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Frequently Asked Questions
Objective:
Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 6.8% to 18% of women of reproductive age. It is a leading cause of infertility, responsible for ovulation-related issues in 55% to 70% of affected women. This study compares the effectiveness of two ovulation induction treatments—Clomid (first-line therapy) and letrozole (second-line therapy)—in women with PCOS experiencing infertility.
Patients and Methods:This randomized clinical trial included 80 women diagnosed with PCOS who were actively trying to conceive. After obtaining informed consent, participants were randomly divided into two groups of 40. One group received Clomid (50 mg daily) and the other letrozole (2.5 mg daily), both administered from day 3 to day 7 of the menstrual cycle for three consecutive cycles. Pregnancy was monitored monthly via BHCG blood tests. Data were analyzed using SPSS software (version 21.0) with independent t-tests and chi-square tests, considering a significance level of p < 0.05.
Results:There were no significant differences between the groups in terms of age, BMI, or infertility duration. A history of infertility treatment was reported in 37.5% of the Clomid group and 30% of the letrozole group. Menstrual cycles consistent with PCOS were observed in 75% of Clomid patients and 82.5% of those on letrozole. Signs of hyperandrogenism were present in 62.5% of the Clomid group and 55% of the letrozole group. PCOS-specific ultrasound findings were found in 77.5% (Clomid) and 87.5% (letrozole). Pregnancy occurred in 45% of women taking Clomid and 50% of those on letrozole, but the difference was not statistically significant.
Conclusion:Both Clomid and letrozole appear to be equally effective for inducing ovulation and achieving pregnancy in women with PCOS. Since neither drug showed clear superiority, the choice of treatment may depend on individual tolerance, cost, and potential side effects.
Keywords: PCOS, Clomid, Letrozole, Ovulation Induction, Female Infertility
Background Information:PCOS is believed to result from a combination of genetic and environmental factors, including insulin resistance, obesity, and hormonal imbalances such as elevated luteinizing hormone (LH). Studies suggest that PCOS has a heritability rate of over 70%. About 90% of affected individuals experience abnormal ovarian function, which contributes to irregular or absent ovulation and a higher risk of infertility, miscarriage, and metabolic complications.
Management of PCOS varies depending on symptoms. Lifestyle modifications like diet and exercise are often first-line approaches. Medication options include hormonal contraceptives, medroxyprogesterone acetate, GnRH agonists, glucocorticoids, spironolactone, and cyproterone acetate.
For patients struggling with ovulation-related infertility, Clomid and letrozole are commonly used. Clomid is a selective estrogen receptor modulator that increases gonadotropin secretion by blocking estrogen feedback in the hypothalamus. However, Clomid has limitations such as a modest live birth rate (~22% after six cycles), risk of multiple pregnancy (3%–8%), mood swings, hot flashes, and possible resistance over time.
Letrozole, an aromatase inhibitor, is gaining popularity due to its shorter half-life and fewer estrogen-related side effects. It promotes ovulation by preventing estrogen synthesis, which boosts gonadotropin release without affecting estrogen receptors directly. Advantages may include better endometrial receptivity, lower chances of multiple gestations, and fewer mood-related side effects. However, concerns remain about its possible teratogenic effects.
Second-line treatments for PCOS-related infertility include FSH injections or laparoscopic ovarian drilling. While both options are effective, surgery carries more risks compared to pharmacological therapy.
Given the wide use of Clomid and letrozole for ovulation induction, this study aimed to assess and compare their outcomes in women with PCOS.Patients and Methods
This randomized clinical trial was conducted at Ali ibn Abitaleb Hospital, affiliated with Zahedan University of Medical Sciences, during 2016–2017. Ethical approval was obtained from the university’s Ethics Committee (IR.ZAUMS.REC.1395.47), and the trial was registered with the Iranian Registry of Clinical Trials (ID: IRCT20180602039952N2).
