Aromatase inhibitor

In contrast to premenopausal women, in whom most of the estrogen is produced in the ovaries, in postmenopausal women estrogen is mainly produced 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.{{cite journal | vauthors = Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS | title = Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer | journal = Lancet | volume = 365 | issue = 9453 | pages = 60–2 | year = 2005 | pmid = 15639680 | doi = 10.1016/S0140-6736(04)17666-6 | s2cid = 8350282 }} Aromatase inhibitors are generally not used to treat breast cancer in premenopausal women because, prior to menopause, the decrease in estrogen activates the hypothalamus and pituitary axis to increase gonadotropin secretion, which in turn stimulates the ovary to increase androgen production. The heightened gonadotropin levels also upregulate the aromatase promoter, increasing aromatase production in the setting of increased androgen substrate. This would counteract the effect of the aromatase inhibitor in premenopausal women, as total estrogen would increase.

Ongoing areas of clinical research include optimizing adjuvant hormonal therapy in postmenopausal women with breast cancer. Tamoxifen (a SERM) traditionally was the drug treatment of choice, but the ATAC trial (Arimidex, Tamoxifen, Alone or in Combination) showed that in women with localized estrogen receptor-positive breast cancer, women receiving the AI anastrozole had better results than the tamoxifen group.{{cite journal | vauthors = Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS | display-authors = 6 | title = Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer | journal = Lancet | volume = 365 | issue = 9453 | pages = 60–2 | year = 2005 | pmid = 15639680 | doi = 10.1016/S0140-6736(04)17666-6 | s2cid = 8350282 | author3-link = Michael Baum (surgeon) }} {{primary-inline|date=June 2018}} Trials of AIs used as adjuvant therapy, when given to prevent relapse after surgery for breast cancer, show that they are associated with a better disease-free survival than tamoxifen, but few conventionally-analyzed clinicals trials have shown that AIs have an overall survival advantage compared with tamoxifen, and there is no good evidence they are better tolerated.{{cite journal | vauthors = Seruga B, Tannock IF | title = Up-front use of aromatase inhibitors as adjuvant therapy for breast cancer: the emperor has no clothes | journal = J. Clin. Oncol. | volume = 27 | issue = 6 | pages = 840–2 | year = 2009 | pmid = 19139426 | doi = 10.1200/JCO.2008.19.5594 | citeseerx = 10.1.1.617.8757 }}

Aromatase inhibitors have been approved for the treatment of gynecomastia in children and adolescents.{{Cite journal |url=http://pediatrics.aappublications.org/content/121/4/e975.long| last1=Shulman| first1=DI| last2=Francis| first2=GL|last3=Palmert|first3=MR|last4=Eugster|first4=EA|last5=Lawson Wilkins Pediatric Endocrine Society Drug and Therapeutics Committee |title=Use of aromatase inhibitors in children and adolescents with disorders of growth and adolescent development |journal=Pediatrics |volume=121 |issue=4 |pages=e975–983 |date=April 2008 |pmid=18381525 |doi=10.1542/peds.2007-2081| s2cid=39852740|url-access=subscription}}

===Ovulation induction===

Ovarian stimulation with the aromatase inhibitor letrozole has been proposed for ovulation induction in order to treat unexplained female infertility. In a multi-center study funded by the National Institute of Child Health and Development, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation (i.e., twins or triplets) but also a lower frequency of live birth, as compared with gonadotropin but not with clomiphene.{{cite journal |vauthors = Diamond MP, Legro RS, Coutifaris R |title = Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility |journal = N Engl J Med |volume = 373 |issue = 13 |pages =1230–1240 |year = 2015 |doi = 10.1056/NEJMoa1414827|pmid = 26398071 |display-authors=etal|pmc = 4739644 }}

In women, side effects include an increased risk for developing osteoporosis and joint disorders such as arthritis, arthrosis, and joint pain. Men do not appear to exhibit the same adverse effects on bone health.{{cite journal |last1=Tan |first1=RB |display-authors=et al |title=Clinical Use of Aromatase Inhibitors in Adult Males |journal=Sexual Medicine Reviews |date=19 October 2015|volume=2 |issue=2 |pages=79–90 |doi=10.1002/smrj.23 |pmid=27784593}} 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, combining a statin with an aromatase inhibitor could help prevent fractures and suspected cardiovascular risks, without potential of causing osteonecrosis of the jaw.{{cite journal | vauthors = Ewer MS, Glück S | title = A woman's heart: the impact of adjuvant endocrine therapy on cardiovascular health | journal = Cancer | volume = 115 | issue = 9 | pages = 1813–26 | year = 2009 | pmid = 19235248 | doi = 10.1002/cncr.24219 | s2cid = 25842353 | doi-access = free }} 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, hair loss,{{Cite journal|last1=Simpson|first1=Dene|last2=Curran|first2=Monique P.|last3=Perry|first3=Caroline M.|date=2004-01-01|title=Letrozole: a review of its use in postmenopausal women with breast cancer|journal=Drugs|volume=64|issue=11|pages=1213–1230|issn=0012-6667|pmid=15161328|doi=10.2165/00003495-200464110-00005|s2cid=195689537 }}{{Cite journal|last1=Rossi|first1=A.|last2=Iorio|first2=A.|last3=Scali|first3=E.|last4=Fortuna|first4=M. C.|last5=Mari|first5=E.|last6=Maxia|first6=C.|last7=Gerardi|first7=M.|last8=Framarino|first8=M.|last9=Carlesimo|first9=M.|date=2013-06-01|title=Aromatase inhibitors induce 'male pattern hair loss' in women?|journal=Annals of Oncology|language=en|volume=24|issue=6|pages=1710–1711|doi=10.1093/annonc/mdt170|pmid=23696617|issn=0923-7534|doi-access=free}} and liver dysfunction. Patients with liver, kidney or adrenal abnormalities are at a higher risk of developing adverse events.{{cite press release |url=https://www.drugs.com/fda/aromatase-inhibitors-products-marketed-dietary-supplements-recall-12803.html |publisher=FDA |title=Aromatase Inhibitors in Products Marketed as Dietary Supplements: Recall |date=September 20, 2010 |access-date=August 9, 2012}}

