Exemestane, sold as Aromasin, is a steroidal aromatase inhibitor (AI) primarily administered in the adjuvant treatment of hormonally responsive breast cancer in postmenopausal women. In that type of cancer, higher estrogen levels are correlated with recurrence of cancer and with more severe manifestations. Exemestane renders the aromatase enzyme permanently inactive by binding permanently to circulating aromatase in the body. Estrogen in pre-menopausal women originates from the ovaries primarily, while in post-menopausal women aromatase converts steroidal compounds reversed from the adrenal glands into estreogen. Exemestane is what is referred to as an irreversible steroidal aromatase inactivator or "suicide inhibitor". Exemestane is structurally similar to the target of the enzymes, and thus permanently binds to those enzymes which disrupts their task of converting androgens into estrogens.
Data comparing exemestane with tamoxifen indicates that exemestane is as effective in the primary adjuvant treatment of early-stage breast cancer in postmenopausal women.
Maurus writes of use of aromatase inhibitors in treatment of childhood growth deficiency:
The approach to the child with growth retardation who is in puberty remains an important clinical challenge. The use of high-dose growth hormone (GH), suppression of puberty with GnRH analogs in combination with GH, and the use of selective inhibitors of the aromatase enzyme with aromatase inhibitors (also in combination with GH) are all therapeutic choices that have been studied. Aromatase blockade effectively blocks estrogen production in males with a reciprocal increase in testosterone, and a new generation of aromatase inhibitors, including anastrozole, letrozole and exemestane, is under investigation in adolescent subjects with severe growth retardation. This class of drugs, if judiciously used for a window of time, offers promise as an adjunct treatment of growth delay in pubertal patients with GH deficiency, idiopathic short stature, testotoxicosis, and other disorders of growth. These evolving uses of aromatase inhibitors, however, represent off-label use of the product, and definitive data on their efficacy are not available for each of the conditions mentioned. Safety issues regarding bone health also require further study.
Exemestane and all AIs are eventually prone to down regulation in effect on the human body with human use. This can be a major detriment to their use as long-term treatments for cancer:
Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy in the effective treatment of hormone-dependent breast cancers. Yet, as with all prolonged drug therapy, resistance to aromatase inhibitors does develop. To date, the precise mechanism responsible for resistance to aromatase inhibitors is not completely understood. ... several mechanisms of de novo/intrinsic resistance and acquired resistance to AIs are [worthy of further discussion]...tudies will generate important information on the mechanisms of AI resistance. Such information can be valuable for the development of treatment strategies against AI-resistant breast cancers.
Exemestane is a teratogen, known for causing birth defects; thus exemestane "is marketed for use only in postmenopausal women. Its labeling includes a contraindication to use in pregnant or lactating women."
Exemestane is not well studied as a monotheray for hypogonadal men or men with such pathologies as azoospermia, but other aromatase inhibitors with comparable effects are frequently used and have been shown to be clinically effective in treating hormonal deficiencies, either alone or with more direct (i.e., testosterone) hormone application.
Coombes RC et al. Survival and safety of exemestane versus tamoxifen after 2–3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369 (9561): 559–70. 2007.
Mauras N. Strategies for maximizing growth in puberty in children with short stature.Endocrinol Metab Clin North Am. 2009 Sep;38(3):613-24.
Chen S, Masri S, Wang X, Phung S, Yuan YC, Wu X. What do we know about the mechanisms of aromatase inhibitor resistance? J Steroid Biochem Mol Biol. 2006 Dec;102(1-5):232-40.
Beltrame D, di Salle E, Giavini E, Gunnarsson K, Brughera M. Reproductive toxicity of exemestane, an antitumoral aromatase inactivator, in rats and rabbits. Reprod Toxicol. 2001 Mar-Apr;15(2):195-213.
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