Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting reproductive-aged women, with a prevalence ranging from 6% to 20% depending on the diagnostic criteria applied [1]. It is characterized by oligo/anovulation, hyperandrogenism, and polycystic ovarian morphology. Among its many consequences, infertility due to chronic anovulation remains a significant clinical concern. Ovulation induction thus plays a central role in the management of infertile women with PCOS, particularly in those desiring conception [2].

Letrozole, a third-generation aromatase inhibitor, has emerged as the first-line pharmacological agent for ovulation induction in PCOS. Its mechanism of action involves suppression of estrogen synthesis, resulting in an upregulation of follicle-stimulating hormone (FSH) secretion from the pituitary and subsequent follicular development [3]. Compared to clomiphene citrate, letrozole has demonstrated superior ovulation and live birth rates, particularly in women with a high body mass index (BMI) or those with clomiphene resistance [4]. However, a subset of PCOS patients fails to respond to letrozole monotherapy even at the maximum permissible dose, thereby representing a clinical challenge known as letrozole-resistant PCOS [5].

Letrozole resistance is a multifactorial phenomenon and may be attributed to severe hyperandrogenemia, insulin resistance, or elevated levels of luteinizing hormone (LH), which impair folliculogenesis despite adequate FSH stimulation [6]. In such cases, combination therapy with adjuvant agents has been explored to overcome this resistance. One such adjunct is dexamethasone, a glucocorticoid with potent anti-androgenic properties. Dexamethasone suppresses adrenal androgen production, which may restore the hypothalamic-pituitary-ovarian axis sensitivity and enhance follicular responsiveness to gonadotropins [7].

Several clinical studies have evaluated the efficacy of dexamethasone in combination with ovulation-inducing agents such as clomiphene citrate and gonadotropins. These trials demonstrated an improvement in ovulation rates, follicular maturation, and pregnancy outcomes, especially in patients with high dehydroepiandrosterone sulfate (DHEAS) levels or those with adrenal hyperandrogenism [8]. Extending this concept, the addition of dexamethasone to letrozole has been proposed as a rational therapeutic strategy for patients with letrozole-resistant PCOS, although evidence in this domain remains limited and emerging.

The potential benefits of this combination include improved ovulation and conception rates without necessitating more invasive or expensive interventions like gonadotropin therapy or laparoscopic ovarian drilling [9]. Moreover, dexamethasone is relatively inexpensive and widely available, making it an attractive adjuvant, particularly in low-resource settings. Nevertheless, the use of corticosteroids is not without risk, and their adverse effect profile—particularly with prolonged use—necessitates careful dosing and monitoring [10].

This study aims to evaluate the efficacy of combined letrozole and dexamethasone therapy in infertile women with letrozole-resistant PCOS. By assessing ovulation and pregnancy outcomes, it seeks to provide evidence-based insights into whether this pharmacological combination could serve as a viable treatment strategy in this challenging subgroup of PCOS patients.

Study Design and Setting

This retrospective observational study was conducted in the Department of Reproductive Medicine at a tertiary care center over a period of 18 months. Ethical clearance was obtained from the institutional review board prior to data collection.

Inclusion and Exclusion Criteria

Women aged between 20 and 35 years, diagnosed with polycystic ovary syndrome based on the Rotterdam criteria (2003) with documented infertility for more than one year and who failed to ovulate after at least three cycles of letrozole (up to 7.5 mg/day) were included in the study. Patients with tubal factor infertility, male factor infertility (total motile sperm count <5 million), thyroid dysfunction, hyperprolactinemia, or other endocrine disorders were excluded.

Sample Size and Grouping

A total of 60 women fulfilling the eligibility criteria were selected from hospital records. All patients were classified as “letrozole-resistant.” These patients were then managed using a combination protocol of letrozole and dexamethasone.

Intervention Protocol

Letrozole was administered at a dose of 5 mg orally once daily from Day 2 to Day 6 of the menstrual cycle. Dexamethasone was added at a dose of 0.5 mg orally at bedtime from Day 2 to Day 12 of the cycle. Serial transvaginal ultrasonography was done starting from Day 10 to monitor follicular growth. When at least one dominant follicle ≥18 mm was identified, 10,000 IU of human chorionic gonadotropin (hCG) was administered to trigger ovulation.