File:Aromatase Inhibitor.svg

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 body's estrogen is produced in peripheral tissues (outside the CNS), and also a few CNS sites in various regions within the brain. Estrogen is produced and acts locally 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.{{cite journal | vauthors = Simpson ER | title = Sources of estrogen and their importance | journal = J. Steroid Biochem. Mol. Biol. | volume = 86 | issue = 3–5 | pages = 225–30 | year = 2003 | pmid = 14623515 | doi = 10.1016/S0960-0760(03)00360-1 | s2cid = 11210435 }}

{{Pharmacodynamics of aromatase inhibitors}}

There are two types of aromatase inhibitors approved to treat breast cancer:{{cite journal | vauthors = Mokbel K | title = The evolving role of aromatase inhibitors in breast cancer | journal = Int. J. Clin. Oncol. | volume = 7 | issue = 5 | pages = 279–83 | year = 2002 | pmid = 12402060 | doi = 10.1007/s101470200040 | s2cid = 2862849 }}

• Irreversible steroidal inhibitors, such as exemestane (Aromasin), forms a permanent and deactivating bond with the aromatase enzyme.
• Nonsteroidal inhibitors, such as the triazoles anastrozole (Arimidex) and letrozole (Femara), inhibit the synthesis of estrogen via reversible competition.

{{See also|Steroidal aromatase inhibitors|l1=Steroidal Aromatase Inhibitors}}

File:Arimidex.jpg) 1 mg tablets]]

Aromatase inhibitors (AIs) include:

• Aminoglutethimide (Elipten, Cytadren, Orimeten)
• Testolactone (Teslac)

• Anastrozole (Arimidex)
• Letrozole (Femara)
• Exemestane (Aromasin)
• Vorozole (R-76713; Rivizor)
• Formestane (Lentaron)
• Fadrozole (Afema)

• 1,4,6-Androstatrien-3,17-dione (ATD)
• 4-Androstene-3,6,17-trione ("6-OXO")

In addition to pharmaceutical AIs, some natural elements have aromatase inhibiting effects, such as damiana leaves.{{cite journal|vauthors=Zhao J, Dasmahapatra AK, Khan SI, Khan IA |year=2008|doi=10.1016/j.jep.2008.09.016|pmid=18948180|journal=Journal of Ethnopharmacology|volume=120|issue=3|pages=387–393|title=Anti-aromatase activity of the constituents from damiana (Turnera diffusa)}}

The development of aromatase inhibitors was first pioneered by the work of British pharmacologist Angela Brodie at the University of Maryland School of Medicine, first demonstrating efficacy of Formestane in clinical trials in 1982.{{cite web|title=Angela Hartley Brodie, PhD|url=http://umm.edu/programs/cancer/research/research/hrc/angela-hartley-brodie|publisher=University of Maryland Medical Centre|access-date=22 January 2016|archive-date=1 February 2016|archive-url=https://web.archive.org/web/20160201180311/http://umm.edu/programs/cancer/research/research/hrc/angela-hartley-brodie|url-status=dead}} The drug was first marketed in 1994.{{cite news|last1=Grohol|first1=John M.|title=Robert A. Weinberg and Angela M. Hartley Brodie awarded 2006 Landon-AACR Prizes for Cancer Research|url=http://psychcentral.com/news/archives/2006-02/aafc-raw022806.html|access-date=23 January 2016|publisher=PsycheCentral|date=21 February 2009|archive-date=11 August 2017|archive-url=https://web.archive.org/web/20170811224408/https://psychcentral.com/news/archives/2006-02/aafc-raw022806.html|url-status=dead}}

