aromatase inhibitors

アロマターゼ阻害薬

WordNet

1. a substance that retards or stops an activity

PrepTutorEJDIC

1. 抑制する人(物) / 化学反応抑制剤

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/05/19 00:12:37」(JST)

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Aromatase inhibitor
Drug class
Anastrozole, a nonsteroidal aromatase inhibitor and a widely used drug in the treatment of breast cancer.
Class identifiers
Synonyms	Estrogen synthesis inhibitors; Estrogen synthase inhibitors; Estrogen blockers
Use	Breast cancer, infertility, precocious puberty, medical abortion, gynecomastia, endometriosis, short stature, others
ATC code	L02BG
Biological target	Aromatase
Chemical class	Steroidal; Nonsteroidal
In Wikidata

Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and gynecomastia in men. They may also be used off-label to reduce increase of estrogen conversion during cycle with external testosterone. They may also be used for chemoprevention in high risk women.

Aromatase is the enzyme that 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.

Medical uses

Cancer

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. 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. The heightened gonadotropin levels also upregulate the aromatase promoter, increasing aromatase production in the setting of increased androgen substrate. This counteracts the effect of the aromatase inhibitor in premenopausal women since total estrogen is increased. 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. Trials of AIs in the adjuvant setting (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.

Gynecomastia

Aromatase inhibitors such as testolactone have been approved for the treatment of gynecomastia in children and adolescents.

Unexplained female infertility

Ovarian stimulation with the aromatase inhibitor letrozole has been proposed as one of the treatments for 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.

Side effects

Side effects include an increased risk for developing osteoporosis and joint disorders such as arthritis, arthrosis, and joint pain. 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. 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, and liver dysfunction. Patients with liver, kidney or adrenal abnormalities are at a higher risk of developing adverse events.

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 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.

Types

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

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

See also: Steroidal Aromatase Inhibitors

Members

Arimidex (anastrozole) 1 mg tablets

Available aromatase inhibitors (AIs) include:

Non-selective

• Aminoglutethimide, also inhibits the enzyme P450scc and so decreases synthesis of all steroid hormones.
• Testolactone (Teslac)

Selective

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

Unknown

• 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.

Research

Investigations and research has been undertaken to study the use of aromatase inhibitors to stimulate ovulation, and also to suppress estrogen production. Aromatase inhibitors have been shown to reverse age-related declines in testosterone, including primary hypogonadism. 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. AIs have also been used experimentally in the treatment of adolescents with delayed puberty.

Table mushroom

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

See also

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

References

UpToDate Contents

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• 1. 非転移性ホルモン受容体陽性乳癌に対する補助内分泌療法 adjuvant endocrine therapy for non metastatic hormone receptor positive breast cancer
• 2. 乳癌予防のための選択的エストロゲン受容体調節因子およびアロマターゼ阻害剤 selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention
• 3. 転移性ホルモン受容体陽性乳癌に対する治療アプローチ：内分泌療法 treatment approach to metastatic hormone receptor positive breast cancer endocrine therapy
• 4. アロマターゼ阻害剤による骨量減少の評価およびマネージメント evaluation and management of aromatase inhibitor induced bone loss
• 5. 女性化乳房のマネージメント management of gynecomastia

English Journal

• Adjuvant treatments of breast cancer increase the risk of depressive disorders: A population-based study.

• Chang CH1, Chen SJ2, Liu CY3.
• Journal of affective disorders.J Affect Disord.2015 Aug 15;182:44-9. doi: 10.1016/j.jad.2015.04.027. Epub 2015 Apr 23.
• BACKGROUND: Previous studies have posited conflicting results regarding depressive disorders among breast cancer survivors who received adjuvant therapies including chemotherapy, radiotherapy, selective estrogen receptor modulator (e.g. tamoxifen), third-generation aromatase inhibitors (AIs; e.g. an
• PMID 25973782

• Synthesis and molecular docking of 1,2,3-triazole-based sulfonamides as aromatase inhibitors.

