LETROZOLE VERSUS TAMOXIFEN IN CLOMIPHEN CITRATE RESISTANT WOMEN WITH POLYCYSTIC OVARIAN SYNDROME IN RANDOMIZED CONTROL TRIAL

Abstract

P olycyctic ovary syndrome (PCOS) is the most common cause of anovulatory infertility which affects 4-7 % of women. It is the most common cause of hyper androgenic anovulatory infertility. The underlying cause of this disorder is still unknown (Wiel s et al., 1999). The classic symptoms of the disease are due to increase ovarian androgen production and chronic anouvlation. There are many clinical and laboratory criteria as anouvlation, oligomenorrhia, hirsutism, acne, obesity. Also there may be an elevated total testosterone and luteinizing hormone to follicle stimulating hormone ratio (Tsilchorozidou et al., 2006). Clomiphene citrate has been the 1st line of treatment for ovulation induction. Clomiphene citrate resistance (failure to ovulate after taking clomiphene citratefor at least 3 cycles) is common, occurring in approximately 15% to 40% of women with PCOS (Koutsa et al., 1997; Wolf et al., 2000; Pritts, 2002). NICE definition is: “Anovulatory women who do not ovulate after receiving the 150 mg dose of clomiphene citrate” (NICE, 2004) Resistance is associated with an increased body mass index (BMI) and weight reduction programmes improve the success rates of clomiphene citrate therapy (Koutsa et al., 1997). The therapeutic techniques for CC –resistant patients are the addition of corticosteroid such as dexamethasone (Elnashar et al., 2006), extended duration of clomiphene citrate (Badway et al., 2008), the use of aromatase inhibitor (Badway et al., 2008), laparoscopic ovarian drilling or in vitro fertilization (Thessaloniki et al., 2008). Aromatase is a cytochrome P450 (CYP450) hemoprotein containing enzyme complex (the product of CYP 19 gene) that catalyzes rate limiting step in the production of estrogens which is the conversion of androstenedione and testosterone to estrone and estradiol, through hydroxylation steps respectively, so recent research has focused on the use of aromatase inhibitors as letrozole for induction of ovulation (Akhtar et al., 1993). They are used for ovulation induction as its administration in early follicular phase to release hypothalamus or pituitary from estrogen negative feedback GNRH leading to increase gonadotropin secretion which stimulates follicular growth (Okman et al., 2003). They also act locally in the ovary to increase follicular sensitivity to FSH as result from increase intraovarian androgen subsequently to blocked conversion of androgen to estrogen. In recent studies letrozole increase endometrial thickness by up-regulation of estrogen receptors and improve pregnancy rate. They are reversible competitive inhibitors of aromatase highly potent, selective and rapidly absorbed from GIT and excreted by the kidney with elimination half life of letrozole is about 2 days (Lidor et al., 2000). Tamoxifen (TMX) is another anti estrogen which is a triphenyl ethylene derivative which is similar to CC in structure, ovulation rates have been reported as 50-90% and pregnancy rates as 30-50%. Tamoxifen has shown reasonably good results in CC failure cases too (Borenstein et al., 1989). The better ovulation and pregnancy rates may be because of higher score of cervical mucus and better functioning of the corpus luteum.The suggested dose is 20-40 mg daily in induction of ovulation, beginning in early follicular phase of the cycle, but it is less common used for ovulation induction as this indication is not licensed yet, although it is sometimes prescribed for women who have side effect of CC (Brown, 2009).