Letrozole and Cabergoline Versus Letrozole Alone in Ovulation Induction

Overview

Polycystic Ovarian Syndrome (PCOS) is the most common endocrine disorders in women of reproductive age. According to the World Health Organization (WHO) estimation revealed over 116 million women (3.4%) are affected by PCOS worldwide. Owing to the intricacy of this condition, various sets of diagnostic criteria have been initiated for the confirmation of PCOS which are: National Institute of Health, Rotterdam's Criteria, Androgen Excess and PCOS society. The prevalence of PCOS is estimated at about 4 to 21 % when it is diagnosed according to the Rotterdam criteria accounting for 75% of cases with anovulatory infertility.

In women with PCOS, the serum FSH levels are slightly lower during the follicular phase, therefore aromatization of excessive androgens is insufficient, and the follicles will not undergo the final FSH-dependent maturation in a dominant follicle. Furthermore, the serum level of anti-Mullerian hormone (AMH) is elevated. AMH counteracts the FSH-driven aromatase complex activity, so high AMH levels will inhibit granulosa cell conversion of androgens to estrogens and have a detrimental effect on final follicular maturation. Previous studies showed that 30% of patients with PCOS show a modest rise in prolactin level. Increasing serum prolactin in these patients could be detected in both follicular and luteal phase of the normal and stimulated cycles. Dopamine release from the hypothalamus inhibits prolactin secretion, and it also affects the secretion of gonadotropins. When this inhibitory effect of dopamine is reduced, prolactin secretion will increase in addition to abnormalities in gonadotropins including luteinizing hormones. Cabergoline which is a dopamine receptor agonist, with higher affinity to dopamine D2 receptors had improved uterine perfusion and achieved a better ovulatory response in PCOS patients, due to its ability to inhibit the vascular endothelial growth factor (VEGF) secretion in luteinized granulosa cells. Other studies concluded that Cabergoline use could normalize androgen level and therefore improve the menstrual irregularity in women with PCOS. Letrozole is a third-generation aromatase inhibitor. It blocks the conversion of C-19 androgens to C-18 estrogens by competitively inhibiting the enzyme, aromatase (cytochrome P-450), which is an essential step in estrogen biosynthesis in the ovary and other tissues.The subsequent feedback to the hypothalamus containing reduced estrogen levels, triggers a compensatory increase in hypothalamic gonadotropin-releasing hormone (GnRH) secretion, and thus an increased release of pituitary gonadotropins FSH \& LH. These gonadotropins subsequently promote growth of the follicles and stimulate ovulation. Letrozole has 99.9% bioavailability after oral administration. It has a single dose terminal half-life of 42 hours.