monofollicular ovulation and better endometrial thickness, which allows a higher implantation and pregnancy rate.

DEX is a safe, inexpensive, and easy adjuvant to ovulation-inducing agents. Addition of DEX during induction of ovulation causes significant improvement in folliculogenesis, ovulation, and pregnancy.

Letrozole and DEX have more success rates in ovulation induction and pregnancy outcome than CC and DEX. Therefore, it is better to use letrozole and DEX as a treatment that is effective, before starting treatment with gonadotropins and laparoscopic ovarian drilling.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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