A total of 80 women aged 18–40 years with a diagnosis of PCOS-related infertility were enrolled. All participants attended the hospital’s Infertility Clinic and met the following inclusion criteria: normal thyroid function and prolactin levels, at least one functioning fallopian tube, a normal uterine cavity, and a partner with normal semen parameters. All had a history of infertility lasting at least one year with regular, unprotected intercourse (2–3 times per week).
Exclusion criteria included thyroid dysfunction, hyperprolactinemia, tubal or uterine abnormalities, abnormal semen analysis, prior use of Clomid or letrozole, concurrent use of medications such as metformin, and any underlying chronic conditions like diabetes, renal or pulmonary diseases, or antiphospholipid syndrome.
Following informed consent and randomized block allocation, patients were divided into two groups of 40. One group received Clomid, and the other received letrozole.
- Clomid group: Patients were prescribed 100 mg daily (two 50 mg tablets) from day 3 to day 7 of the menstrual cycle.
- Letrozole group: Patients received 5 mg daily (two 2.5 mg tablets) during the same cycle days.
Each patient underwent transvaginal ultrasound monitoring. If one or more dominant follicles with a trilaminar endometrial pattern were detected, an HCG trigger was administered. Serum BHCG testing was performed 12 days later to confirm pregnancy. This process was repeated for three menstrual cycles.
Data were collected and analyzed using SPSS v21.0. Statistical analysis included chi-square and independent t-tests with a significance level of p < 0.05. Quantitative variables were expressed as means with standard deviations; categorical variables were presented as frequencies and percentages. Repeated-measures ANOVA was used to compare outcomes across time and between groups.
ResultsA total of 80 participants completed the study—40 in the Clomid group and 40 in the letrozole group. The average age was similar: 29.85 ± 6.39 years for the Clomid group and 29.92 ± 6.97 years for the letrozole group. BMI values were also close, with 24.82 ± 3.38 kg/m² for Clomid and 25.55 ± 3.49 kg/m² for letrozole.
At the end of the study, 18 women (45%) in the Clomid group and 20 (50%) in the letrozole group achieved pregnancy. The difference was not statistically significant (P > 0.05).
Duration of infertility:Clomid group: 5.62 ± 3.95 years (range: 2–15 years)
Letrozole group: 4.07 ± 4.77 years (range: 1–15 years)
Mann-Whitney test showed no significant difference (P = 0.07).
History of previous infertility treatment:Reported by 15 patients (37.5%) in the Clomid group and 12 (30%) in the letrozole group (P = 0.47).
Menstrual cycles consistent with PCOS:75% (30 patients) in the Clomid group vs. 82.5% (33 patients) in the letrozole group (P = 0.41).
Clinical signs of hyperandrogenism:Present in 62.5% (25 patients) of the Clomid group and 55% (22 patients) in the letrozole group (P = 0.49).
Ultrasound findings consistent with PCOS:Found in 77.5% of the Clomid group (31 patients) and 87.5% of the letrozole group (35 patients) (P = 0.23).
Although the pregnancy rate was slightly higher in the letrozole group (50% vs. 45%), this difference was not statistically significant.
DiscussionClomiphene Citrate is commonly the first-line medication for ovulation induction in women with WHO Group II anovulation. It works by blocking estrogen's negative feedback at the hypothalamus, which stimulates increased secretion of gonadotropins and promotes ovulation. Although ovulation occurs in 60%–80% of cases, the actual pregnancy rate remains below 50%.
This discrepancy may result from Clomid’s adverse effects on cervical mucus, endometrial thickness, and oocyte quality. The drug exists in two isomeric forms: En-clomiphene and Zu-clomiphene. En-clomiphene is rapidly cleared from the body, while Zu-clomiphene persists longer and may contribute to side effects, including reduced endometrial receptivity and poor cervical mucus, which can impair fertilization and implantation.
