One of the most prevalent endocrine disorders that lead to infertility resulting from chronic anovulation is polycystic ovary syndrome (PCOS) which occurs in 5-20% of women depending on the diagnostic criteria and the population studied^1,2. It is usually accompanied by oligo- or anovulation, clinical and/or biochemical hyperandrogenism and polycystic ovarian morphology.³ Though known, the pathophysiology of PCOS is quite complex and not fully understood, and is highly heterogeneous in clinical presentation.⁴

In women who want to conceive with PCOS, the fundamental basis of treatment is ovulation induction (OI). There are currently international guidelines recommending use of letrozole as the first line choice for pharmacological ovulation because it has greater ovulation and live birth rates than other agents.⁵ But about 15% of patients are unresponsive to letrozole, even when doses are increased, and are said to be "letrozole-resistant".⁶ However, alternative treatments like in vitro fertilization (IVF) might help in this case, as well as elective single embryo transfer to lower the chances of having multiple pregnancies. Many patients, however, are not able to access IVF due to the high price tag associated with the treatment.⁷

Other proven treatments for letrozole-resistant PCOS include gonadotropin therapy and laparoscopic ovarian drilling (LOD).⁸ These strategies can work but have many drawbacks. The side effects of gonadotropin use include the potential for ovarian hyperstimulation syndrome, multiple gestation, cycle cancellation and multifollicular development, and LOD is a surgical procedure with the risk of adhesion formation and potential long-term decrease in ovarian reserve.⁹ Hence, safer and cost-effective methods to enhance the success rate of OI are clinically needed for this population.

Hyperandrogenism is one of the key pathophysiological features of PCOS and is found in 60-80% of patients.¹⁰ Hyperadrenocorticism and hyperandrogenism of the ovaries cause follicular arrest and anovulation. Adrenal androgen suppression by the use of glucocorticoids (e.g. dexamethasone) and correction of hyperandrogenism can improve the ovulatory function. Moreover, glucocorticoids can regulate gonadotropin-releasing hormone (GnRH) pulsatility, which can increase the secretion of follicle-stimulating hormone (FSH) and follicular development.^11,12

Dexamethasone has been studied in PCOS patients who are not responding to clomiphene citrate, and has been shown to increase ovulation and the pregnancy rate.^13–15 Previous studies indicated that steroid treatment may be more effective in patients with high levels of dehydroepiandrosterone sulfate (DHEA-S).^16,17 More recent studies, however, have suggested that administering dexamethasone could be beneficial in patients with and without DHEA-S.

Based on this background, the aim of the present study was to assess the efficacy of letrozole plus dexamethasone in women with letrozole-resistant PCOS when undergoing induction of ovulation, regardless of their baseline androgen levels.

After approval from the institutional review board, data from the electronic medical record were collected for this retrospective, observational study at a tertiary fertility center from September 2024 to November 2025. Infertile women aged between 18 and 35 years wh AZSXo had a diagnosis of polycystic ovary syndrome (PCOS) (at least 2 Rotterdam criteria) were included in the study. The patients were those who had failed to develop a dominant follicle (14 mm or greater) on transvaginal ultrasound after a standard stair-step letrozole protocol up to 7.5 mg/day. Other cause of infertility such as thyroid disorders, hyperprolactinemia and other known infertility factors were not included. Letrozole was used for 5 days beginning on cycle day 3 to induce ovulation, and then escalated in a "stair step" fashion until the maximum dose was achieved in cases where no follicular development was seen. Transvaginal ultrasound was used to monitor the follicles either on cycle days 10–12 or a few days after the last dose in a randomly selected cycle, and the size of the follicles was determined in 2 perpendicular planes and averaged. If patients did not respond, an additional 5 day course of letrozole (7.5 mg) plus dexamethasone (0.5 mg/day) for 7 days was administered and repeat ultrasound imaging performed about 1 week later. A dominant follicle was considered to be ≥14 mm and ovulation was induced by urinary LH detected with an ovulation predictor kit or human chorionic gonadotropin (hCG) 250 mcg when appropriate follicular maturity was achieved. The timing of intercourse or intrauterine insemination was conducted as per clinical judgement and patient preference. The main outcome measured was ovulation rate, as evidenced by an ultrasound scan showing dominant follicles developing or by biochemical or blood tests of the ability to implant, as evidenced by positive ovulation predictor kit, timetable menstrual period or serum hCG. Secondary outcomes were endometrial thickness, follicular number > 10 mm, size of the largest follicle, clinical pregnancy (visualisation of a gestational sac by ultrasound examination) and live birth (beyond 22 weeks gestation). BlueSky Statistics 7.40 software was used for statistical analysis. Continuous variables were analysed using Student's t-test or Wilcoxon rank sum test and categorical variables analysed using chi-square or Fisher's exact test with significance set at p < 0.05.

