<P> In contrast to premenopausal women, in whom most of the estrogen is produced in the ovaries, in postmenopausal women estrogen is mainly produced in peripheral tissues of the body . Because some breast cancers respond to estrogen, lowering estrogen production at the site of the cancer (i.e. the adipose tissue of the breast) with aromatase inhibitors has been proven to be an effective treatment for hormone - sensitive breast cancer in postmenopausal women . Aromatase inhibitors are generally not used to treat breast cancer in premenopausal women . When aromatase inhibitors are used in premenopausal women, the decrease in estrogen activates the hypothalamus and pituitary axis to increase gonadotropin secretion, which in turn stimulates the ovary to increase androgen production . The heightened gonadotropin levels also upregulate the aromatase promoter, increasing aromatase production in the setting of increased androgen substrate . This counteracts the effect of the aromatase inhibitor in premenopausal women since total estrogen is increased . Ongoing areas of clinical research is optimizing adjuvant hormonal therapy in postmenopausal women with breast cancer . Although tamoxifen (SERM) had been the traditional drug treatment of choice, the ATAC trial has shown that clinical results are superior with an AI in postmenopausal women with localized breast cancer that is estrogen receptor positive . Trials of AIs in the adjuvant setting (given to prevent relapse after surgery for breast cancer) show that they are associated with a better disease - free survival than tamoxifen, but few conventionally - analyzed clinicals trials have shown that AIs have an overall survival advantage compared with tamoxifen, and there is no good evidence they are better tolerated . </P> <P> Aromatase inhibitors such as testolactone have been approved for the treatment of gynecomastia in children and adolescents . </P> <P> Ovarian stimulation with the aromatase inhibitor letrozole has been proposed as one of the treatments for unexplained female infertility . In a multi-center study funded by the National Institute of Child Health and Development, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation (i.e., twins or triplets) but also a lower frequency of live birth, as compared with gonadotropin but not with clomiphene . </P> <P> Side effects include an increased risk for developing osteoporosis and joint disorders such as arthritis, arthrosis, and joint pain . Bisphosphonates are sometimes prescribed to prevent the osteoporosis induced by aromatase inhibitors, but also have another serious side effect, osteonecrosis of the jaw . As statins have a bone strengthening effect, combining a statin with an aromatase inhibitor could help prevent fractures and suspected cardiovascular risks, without potential of causing osteonecrosis of the jaw . The more common adverse events associated with the use of aromatase inhibitors include decreased rate of bone maturation and growth, infertility, aggressive behavior, adrenal insufficiency, kidney failure, hair loss, and liver dysfunction . Patients with liver, kidney or adrenal abnormalities are at a higher risk of developing adverse events . </P>

When did aromatase inhibitors come on the market