Introduction
Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorders, affecting 4% to 8% of reproductive-aged women and contributing significantly to infertility through oligo-anovulation [1]. However, recent population-based studies using the Rotterdam diagnostic criteria suggest an even higher prevalence, ranging from 17.8% to 19.9% [2]. PCOS is diagnosed when at least two of the following three criteria are met—oligo- and/or anovulation, hyperandrogenism, and polycystic ovaries—after excluding other etiologies [3]. Infertility treatment for these women primarily aims to induce ovulation, with clomiphene citrate (CC), a selective estrogen receptor modulator, serving as the traditional first-line therapy. Although approximately 80% of women ovulate in response to CC, only 35% to 40% achieve pregnancy; indeed, up to 40% are classified as having CC resistance [3,4], defined as failure to ovulate after receiving a maximum dose of 150 mg per day for 5 days beginning on day 3 of the menstrual cycle [5]. These CC-resistant cases require alternative strategies to improve reproductive outcomes. Metformin has shown limited success as monotherapy but demonstrates some efficacy when combined with CC [6]. Gonadotropins, considered the gold standard for CC-resistant women, effectively stimulate ovulation but carry significant risks, such as multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) [7].
Letrozole, an aromatase inhibitor that inhibits the conversion of androgens to estrogen, has emerged as a superior alternative to CC. Notably, letrozole is associated with higher ovulation and live birth rates and carries a lower risk of OHSS and miscarriage, leading to its recommendation as a first-line treatment in anovulatory women with PCOS [8]. However, both gonadotropins and letrozole require careful monitoring and may confer long-term risks, leaving room for surgical alternatives such as laparoscopic ovarian drilling (LOD). Moreover, few studies have directly compared letrozole with surgical interventions like LOD [9-11]. LOD is a minimally invasive procedure that decreases ovarian androgen production and stimulates ovulation by mechanically disrupting the ovarian stroma [12]. Unlike gonadotropins, LOD circumvents the risks of OHSS and multiple pregnancy, making it an attractive option for women unresponsive to pharmacotherapy or at high risk for these complications. Additionally, LOD can provide lasting improvements in ovarian function without ongoing medication [13]. Nevertheless, concerns about tubo-ovarian adhesions and diminished ovarian reserve persist, although these risks can be minimized through meticulous surgical technique [13,14]. Despite its potential benefits, LOD remains underutilized in clinical practice, likely due to a lack of comparative data and uncertainty regarding long-term safety.
The significance of this study lies in its potential to clarify the role of LOD in improving reproductive outcomes for women with CC-resistant PCOS, particularly those experiencing oligomenorrhea. Although letrozole and gonadotropins are generally effective, some patients either fail to respond to pharmacological therapy or face treatment-related risks. LOD may offer an alternative that avoids systemic side effects while still inducing ovulation and achieving pregnancy. By providing a direct comparison of LOD, letrozole, and gonadotropins, this study will generate crucial data on the relative efficacy, safety, and clinical outcomes associated with each modality. The primary objective is to compare clinical outcomes such as ovulation and pregnancy rate, as well as the incidence of adverse effects, across the three treatment arms in women with CC-resistant PCOS. This study addresses the current lack of head-to-head comparative evidence, equipping clinicians with evidence-based guidance to individualize treatment strategies. Ultimately, these findings could refine PCOS management and expand the array of viable options to promote reproductive success.
Methods
This randomized controlled clinical trial adhered to the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement to compare the effects of gonadotropins, letrozole, and unilateral LOD in infertile women with PCOS. The study was conducted at the gynecology and infertility clinics of the Maternity Hospital from May 2021 to May 2024, after approval by the Scientific and Ethics Committee of the Obstetrics and Gynecology Department, Cairo University (MD-302-2020) and receipt of written informed consent from all participants. Of 247 women screened for eligibility, 51 did not meet the inclusion criteria and 13 declined to participate, leaving 183 oligo/anovulatory infertile women aged 20–35 years. All were diagnosed with PCOS according to the Rotterdam criteria, requiring at least two of the following: ovulatory disturbance, hyperandrogenism, and polycystic ovarian morphology (more than 12 follicles of 2–9 mm per ovary on ultrasound). Participants were randomized (n=61 per arm) to receive letrozole, gonadotropins, or undergo unilateral LOD. Randomization used computer-generated numbers with allocation concealed in sealed envelopes. The study was conducted as an open-label trial. Because surgical intervention precluded blinding, the trial was open-label; this may introduce performance bias. To minimize bias, assessment methods were standardized and outcomes were based on objective measures, notably pregnancy confirmed by serum beta-human chorionic gonadotropin (β-hCG) levels.