While both Clomid and letrozole are effective ovulation inducers, letrozole may offer some advantages such as better endometrial response, lower risk of multiple pregnancies, and fewer side effects. However, in this study, no significant difference in pregnancy outcomes was observed, suggesting that both treatments can be considered viable options for women with PCOS-related infertility.
In recent years, aromatase inhibitors like letrozole have emerged as promising alternatives to traditional ovulation inducers such as Clomid. Letrozole, a third-generation aromatase inhibitor, has shown encouraging results in several studies, particularly in women with polycystic ovary syndrome (PCOS). Compared to Clomid, letrozole is more likely to produce monofollicular ovulation and result in thicker endometrial lining, which may enhance implantation potential. Because of its mechanism of action—suppressing estrogen production rather than blocking estrogen receptors—letrozole is also preferred in certain clinical scenarios, such as in patients resistant to Clomid or in individuals with hormone-sensitive cancers (e.g., breast or ovarian), where estrogen elevation must be avoided. Despite Clomid’s long-standing use and high ovulation rates, its lower pregnancy rates and associated side effects have led clinicians to explore alternative treatments like letrozole.
Study Observations
–In this study, both treatment groups were age-matched, and no significant differences were observed in body mass index (BMI) or baseline infertility history. While the duration of infertility ranged from 1 to 15 years across the two groups, 37.5% of Clomid users and 30% of letrozole users reported prior infertility treatments. Cycles compatible with PCOS were observed in 75% of Clomid users and 82.5% of those on letrozole, while signs of hyperandrogenism were present in 62.5% and 55% of the respective groups. PCOS-related ultrasound findings were noted in 77.5% (Clomid) and 87.5% (letrozole), with no significant differences in any of these clinical markers. Ovulation occurred in both groups, supporting the use of either drug as a valid first-line therapy for women with PCOS-related infertility.
Literature Review and Meta-Analyses
Multiple studies support the use of letrozole as a safe and effective ovulation inducer in women with PCOS:
- Casper noted that letrozole is as effective as Clomid but requires less intensive monitoring due to fewer side effects.
- Badawy et al and Jiang & He found comparable pregnancy and miscarriage rates between the two drugs in multiple-cycle analyses, concluding that letrozole is a suitable alternative to Clomid.
- Elham et al explored letrozole dosing in Clomid-resistant PCOS patients, recommending starting with low doses and adjusting based on ultrasound and hormonal feedback (e.g., AMH, LH/FSH ratios, estradiol).
- Franik et al observed that letrozole increased live birth and pregnancy rates compared to Clomid, while laparoscopic findings showed no structural ovarian differences between the two treatments.
- Legro et al, in a large multicenter blinded trial, reported higher live birth and pregnancy rates in the letrozole group.
- Roque et al, through a meta-analysis, confirmed letrozole’s superiority in achieving higher live birth and conception rates, with similar miscarriage rates to Clomid.
- Al-Fozan et al noted a higher miscarriage rate in the Clomiphene Citrate group, although endometrial thickness was similar in both.
- Polyzos et al recommended beginning treatment with lower doses of either drug and adjusting based on individual ovarian response, especially due to the financial and physiological burden of higher doses.
- While letrozole showed slightly better outcomes in some studies, Clomid remains a cost-effective option that many patients prefer for financial reasons.
Conclusion
Based on the findings of this study and the broader scientific literature, both letrozole and Clomid are effective for inducing ovulation in women with PCOS. While letrozole may offer advantages in certain subgroups, particularly in Clomid-resistant patients or those with concerns about estrogen elevation, the overall effectiveness of both treatments is comparable. Therefore, the choice between these medications can be tailored to individual patient needs, including factors such as tolerance, cost, access, and risk of side effects. Some evidence also supports the use of Clomid in combination with metformin as a first-line treatment. Further studies are needed to fully assess the comparative benefits of letrozole plus metformin versus Clomid-based regimens.