Tools
Aromatase Inhibitors
Indications
Aromatase inhibitors (AIs) are indicated in the treatment of hormone-receptive breast cancer in postmenopausal women in various settings. Studies have shown that they are effective when used as adjuvant therapy to chemotherapy and surgery in metastatic estrogen-dependent breast cancer. Their use in preventative and adjuvant therapies for other conditions is currently under investigation.[1][2]
FDA Approved Indications
- Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer[3]
- First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer[4]
- Second-line treatment of advanced breast cancer that has progressed on Tamoxifen therapy[5]
- Treatment of male gynecomastia[6]
- Second-line treatment for the prevention of hormone-receptor-positive breast cancer[7]
FDA Non-approved Indications
- Treatment of benign conditions like cyclical breast pain and recurrent fibrocystic disease[6]
- Treatment of symptomatic myomas and endometriosis as an alternative to surgical intervention [8]
- Ovulation induction in the treatment of infertility[9]
- Treatment of male breast cancer[10]
- Treatment of prostate cancer[6]
- Treatment of late-onset hypogonadism or partial androgen deficiency, obesity-related hypogonadotropic hypogonadism, and male subfertility[11]
- Treatment of rare pediatric conditions associated with sex steroid excess[12]
- Treatment of boys with short stature and constitutional delay of puberty[12]
- Prevention of the initial estrogen flare effect of gonadotropin-releasing hormone agonist treatment[8]
Mechanism of Action
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Mechanism of Action
Aromatase inhibitors (AIs) inhibit the action of the enzyme aromatase. Aromatase (estrogen synthetase) is a member of the cytochrome P450 superfamily of monooxygenases and catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens.[13] In postmenopausal women, the conversion of androgens to estrogens via this pathway in the adrenal glands, the skin, the muscle, and the adipose tissue, is the primary source of estrogen. Aromatase inhibitors block this pathway and consequently suppress estrogen levels in postmenopausal women. The breast cancer cells also demonstrate aromatase activity, a likely source of local estrogen for the tumor cells. The inhibition or inactivation of aromatase suppresses serum estrogen levels, which decrease estrogen-mediated cancer cell proliferation in hormone receptor-positive breast cancer.[14]
In premenopausal women, AIs induce an increase in gonadotropin secretion secondary to the reduced negative feedback of estrogen to the pituitary, resulting in ovarian stimulation. Clinicians can use AIs to induce ovulation in the treatment of infertility.[15][14] Aromatase activity increases in endometriosis with extrauterine endometrial tissue acting as a source of estrogens. Estrogen stimulates the synthesis of PGE2, which causes increased aromatase activity in the endometrium. This vicious cycle leads to the growth of ectopic endometrial tissue, which is blocked by aromatase inhibitors by inhibiting the synthesis of estrogen in extrauterine endometrial tissue.[16][17]
In men, estrogen excess shows an association with premature closure of the epiphyses. Aromatase inhibitors decrease estrogen by inhibiting the conversion of testosterone to estrogen and have therefore been used in patients with short stature and/or constitutional delay of puberty. Lowering estrogen levels is associated with an increase in LH, FSH, and testosterone. Therefore aromatase inhibitors have also been used in late-onset hypogonadism or partial androgen deficiency. In obese men, there is an increased conversion of androgens to estrogen in the adipose tissue, leading to increased estrogen levels. Aromatase inhibitors also decrease this conversion causing decreased estrogen and increased testosterone and FSH in men with obesity-related hypogonadotropic hypogonadism and male subfertility.[18]
Administration
Anastrozole, a selective aromatase inhibitor, is available as a 1 mg tablet, which is to be taken orally once a day, with or without food. No dose adjustment is necessary for patients with renal or liver impairment or elderly patients. The American Society of Clinical Oncology recommends the use of aromatase inhibitors as a component of adjuvant hormonal therapy after surgery for ten years in postmenopausal patients who have a diagnosis of early-stage, node-positive, and hormone receptive breast cancer.