The inclusion criteria were women aged 20 to 35 years with anovulatory infertility due to PCOS (diagnosed according to the Rotterdam criteria), a body mass index (BMI) of 18–30 kg/m2, and resistance to CC—defined as failure to respond after up to 150 mg daily for at least three consecutive cycles. Exclusion criteria included extreme age; recent hormonal therapy or use of oral contraceptives within the previous 3 months; other causes of infertility; preexisting endocrine disorders; prior ovarian surgery; obesity (BMI >30 kg/m2); and diminished ovarian reserve (anti-Müllerian hormone [AMH] <1 ng/mL). The BMI cut-off of 30 kg/m2 was chosen in accordance with local guidelines and international recommendations and reflects regional epidemiology and clinical practice, excluding women with obesity to avoid confounding.
1. Study intervention
The study adhered to relevant ethical guidelines. Informed consent was obtained from all participants, who were assured of their right to withdraw at any time. All participants underwent a comprehensive evaluation, including a full medical history, general examination, hormone assays, and transvaginal ultrasound to assess antral follicle count (AFC) and ovarian volume. In the letrozole group, patients received 5 mg of letrozole orally for 5 days starting on the third through the fifth day of menses for up to six cycles, with timed intercourse after ovulation was confirmed. In the gonadotropin group, human menopausal gonadotropin (hMG) was administered at 75 IU on alternate days starting on cycle day 3; doses were adjusted according to follicular response to target mono-ovulation, and timed intercourse was advised following ovulation. For the LOD group, the ovary selected for drilling was the one with the higher AFC (≥15–20 follicles of 2–9 mm) and larger volume (>10 cm3) on the initial ultrasound; if both ovaries were similar, selection was based on ease of surgical access. LOD was performed using a monopolar electrosurgical needle with up to four cauterization points on the chosen ovary—each point treated for 4 seconds at 40 W, with a 3 mm diameter and 4 mm depth—and patients were subsequently monitored for natural conception.
In all groups, ovulation monitoring began on cycle day 9 and continued with serial transvaginal ultrasounds to assess follicular development and endometrial thickness. Ovulation was defined uniformly across all three groups as the presence of a dominant follicle ≥18 mm on ultrasound followed by evidence of follicular rupture or a serum progesterone rise >3 ng/mL on cycle day 21. Monitoring continued for up to six cycles, and pregnancy was confirmed by a serum β-hCG level >50 IU/L together with ultrasound visualization of a gestational sac.
A single dose of 10,000 IU hCG was administered when a follicle reached ≥18 mm. hMG stimulation cycles were canceled for either under-response or over-response. Under-response was diagnosed when no follicular growth occurred after 14 days of stimulation despite escalating hMG doses, or when growth arrested after an initial response. Over-response was diagnosed when three or more follicles reached ≥17 mm and/or estradiol levels exceeded 5,000 nmol/L. All patients received 400 mg of vaginal micronized progesterone for 2 weeks for luteal support to prevent luteal phase defect or insufficiency.
Participants were followed for 6 months post‐intervention with uniform follow‐up across all groups to assess pregnancy rates. The primary endpoint was pregnancy, confirmed by a serum β-hCG level above 50 IU/L and ultrasound visualization of a gestational sac. Secondary outcomes included ovulation rate, multiple pregnancy rate, miscarriage rate, incidence of OHSS, and changes in hormonal profile 6 months after treatment. These secondary endpoints were chosen to provide a comprehensive assessment of both efficacy and safety, offering insights into the broader clinical management of infertile women with PCOS beyond pregnancy rates alone.
2. Sample size calculation
Sample size was calculated based on the primary outcome—pregnancy rate—by comparing three proportions from independent samples using the chi-square test. The significance threshold (α=0.05), power (80%), and group allocation ratio (1:1:1) were chosen to align with standard practice, ensuring robust detection of clinically meaningful differences. Drawing on previously published clinical pregnancy rates—45.2% for letrozole, 50% for gonadotropins, and 30% for LOD [9,14]—and hypothesizing superior performance of letrozole and gonadotropins over LOD, we determined that 48 women per group would be required. Allowing for a 20% dropout rate, each arm was increased to 60 participants, yielding a total sample size of 180. All calculations were performed using G*Power ver. 3.1.2 for MS Windows (Franz Faul, Kiel University).
