Efficacy of coadministration of clomiphene citrate and letrozole to conventional GnRH antagonist protocol in expected poor responders undergoing IVF or ICSI cycles A Randomized Controlled Trial

GnRH antagonist protocol is a conventional ovarian stimulation protocol in IVF. In expected poor responders (POSEIDON group 3 and 4), usually higher amount of gonadotropin is required along with prolonged duration of stimulation in order to achieve the target follicular stimulation. Few studies have been done lately on effect of addition of aromatase inhibitors (letrozole) and/or clomiphene citrate (CC) to gonadotropins (Gn) in women undergoing IVF/ICSI cycles. The addition of these oral drugs have shown comparable or non-inferior results in terms of oocyte yield in expected poor responders, along with decreasing the overall cost of the cycle. But most of the studies have used either Let or CC. The data on combined addition of CC and Let is sparse. Only one retrospective study on combined addition of CC+ Let to Gn found on literature review.The rationale for protocols using combination of oral agents such as CC and/or Let with relatively low-dose gonadotropins is:

• To reduce cost of IVF cycle
• To reduce time required for controlled ovarian stimulation
• To combat side-effects of high dose of Gn on endometrium

CC and Let both stimulate GnRH secretion by decreasing the negative feedback effect of estrogen. CC depletes central estrogen receptors whereas Let decreases estrogen production directly and increases androgen levels in the ovary. The increase of intraovarian androgen by Let also prevents follicular atresia during the preantral-early antral transition phase, and stimulates granulosa cell mitosis and proliferation, thereby facilitating follicular growth and enhanced quality of oocyte. These different mechanisms of both oral agents may result in an additive effect to improve the IVF outcomes in expected poor responders.