Polycystic Ovary Syndrome (PCOS) is a complex and prevalent endocrine disorder that affects approximately 6-12% of women of reproductive age worldwide. Characterized by hyperandrogenism, chronic anovulation, and polycystic ovarian morphology, PCOS is a leading cause of infertility due to its impact on regular ovulation. Women with PCOS often experience irregular menstrual cycles, making it difficult to predict ovulation, which is a key factor in achieving pregnancy [1]. The syndrome is also associated with a variety of metabolic disturbances, including insulin resistance, obesity, and an increased risk of developing type 2 diabetes and cardiovascular disease. The management of infertility in women with PCOS typically involves ovulation induction, a process that aims to stimulate the ovaries to produce and release eggs [2]. Clomiphene Citrate (CC) has been the cornerstone of ovulation induction therapy for decades. It functions as a selective estrogen receptor modulator (SERM) by binding to estrogen receptors in the hypothalamus, leading to an increase in the secretion of gonadotropins and subsequent stimulation of the ovaries [3]. Despite its widespread use, Clomiphene Citrate has several limitations, including a significant rate of ovulation failure in some women, known as Clomiphene resistance [4]. Additionally, it has been associated with several side effects, such as hot flashes, mood swings, and a potential risk of multiple pregnancies, which can lead to complications [5]. In recent years, Letrozole, an aromatase inhibitor, has emerged as a promising alternative to Clomiphene Citrate for ovulation induction in women with PCOS [6] . Letrozole works by inhibiting the enzyme aromatase, which is responsible for converting androgens to estrogens in the body. The reduction in estrogen levels leads to an increase in follicle-stimulating hormone (FSH) production, which stimulates the ovaries to produce eggs[7]. Unlike Clomiphene Citrate, Letrozole does not deplete estrogen receptors, which may result in a more favorable endometrial environment for implantation and potentially lower rates of multiple pregnancies [8]. Several studies have suggested that Letrozole may be more effective than Clomiphene Citrate in inducing ovulation in women with PCOS, particularly in those who are resistant to Clomiphene [9,10]. Furthermore, Letrozole has been associated with a higher rate of live births compared to Clomiphene Citrate, making it an increasingly preferred option for many clinicians. However, the long-term effects of Letrozole versus Clomiphene Citrate on ovulation induction and overall reproductive outcomes remain a subject of ongoing research [11-13].

OBJECTIVE

The main objective of the study is to find the long-term effects of letrozole versus clomiphene citrate on ovulation induction in women with polycystic ovary syndrome.

This prospective study was conducted at Medical and Dental College Sargodha during June 2020 to June 2021 to compare the long-term effects of Letrozole and Clomiphene Citrate on ovulation induction in women diagnosed with Polycystic Ovary Syndrome (PCOS). A total of 185 women with PCOS, aged between 18 and 35 years, who sought treatment for infertility were enrolled in the study. All participants met the Rotterdam criteria for PCOS, which includes at least two of the following: oligo/anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries as identified by ultrasound.

Inclusion criteria

1. Women aged 18-35 years.
2. Diagnosed with PCOS according to the Rotterdam criteria.
3. Body Mass Index (BMI) between 18 and 35 kg/m².
4. No previous history of other infertility causes, such as tubal or male factor infertility.

Exclusion criteria

1. Women with known hypersensitivity to Letrozole or Clomiphene Citrate.
2. History of severe hepatic or renal impairment.
3. Presence of any contraindication to pregnancy.
4. Use of any other ovulation-inducing agents within the last three months.
5. Women with hyperprolactinemia or thyroid disorders that were not controlled.

Data collection

The Letrozole group received 2.5 mg of Letrozole daily from day 3 to day 7 of the menstrual cycle, while the Clomiphene Citrate group received 50 mg of Clomiphene Citrate daily for the same duration. If ovulation did not occur, the dose was increased in subsequent cycles up to a maximum of 7.5 mg for Letrozole and 150 mg for Clomiphene Citrate. Ovulation was monitored using transvaginal ultrasound, starting from day 10 of the cycle, to assess follicular development. Ovulation was confirmed by the presence of a dominant follicle measuring ≥18 mm and subsequent luteinization. Data were collected at each treatment cycle, with participants followed for up to six cycles or until pregnancy was achieved. The data collected included ovulation rates, pregnancy outcomes, and any side effects or complications associated with the treatment.

Statistical analysis

Statistical analysis was performed using SPSS software, with comparisons between the two groups made using chi-square tests for categorical variables and t-tests for continuous variables. A p-value of <0.05 was considered statistically significant.

The study enrolled 185 women with PCOS, randomized into two groups: 92 in the Letrozole group and 93 in the Clomiphene Citrate group. Both groups were comparable in terms of baseline characteristics such as age, BMI, and duration of infertility, with no statistically significant differences between them.

Table 1: Demographic and Baseline Characteristics of Participants

The Letrozole group demonstrated a significantly higher ovulation rate compared to the Clomiphene Citrate group. Specifically, ovulation occurred in 80% of the cycles in the Letrozole group (n = 74) versus 65% of the cycles in the Clomiphene Citrate group (n = 60). The difference was statistically significant (p = 0.02), indicating that Letrozole was more effective in inducing ovulation in women with PCOS.