Twenty-eight women with letrozole-resistant polycystic ovary syndrome (P.O.S) were treated with letrozole plus dexamethasone for a total of 42 ovulation induction cycles. The median age of participants was around 30 years and the median BMI was around 30 kg/m², which means that the majority of patients were overweight or obese. The mean time of infertility was 2 years and most had either oligoovulatory or anovulatory cycles before treatment. There were no statistically significant differences between the baseline hormonal parameters (total testosterone, free testosterone, FSH, LH, AMH, DHEA-S) between the responders and non-responders. The glycemic profile was normal in the majority of patients, impaired glucose tolerance in a minority and no patient had a pre-existing DM.

The addition of dexamethasone resulted in ovulation in 22/28 patients (79%) and no response was seen in 6 patients. In the cycle basis, 35/42 cycles ovulated (83%) showing a very good response to combination therapy. Of those who responded, 83% were observed to have been stimulated to ovulate with human chorionic gonadotropin (hCG) and the remaining 17% with ovulation predictor kits. Subsequent conception attempts were made by timed intercourse or intrauterine insemination as clinically warranted and desired. No significant differences were seen between pregnancy and non-pregnancy cycles with a mean endometrial thickness of ~7 mm, mean number of follicles >10 mm of 2, and a mean leading follicle diameter of 19 mm.

Biochemical pregnancy (positive serum hCG) was seen in 29% of cycles and cumulative pregnancy after one or more cycles was noted in 41% of patients. The overall cumulative live birth rate was 32% with clinical pregnancy (defined as detection of a gestational sac by ultrasound) occurring in 20% of all ovulatory cycles. Importantly, all clinical pregnancies were delivered as live births (one twin gestation). During treatment, there were no significant adverse effects reported and the treatment was well tolerated in all patients.

Table 1: Baseline Characteristics of Study Population

Table 2: Hormonal Profile (Responders vs Non-Responders)

(NS = not significant)

Table 3: Cycle Characteristics and Outcomes

Table 4: Pregnancy Outcomes

Figure 1: Pregnancy Outcomes Per Cycle Vs Cumulative

Figure 1 shows the pregnancy rates after use of letrozole with dexamethasone in letrozole-resistant PCOS cases. The biochemical pregnancy rate was 29% and the clinical pregnancy rate was 20% for per-cycle outcomes; and 41% and 32%, respectively, after multiple cycles. This suggests that there is improved overall success in repeated cycles of ovulation induction.

Twenty-eight women with letrozole-resistant polycystic ovary syndrome (P.O.S) were treated with letrozole plus dexamethasone for a total of 42 ovulation induction cycles. The median age of participants was around 30 years and the median BMI was around 30 kg/m², which means that the majority of patients were overweight or obese. The mean time of infertility was 2 years and most had either oligoovulatory or anovulatory cycles before treatment. There were no statistically significant differences between the baseline hormonal parameters (total testosterone, free testosterone, FSH, LH, AMH, DHEA-S) between the responders and non-responders. The glycemic profile was normal in the majority of patients, impaired glucose tolerance in a minority and no patient had a pre-existing DM.

The addition of dexamethasone resulted in ovulation in 22/28 patients (79%) and no response was seen in 6 patients. In the cycle basis, 35/42 cycles ovulated (83%) showing a very good response to combination therapy. Of those who responded, 83% were observed to have been stimulated to ovulate with human chorionic gonadotropin (hCG) and the remaining 17% with ovulation predictor kits. Subsequent conception attempts were made by timed intercourse or intrauterine insemination as clinically warranted and desired. No significant differences were seen between pregnancy and non-pregnancy cycles with a mean endometrial thickness of ~7 mm, mean number of follicles >10 mm of 2, and a mean leading follicle diameter of 19 mm.

Biochemical pregnancy (positive serum hCG) was seen in 29% of cycles and cumulative pregnancy after one or more cycles was noted in 41% of patients. The overall cumulative live birth rate was 32% with clinical pregnancy (defined as detection of a gestational sac by ultrasound) occurring in 20% of all ovulatory cycles. Importantly, all clinical pregnancies were delivered as live births (one twin gestation). During treatment, there were no significant adverse effects reported and the treatment was well tolerated in all patients.

Table 1: Baseline Characteristics of Study Population

Table 2: Hormonal Profile (Responders vs Non-Responders)

(NS = not significant)

Table 3: Cycle Characteristics and Outcomes

Table 4: Pregnancy Outcomes

Figure 1: Pregnancy Outcomes Per Cycle Vs Cumulative

Figure 1 shows the pregnancy rates after use of letrozole with dexamethasone in letrozole-resistant PCOS cases. The biochemical pregnancy rate was 29% and the clinical pregnancy rate was 20% for per-cycle outcomes; and 41% and 32%, respectively, after multiple cycles. This suggests that there is improved overall success in repeated cycles of ovulation induction.

