ORIGINAL ARTICLE Year : 2023  |  Volume : 9  |  Issue : 2  |  Page : 47-52

Therapeutic impact of letrozole and clomiphene citrate for ovulation induction in Iraqi female patients with polycystic ovary syndrome

Hadeel Delman Najim1, Wrood S Al-Khfajy2, Zahraa Albasry1, Anmar Al-Taie3
1 Department of Clinical Pharmacy, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
2 Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
3 Department of Pharmacy, Osol Aldeen University College, Baghdad, Iraq

Date of Submission26-Sep-2022Date of Acceptance03-May-2023Date of Web Publication26-Jun-2023

Correspondence Address:
Dr. Anmar Al-Taie
Department of Pharmacy, Osol Aldeen University College, Baghdad
Iraq

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ijam.ijam_90_22

Introduction: Clomiphene citrate (CC) is the most commonly used ovulation induction agent in women with polycystic ovary syndrome (PCOS). Letrozole has attracted attention for its ovulation induction effects as a safe, potentially better alternative to CC. The aim of this study was to compare the therapeutic efficacy of letrozole in comparison to CC for ovulation induction in female patients with PCOS in Baghdad Province, Iraq.
Materials and Methods: A prospective, randomized, controlled study was carried out on 166 female patients diagnosed with anovulatory infertility due to PCOS and randomly assigned into two groups. Group A included ninety-four participants who received CC. Group B included 85 participants who received letrozole. The main outcomes were the ovulation induction and therapeutic outcomes of CC and letrozole, including endometrial thickness, number of mature follicles, pregnancy rate, number of stimulated cycles and mono-ovulation rate.
Results: Endometrial thickness improved significantly more with CC than with letrozole (8.08 ± 1.28 vs. 7.66 ± 1.41; P = 0.05), as did the number of mature follicles (3.07 ± 1.23 vs. 1.97 ± 0.83; P = 0.0001). Nevertheless, Group B patients reported a higher significant rate compared to Group A regarding pregnancy rate (62% vs. 38%; P < 0.01), number of stimulated cycles (91% vs. 78%; P < 0.05), and mono-ovulation rate (29% vs. 5.75%; P = 0.0001).
Conclusion: Letrozole is preferable to CC in terms of a higher pregnancy rate as well as mono-follicles' ability to decrease the risk of multiple pregnancies, which is clearly observed with CC. The higher success of letrozole over CC is thought to be related to the higher ovulation rate per cycle.
The following core competencies are addressed in this article: Patient care and procedural skills, medical knowledge.

Keywords: Clomiphene citrate, letrozole, ovulation, polycystic ovary syndrome, pregnancy

How to cite this article:
Najim HD, Al-Khfajy WS, Albasry Z, Al-Taie A. Therapeutic impact of letrozole and clomiphene citrate for ovulation induction in Iraqi female patients with polycystic ovary syndrome. Int J Acad Med 2023;9:47-52
How to cite this URL:
Najim HD, Al-Khfajy WS, Albasry Z, Al-Taie A. Therapeutic impact of letrozole and clomiphene citrate for ovulation induction in Iraqi female patients with polycystic ovary syndrome. Int J Acad Med [serial online] 2023 [cited 2023 Jun 26];9:47-52. Available from: https://www.ijam-web.org/text.asp?2023/9/2/47/379350   Introduction 

Polycystic ovary syndrome (PCOS) is manifested by oligo-or anovulation and hormonal abnormalities.[1],[2] It results from defects in the hypothalamic-pituitary axis (HPA), which cause an elevation in luteinizing hormone (LH) and gonadotropin-releasing hormone levels, while follicular-stimulating hormone (FSH) levels may remain unchanged.[3],[4] PCOS is one of the most common causes of anovulation and infertility, accounting for up to 75% of women with this disorder.[5]