Table 2: Ovulation and Follicular Development

The average number of mature follicles (≥18 mm) developed per cycle was also higher in the Letrozole group. On average, participants in the Letrozole group developed 1.7 follicles per cycle compared to 1.3 follicles per cycle in the Clomiphene Citrate group. This difference was statistically significant (p = 0.01). Endometrial thickness, measured on the day of ovulation, was significantly greater in the Letrozole group compared to the Clomiphene Citrate group. The mean endometrial thickness was 9.5 mm in the Letrozole group versus 7.8 mm in the Clomiphene Citrate group (p = 0.03). This suggests that Letrozole may provide a more favourable endometrial environment for implantation.

Table 3: Pregnancy Outcomes

The pregnancy rates were also higher in the Letrozole group. The cumulative pregnancy rate after six treatment cycles was 45% (n = 41) in the Letrozole group compared to 32% (n = 30) in the Clomiphene Citrate group. The difference was statistically significant (p = 0.04). The median time to achieve pregnancy was shorter in the Letrozole group, with most pregnancies occurring within the first three cycles of treatment. Specifically, 60% of pregnancies in the Letrozole group occurred within the first three cycles, compared to 40% in the Clomiphene Citrate group. The live birth rate was also higher in the Letrozole group. Of the pregnancies that occurred, 80% (n = 33) in the Letrozole group resulted in live births, while 70% (n = 21) in the Clomiphene Citrate group resulted in live births. However, this difference was not statistically significant (p = 0.15). The miscarriage rate was slightly lower in the Letrozole group at 10% (n = 4) compared to 15% (n = 5) in the Clomiphene Citrate group, but this difference was not statistically significant (p = 0.45).

Table 4: Adverse Effects

The findings of this prospective study provide important insights into the long-term effects of Letrozole versus Clomiphene Citrate on ovulation induction in women with Polycystic Ovary Syndrome (PCOS). Our results suggest that Letrozole is not only more effective in inducing ovulation but also has a better overall profile in terms of pregnancy outcomes and the incidence of adverse effects compared to Clomiphene Citrate [14-16]. One of the key findings from our study is the significantly higher ovulation rate observed in the Letrozole group (80%) compared to the Clomiphene Citrate group (65%). This result aligns with previous studies that have suggested the superiority of Letrozole in overcoming the challenge of Clomiphene resistance, which is a common issue in women with PCOS [17]. The higher ovulation rate with Letrozole can be attributed to its mechanism of action, which enhances follicular development without depleting estrogen receptors. This mechanism not only stimulates ovulation more effectively but also contributes to a more favorable endometrial environment, which may explain the higher pregnancy rates observed with Letrozole [18].

The cumulative pregnancy rate was also higher in the Letrozole group (45%) compared to the Clomiphene Citrate group (32%). This finding is significant because it suggests that Letrozole may lead to quicker conception in women with PCOS. The shorter time to pregnancy in the Letrozole group further supports its efficacy, making it a more desirable first-line treatment option for ovulation induction in this population [19]. Additionally, the higher live birth rate (80% in the Letrozole group vs. 70% in the Clomiphene Citrate group) underscores the potential of Letrozole to improve reproductive outcomes, although the difference in live birth rates was not statistically significant. Endometrial thickness is a crucial factor in the successful implantation of the embryo [20]. Our study found that women treated with Letrozole had a significantly thicker endometrium (9.5 mm) compared to those treated with Clomiphene Citrate (7.8 mm). A thicker endometrium is generally associated with higher implantation and pregnancy rates, further supporting the superiority of Letrozole in creating a more conducive environment for pregnancy [21]. Moreover, the average number of mature follicles was higher in the Letrozole group, which is indicative of its efficacy in stimulating follicular development. However, the development of multiple follicles can also increase the risk of multiple pregnancies, which is a concern in fertility treatments. Interestingly, our study found that the incidence of multiple pregnancies was significantly lower in the Letrozole group (5%) compared to the Clomiphene Citrate group (15%), suggesting that Letrozole may offer a safer profile in terms of reducing the risk of multiple pregnancies while still effectively stimulating ovulation [22].

In terms of adverse effects, Letrozole was associated with fewer side effects compared to Clomiphene Citrate. The incidence of hot flashes and mood swings was significantly lower in the Letrozole group, making it a more tolerable option for patients. This difference in side effects could be related to the different mechanisms of action of the two drugs; while Clomiphene Citrate is known to have anti-estrogenic effects on multiple tissues, Letrozole’s effect is more localized to the inhibition of estrogen production, potentially resulting in fewer systemic side effects [3]. The results of this study have significant clinical implications for the management of infertility in women with PCOS. Given the higher ovulation and pregnancy rates, combined with a lower incidence of adverse effects and multiple pregnancies, Letrozole should be considered as a first-line treatment for ovulation induction in women with PCOS. While Clomiphene Citrate has been the standard treatment for many years, the growing body of evidence supporting Letrozole suggests a shift in clinical practice may be warranted. Despite the strengths of this study, including its prospective design and relatively large sample size, there are some limitations that should be acknowledged. The study did not assess long-term outcomes beyond the initial pregnancy, such as child health or subsequent fertility issues. Additionally, while the study population was randomized, future research could benefit from a multicenter approach to ensure broader applicability of the findings.

ovulation induction in women with PCOS, offering higher ovulation and pregnancy rates, a more favorable endometrial environment, and fewer adverse effects compared to Clomiphene Citrate. These findings support the use of Letrozole as a first-line treatment for enhancing reproductive outcomes in this population.

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