3. Statistical analysis
Statistical analysis was performed using IBM SPSS Statistics ver. 24 (IBM Corp.). Data collection, tabulation, and analysis were conducted to evaluate the study outcomes. Continuous variables exhibiting a normal distribution were expressed as mean±standard deviation, while non-normally distributed variables were summarized as median and interquartile range. Categorical variables were presented as numbers and percentages. The Kolmogorov–Smirnov test assessed the normality of continuous data. For normally distributed variables, group comparisons were made using one-way analysis of variance; if significant differences were observed, the Tukey honestly significant difference test was applied for pairwise post hoc comparisons. For non-normally distributed variables, the Kruskal-Wallis test was used, followed by Mann-Whitney U tests with Bonferroni correction for multiple comparisons when warranted. Categorical data were compared using the chi-square test, with the Fisher exact test employed for cells with small expected frequencies. A p-value of less than 0.05 was considered to indicate statistical significance for all tests.
Results
This prospective, randomized clinical trial included 183 infertile women with PCOS (Figure 1) diagnosed according to the Rotterdam criteria. Participants were allocated evenly to three groups: 61 received letrozole, 61 received gonadotropins, and 61 underwent unilateral LOD. Demographic data presented in Table 1 showed no significant differences among the gonadotropin, letrozole, and LOD groups in age, BMI, infertility type, duration of infertility, or menstrual pattern prior to treatment. All p-values exceeded 0.05, indicating that the groups were well-matched for these variables. Baseline hormonal profiles and AFCs, as shown in Table 2, were similarly matched across all three groups. None of these pre‐treatment parameters differed significantly, suggesting comparable ovarian reserve and endocrine status at baseline. Post‐intervention results, shown in Table 3, revealed significant differences in several hormonal markers and AFC among the three treatment arms. Specifically, the LOD group consistently exhibited lower luteinizing hormone (LH), AMH, and AFC values than the gonadotropin and letrozole groups. Moreover, after treatment the LH/follicle-stimulating hormone (FSH) ratio was significantly reduced in the LOD group compared to the other two modalities. Menstrual patterns also varied significantly following treatment across the three groups. The letrozole group experienced a higher rate of oligo/amenorrhea than the gonadotropin and LOD groups, suggesting increased cycle irregularity with letrozole. In contrast, the LOD group had the greatest proportion of patients achieving regular menstruation, indicating superior restoration of cyclicity in this arm. A p-value of 0.0154 confirmed that these between-group differences were statistically significant.
The data in Table 4 indicate that the gonadotropin group consistently exhibited higher ovulation rates across most months compared to the letrozole and laparoscopy groups, with the difference becoming highly significant after 6 months. The letrozole group demonstrated intermediate ovulation rates, while the laparoscopy group had the lowest rates, suggesting that gonadotropins may be the most effective treatment for ovulation induction over a 6-month period. Regarding pregnancy, the gonadotropin group achieved the highest cumulative chemical and clinical pregnancy rates, underscoring its effectiveness in achieving pregnancies over the same period. The letrozole group exhibited intermediate pregnancy outcomes, whereas the laparoscopy group had the lowest rates, with statistically significant differences in both cumulative and clinical pregnancy rates (Figure 2). As shown in Table 5, no significant differences were noted between the three groups in secondary reproductive outcomes, including ongoing pregnancy up to 13 weeks, abortion rates, OHSS incidence, and multiple pregnancy rates. The gonadotropin group had the highest rates of OHSS and multiple pregnancies, whereas the laparoscopy group had the lowest rates in these categories. Despite these differences, the p-values indicate that none of these variations reached statistical significance.
Discussion
PCOS is a prevalent cause of infertility due to oligo-anovulation, affecting a significant proportion of reproductive-aged women, with prevalence rates ranging from 17.8% to 19.9% using the Rotterdam diagnostic criteria [1,2]. Approximately 75% of women with infertility due to anovulation exhibit PCOS [15]. CC is the typical first-line fertility treatment; however, 15% to 40% of women do not respond to CC, in what is termed CC resistance [4]. While gonadotropins are the standard therapy for CC-resistant patients, they carry risks such as multiple pregnancies and OHSS [7]. Letrozole, an aromatase inhibitor, has demonstrated superior ovulation and live birth rates compared to CC and is now recommended as a first-line treatment for anovulation in women with PCOS [8]. LOD is another option for women displaying CC resistance, matching gonadotropin efficacy without the attendant risks of multiple pregnancy or OHSS [13].