Clomiphene citrate (CC) is considered the drug of choice for anovulatory infertility and can produce ovulation in 70%–75% of cases.[6] During the early follicular phase, CC acts as an estrogen receptor (ER) modulator and can reverse the negative feedback mechanism by competing with estrogen for its receptors in the hypothalamus and pituitary glands. Thus, endogenous gonadotropin levels increase, and the dominant follicle is inducted.[7] CC can produce a high ovulation rate of around 60%–85%.[6] However, the pregnancy rate ranges between 10% and 20% per cycle.[8] This discrepancy between the ovulation and pregnancy rates caused by CC could be attributed to its anti-estrogenic effects, which cause long-lasting ER depletion along with adverse effects on the cervical mucus and endometrial thickness, leading to implantation failure and luteal phase defects.[9],[10]

Therefore, a safe, potentially better alternative to CC, such as letrozole, was necessary as it has attracted attention for its ovulation induction effects. Letrozole is a specific, potent, reversible, highly selective nonsteroidal aromatase inhibitor. It prevents androgen-to-estrogen conversion, thereby inhibiting estrogen biosynthesis. Increased gonadotropin secretions, which stimulate follicular development, will prevent the negative feedback to HPA.[11] Due to its minimal anti-estrogenic effect on endometrium as compared to CC, letrozole does not down-regulate the ER, rapidly eliminated from the circulation owing to a short half-life (45 h) without producing long-lasting adverse effects on the cervical mucus.[12],[13] Furthermore, its efficacy has been proven for ovulation induction, with a high pregnancy rate of around 80% in women who inadequately respond to CC.[14] Therefore, the aim of this study was to compare the therapeutic efficacy of letrozole in comparison to CC for ovulation induction in female patients with PCOS in Baghdad Province, Iraq.

  Materials and Methods 

Study design

This was a single-center; prospective, randomized-controlled study enrolled and followed-up female patients between January 2018 and September 2019. The study was approved by the ethical committee of college of Pharmacy, Mustansiriyah University and conducted at the in vitro Infertility Treatment Centre-College of Medicine, Al-Nahrain University, Baghdad Province, Iraq (19.11.2017.201450310202). All procedures performed in the study involving human participants followed the ethical standards of the institutional research committee and the 1964 Helsinki Declaration and its later amendments.

Study participants, setting, and outcomes

Infertility is defined as 1 year of unprotected intercourse without conception.[15] Female patients diagnosed with anovulatory infertility and the inability to achieve pregnancy for at least 1 year due to PCOS based on the criteria of the Rotterdam consensus meeting (2003) were enrolled in the study after meeting the inclusion criteria. The Rotterdam criteria is a globally reliable test that entails finding any two of the following: Oligo or-anovulation, clinical or biochemical signs of hyperandrogenism, and polycystic ovaries on ultrasound examination.[16]

Inclusion criteria included female patients within the age range of 18–39 years old; those with PC morphology ≥12 follicles of 10 ml, those with clinical history and hysterosalpingography testing for patent  Fallopian tube More Detailss and thickness of the endometrium and those who had male partners with normal semen analysis according to the modified criteria of the WHO. Exclusion criteria included patients with thyroid gland disorders, hyperprolactinemia, those with male factor infertility, major medical illness related to tubal abnormalities and infertility, such as endometriosis or pelvic inflammatory disease, and those who received ovulation induction. The participants who expressed readiness to take part were provided with full verbal information regarding the objective of the study and written informed consent. Furthermore, all participants were informed that participation was voluntary, and they were assured of their anonymity and confidentiality of response.

The sample size was calculated using the Cochran's sample size formula for a population with an unknown degree of variability and assuming the maximum variability is 95% confidence level with 5% precision.