Outcome Measures

Primary outcome measures included:

1. Ovulation rate (confirmed by follicular rupture or serum progesterone >3 ng/mL in mid-luteal phase)
2. Endometrial thickness on the day of hCG trigger
3. Number of mature follicles (>18 mm)
4. Clinical pregnancy rate per cycle (defined as presence of intrauterine gestational sac with fetal cardiac activity at 6–7 weeks by ultrasound)

Secondary outcomes included cycle cancellation rate, adverse effects of medication, and multiple gestation rate.

Data Collection and Analysis

Patient demographics, hormonal profiles (baseline FSH, LH, TSH, DHEAS), BMI, cycle monitoring data, and pregnancy outcomes were extracted from medical records. Statistical analysis was performed using SPSS software version 25.0. Continuous variables were expressed as mean ± standard deviation and compared using Student’s t-test. Categorical variables were expressed as percentages and compared using Chi-square test or Fisher’s exact test where appropriate. A p-value <0.05 was considered statistically significant.

Table 1: Baseline Characteristics of Study Population

The mean age of the 60 included patients was 27.4 ± 3.6 years, and the average duration of infertility was 3.2 ± 1.1 years. The participants had a mean BMI of 28.9 ± 2.7 kg/m², indicating a predominantly overweight population. Hormonal profiling showed an elevated mean LH of 12.8 ± 4.1 mIU/mL, and the LH/FSH ratio averaged 2.3 ± 0.6, which is consistent with PCOS-related endocrine dysfunction. Notably, 36.6% of patients had elevated DHEAS levels, suggestive of adrenal hyperandrogenism.

Table 2: Ovulation and Pregnancy Outcomes

Following combination therapy, ovulation was confirmed in 70% (n=42) of the patients. A clinical pregnancy was achieved in 30% (n=18), while 3.3% (n=2) had biochemical pregnancies and 3.3% (n=2) experienced early miscarriages. Only one case of multiple pregnancy (1.6%) was observed, and no cases of ovarian hyperstimulation syndrome (OHSS) were reported. These results suggest that the combination therapy was effective and well-tolerated.

Table 3: Follicular and Endometrial Characteristics at Trigger

On average, 1.6 ± 0.8 mature follicles (≥18 mm) were observed per patient at the time of hCG trigger. The mean endometrial thickness was 8.4 ± 1.3 mm, indicating favorable endometrial receptivity for implantation. Ovulation was generally triggered on Day 12.1 ± 1.5 of the menstrual cycle. These findings support the effectiveness of the combined protocol in stimulating mono-ovulation with adequate endometrial development.

Table 4: Comparison between Ovulatory and Non-Ovulatory Cycles

Statistically significant differences were observed between ovulatory and non-ovulatory groups. Women who ovulated had a lower BMI (27.8 ± 2.3 vs. 30.2 ± 2.4, p = 0.01) and a lower LH/FSH ratio (2.1 vs. 2.6, p = 0.03). Elevated DHEAS levels were also more prevalent in non-responders (55.5% vs. 28.6%, p = 0.04). Moreover, ovulatory patients had a significantly thicker endometrium at trigger (8.7 mm vs. 7.5 mm, p = 0.02). These findings highlight predictive markers of response to therapy.

Table 1: Baseline Characteristics of Study Population (n = 60)

Table 2: Ovulation and Pregnancy Outcomes

Table 3: Follicular and Endometrial Characteristics at Trigger

Table 4: Comparison between Ovulatory and Non-Ovulatory Cycles

                        *Significant at p < 0.05

Polycystic ovary syndrome (PCOS) remains a predominant cause of anovulatory infertility, and ovulation induction is the cornerstone of its reproductive management. Letrozole has overtaken clomiphene citrate as the preferred first-line agent due to its favorable endometrial effects, mono-follicular response, and superior live birth rates [6]. However, a notable subset of women does not respond to even the highest permissible doses of letrozole—a condition termed letrozole resistance. This study evaluated the efficacy of combining letrozole with dexamethasone in this challenging group, showing a promising ovulation rate of 70% and a clinical pregnancy rate of 30%.

