For over 40 years, the first-line therapy for ovulation induction (OI) has been clomiphene citrate (CC) [¹]. Its inherent properties such as low price, oral route of administration and high ovulation success rate (60-90%) make it an attractive therapy. However, the pregnancy rate is [²] disappointing. Sub-optimal pregnancy rates with CC have been attributed to peripheral anti-estrogenic effects, mainly on the endometrium and the cervical mucus[³] Gonadotropins are more effective in ovulation induction and are associated with higher pregnancy rates than CC, but are expensive and carry higher risk for ovarian hyperstimulation syndrome and multiple gestations [⁴].

Newer options for ovulation induction are the third-generation aromatase inhibitors (AIs), the most commonly used being letrozole. Initially introduced to treat postmenopausal breast cancer, AIs are now also being used for ovulation induction or enhancement. A recent meta-analysis addressing the use of letrozole in assisted conception concluded that letrozole is as effective as other methods of ovulation induction [⁵]. When letrozole is used in combination with gonadotropins, it leads to lower gonadotropin requirements and pregnancy rates similar to gonadotropin treatment alone [⁶]. In a study comparing combined therapy of letrozole (2.5 mg/day or 5.0 mg/day) and recombinant FSH with recombinant FSH alone in an intrauterine insemination (IUI) program, 5 mg/day of letrozole was more cost-effective than the 2.5 mg/day in co-treatment with no adverse effect on pregnancy rate or outcome [⁷].

Aromatase inhibitors for ovulation induction are orally administered, and are relatively inexpensive with minor side effects such as very infrequent headaches and leg cramps[⁸]. Aromatase inhibitors increase endogenous FSH production in response to decreased estrogen biosynthesis in the ovary and extraovarian tissues, including the brain [⁹]. Because they do not deplete estrogen receptors like CC, normal central feedback mechanisms remain intact[¹⁰]. As the dominant follicle grows and estrogen levels rise, normal negative feedback occurs centrally resulting in suppression of FSH and atresia of the smaller growing follicles. Therefore, a single dominant follicle, and mono-ovulation, is the rule in most cases[¹¹] with the clear advantage of reducing multiple-gestation pregnancies.

Compared to CC, letrozole has been associated with lower preovulatory estradiol (E₂) levels [¹²], as well as thicker endometrium and a trend towards higher pregnancy rates[¹³]. Standard ovarian stimulation protocols often produce high preovulatory E₂ levels that could adversely affect the development of the endometrium, the follicles, and the embryo. Therefore, the lower E₂ when using AIs may lead to an improvement of implantation [¹⁴,¹⁵].

There have been several studies comparing letrozole to CC. However, there is a paucity of research comparing letrozole with natural cycles. Larger studies comparing CC, letrozole, and natural cycles in a single study are necessary to further characterize the effect of letrozole on hormonal dynamics and pregnancy rates. Our hypothesis is that letrozole-treated cycles mimic natural cycles in hormonal and endometrial parameters. The aim of this study was to compare cycle dynamics in letrozole-treated versus natural cycles in infertile patients undergoing intrauterine insemination (IUI).

Endometrial sparing, increased folliculogenesis, and an increase in pregnancy rate were observed in our letrozole-treated patients as compared to naturally-cycling patients. The endometrial-sparing effect of letrozole is well-demonstrated in this study by the lack of significant difference in endometrial thickness compared to the natural cycle group, and also has been confirmed by previous studies [¹⁷,¹⁸]. In addition, our ovulation monitoring findings agree with a previous study showing multifollicular development and better pregnancy outcomes with the use of letrozole 5 mg/day [¹⁴,¹⁷]. Our finding that serial serum progesterone levels were comparable between the three groups agrees with a previous study [¹⁸], and suggests that letrozole does not have a premature luteinizing effect on the developing follicle. Table 6 summarizes the results of some trials using letrozole as an ovulation inducing agent in different clinical scenaria with different results and conclusions.

Although basal LH levels were comparable among the 3 groups, there was a trend towards higher LH (although non-significant) on day 7 in the letrozole groups. This rise might be due to the release of the anterior pituitary from the negative feedback of E₂. Three important observations deserve mentioning. First, the increase in LH is still well-below the levels for definition of premature LH surge. Second, after discontinuation of letrozole (days 9-11), serum LH returned to levels similar to the non-stimulated group reflecting the short half life of the letrozole. Thirdly, a natural LH surge was observed more frequently in non-stimulated cycles than in the letrozole stimulated cycles. This finding is likely artifactual since we suggest hCG administration to all women undergoing IUI so that timing of insemination can be optimized. The women undergoing natural cycle monitoring usually requested everything to be natural including no hCG trigger so the difference between the groups is unlikely to be related to the letrozole. Spontaneous LH surges do occur with letrozole for ovulation induction.

This study has some limitations, the most important of which include that it is retrospective, non-powered, non-randomized and not blinded. These issues are inherent in retrospective studies. However, we believe the results are of interest since there are few studies comparing natural cycles to letrozole-stimulated cycles. The main distinguishing features of letrozole as an ovulation inducing agent is its endometrial sparing effect and the early cycle multi-follicular development that may have translated into a better pregnancy rate in the present study. In addition, a recent study demonstrated that letrozole improves blood flow compared to CC and this observation may also be associated with improved pregnancy rates [¹⁹]. A well-designed and powered randomized clinical trial will be needed to confirm this result.

The authors declare that they have no competing interests.

The authors declare that they have no competing interests.

MAB collected and analyzed the data and drafted the manuscript. MAA Collected the data and drafting the manuscript. MH participated in the data collection. NM participated in the design of the study and performed the statistical analysis. LNB: participated in the data collection and helped to draft the manuscript. RC Conceived the idea of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.