An independent observer not involved in the study allocated eligible patients. The eligible patients were randomly assigned using the registration number into two groups (A and B) as 1:1 block randomization by an independent observer [Figure 1]. Data from medical records and one-on-one interviews with study participants were used to create a detailed health report for the patients. Group A included ninety-four participants who received CC 50 mg tablets twice daily from day 2 of the menstrual cycle for 5 days. Group B included 85 participants who received letrozole 5 mg tablets once daily from day 2 of the menstrual cycle for 5 days. However, 13 participants could not complete the study for follow-up (seven participants from Group A and six participants from Group B), leaving a total of 166 participants who passed the follow-up successfully (87 from Group A and 79 from Group B), as shown in [Figure 1].

All patients were monitored by serial transvaginal ultrasound examination by a consultant at each visit for the mean follicular size, volume, and endometrial lining thickness on days 10, 12, and 14 of the cycle. The main study outcomes measured were the number of stimulated cycles, number, and size of mature growing follicles (≥18 mm), size of endometrial thickness, ovulation rate and pregnancy rate, live birth rate, and rate of miscarriage.

Statistical analysis

Statistical analysis was performed using Microsoft Excel 2007. Data are presented as a mean, standard deviation, number, and percentage. Paired the Student's t-test was used to compare means, while the Chi-square test was used to compare percentages between the groups. A P < 0.05 was considered statistically significant.

  Results 

As shown in [Table 1], there was no statistically significant difference between both groups (CC group and letrozole group) regarding age, duration of infertility, and endometrial thickness at the baseline level. [Table 2] presents the outcomes of ovulation induction for patients who received CC versus letrozole. Compared to the baseline findings, patients within both groups showed significant improvement in endometrial thickness after receiving CC (6.67 ± 1.86 vs. 8.08 ± 1.28; P < 0.0001) and letrozole (6.71 ± 1.69 vs. 7.66 ± 1.41; P < 0.001). However, CC showed significantly greater improvement in endometrial thickness in comparison to letrozole (8.08 ± 1.28 vs. 7.66 ± 1.41, P < 0.05), as well as number of mature follicles (3.07 ± 1.23 vs. 1.97 ± 0.83; P < 0.0001), as shown in [Table 2].

Table 2: Comparison of the ovulation induction of clomiphene citrate and letrozole

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Group B patients who received letrozole reported a higher significant rate compared to Group A patients regarding pregnancy rate (62% vs. 38%; P < 0.01), number of stimulated cycles (91% vs. 78%; P < 0.05), and mono-ovulation rate (29% vs. 5.75%; P = 0.0001). However, the number of multiple pregnancies was significantly higher among Group A patients who received CC in comparison to Group B patients (30% vs. 12%; P < 0.05), as shown in [Table 3]. Patients in both groups showed no significant difference regarding the rate of miscarriage and the rate of live birth [Table 3].

Table 3: Comparison of the therapeutic outcomes of clomiphene citrate and letrozole

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  Discussion 

Ovulation induction is an essential approach for patients with PCOS. Many fertility guidelines recommend CC as the first-line treatment for women with anovulation due to PCOS.[17],[18],[19] Other guidelines also recommend that both CC and letrozole be considered first-line therapeutic approaches.[20],[21] Moreover, recent studies found that treatment of anovulatory infertility with letrozole is superior to CC citrate in many respects.[22],[23] The findings of the present study were compatible with earlier studies which found that the percentage of stimulated cycles following letrozole treatment was higher than those following CC treatment, while the mean number of mature follicles (≥18 mm) among patients treated with CC was higher compared to those treated with letrozole.[24],[25],[26],[27] Nevertheless, the dominant follicle size produced was comparable in both groups (>18 mm).[27],[28],[29]