Letrozole is also a selective aromatase inhibitor. It is manufactured in 2.5 mg tablets. For postmenopausal breast cancer, dosing is 2.5 mg daily. As an agent to induce ovulation, dosing is 2.5 mg to 5 mg daily for 5 days starting on day 3 of the menstrual cycle. Renal adjustment is unnecessary if creatinine clearance is above 10. In patients with cirrhosis of the liver, CHild-Pugh Class C, increase the dosing interval to every 48 hours.
Exemestane, another selective agent, comes in 25 mg tablets, and for postmenopausal breast cancer, dosing is 25 mg daily for 2 to 3 years. No renal or hepatic dose adjustments are necessary.
Adverse Effects
Various adverse reactions can happen with aromatase inhibitors. (Seen in less than 1 in 10,000 patients). Some of them are as follows:
- Ulcers and blisters are the common skin manifestations;
- Allergic reactions, such as swelling of the face along with lips and tongue and occasionally throat; these reactions can result in difficulty swallowing and/or breathing;
- Liver function abnormality with or without jaundice due to inflammation of the liver;
- Bone loss due to estrogen deficiency with long-term use.
Common adverse reactions (10% incidence) include the following: hot flashes, asthenia, joint disorders such as arthritis or arthralgia, osteoporosis, fractures, bone pain, back pain, vaginal dryness, dyspareunia, sexual dysfunction, uterine atrophy, hypertension, hyperlipidemia, hypercholesterolemia, thromboembolic disease, cardiac and cerebrovascular events, insomnia, nausea.[19][20][21][22][14]
The most common reason for discontinuing aromatase inhibitor therapy is the development of arthralgias, known as aromatase inhibitor-associated arthralgia syndrome. Patients will present with joint pain and mild swelling in the absence of other systemic diseases or other causes. The deficiency of estrogen causes a decrease in bone mineral density, which contributes to joint pain. Estrogen also shows links to the regulation of cytokine activity as well as the modulation of pain reception in the nervous system.[23]
Contraindications
There are two major contraindications to aromatase inhibitors.
- Hypersensitivity: Aromatase inhibitors are contraindicated in patients with hypersensitivity reactions to AI. Hypersensitivity can present as anaphylaxis, angioedema, and urticaria.
- Pregnancy and Premenopausal women: Aromatase inhibitors can harm the fetus or cause loss of pregnancy in pregnant patients.[24] Due to their mechanism of action, AIs have no clinical benefit in breast cancer patients who are premenopausal.
Monitoring
All patients on aromatase inhibitors should have initial routine lab work, including a complete blood count, serum calcium, vitamin D levels, lipid profile, and liver function tests.[25][26] Patients should also have a baseline bone mineral density test (DEXA scan) before initiating the treatment.[27][14]
Toxicity
Clinical trials have shown aromatase inhibitors were well tolerated, even at high doses.[27] There is no established dose of aromatase inhibitors considered life-threatening. There is no specific treatment for the overdose of this class of medications. Standard treatment of care, such as frequent vital sign checks, induced emesis, and management of symptoms, is recommended.
