Exemestane (Aromasin) is a steroidal aromatase inhibitor (AI) most often used for ancillary treatment of ER-positive hormonally responsive breast cancer in postmenopausal women. Exemestane is an irreversible suicidal AI; upon binding permanently to circulating aromatase in the body it is rendered inactive, and estrogen levels are thereby reduced. The structure of exemestane resembles the enzyme target and, after forming a complex, prevents the aromatase from fulfilling its task.
Exemestane is as effective as tamoxifen in “primary adjuvant treatment” of early breast cancer in postmenopausal women.
Mauras (2009) discusses off-label use of aromatase for short stature syndrome:
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.
Like all AIs, exemestane is prone to a downregulation or resistance effect after time, although the mechanism is not currently well-characterized:
Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy ...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]...studies will generate important information on the mechanisms of AI resistance
Like other AIs, exemestane is sometimes used off-label as a “monotherapy” by men in restoring testosterone levels in hypogonadotrophic hypogonadism. However, unlike anastrazole, exemestane has not been studied extensively in this role.
The half-life of exemestane is 9 hours, requiring daily dosing.
An unusual characteristic of exemestane is that in addition to requiring daily dosing for a consistent therapeutic effect, in healthy non-hypogonadal men doubling the “standard” dose of 25mg did not increase estrogen suppression:
Exemestane suppressed plasma estradiol comparably with either dose [25 mg, 38% (P <or= 0.002); 50 mg, 32% (P <or= 0.008)], with a reciprocal increase in testosterone concentrations (60% and 56%; P <or= 0.003 for both). The PK properties of the 25-mg dose showed the highest exemestane concentrations 1 h after administration, indicating rapid absorption. The terminal half-life was 8.9 h. Maximal estradiol suppression of 62 +/- 14% was observed at 12 h. The drug was well tolerated. In conclusion, exemestane is a potent aromatase inhibitor in men and an alternative to the choice of available inhibitors.
Although it is possible that with a longer period of administration than used by the authors (Mauras et al, 2003) different effects would emerge in the higher dose group, this is not determined; therefore, compared to other AIs, exemestane may not work for patients who need to titrate to achieve a preferred level of inhibition of estrogen production.
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.
Mauras N, Lima J, Patel D, Rini A, di Salle E, Kwok A, Lippe B. Pharmacokinetics and dose finding of a potent aromatase inhibitor, aromasin (exemestane), in young males. J Clin Endocrinol Metab. 2003 Dec;88(12):5951-6.