Aromatases

R)-3-Eth5i-3(4-pyridyl)piperidine-2,6-dione (197), useful in the treatment of certain breast cancers, is a 20-fold more potent aromatase inhibitor... 

The alkynyl steroid (96) inactivates aromatase, an enzyme which catalyzes the conversion of androgen to estrogen. It has been suggested (81JA3221) that the inactivation process involves the oxidation of (96) to an oxirene which rearranges to an oxocarbene which then binds to the enzyme prosthetic group, thus inactivating it. 

Table 1 Sites of androgen and oestrogen reeeptors and aromatase aetivity in the testis and assoeiated duets during fetal/perinatal life in the rat ...

The pattern of expression of the reeeptors is based on immunoloealisation studies eondueted by eolleagues where + represents the intensity of immunostaining and — where expression eould not be deteeted. The presenee of aromatase aetivity in Sertoli eells has been reported in the literature. Aromatase may also be expressed in fetal Leydig eells and efferent duets (K. J. Turner, unpublished observations). 

The presence of aromatase in the testis and in sperm further emphasises the likelihood that the local production of oestradiol within the male reproductive... 

Aromatase inhibitors (aminogluthetimide, formes-tane, trilostane) block the formation of estrogens from precursor steroids and thus lower estrogen levels. They have been used for treating breast cancer. 

Aromatase activity, and hence the capacity to synthesize estrogens, is found in a variety of tissues in the body. Gonadal sites include the ovaries in premenopausal women and the testes in men. Important extragonadal sites of aromatase activity include the placenta, chondrocytes and osteoblasts of bone, adipose tissue, muscle and brain. Aromatase plays an important... 

Aromatase. Figure 1 Androgens converted to estrogens by aromatase. 

In premenopausal women the ovary is the richest source of aromatase and hence estrogen. Aromatase is confined to the granulosa cells and is produced under the influence of gonadotropins (FSH and LH). Despite being a rich source of aromatase, three separate studies have shown that aromatase inhibitors are unable to sufficiently suppress ovarian estrogen production to postmenopausal levels. One explanation for this phenomenon may be a compensatory rise in gonadotrophins which maintains adequate estrogen production, despite the presence of the inhibitor. As such aromatase inhibitors cannot be used in premenopausal breast cancer patients. After menopause, ovarian... 

Aminooglutethimide was the fust aromatase inhibitor to be used in patients with metastatic breast cancer, where response rates of up to 30% have been reported. Unfortunately, due to its lack of selectivity for aromatase, it induced a medical adrenelectomy that resulted in suppression of aldosterone and cortisol. With the development of more selective aromatase... 

Anastrazole is a nonsteroidal, type H, aromatase inhibitor that is 200 times more potent than aminoglutethimide. It is eliminated primarily via hqDatic metabolism, has a terminal half life of 50 h with steady state concentrations achieved approximately 10 days with once daily dosing regimens. It is administered orally at a dose of 1 mg/day that achieves near maximal aromatase inhibition and hence estrogen suppression in breast cancer patients. No effect on adrenal steroidogenesis has been observed at up to ten times the daily recommended dose. When used in the metastatic setting, anastrozole has been shown... 

Like anastrozole, letrozole is a third generation, type II nonsteroidal aromatase inhibitor. Renal excretion of its... 

Aromatase inhibitors are relatively well tolerated however have a number of distinct side effects are observed that stem from the state of estrogen deprivation induced by aromatase inhibitors. Side effects include hot flashes, joint and muscle aches, vasomotor symptoms and vaginal dryness. Variable effects of aromatase inhibitors on lipid levels have been observed. Trials comparing third generation aromatase inhibitors to tamoxifen have also repotted an increased risk of cardiovascular events in the group receiving aromatase inhibitors. 

Aromatase inhibitors have also been used in premenopausal women for the treatment of endometriosis and to induce ovarian folliculogenesis as part of the treatment for infertility. 

Simpson ER, Clyne C, Rubin G et al (2002) Aromatase -A Brief Overview. Annu Rev Physiol 54 93-127... 

Dowsett M (1996) Biological background to aromatase inhibition. Breast 5 196-201... 

Dixon MJ (2006) Aromatase inhibitors in early beast cancer therapy a variety of treatment strategies. Expert Opin 7 (18)2465-2479... 

Buzdar AU (2005—2006) Aromatase inhibitors changing the face of endocrine therapy for breast cancer. Breast dis 24 107-117... 

Pandya N, Morris GJ (2006) Toxicity of Aromatase Inhibitors. Semin Oncol 33 688-695... 

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