Enhancing Healthcare Team Outcomes
Interprofessional communication between healthcare teams is essential, especially in the management of cancer patients. Every professional has a vital role to play. Oncologists should select the treatment regimen based on the guidelines after thoroughly assessing the patient factors. For example, in hormone receptor-negative breast cancer or premenopausal patients with breast cancer, aromatase inhibitors may not be appropriate. Clinicians and nurses should be concerned enough about the adverse effects of long-term therapy with aromatase inhibitors, especially osteoporosis and hyperlipidemia. Pharmacists should evaluate the patient's medication history to prevent any drug interactions, especially with tamoxifen and warfarin. Nursing will provide patient counseling on the medication, answer patient questions, and serve as a contact point for patients and other interprofessional team members. Case management should include counseling regarding improving bone health and early initiation of bisphosphonates in the case of osteopenia. Utilizing these interprofessional strategies when using aromatase inhibitor therapy will lead to improved therapeutic patient results with fewer adverse events. [Level 5]
References
Arora A, Potter JF. Aromatase inhibitors: current indications and future prospects for treatment of postmenopausal breast cancer. Journal of the American Geriatrics Society. 2004 Apr:52(4):611-6 [PubMed PMID: 15066080]
Brueggemeier RW, Hackett JC, Diaz-Cruz ES. Aromatase inhibitors in the treatment of breast cancer. Endocrine reviews. 2005 May:26(3):331-45 [PubMed PMID: 15814851]
Level 3 (low-level) evidenceBurstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Rowden D, Solky AJ, Stearns V, Winer EP, Griggs JJ. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014 Jul 20:32(21):2255-69. doi: 10.1200/JCO.2013.54.2258. Epub 2014 May 27 [PubMed PMID: 24868023]
Level 1 (high-level) evidenceParidaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, Piccart MJ, Bogaerts J, Therasse P. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008 Oct 20:26(30):4883-90. doi: 10.1200/JCO.2007.14.4659. Epub 2008 Sep 15 [PubMed PMID: 18794551]
Level 1 (high-level) evidenceSimpson D, Curran MP, Perry CM. Letrozole: a review of its use in postmenopausal women with breast cancer. Drugs. 2004:64(11):1213-30 [PubMed PMID: 15161328]
Miller WR, Jackson J. The therapeutic potential of aromatase inhibitors. Expert opinion on investigational drugs. 2003 Mar:12(3):337-51 [PubMed PMID: 12605559]
Level 3 (low-level) evidenceBehan LA, Amir E, Casper RF. Aromatase inhibitors for prevention of breast cancer in postmenopausal women: a narrative review. Menopause (New York, N.Y.). 2015 Mar:22(3):342-50. doi: 10.1097/GME.0000000000000426. Epub [PubMed PMID: 25692874]
Level 3 (low-level) evidenceBedaiwy MA, Mousa NA, Casper RF. Aromatase inhibitors: potential reproductive implications. Journal of minimally invasive gynecology. 2009 Sep-Oct:16(5):533-9. doi: 10.1016/j.jmig.2009.05.009. Epub 2009 Jul 15 [PubMed PMID: 19608462]
Santen RJ. Inhibition of aromatase: insights from recent studies. Steroids. 2003 Sep:68(7-8):559-67 [PubMed PMID: 12957661]
Level 3 (low-level) evidenceZagouri F, Sergentanis TN, Azim HA Jr, Chrysikos D, Dimopoulos MA, Psaltopoulou T. Aromatase inhibitors in male breast cancer: a pooled analysis. Breast cancer research and treatment. 2015 May:151(1):141-7. doi: 10.1007/s10549-015-3356-9. Epub 2015 Apr 8 [PubMed PMID: 25850534]
Tan RB, Guay AT, Hellstrom WJ. Clinical Use of Aromatase Inhibitors in Adult Males. Sexual medicine reviews. 2014 Apr:2(2):79-90. doi: 10.1002/smrj.23. Epub 2015 Oct 19 [PubMed PMID: 27784593]