Our study aimed to compare the effects of gonadotropins, letrozole, and LOD on reproductive outcomes in infertile women with CC-resistant PCOS. No significant differences were observed between the groups in age, infertility type, BMI, or ultrasonographic findings. However, the results indicated that gonadotropins and letrozole were more effective than LOD in inducing ovulation and achieving pregnancy. These findings align with some studies but diverge from others, offering new insights into managing CC-resistant PCOS. In agreement with the existing literature, our study supports the superior efficacy of gonadotropins and letrozole over LOD in this patient population. Gonadotropins directly stimulate follicular development, leading to a 96.07% ovulation rate in the gonadotropin group. Letrozole, an aromatase inhibitor, promotes follicular recruitment by increasing FSH secretion, resulting in a 64.15% ovulation rate, which, although lower than gonadotropins, remains effective. LOD, which reduces ovarian androgen production, was less effective in stimulating follicular growth, with an ovulation rate of 42.85%, particularly in women with higher BMI or insulin resistance [13,16].
Our pregnancy rate findings are consistent with other studies, showing gonadotropins to be the most effective therapy, with a pregnancy rate of 49.01% after six cycles. Letrozole achieved a pregnancy rate of 37.73%, while the LOD group had a pregnancy rate of 24.44%. Despite being less effective than both pharmacological treatments, LOD remains a valuable alternative for certain patient populations, particularly those wishing to avoid medication or those at risk of OHSS. Ibrahim et al. [10] reported similar findings, with letrozole yielding ovulation rates of 70% compared to 57.5% for LOD, and pregnancy rates of 35% versus 27.5%, respectively. Baradwan et al. [17] found that combining letrozole with gonadotropins improved ovulation and pregnancy rates, supporting our observation of the efficacy of letrozole but suggesting an even more potent effect when combined with gonadotropins. Abdelazim [18] reported that administering letrozole after LOD significantly improved ovulation and pregnancy rates, thus reinforcing the value of letrozole in ovulation induction. Liu et al. [9] found that letrozole was associated with a higher clinical pregnancy rate (40.8%) compared to LOD (27.1%), as well as a higher ovulation rate (79.8% vs. 66.2%), aligning with our findings. Morad et al. [19] concluded that extended letrozole regimens and LOD were similarly effective in inducing ovulation and achieving pregnancy in patients with CC-resistant PCOS, suggesting both methods are viable options depending on patient preferences and risk factors. Abdellah [20] also found letrozole to be more effective, with pregnancy rates of 35.7% compared to 28.6% for LOD, although the differences were not statistically significant. Our study also revealed no significant differences between the three groups in terms of ongoing pregnancy rates, miscarriage rates, OHSS, or multiple pregnancy rates. The gonadotropin group had the highest rates of OHSS and multiple pregnancies, while the LOD group had the lowest, aligning with previous studies [10,21].
These findings have important clinical implications for personalizing treatment strategies in women with CC-resistant PCOS. Gonadotropins, although highly effective, carry an elevated risk of OHSS and multiple pregnancies, making them most appropriate when close monitoring is available. Letrozole offers a safer alternative, particularly for those at higher risk of OHSS. LOD, while less effective, remains a valuable option for patients wishing to avoid pharmacotherapy or with contraindications to gonadotropins or letrozole. Treatment should be tailored to individual factors such as BMI, insulin resistance, and the risks associated with each therapy. Further research is needed to refine these strategies and to assess long‐term reproductive outcomes. Larger randomized controlled trials with extended follow‐up are warranted to evaluate live birth rates and neonatal outcomes. Future studies should also investigate combined approaches—such as low‐dose gonadotropin plus letrozole protocols—to improve efficacy while minimizing adverse effects. A better understanding of factors like BMI, insulin resistance, and genetic predisposition will further optimize treatment selection, enabling more personalized management of patients with PCOS.
In conclusion, gonadotropins and letrozole are more effective than LOD in inducing ovulation and achieving pregnancy in women with CC-resistant PCOS. LOD remains a viable alternative, offering the benefit of reducing the risk of multiple pregnancies and OHSS.
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