For over 40 years, the first-line therapy for ovulation induction (OI) has been clomiphene citrate (CC) . 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  disappointing. Sub-optimal pregnancy rates with CC have been attributed to peripheral anti-estrogenic effects, mainly on the endometrium and the cervical mucus 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 .
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 . When letrozole is used in combination with gonadotropins, it leads to lower gonadotropin requirements and pregnancy rates similar to gonadotropin treatment alone . 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 .
Aromatase inhibitors for ovulation induction are orally administered, and are relatively inexpensive with minor side effects such as very infrequent headaches and leg cramps. Aromatase inhibitors increase endogenous FSH production in response to decreased estrogen biosynthesis in the ovary and extraovarian tissues, including the brain . Because they do not deplete estrogen receptors like CC, normal central feedback mechanisms remain intact. 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 with the clear advantage of reducing multiple-gestation pregnancies.
Compared to CC, letrozole has been associated with lower preovulatory estradiol (E2) levels , as well as thicker endometrium and a trend towards higher pregnancy rates. 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).