The lower number of mature follicles in the letrozole group (29%) supports the high mono-ovulation rate recorded in the present study, which is consistent with previous studies that found that the mono-follicular cycles were greater in letrozole-treated females compared to CC.[29],[30] Within the ovarian tissue, aromatase inhibitors increase androgen production, thus increasing follicular sensitivity to FSH. As estrogen levels increase and the dominant follicle grows, repression of FSH secretion because of central negative feedback occurs, resulting in shrinkage of the smaller follicles. This results in a single dominant follicle and mono-ovulation.[31],[32] A study by Polyzos et al.[33] found that the hypoestrogenic state produced by letrozole does not last late in the follicular phase of the menstrual cycle due to its short half-life, resulting in a higher probability of mono-follicular occurrence. Meanwhile, the study by Casper and Mitwally.[34] reported that aromatase inhibition does not antagonize ERs in the brain, and the initiation of follicle growth accompanied by increasing concentrations of both estradiol and inhibin results in a normal negative feedback loop that limits the FSH response, thereby avoiding the risk of high multiple ovulation and ovarian hyperstimulation syndrome. Therefore, this limitation in the number of mature follicles in the letrozole group contributes to reducing the risk of multiple pregnancy.

The main benefit of aromatase inhibitors for ovulation induction in women with PCOS is mono-ovulation,[35] whereas multiple pregnancy may increase the incidence of maternal and neonatal complications, which has been well documented in previous studies.[36],[37]

This may be linked to an increased risk of developing ovarian hyperstimulation syndrome because of CC-induced ovulation induction.[38],[39] A randomized prospective clinical trial study by Diamond et al.[40] found that the use of letrozole for ovarian stimulation can reduce the rates of multiple pregnancies compared to those observed with CC treatment. This is consistent with the findings of the present study, which reported a low rate of multiple pregnancies in females treated with letrozole compared to those treated with CC (12% vs. 30%).

Endometrial thickness measurement is a predictor of endometrial capability for follicle implantation.[41] The superiority of CC over letrozole regarding endometrial thickness may be related to the high level of estrogen released with each single follicle, which is actively correlated with the development and growth of the endometrium.[27] The findings of the present study were in accordance with a study by Suhaila et al.[24] and Amer et al.[42] which reported an improvement in mid-cycle endometrial thickness after treatment with both letrozole and CC, although the latter was superior in such increment. Therefore, the higher pregnancy rate with letrozole could be related to a combination of better ovulation induction rates and endometrial thickness, which facilitates implantation of the fertilized ovum. This could also be related to lower estradiol levels and higher progesterone levels in the mid-luteal phase, which may be related to sustained aromatase inhibition into the luteal phase.[43] The pregnancy rate reported in the present study was higher in patients treated with letrozole compared to those treated with CC. These findings coincided with those reported by Pourali et al.[38] Amer et al.[42] and Legro et al.[43]

To the best of our knowledge, this is the first prospective, randomized-controlled study conducted to assess the therapeutic efficacy of letrozole in comparison to CC for ovulation induction in female patients with PCOS in Baghdad Province, Iraq. Nevertheless, the present study has some limitations. First, the study was conducted and enrolled participants at a single center. Second, to remove the effect of earlier interventions, the exclusion criteria of the study might lead to a limited sample size. Third, the study did not consider the biochemical measurement of hormones, particularly estradiol, FSH, LH, and testosterone, to follow the changes during the treatment time. Given these limitations into account, further prospective cohort studies with a larger sample size have to be conducted to further give insights into the therapeutic effects and positive impact of letrozole for ovulation induction in female patients with PCOS.

  Conclusion 

The findings of the present study revealed that letrozole can be considered as first-line therapy for ovulation induction in female patients with anovulatory infertility due to PCOS as it is equally efficacious, preferable, and a superior alternative to CC in terms of ovulation induction, ovulation rate per cycle, pregnancy rate, and mono-follicle production that will decrease the risk of multiple pregnancy and its consequences.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Ethical conduct of research

The study was approved by the Research Ethics Committee of College of Pharmacy, University of Al-Mustansiryah, Baghdad, Iraq (19.11.2017.201450310202). This study was done according to the reporting quality, formatting, and reproducibility guidelines set forth by the EQUATOR Network.

 

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  [Figure 1]
 
 
  [Table 1], [Table 2], [Table 3]