Hero M. Aromatase Inhibitors in the Treatment of Short Stature. Endocrine development. 2016:30():130-40. doi: 10.1159/000439338. Epub 2015 Dec 10 [PubMed PMID: 26684331]
Blakemore J, Naftolin F. Aromatase: Contributions to Physiology and Disease in Women and Men. Physiology (Bethesda, Md.). 2016 Jul:31(4):258-69. doi: 10.1152/physiol.00054.2015. Epub [PubMed PMID: 27252161]
Nabholtz JM. Long-term safety of aromatase inhibitors in the treatment of breast cancer. Therapeutics and clinical risk management. 2008 Feb:4(1):189-204 [PubMed PMID: 18728707]
Forbes JF. The use of early adjuvant aromatase inhibitor therapy: contributions from the BIG 1-98 letrozole trial. Seminars in oncology. 2006 Apr:33(2 Suppl 7):S2-7 [PubMed PMID: 16730270]
Level 1 (high-level) evidenceSłopień R, Męczekalski B. Aromatase inhibitors in the treatment of endometriosis. Przeglad menopauzalny = Menopause review. 2016 Mar:15(1):43-7. doi: 10.5114/pm.2016.58773. Epub 2016 Mar 29 [PubMed PMID: 27095958]
Abu Hashim H. Potential role of aromatase inhibitors in the treatment of endometriosis. International journal of women's health. 2014:6():671-80. doi: 10.2147/IJWH.S34684. Epub 2014 Jul 21 [PubMed PMID: 25092998]
de Ronde W,de Jong FH, Aromatase inhibitors in men: effects and therapeutic options. Reproductive biology and endocrinology : RB [PubMed PMID: 21693046]
Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF, ATAC/LATTE investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. The Lancet. Oncology. 2010 Dec:11(12):1135-41. doi: 10.1016/S1470-2045(10)70257-6. Epub 2010 Nov 17 [PubMed PMID: 21087898]
Level 1 (high-level) evidenceSini V, Botticelli A, Lunardi G, Gori S, Marchetti P. Pharmacogenetics and aromatase inhibitor induced side effects in breast cancer patients. Pharmacogenomics. 2017 Jun:18(8):821-830. doi: 10.2217/pgs-2017-0006. Epub 2017 Jun 8 [PubMed PMID: 28592202]
Krásenská M. [Treatment with Aromatase Inhibitors in Postmenopausal Women with Breast Cancer and the Possibility of Influencing Side Effects]. Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti. 2016 Fall:29 Suppl 3():S39-49. doi: 10.14735/amko20163S39. Epub [PubMed PMID: 28118723]
Foglietta J, Inno A, de Iuliis F, Sini V, Duranti S, Turazza M, Tarantini L, Gori S. Cardiotoxicity of Aromatase Inhibitors in Breast Cancer Patients. Clinical breast cancer. 2017 Feb:17(1):11-17. doi: 10.1016/j.clbc.2016.07.003. Epub 2016 Jul 25 [PubMed PMID: 27561703]
Burstein HJ. Aromatase inhibitor-associated arthralgia syndrome. Breast (Edinburgh, Scotland). 2007 Jun:16(3):223-34 [PubMed PMID: 17368903]
Tiboni GM, Ponzano A. Fetal safety profile of aromatase inhibitors: Animal data. Reproductive toxicology (Elmsford, N.Y.). 2016 Dec:66():84-92. doi: 10.1016/j.reprotox.2016.09.016. Epub 2016 Sep 30 [PubMed PMID: 27697604]
Level 3 (low-level) evidenceVan Poznak C, Makris A, Clack G, Barlow DH, Eastell R. Lipid profiles within the SABRE trial of anastrozole with and without risedronate. Breast cancer research and treatment. 2012 Aug:134(3):1141-7. doi: 10.1007/s10549-012-2147-9. Epub 2012 Jul 5 [PubMed PMID: 22763465]
Level 1 (high-level) evidenceGonnelli S, Petrioli R. Aromatase inhibitors, efficacy and metabolic risk in the treatment of postmenopausal women with early breast cancer. Clinical interventions in aging. 2008:3(4):647-57 [PubMed PMID: 19281057]
Jonat W, Howell A, Blomqvist C, Eiermann W, Winblad G, Tyrrell C, Mauriac L, Roche H, Lundgren S, Hellmund R, Azab M. A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. European journal of cancer (Oxford, England : 1990). 1996 Mar:32A(3):404-12 [PubMed PMID: 8814682]
Level 1 (high-level) evidence