• Pingaew R1, Prachayasittikul V2, Mandi P3, Nantasenamat C3, Prachayasittikul S4, Ruchirawat S5, Prachayasittikul V6.
• Bioorganic & medicinal chemistry.Bioorg Med Chem.2015 Jul 1;23(13):3472-80. doi: 10.1016/j.bmc.2015.04.036. Epub 2015 Apr 17.
• A series of 1,4-disubstituted-1,2,3-triazoles (13-35) containing sulfonamide moiety were synthesized and evaluated for their aromatase inhibitory effects. Most triazoles with open-chain sulfonamide showed significant aromatase inhibitory activity (IC50=1.3-9.4μM). Interestingly, the meta analog of
• PMID 25934226

• Pattern of hormone receptors and human epidermal growth factor receptor 2 status in sub-Saharan breast cancer cases: Private practice experience.

• Nwafor CC1, Keshinro SO.
• Nigerian journal of clinical practice.Niger J Clin Pract.2015 Jul-Aug;18(4):553-8. doi: 10.4103/1119-3077.156905.
• INTRODUCTION: Breast cancer is the most common cancer among women globally. With immunohistochemistry (IHC), breast cancer is classified into four groups based on IHC profile of estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2/neu) expression, posi
• PMID 25966732

Japanese Journal

• p53 accumulation is a strong predictor of recurrence in estrogen receptor-positive breast cancer patients treated with aromatase inhibitors

• Yamamoto Mitsugu,Hosoda Mitsuchika,Nakano Kiichiroh,Jia Shusheng,Hatanaka Kanako C.,Takakuwa Emi,Hatanaka Yutaka,Matsuno Yoshihiro,Yamashita Hiroko
• Cancer science 105(1), 81-88, 2014-01
• … Aromatase inhibitors have played a central role in endocrine therapy for estrogen receptor (ER)-positive breast cancer in postmenopausal women. … However, factors predictive of the efficacy of aromatase inhibitors, and prognostic factors, both for early and late recurrence in women treated with adjuvant aromatase inhibitors have not been identified. …
• NAID 120005411143

• Third-generation Aromatase Inhibitor Improved Adult Height in a Japanese Boy with Testotoxicosis

• , , , , ,
• Clinical Pediatric Endocrinology 23(2), 53-58, 2014
• … A572V] in the LH/CGR gene, who was the first boy treated with a third-generation aromatase inhibitor (AI) and reached his adult height in Japan. …
• NAID 130004853602

• レトロゾールによる内分泌療法が有効であった91歳男性乳癌の1例

• 中田 琢巳,森川 あけみ,杉山 保幸,山田 鉄也
• 日本臨床外科学会雑誌 75(4), 906-910, 2014
• 症例は91歳，男性．併存症として，閉塞性動脈硬化症・狭心症・2型糖尿病・高血圧症などがあり，当院内科での治療中に左乳頭下に3.5cmの腫瘤を自覚するようになり当科を受診した．男性乳癌と診断されたが初期治療としては合併症を考慮してレトロゾール内服による内分泌療法が選択された．投与開始後から腫瘍の縮小が認められ，約6カ月間で腫瘤は1.7cmまでの縮小を認め，自覚症状は著明に改善した．症例の少なさから女 …
• NAID 130004713878

Related Links

• Aromatase Inhibitors | Breastcancer.org

Aromatase inhibitors stop the production of estrogen in postmenopausal women. Aromatase inhibitors work by blocking the enzyme aromatase, which turns the hormone androgen into small amounts of estrogen in the body. This ...

• Aromatase inhibitors and other compounds for lowering ...

Aromatase inhibitors (drugs that lower estrogen levels) may someday prove to be as good as or even better than tamoxifen or raloxifene in reducing breast cancer risk, but they haven’t been well studied for this use. More ...

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関連記事	「inhibitor」

「inhibitor」

　　[★]

• n.

• 阻害剤、阻害薬、抑制薬、抑制剤、(内在性物質について)インヒビター、抑制物質

関

blocker、depressant、suppressant