To our knowledge, no study has yet shown that dexamethasone can be used successfully to induce ovulation in a high percentage of women with letrozole-resistant polycystic ovary syndrome (PCOS) who are undergoing ovulation induction cycles. Combined therapy resulted in a cumulative live birth rate of 32% of the patients who ovulated and about 79% of our cohort did so. The results indicate that dexamethasone could have a potentially significant clinical impact on enhancing ovarian response in women who have not responded to conventional letrozole treatment. Interestingly, the duration of infertility was shorter for patients who responded to treatment, but no other significant differences between baseline characteristics, hormonal profile or metabolic parameters were observed between responders and non-responders. In particular, levels of serum androgens, such as DHEA-S, were not significantly different between groups, meaning that it may not be strictly necessary that the patient have biochemical evidence of adrenal hyperandrogenism to respond to dexamethasone.

The same positive effects of the use of glucocorticoids in the induction of ovulation have been shown in previous studies in groups of women resistant to clomiphene citrate in PCOS [13–15]. Previous research showed that dexamethasone treatment either alone or in conjunction with clomiphene citrate resulted in improved ovulation and pregnancy rates, which led to the speculation that adrenal androgen suppression may promote follicular development. Although early studies indicated that dexamethasone might be most beneficial in patients with high levels of DHEA-S [16,17], more recent data have suggested that dexamethasone could be effective in women with normal levels of androgens [13–15] and that this is also the case in our study.

Letrozole is now recommended as the first choice for women with PCOS for induction of ovulation over clomiphene citrate because it has better live birth rates [5,6]. But a group of patients is not responsive to the treatment with letrozole and thus is a therapeutic challenge. In this context other methods like in vitro fertilization can be effective but are expensive and not always available [7]. Other procedures such as gonadotropin therapy and laparoscopic ovarian drilling have greater risks such as ovarian hyperstimulation syndrome, multiple gestation, surgical risks, and potential long-term effects on ovarian reserve [8,9]. Thus, more simple and non-invasive methods are still very much desirable.

Recently, benzodiazepines were shown to be effective in improving the pregnancy rates of women with PCOS who received dexamethasone in addition to letrozole versus those who received letrozole alone in a randomized controlled trial [22]. This study, however, did not target letrozole-resistant patients or assess detailed hormonal subgroups, like the levels of DHEA-S. We found this to be true and our work specifically in a resistant population indicates that dexamethasone may be especially useful in overcoming the standard letrozole protocol.

Other strategies to help overcome resistance to letrozole have also been investigated. Inovarian patients have been found to have better ovulatory outcomes after extended therapy of letrozole [23]. In addition, some studies have shown that the use of a combined ovulation induction protocol of letrozole and clomiphene citrate has resulted in increased ovulation rates relative to letrozole alone. The best treatment for letrozole-resistant PCOS, however, is not clear and there is no agreement on which is the most effective stepwise treatment.

There are a number of strengths to this study, such as studying a clearly defined population of patients who were on letrozole, using the same monitoring protocols, and ensuring that follow-up was made to pregnancy and live birth outcomes. Importantly, all clinical pregnancies led to live birth indicating the clinical relevance of the observed ovulation rates. Additionally, dexamethasone could be used in all patients, irrespective of their baseline DHEA-S status, indicating that this treatment strategy may be more widely applicable.

It is important to recognize, however, a number of restrictions. The design is retrospective and the patient number is not large, so it is difficult to draw a definite causal conclusion. Also, the study population was not racially diverse, so the results may not be generalizable. This may have been confounded by variations in the ways ovulation was monitored, whether or not ovulation was triggered and whether or not timed intercourse was used, or by intrauterine insemination. In addition, levels of progesterone did not routinely get measured during the luteal phase and metabolic follow-up after dexamethasone exposure was limited, but no adverse effects were reported. Lastly, the dose of letrozole was prolonged, making it hard to attribute independent effects of dexamethasone to the effects seen.

Finally, adding dexamethasone to letrozole treatment is highly beneficial to promote ovulation in women who are not responding to letrozole, with positive pregnancy and live birth rates. This therapy is simple, low cost and effective, and can be considered prior to more invasive or costly fertility treatments like gonadotropins, in-vitro fertilization, or laparoscopic ovarian drilling. There is a need for further large scale prospective randomized studies to validate these results, and to further identify patient populations that may benefit from this approach.

This study shows that low dose dexamethasone in addition to letrozole is highly effective in increasing the ovulation rate in letrozole resistant PCOS women. Combination therapy resulted in successful follicular development and ovulation in a significant number of former resistant patients, and good pregnancy and live birth rates. Notably, there were no major side effects associated with this treatment and it proved to be quite safe. The present results indicate that dexamethasone can be used as a simple, safe and cost-effective add-on in ovulation induction protocols in patients who have not responded to letrozole alone. Increased awareness of this possibility may make ovarian hyperstimulation with letrozole an alternative option between the initial phase of management of letrozole-resistant PCOS and more invasive and expensive procedures like gonadotropin therapy, laparoscopy of the ovary or in vitro fertilization. Larger prospective randomized controlled trials are needed, however, to validate these findings and better identify the ideal patient population for this treatment approach.

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