Inibitori aromatasi steroidei

Side effects are related to low estrogen levels:
- muscoloskeletal diseases:
→ osteoporosis → estrogen decreases the osteoblastic production of resorptive cytokines (RANK-L, CSF -1,IL-1 and TNF ) and at the same time increases the production of antireceptive cytokines (mainly osteoprotegerin). This leads to increased osteoclastic apoptosis and increased osteoblastic activity, favouring bone apposition. Futhermore, estrogen increases the intestinal absorption and the renal re-absorption of calcium. If plasma estrogen levels are low, there is a rise in the serum-parathyroid hormone stimulating the osteoclasts that result in the increased bone loss ( 3 ) → calcium and vitamin D supplements can reduce the risk of fracture ( 4 )
→ arthralgia and joint pain → joint pain is perceived by the nociceptive fibers innervating the articular structures and inflammatory mediators, such as prostaglandins and bradykinin, which activate these nociceptors, augmenting their sensitivity to pain with mechanical stimuli. Estrogen has been associated with anti-nociceptive effects, activating the spinal cord kappa-opioid analgesic system. ( 5 )
→ morning stiffness ( 6 ) → probably caused by sleep-related hypoventilation and hypoxemia
- cardiovascular disease ( 7 ) → estrogens protect cardiovascular system through three mechanism: enhancement of vasodilator capacity, suppression of vascular inflammation and increase in mitochondrial efficiency. Estrogen increases eNOS activity binding ERα, causing vasodilation. Estrogen also decrease NF-kB, an important transcription factor involved in the activation of infiammatory pathway. Futhermore, estrogen can increase mitochondrial biogenesis and decrease ROS formation. ( 8 )
- cephalgia
Weak androgenic effects (weight gain and acne) and cutaneous vasculitis have been associated with exemestane ( 9 ) ( 10 )

Aromatase enzyme is expressed in ovarian granulosa cells, placental syncytiotrophoblast, adipose tissue, brain, and skin fibroblasts. The primary sources of aromatase are ovarian granulosa cells in premenopausal women and adipose cells in postmenopausal women. Aromatase inhibitors suppress oestrogen synthesis in the ovaries and in peripheral tissues, starting from the next day after dosing. They work by inhibiting the action of aromatase, which converts androgens into oestrogens (testosterone into estradiol and androstenedione into oestrone). There are three generations of aromatase inhibitors (AIs). Aminoglutethimide is a first-generation aromatase inhibitor. The second-generation inhibitors include Fadrozole and Formestane. Anastrozole, Letrozole, and Exemestane are third-generation inhibitors.

Research suggests the common table mushroom has anti- aromatase [17] 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. [18] However the study was relatively small (2,018 patients participating) and limited to Chinese women of southeast China.

Estrogen plays a crucial role in the development of breast cancer, and the inhibition of estrogen synthesis has been an important target for the prevention and treatment of this disease. The rate-limiting reaction of the hormone biosynthesis is catalyzed by cytochrome P450 (CYP) 19 enzyme or aromatase. It has been of genuine interest to uncover an aromatase-inhibitory compound from a dietary source. Resveratrol is a polyphenolic compound that can be isolated from grape peel. Because of its structural resemblance to estrogen, resveratrol's agonistic and antagonistic properties on estrogen receptor have been examined and demonstrated. In the present study, the effect of resveratrol on the expression and enzyme activity of aromatase was investigated. By assaying on MCF-7 cells stably transfected with CYP19 (MCF-7aro cells), resveratrol inhibited the aromatase activity with an IC(50) value of 25 microM. Kinetic analysis indicated that both competitive and noncompetitive inhibition might be involved. The administration of 10 nmol/l testosterone-a substrate of aromatase-produced a 50% increase in the MCF-7aro cell number. This cell proliferation specifically induced by testosterone was significantly reduced by 10 microM resveratrol. In addition, 50 microM resveratrol significantly reduced the CYP19-encoding mRNA abundance in SK-BR-3 cells. The transcriptional control of CYP19 gene is tissue specific, and promoter regions and II have previously been shown to be responsible for CYP19 expression in breast cancer cells. Luciferase reporter gene assays revealed that resveratrol could repress the transcriptional control dictated by the promoter regulation. The present study illustrated that pharmacological dosage of resveratrol inhibited aromatase at both the enzyme and mRNA levels.

Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens to estrogens, is the major mechanism of estrogen synthesis in the post-menopausal woman. We review some of the recent scientific advances which shed light on the biologic significance, physiology, expression and regulation of aromatase in breast tissue. Inhibition of aromatase, the terminal step in estrogen biosynthesis, provides a way of treating hormone-dependent breast cancer in older patients. Aminoglutethimide was the first widely used aromatase inhibitor but had several clinical drawbacks. Newer agents are considerably more selective, more potent, less toxic and easier to use in the clinical setting. This article reviews the clinical data supporting the use of the potent, oral competitive aromatase inhibitors anastrozole, letrozole and vorozole and the irreversible inhibitors 4-OH androstenedione and exemestane. The more potent compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the evidence supporting the notion that aromatase inhibitors lack cross-resistance with antiestrogens and suggest that the newer, more potent compounds may have a particular application in breast cancer treatment in a setting of adaptive hypersensitivity to estrogens. Currently available aromatase inhibitors are safe and effective in the management of hormone-dependent breast cancer in post-menopausal women failing antiestrogen therapy and should now be used before progestational agents. There is abundant evidence to support testing these compounds as first-line hormonal therapy for metastatic breast cancer as well as part of adjuvant regimens in older patients and quite possibly in chemoprevention trials of breast cancer.

Inibitori aromatasi steroidei

inibitori aromatasi steroidei

Estrogen plays a crucial role in the development of breast cancer, and the inhibition of estrogen synthesis has been an important target for the prevention and treatment of this disease. The rate-limiting reaction of the hormone biosynthesis is catalyzed by cytochrome P450 (CYP) 19 enzyme or aromatase. It has been of genuine interest to uncover an aromatase-inhibitory compound from a dietary source. Resveratrol is a polyphenolic compound that can be isolated from grape peel. Because of its structural resemblance to estrogen, resveratrol's agonistic and antagonistic properties on estrogen receptor have been examined and demonstrated. In the present study, the effect of resveratrol on the expression and enzyme activity of aromatase was investigated. By assaying on MCF-7 cells stably transfected with CYP19 (MCF-7aro cells), resveratrol inhibited the aromatase activity with an IC(50) value of 25 microM. Kinetic analysis indicated that both competitive and noncompetitive inhibition might be involved. The administration of 10 nmol/l testosterone-a substrate of aromatase-produced a 50% increase in the MCF-7aro cell number. This cell proliferation specifically induced by testosterone was significantly reduced by 10 microM resveratrol. In addition, 50 microM resveratrol significantly reduced the CYP19-encoding mRNA abundance in SK-BR-3 cells. The transcriptional control of CYP19 gene is tissue specific, and promoter regions and II have previously been shown to be responsible for CYP19 expression in breast cancer cells. Luciferase reporter gene assays revealed that resveratrol could repress the transcriptional control dictated by the promoter regulation. The present study illustrated that pharmacological dosage of resveratrol inhibited aromatase at both the enzyme and mRNA levels.

Media:

inibitori aromatasi steroideiinibitori aromatasi steroideiinibitori aromatasi steroideiinibitori aromatasi steroideiinibitori aromatasi steroidei