Investigations and research has been undertaken to study the use of aromatase inhibitors to stimulate ovulation, and also to suppress estrogen production.{{cite journal | vauthors = Attar E, Bulun SE | title = Aromatase inhibitors: the next generation of therapeutics for endometriosis? | journal = Fertil. Steril. | volume = 85 | issue = 5 | pages = 1307–18 | year = 2006 | pmid = 16647373 | doi = 10.1016/j.fertnstert.2005.09.064 | doi-access = free }} Aromatase inhibitors have been shown to reverse age-related declines in testosterone, including primary hypogonadism.{{cite journal | vauthors = Leder BZ, Rohrer JL, Rubin SD, Gallo J, Longcope C | title = Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels | journal = J. Clin. Endocrinol. Metab. | volume = 89 | issue = 3 | pages = 1174–80 | year = 2004 | pmid = 15001605 | doi = 10.1210/jc.2003-031467 | doi-access = free }} 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.{{cite journal | vauthors = Grube BJ, Eng ET, Kao YC, Kwon A, Chen S | title = White button mushroom phytochemicals inhibit aromatase activity and breast cancer cell proliferation | journal = J. Nutr. | volume = 131 | issue = 12 | pages = 3288–93 | year = 2001 | pmid = 11739882 | doi = 10.1093/jn/131.12.3288| doi-access = free }}{{cite journal | vauthors = Chen S, Oh SR, Phung S, Hur G, Ye JJ, Kwok SL, Shrode GE, Belury M, Adams LS, Williams D | title = Anti-aromatase activity of phytochemicals in white button mushrooms (Agaricus bisporus) | journal = Cancer Res. | volume = 66 | issue = 24 | pages = 12026–34 | year = 2006 | pmid = 17178902 | doi = 10.1158/0008-5472.CAN-06-2206 | doi-access = free }} AIs have also been used experimentally in the treatment of adolescents with delayed puberty.{{cite journal | vauthors = Hero M, Wickman S, Dunkel L | title = Treatment with the aromatase inhibitor letrozole during adolescence increases near-final height in boys with constitutional delay of puberty | journal = Clin. Endocrinol. | volume = 64 | issue = 5 | pages = 510–3 | year = 2006 | pmid = 16649968 | doi = 10.1111/j.1365-2265.2006.02499.x | s2cid = 41008940 }}

Research suggests the common table mushroom has anti-aromatase{{cite journal | vauthors = Chen S, Kao YC, Laughton CA | title = Binding characteristics of aromatase inhibitors and phytoestrogens to human aromatase | journal = J. Steroid Biochem. Mol. Biol. | volume = 61 | issue = 3–6 | pages = 107–15 | year = 1997 | pmid = 9365179 | doi = 10.1016/S0960-0760(97)80001-5 | s2cid = 28593509 }} properties and therefore possible anti-estrogen activity. In 2009, a case-control study of the eating habits of 2,018 women in southeast China revealed that women who consumed greater than 10 grams of fresh mushrooms or greater than 4 grams of dried mushrooms per day had an approximately 50% lower incidence of breast cancer. Chinese women who consumed mushrooms and green tea had a 90% lower incidence of breast cancer.{{cite journal | vauthors = Zhang M, Huang J, Xie X, Holman CD | title = Dietary intakes of mushrooms and green tea combine to reduce the risk of breast cancer in Chinese women | journal = Int. J. Cancer | volume = 124 | issue = 6 | pages = 1404–8 |date=March 2009 | pmid = 19048616 | doi = 10.1002/ijc.24047 | s2cid = 22781113 | doi-access = free }} However the study was relatively small (2,018 patients participating) and limited to Chinese women of southeast China.

The extract from the herb damiana (Turnera diffusa) has been found to suppress aromatase activity, including the isolated compounds pinocembrin and acacetin.{{cite journal|vauthors = Zhao J, Dasmahapatra AK, Khan SI, Khan IA|year=2008|doi=10.1016/j.jep.2008.09.016|pmid=18948180|journal=Journal of Ethnopharmacology|volume=120|issue=3|pages=387–393|title=Anti-aromatase activity of the constituents from damiana (Turnera diffusa)}}{{better source needed|date=September 2019}}{{cite journal|vauthors = Szewczyka K, Zidorn C|year=2014|doi=10.1016/j.jep.2014.01.019|pmid=24468305|journal=Journal of Ethnopharmacology|volume=152|issue=3|pages=424–443|title=Ethnobotany, phytochemistry, and bioactivity of the genus Turnera (Passifloraceae) with a focus on damiana—Turnera diffusa}}{{better source needed|date=September 2019}}

{{Cite journal|pmid = 18690828|year = 2008|last1 = Balunas|first1 = M. J.|last2 = Su|first2 = B.|last3 = Brueggemeier|first3 = R. W.|last4 = Kinghorn|first4 = A. D.|title = Natural products as aromatase inhibitors|journal = Anti-Cancer Agents in Medicinal Chemistry|volume = 8|issue = 6|pages = 646–682|doi = 10.2174/187152008785133092|pmc = 3074486}}

• CYP17A1 inhibitor
• Estrogen deprivation therapy
• Selective estrogen receptor degrader

{{Reflist|35em}}

• {{Commonscatinline|Aromatase inhibitors}}
• [https://healingjourney.ai/ AI therapy]

{{Estrogens and antiestrogens}}

{{Enzyme inhibition}}

{{Assisted reproductive technology}}

Category:Hormonal antineoplastic drugs

Category:Progonadotropins