The rationale for combining dexamethasone with letrozole lies in the hypothesis that excess adrenal androgens—particularly dehydroepiandrosterone sulfate (DHEAS)—may contribute to persistent anovulation in letrozole-resistant PCOS patients [7]. Glucocorticoids like dexamethasone inhibit adrenal steroidogenesis and suppress DHEAS, potentially restoring ovulatory function. In this study, elevated DHEAS levels were significantly more frequent in non-responders than responders (55.5% vs. 28.6%), reinforcing the role of adrenal hyperactivity in letrozole resistance.

Previous research has reported improved ovulation and pregnancy rates with the addition of corticosteroids in clomiphene-resistant women [8]. The extrapolation of this approach to letrozole-resistant cases has been less studied, but initial findings are encouraging. A similar study showed ovulation in 68–72% of patients with combined letrozole-dexamethasone therapy, with live birth rates ranging from 20–28% [9], which aligns well with the present study’s ovulation and pregnancy rates. This suggests that the addition of dexamethasone may indeed offer a viable, cost-effective, and minimally invasive alternative to gonadotropins or laparoscopic ovarian drilling in letrozole-resistant patients.

Endometrial receptivity is a critical factor in conception. Letrozole is known to maintain a favorable endometrial profile compared to clomiphene, which is associated with endometrial thinning due to its anti-estrogenic effect [10]. In our study, the mean endometrial thickness among ovulatory cycles was 8.7 ± 1.1 mm, which is within the optimal range for implantation. Interestingly, a statistically significant difference in endometrial thickness was observed between ovulatory and non-ovulatory cycles, suggesting that endometrial development could potentially predict ovulatory response and treatment success.

Obesity is an established contributor to ovulatory dysfunction in PCOS. In this study, non-responders had a significantly higher mean BMI (30.2 ± 2.4 kg/m²) than responders (27.8 ± 2.3 kg/m²), consistent with the understanding that insulin resistance and hyperinsulinemia associated with obesity impair the follicular environment [11]. These findings highlight the necessity of adjunctive weight management and metabolic correction strategies alongside pharmacologic ovulation induction.

The ovulation rate of 70% and pregnancy rate of 30% seen in this study, while encouraging, are still suboptimal compared to gonadotropin therapy, which typically results in ovulation in 75–85% of cycles and pregnancy in 20–30% per cycle [12]. However, gonadotropin use is associated with a higher cost, need for intensive monitoring, and elevated risk of ovarian hyperstimulation syndrome (OHSS) and multiple gestation. In contrast, the letrozole-dexamethasone protocol reported no significant adverse events or multiple pregnancies in this study, supporting its safety and patient acceptability.

Another interesting finding is the significant difference in LH/FSH ratios between ovulatory and non-ovulatory groups. Hypersecretion of LH is a common feature in PCOS and can disrupt follicular maturation. A ratio exceeding 2:1 was found to be significantly more common in the non-responder group, consistent with reports that elevated LH levels can impair granulosa cell function and inhibit dominant follicle selection [13].

It is also worth considering the psychologic and economic impacts. For women unable to conceive after first-line agents, proceeding directly to gonadotropin therapy or surgical options can be both distressing and financially burdensome. The inclusion of a simple adjuvant like dexamethasone may delay or obviate the need for more invasive procedures while offering a reasonable chance at success [14].

This study's limitations include its retrospective design, modest sample size, and lack of a control arm. Prospective randomized controlled trials comparing letrozole alone, letrozole plus dexamethasone, and gonadotropins would be invaluable to establish definitive efficacy and cost-effectiveness. Furthermore, biochemical confirmation of adrenal androgen suppression and serum progesterone levels post-ovulation were not uniformly available, limiting hormonal correlation with ovulatory outcomes.

Nevertheless, the findings strongly suggest that dexamethasone addition can improve responsiveness to letrozole in women with PCOS who have previously failed to ovulate. As letrozole resistance remains a frustrating barrier in the management of infertility in PCOS, this combination protocol offers a promising and pragmatic solution with minimal added burden [15].

In infertile women with letrozole-resistant PCOS, the addition of dexamethasone significantly improved ovulation and clinical pregnancy rates without major adverse effects. The combination appears especially beneficial in patients with elevated adrenal androgens and those with lower BMI. This dual-drug protocol offers a safe, cost-effective alternative to more aggressive interventions and can serve as a valuable second-line therapy. However, further prospective trials are warranted to confirm these findings and establish standardized clinical guidelines.

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