french_muscle
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I came across a very interesting abstract that described in depth the mechanism of action of letrozole and in what it differs with other AIs ...
First, Letrozole is a third generation type 2 AI. There are 2 types of AIs. Type 1 are also referred to as steroidal inhibitors because they specifically attach to the substrate binding site on the enzyme because of their androgen-like structure. Thus, they compete at the aromatase enzyme binding site with androstenedione. On the other hand, Type 2 AIs are NON-steroidal because they bind competitively to the aromatase enzyme’s heme component of the cytochrome P450 subunit.
From what I've read, letrozole is the most effective and the most side effects free AI to use. When Letrozole studies first began, it was compared to other second generation AIs like aminoglutethimide, fadrozole hydrocholoride, and lentaron, which I've never heard of, except for aminoglutethimide, which is also a biosynthesis inhibitor (inhibit the conversion of cholesterol to pregnenolone). These drugs all caused side effects such as a decrease in aldosterone levels, fluctuation of electrolyte balance, androgenic effects, central nervous system toxicity, and adrenal insufficiency (note that cytadren is well known for that). On the opposite, letro did not cause any of these effects in patients. Adrenal gland was not affected, and cortisol and aldosterone levels were not decreased as they were with the other drugs. When letro was given to patients with breast cancers, they are able to maintain synthesis of the mineralocorticoids and glucocorticoids. Plus the first studies of letrozole showed that thyroid function was not affected. The inhibitory effects on estrogen biosynthesis were observable within twenty-four hours of taking the medication.
Here is a comparative potencies of different AIs...
Aminogluthetimide @ 1000mg ED / Average percentage of total body aromatase inhibition : 90.6%
Anastrazole @ 1mg ED / Average percentage of total body aromatase inhibition : 97.3%
Exemestane @ 25mg ED / Average percentage of total body aromatase inhibition : 97.9%
Formestane @ 250mg IM every two weeks / Average percentage of total body aromatase inhibition : 84.8%
Letrozole @ 2.5mg ED / Average percentage of total body aromatase inhibition : >99.1%
Third generation AIs are completely absorbed after oral administration, with an average terminal half-life of roughly 45 hours.
And finally, a study showing that letrozole increase IGF-1 serum levels.. I think it has already been posted somewhere, for those who didn't read it:
The aromatase inhibitor letrozole in advanced breast cancer: effects on serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels.
Bajetta E, Ferrari L, Celio L, Mariani L, Miceli R, Di Leo A, Zilembo N, Buzzoni R, Spagnoli I, Martinetti A, Bichisao E, Seregni E.
Medical Oncology B Division, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels were measured in two groups of postmenopausal women with advanced breast cancer, who received the aromatase inhibitor letrozole 0.5 or 2.5 mg p.o. once daily. Blood samples were obtained from 15 patients in each dose group at baseline, and one and three months after starting therapy. Circulating IGF-I and IGFBP-3 concentrations were determined by means of radioimmunoassay. In both dosage groups a statistically significant increase in the IGF-I levels was observed during three months of letrozole treatment (P=0.003). In addition, the multiple testing procedure yielded in the whole patient population a significant result in the comparison between mean IGF-I values after three months of therapy and those observed at baseline (P=0.004), the estimated average increase being of 24%. No significant result was obtained in the analysis for the dose effect (P=0.077) and for the time x dose interaction (P=0.208). Circulating IGFBP-3 levels did not appear to be affected by letrozole treatment in either of the dose groups. This is the first report concerning the short-term effects of letrozole on components of the IGF system in breast cancer patients; further investigations are warranted in order to confirm these preliminary data.
First, Letrozole is a third generation type 2 AI. There are 2 types of AIs. Type 1 are also referred to as steroidal inhibitors because they specifically attach to the substrate binding site on the enzyme because of their androgen-like structure. Thus, they compete at the aromatase enzyme binding site with androstenedione. On the other hand, Type 2 AIs are NON-steroidal because they bind competitively to the aromatase enzyme’s heme component of the cytochrome P450 subunit.
From what I've read, letrozole is the most effective and the most side effects free AI to use. When Letrozole studies first began, it was compared to other second generation AIs like aminoglutethimide, fadrozole hydrocholoride, and lentaron, which I've never heard of, except for aminoglutethimide, which is also a biosynthesis inhibitor (inhibit the conversion of cholesterol to pregnenolone). These drugs all caused side effects such as a decrease in aldosterone levels, fluctuation of electrolyte balance, androgenic effects, central nervous system toxicity, and adrenal insufficiency (note that cytadren is well known for that). On the opposite, letro did not cause any of these effects in patients. Adrenal gland was not affected, and cortisol and aldosterone levels were not decreased as they were with the other drugs. When letro was given to patients with breast cancers, they are able to maintain synthesis of the mineralocorticoids and glucocorticoids. Plus the first studies of letrozole showed that thyroid function was not affected. The inhibitory effects on estrogen biosynthesis were observable within twenty-four hours of taking the medication.
Here is a comparative potencies of different AIs...
Aminogluthetimide @ 1000mg ED / Average percentage of total body aromatase inhibition : 90.6%
Anastrazole @ 1mg ED / Average percentage of total body aromatase inhibition : 97.3%
Exemestane @ 25mg ED / Average percentage of total body aromatase inhibition : 97.9%
Formestane @ 250mg IM every two weeks / Average percentage of total body aromatase inhibition : 84.8%
Letrozole @ 2.5mg ED / Average percentage of total body aromatase inhibition : >99.1%
Third generation AIs are completely absorbed after oral administration, with an average terminal half-life of roughly 45 hours.
And finally, a study showing that letrozole increase IGF-1 serum levels.. I think it has already been posted somewhere, for those who didn't read it:
The aromatase inhibitor letrozole in advanced breast cancer: effects on serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels.
Bajetta E, Ferrari L, Celio L, Mariani L, Miceli R, Di Leo A, Zilembo N, Buzzoni R, Spagnoli I, Martinetti A, Bichisao E, Seregni E.
Medical Oncology B Division, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels were measured in two groups of postmenopausal women with advanced breast cancer, who received the aromatase inhibitor letrozole 0.5 or 2.5 mg p.o. once daily. Blood samples were obtained from 15 patients in each dose group at baseline, and one and three months after starting therapy. Circulating IGF-I and IGFBP-3 concentrations were determined by means of radioimmunoassay. In both dosage groups a statistically significant increase in the IGF-I levels was observed during three months of letrozole treatment (P=0.003). In addition, the multiple testing procedure yielded in the whole patient population a significant result in the comparison between mean IGF-I values after three months of therapy and those observed at baseline (P=0.004), the estimated average increase being of 24%. No significant result was obtained in the analysis for the dose effect (P=0.077) and for the time x dose interaction (P=0.208). Circulating IGFBP-3 levels did not appear to be affected by letrozole treatment in either of the dose groups. This is the first report concerning the short-term effects of letrozole on components of the IGF system in breast cancer patients; further investigations are warranted in order to confirm these preliminary data.
