Aromatase inhibitor

Aromatase converts testosterone to estradiol

Aromatase converts androstenedione to estrone

Aromatase inhibitors (AI) are a class of drugs used in the treatment of breast cancer and ovarian cancer in postmenopausal women.

Some cancers require estrogen to grow. Aromatase is an enzyme that synthesizes estrogen. Aromatase inhibitors block the synthesis of estrogen. This lowers the estrogen level, and slows the growth of cancers.

Type I and II

AIs are categorized into two types: ^[1]

• Irreversible steroidal inhibitors such as exemestane form a permanent bond with the aromatase enzyme complex.
• Non-steroidal inhibitors (such as anastrozole, letrozole) inhibit the enzyme by reversible competition.

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.

Indication

Cancer

In contrast to pre-menopausal women, in whom most of the estrogen is produced in the ovaries, in post-menopausal women most of the body's estrogen is produced in the adrenal gland from the conversion of androgens. The other main source of estrogen post-menopausally is adipose tissue^{[citation needed]}. Because some breast cancers respond to estrogen, lowering the estrogen level in post-menopausal women using aromatase inhibitors has been proven to be effective in breast cancer treatment.^[2]

Aromatase inhibitors are generally not used to treat breast cancer in premenopausal women. Since most of the circulating estrogen is produced by the ovaries, not by conversion of androgens to estrogen, blocking the enzyme aromatase does not significantly decrease the production of estrogen. 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.

An ongoing area of clinical research is optimizing adjuvant hormonal therapy in postmenopausal women with breast cancer. Tamoxifen has been standard treatment, however 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. Further studies of various AIs are ongoing.

Other uses and sources of aromatase inhibitors

Results of an enzyme assay conducted with the white mushroom and the enzyme aromatase.^[3][4]

Investigations are ongoing to look for other applications. Researchers are studying aromatase inhibitors to stimulate ovulation (in a manner similar to, but not exactly the same as, clomiphene citrate) or suppress estrogen production, ie in endometriosis.^[5]

AIs have also been used experimentally in the treatment of adolescents whose predicted adult height is low.^[6]

Bodybuilders who take anabolic steroids may also take AIs to prevent the steroids from being converted to estrogen; an increase in estrogen levels has undesirable consequences for a bodybuilder, such as gynecomastia. This is often the case when a natural aromatase inhibitor 4-OHAD [2] has itself been inhibited. 4-OHAD is a metabolite of testosterone, which can mean 4-OHAD remains inhibited whilst aromatase levels are allowed high.

In one recent study, aromatase inhibitors were found to be no more successful at treating pubertal gynecomastia than a placebo. ^[7]

Aromatase inhibitors have also been shown to reverse age-related declines in testosterone, as well as primary hypogonadism.^[8]

Extracts of certain mushrooms have been shown to inhibit aromatase when evaluated by enzyme assays, the white mushroom has shown the greatest ability to inhibit the enzyme.^[4]

Members

Some of the aromatase inhibitors in use include:

Non-selective

• Aminoglutethimide
• Testolactone (Teslac)

Selective

• Anastrozole (Arimidex)
• Letrozole (Femara)
• Exemestane (Aromasin)
• Vorozole (Rivizor)
• Formestane (Lentaron)
• Fadrozole (Afema)

Unknown/ungrouped

• 4-androstene-3,6,17-trione ("6-OXO", marketed as a nutritional supplement for athletes and weight lifters)
• 1,4,6-androstatrien-3,17-dione (ATD)
• 4-hydroxyandrostenedione <Goss PE et al.Cancer Research:46,4823-4826.1986.>

Side Effects of Aromatase Inhibitors

• An increase in joint disorders (including arthritis, arthrosis and arthralgia).

• An increase in the incidence of osteoporosis and fractures (specifically fractures of spine, hip and wrist). A hip fracture often results in prolonged hospitalization and long term care in a post-menopausal woman.

• Hypercholesterolemia

Bisphosphonates are sometimes prescribed to prevent the osteoporosis induced by aromatase inhibitors but have another serious side effect, osteonecrosis of the jaws. Since statins have a bone strengthening effect ^[9], combining a statin with an aromatase inhibitor may avoid both fractures and possible cardiovascular risks ^[10] without jaw osteonecrosis.^[11] In one study of women with breast cancer taking anastrozole, statin use was associated with a 38% reduced fracture risk, or approximately the equivalent of 10 mg Fosamax daily.^[12]

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. ^ Howell A, et al.; ATAC Trialists Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005 Jan 1-7;365(9453):60-2. PMID 15639680
3. ^ Grube BJ, Eng ET, Kao YC, Kwon A, Chen S (December 2001), "White button mushroom phytochemicals inhibit aromatase activity and breast cancer cell proliferation", J. Nutr. 131 (12): 3288–93, PMID 11739882 
4. ^ ^{a b} Chen S, Oh SR, Phung S, Hur G, Ye JJ, Kwok SL, Shrode GE, Belury M, Adams LS, Williams D (December 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 
5. ^ Attar E, Bulun SE. Aromatase inhibitors: the next generation of therapeutics for endometriosis? Fertil Steril 2006;85:1307-18. PMID 16647373
6. ^ 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. 
7. ^ Plourde PV, Reiter EO, Jou HC, Desrochers PE, Rubin SD, Bercu BB, Diamond FB Jr, Backeljauw PF. "Safety and efficacy of anastrozole for the treatment of pubertal gynecomastia: a randomized, double-blind, placebo-controlled trial". Clin Endocrinol (Oxf). PMID 15356042. 
8. ^ Leder BZ, Rohrer JL, Rubin SD, Gallo J, Longcope C.. "Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels". Clin Endocrinol (Oxf). PMID 15001605. 
9. ^ 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]
10. ^ Ewer MS, Glück S. A woman's heart: the impact of adjuvant endocrine therapy on cardiovascular health. Cancer. 2009 May 1;115(9):1813-26.
11. ^ Lehrer, S. Statin use to prevent aromatase inhibitor-induced fracture and cardiovascular complications. Med Hypotheses. 2007;68(6)1417. Epub 2006 Dec 29.
12. ^ R. Eastell. Risk factors for fracture: 5-year results of the 'arimidex' (anastrozole), tamoxifen, alone or in combination (ATAC) trial. 33rd European Calcified Tissue Symposium 2006. abstract OC008. Calcif Tissue Int (2006) 78(Suppl 1):S27.