Letrozole has become the standard of care for inducing ovulation in polycystic ovarian syndrome patients, who comprise most of the anovulatory patients . By preventing estrogen formation, inhibition of aromatization frees the hypothalamo-pituitary axis from the harmful effects of estrogen. The enzyme aromatase, which catalyzes the rate-limiting step in estrogen synthesis, is competitively inhibited by it . The most popular aromatase inhibitor for ovulation induction is letrozole. The primary treatment for anovulatory infertility is the induction of ovulation . This review focuses on our current knowledge of the uses of letrozole for female and male infertility, its mechanisms, and its benefits. While clomiphene citrate has certain limitations, letrozole successfully overcomes these limitations because of its lack of prolonged anti-estrogenic activity, short half-life, and lack of estrogen receptor activation.
Androgens, including T, are candidates for such treatments since they modulate immune function.30,32-34 Novel cancer therapeutic strategies focus on supporting the immune system. Although the data on nolvadex are conflicting,21 preclinical evidence does not support this concern for T. The patient had no signs or symptoms of cardiac toxicity or compromise.
However, no beneficial effects were seen on muscle strength, body composition or quality-of-life scores. Aromatase inhibitors may be an attractive alternative for traditional testosterone substitution in elderly men because these compounds can be administered orally once daily and may result in physiological 24 h testosterone profiles. As aromatase inhibition is dose dependent it has been suggested that aromatase is less suppressed in the testis compared to adipose and muscle tissue, explaining the incomplete efficacy of aromatase inhibition in men. Third-generation inhibitors such as letrozole and anastrozole are potent and do not inhibit related enzymes. Nonsteroidal enzyme inhibitors such as anastrozole and letrozole inhibit enzyme activity by binding with the heme iron of the enzyme. Steroidal inhibitors such as formestane and exemestane inhibit aromatase activity by mimicking the substrate androstenedione. A major concern of aromatase inhibition is the possible detrimental effect on bone mineralization.
Eliminating aromatization prevents estrogen synthesis and releases estrogen's negative feedback on the hypothalamo-pituitary axis. This enzyme has the rate-limiting step in synthesizing estrogen . It is short-acting and lacks the antiestrogenic effect; hence it does not alter cervical mucus and endometrial growth.
Anastrozole and letrozole are examples of third generation non-steroidal AIs originally used in breast cancer therapy that are generally well tolerated. Recent studies looking at the trans isomer, enclomiphene, have shown its ability to increase testosterone levels while preserving sperm concentrations at a normal level (15,16). Observation of these relatively consistent and reproducible properties in female infertility patients led to studies evaluating the role of CC as a potential treatment for infertile men.
(ii) The estrogen receptors are not negatively affected by aromatase inhibitors. It serves as a catalyst for the rate-limiting stage in the synthesis of estrogen, which is the three-step hydroxylation process that turns androstenedione and testosterone into estrone and estradiol. Because of their poor potency, lack of selectivity, and adverse side effects, aromatase inhibitors' first- and second-generation variants are no longer utilized . After 40 years of clomiphene citrate being the primary treatment for the problem of ovulation induction, a new way of ovulation induction using aromatase inhibitors has finally been initiated . The ratio of testosterone to estradiol levels and sperm parameters were found to have improved . According to the most recent research, letrozole can be used as the first-line therapy to treat infertility caused by polycystic ovarian syndrome and other causes. Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats.
Also, some studies have shown that letrozole is superior to anastrozole in suppressing breast cancer tissue and plasma estrogen levels.20 Because chemotherapy was added at day 43, it remains unknown if the tumor would have eventually become resistant to hormonal therapy. Subcutaneous testosterone-letrozole was an effective treatment for this patient's breast cancer and did not interfere with chemotherapy. This study investigated the effect of testosterone-letrozole implants on breast cancer tumor response before and during neoadjuvant chemotherapy. Preclinical and clinical evidence support that androgens, including T, inhibit proliferation of both benign and malignant breast tissue, and would not be directly causative.4,5 However, caution must be observed when treating breast cancer patients with T therapy where adequate aromatase inhibition is critical. Novel treatments that can reduce the occurrence of breast cancer, increase tumor response to therapy, and prevent side effects from cancer therapies should be investigated. Although currently prescribed "off-label," the combination T + AI may also be an option for hormone therapy in perimenopausal and menopausal women at significant increased risk for breast cancer where excess estrogen is contraindicated. A recent study demonstrated that androgen receptor agonists inhibited proliferation additively with chemotherapy in breast cancer cell lines.14 Even more compelling is Stolfi et al's data demonstrating that coadministration of T with chemotherapy did not reduce the antitumor activity of chemotherapy in a murine breast tumor model.