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Aromatase inhibitor

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Aromatase converts testosterone to estradiol
Aromatase converts androstenedione to estrone

Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer and ovarian cancer in postmenopausal women. AIs may also be used off-label to treat or prevent gynaecomastia in men.

Aromatase is the enzyme which synthesizes estrogen. As breast and ovarian cancers require estrogen to grow, AIs are taken to either block the production of estrogen or block the action of estrogen on receptors.

Types of AIs

There are 2 types of aromatase inhibitors (AIs) approved to treat breast cancer:[1]

  • Irreversible steroidal inhibitors, such as exemestane (Aromasin), forms a permanent and deactivating bond with the aromatase enzyme.
  • Non-steroidal inhibitors, such as anastrozole (Arimidex), inhibits the synthesis of estrogen via reversible competition for the aromatase enzyme.

Mode of action

Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue. The main source of estrogen is the ovaries in premenopausal women, while in post-menopausal women most of the bodies estrogen is produced in the conversion of androgens to estrogen by the aromatase enzyme in peripheral tissues (outside the CNS), and also a few CNS sites in various regions within the brain. Estrogen is produced and acts locally via action of the aromatase enzyme in these tissues, but any circulating estrogen, which exerts systemic estrogenic effects in men and women, is the result of estrogen escaping local metabolism and spreading to the circulatory system.[2]

Members

Arimidex (anastrozole) 1 mg tablets

Available aromatase inhibitors (AIs) include:

Non-selective

Selective

Other

Indications

Cancer

In contrast to premenopausal women, in whom most of the estrogen is produced in the ovaries, in postmenopausal women estrogen is mainly produced via the enzyme aromatase 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.[4] 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. This counteracts the effect of the aromatase inhibitor. 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.

Investigational/off-label

Results from enzyme assay with white mushroom and aromatase enzyme.[5][6]

Bodybuilders who take anabolic steroids may also use AIs, such as anastrozole, to avoid estrogenic effects, such as gynecomastia, via preventing their elevated levels of testosterone from being converted to excess estrogen. Although anastrozole is reported by steroid users to work well in preventing and also reversing minor symptoms of gynecomastia, only the selective estrogen receptor modulator, tamoxifen, has been shown to be more successful at treating pubertal gynecomastia than placebo. These results are not unexpected due to the significant etiological differences in steroid-induced gynecomastia (excess estrogen) and pubertal gynecomastia (hypersensitive tissue). Tamoxifen has been reported to be effective in treating both groups, showing the acute anti-estrogen action of tamoxifen on the affected tissue provides faster relief in the initial stages of treatment, especially as nipple pain or sensitivity is common in the steroid group, often occurring independently of tissue growth.[7][8]

Investigations and research has been undertaken to study the use of aromatase inhibitors to stimulate ovulation, and also to suppress estrogen production.[9] Aromatase inhibitors have been shown to reverse age-related declines in testosterone, including primary hypogonadism.[10] Extracts of certain mushrooms have been shown to inhibit aromatase when evaluated by enzyme assays, with white mushroom having shown the greatest ability to inhibit the enzyme.[6] AIs have also been used experimentally in the treatment of adolescents whose predicted adult height was low.[11]

Side effects

Side effects include an increased risk for developing osteoporosis and joint disorders such as arthritis, arthrosis and arthralgia. 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,[12] combining a statin with an aromatase inhibitor could help prevent fractures and suspected cardiovascular risks, without potential of causing osteonecrosis of the jaw.[13][14] 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, and liver dysfunction. Patients with liver, kidney or adrenal abnormalities are at a higher risk of developing adverse events.[15]

References

  1. ^ Mokbel K (2002). "The evolving role of aromatase inhibitors in breast cancer". Int J Clin Oncol. 7 (5): 279–83. doi:10.1007/s101470200040. PMID 12402060.
  2. ^ Simpson ER (2003). "Sources of estrogen and their importance". The Journal of Steroid Biochemistry and Molecular Biology. 86 (3–5): 225–30. doi:10.1016/S0960-0760(03)00360-1. PMID 14623515.
  3. ^ Goss PE; et al. (1986). "Treatment of advanced postmenopausal breast cancer with an aromatase inhibitor, 4-hydroxyandrostenedione: phase II report". Cancer Research. 46 (9): 4823–4826. PMID 2942241. {{cite journal}}: Explicit use of et al. in: |author= (help)
  4. ^ Howell A, Cuzick J, Baum M; et al. (2005). "Results of the ATAC (anastrozole, tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for breast cancer". The Lancet. 365 (9453): 60–2. doi:10.1016/S0140-6736(04)17666-6. PMID 15639680. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  5. ^ Grube BJ, Eng ET, Kao YC, Kwon A, Chen S (2001). "White button mushroom phytochemicals inhibit aromatase activity and breast cancer cell proliferation". J. Nutr. 131 (12): 3288–93. PMID 11739882. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ a b Chen S, Oh SR, Phung S, Hur G, Ye JJ, Kwok SL, Shrode GE, Belury M, Adams LS, Williams D (2006). "Anti-aromatase activity of phytochemicals in white button mushrooms (Agaricus bisporus)". Cancer Res. 66 (24): 12026–34. doi:10.1158/0008-5472.CAN-06-2206. PMID 17178902. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid17178902" was defined multiple times with different content (see the help page).
  7. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 14719418, please use {{cite journal}} with |pmid=14719418 instead.
  8. ^ Plourde PV, Reiter EO, Jou HC, Desrochers PE, Rubin SD, Bercu BB, Diamond FB Jr, Backeljauw PF (2004). "Safety and efficacy of anastrozole for the treatment of pubertal gynecomastia: a randomized, double-blind, placebo-controlled trial". Clin Endocrinol (Oxf). 89 (9): 4428–33. doi:10.1210/jc.2004-0082. PMID 15356042.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Attar E, Bulun SE (2006). "Aromatase inhibitors: the next generation of therapeutics for endometriosis?". Fertility and Sterility. 85 (5): 1307–18. doi:10.1016/j.fertnstert.2005.09.064. PMID 16647373. {{cite journal}}: Unknown parameter |month= ignored (help)
  10. ^ Leder BZ, Rohrer JL, Rubin SD, Gallo J, Longcope C. (2004). "Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels". Clin Endocrinol (Oxf). 89 (3): 1174–80. doi:10.1210/jc.2003-031467. PMID 15001605.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Hero M, Wickman S, Dunkel L (2006). "Treatment with the aromatase inhibitor letrozole during adolescence increases near-final height in boys with constitutional delay of puberty". Clin Endocrinol (Oxf). 64 (5): 510–3. doi:10.1111/j.1365-2265.2006.02499.x. PMID 16649968.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Rejnmark L, Vestergaard P, Mosekilde L. Statin but not nonstatin lipid-lowering drugs decrease fracture risk: a nationwide case-control study. Calcif Tissue Int 2006; 79:27–36 [1]
  13. ^ Lehrer, S (2007). "Statin use to prevent aromatase inhibitor-induced fracture and cardiovascular complications" (PDF). Medical hypotheses. 68 (6): 1417. doi:10.1016/j.mehy.2006.11.022. PMID 17196764.
  14. ^ Ewer, MS; Gl�ck, S (2009). "A woman's heart: the impact of adjuvant endocrine therapy on cardiovascular health". Cancer. 115 (9): 1813–26. doi:10.1002/cncr.24219. PMID 19235248. {{cite journal}}: replacement character in |last2= at position 3 (help)
  15. ^ FDA Alert: Aromatase Inhibitors in Products Marketed as Dietary Supplements: Recall. Drugs.com. Retrieved on 2010-12-25.

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