Aromatase inhibitor

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Aromatase inhibitor
Chemical class
Steroidal; Nonsteroidal
Legal status
In Wikidata

Aromatase inhibitors (AIs) are a class of

chemoprevention
in women at high risk for breast cancer.

enone ring of androgen precursors such as testosterone, to a phenol, completing the synthesis of estrogen. As such, AIs are estrogen synthesis inhibitors
. Because hormone-positive breast and ovarian cancers are dependent on estrogen for growth, AIs are taken to either block the production of estrogen or block the action of estrogen on receptors.

Medical uses

Cancer

In contrast to

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.[3] 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.

overall survival advantage compared with tamoxifen, and there is no good evidence they are better tolerated.[5]

Gynecomastia

Aromatase inhibitors have been approved for the treatment of gynecomastia in children and adolescents.[6]

Ovulation induction

Ovarian stimulation with the aromatase inhibitor

clomiphene.[7]

Side effects

In women, side effects include an increased risk for developing

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.[9] 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,[10][11] and liver dysfunction. Patients with liver, kidney or adrenal abnormalities are at a higher risk of developing adverse events.[12]

Mechanism of action

Often used as a cancer treatment in postmenopausal women, AIs work by blocking the conversion of androstenedione and testosterone into estrone and estradiol, respectively, which are both crucial to the growth of developing breast cancers (AIs are also effective at treating ovarian cancer, but less commonly so). In the diagram, the adrenal gland (1) releases androstenedione (3) while the ovaries (2) secrete testosterone (4). Both hormones travel to peripheral tissues or a breast cell (5), where they would be converted into estrone (8) or estradiol (9) if not for AIs (7), which prevent the enzyme CYP19A1 (also known as aromatase or estrogen synthase) (6) from catalyzing the reaction that turns androstenedione and testosterone into estrone and estradiol. In the diagram, Part A represents the successful conversion of androstenedione and testosterone into estrone and estradiol in the liver. Part B represents the blockage of this conversion by aromatase inhibitors both in peripheral tissues and in the breast tumor itself.

Aromatase inhibitors work by inhibiting the action of the enzyme

systemic estrogenic effects in men and women, is the result of estrogen escaping local metabolism and spreading to the circulatory system.[13]

Pharmacodynamics of aromatase inhibitors
Generation Medication Dosage % inhibitiona Classb IC50c
First Testolactone 250 mg 4x/day p.o. ? Type I ?
100 mg 3x/week i.m. ?
Rogletimide 200 mg 2x/day p.o.
400 mg 2x/day p.o.
800 mg 2x/day p.o.		 50.6%
63.5%
73.8%		 Type II ?
Aminoglutethimide 250 mg mg 4x/day p.o. 90.6% Type II 4,500 nM
Second Formestane 125 mg 1x/day p.o.
125 mg 2x/day p.o.
250 mg 1x/day p.o.		 72.3%
70.0%
57.3%		 Type I 30 nM
250 mg 1x/2 weeks i.m.
500 mg 1x/2 weeks i.m.
500 mg 1x/1 week i.m.		 84.8%
91.9%
92.5%
Fadrozole 1 mg 1x/day p.o.
2 mg 2x/day p.o.		 82.4%
92.6%		 Type II ?
Third Exemestane 25 mg 1x/day p.o. 97.9% Type I 15 nM
Anastrozole 1 mg 1x/day p.o.
10 mg 1x/day p.o.		 96.7–97.3%
98.1%		 Type II 10 nM
Letrozole 0.5 mg 1x/day p.o.
2.5 mg 1x/day p.o.		 98.4%
98.9%–>99.1%		 Type II 2.5 nM
Footnotes: a = In
homogenates
. Sources: See template.

Types

There are two types of aromatase inhibitors approved to treat breast cancer:[14]

  • 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

Members

Arimidex (anastrozole) 1 mg tablets

Aromatase inhibitors (AIs) include:

Non-selective

Selective

Unknown

In addition to pharmaceutical AIs, some natural elements have aromatase inhibiting effects, such as damiana leaves.

History

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.[15] The drug was first marketed in 1994.[16]

Investigations and research has been undertaken to study the use of aromatase inhibitors to stimulate ovulation, and also to suppress estrogen production.

white mushroom having shown the greatest ability to inhibit the enzyme.[19][20] AIs have also been used experimentally in the treatment of adolescents with delayed puberty.[21]

Research

Research suggests the common

table mushroom has anti-aromatase[22] 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.[23]
However the study was relatively small (2,018 patients participating) and limited to Chinese women of southeast China.

The extract from the herb

better source needed
]

Natural aromatase inhibitors

Species Name Common Name Family Type
Aesculus glabra Ohio buckeye Hippocastanaceae Plant
Agaricus bisporus Baby button mushroom Agaricaceae Fungus
Allium sp. White onions Liliaceae Plant
Alpinia purpurata Red ginger Zingerberaceae Plant
Brassica oleracea Cauliflower Brassicaceae Plant

[26]

See also

References

  1. S2CID 211475185
    .
  2. ^ "Hormone Therapy for Breast Cancer in Men".
  3. S2CID 8350282
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  4. S2CID 8350282. [non-primary source needed
    ]
  5. PMID 19139426
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  6. S2CID 39852740
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  7. PMID 26398071
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  8. PMID 27784593
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  9. S2CID 25842353
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  10. S2CID 195689537
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  11. PMID 23696617
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  12. ^ "Aromatase Inhibitors in Products Marketed as Dietary Supplements: Recall" (Press release). FDA. September 20, 2010. Retrieved August 9, 2012.
  13. S2CID 11210435
    .
  14. S2CID 2862849
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  15. ^ "Angela Hartley Brodie, PhD". University of Maryland Medical Centre. Archived from the original on 1 February 2016. Retrieved 22 January 2016.
  16. ^ Grohol, John M. (21 February 2009). "Robert A. Weinberg and Angela M. Hartley Brodie awarded 2006 Landon-AACR Prizes for Cancer Research". PsycheCentral. Archived from the original on 11 August 2017. Retrieved 23 January 2016.
  17. PMID 16647373
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  18. PMID 15001605
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  19. PMID 11739882
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  20. PMID 17178902
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  21. S2CID 41008940
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  22. S2CID 28593509
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  23. S2CID 22781113
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  24. PMID 18948180
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  25. PMID 24468305
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  26. PMID 18690828
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External links
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