Exemestane/Aromasin Exemestane is a steroidal suicidal Type 1 irreversible Aromatace inhibitor. It was originally created for breast cancer patients to block estradiol from creating more onceogenes. These same onceogenes are responsible for the growth of tumors and cancer cells. It’s a naturally occurring substance from androstenedione which makes it very similar to formestane, one can call them brothers if they would like. Its steroid skeleton is comprised of of an ethyl group on C6 making it similar to Boldenone, similar to that of ATD. It’s a newer generation AI which shows lots of promising potential as it does not abuse cholesterol as bad as other AI’s have been reported to do so along positive effects on bone mineral density. It also does not lower IGF levels which pretty much all other AI’s with the exception of formestane (raises IGF) lowers them. Since Exemestane is a steroidal AI, it does have some androgenic properties which can lead to some minor strength and size gain along an increase in masculinity. The byproduct from the liver called 17-hydroxyexemestane is a metabolite which is created by the reduction of the 17-oxo group by way of the 17-beta-hydroxysteroid dehydrogenase which is responsible for its potent anti-estrogenic properties. This is the same metabolite believed to be responsible for the protection and growth of bone cells. Studies suggest Exemestane will block circulating estrogen up to 85% in women and 65% in men within a 12 hour span. When exemestane reaches full blood plasma concentration within the blood, it will block up to 98% of estrogen which means its POTENT. Based on a couple of studies I have read the only AI that can be taken with Novladex to reduce the estrogen that comes from increased testosterone would be Exemestane. Novladex inhibits the effectiveness of arimadex and other AI’s based on this study: J Steroid Biochem Mol Biol. 2001 Dec;79(1-5):85-91. I present the study to you good bros so you see that I am not trying pull the wool over your eyes. The suggested use of Aromasin/Exemestane is 25mg to see the 20% decrease in SHBG, 65% decrease in estradiol, and 60% increase in total/ 117% in free testosterone. The estrogen suppression rate for exemestane can vary from 85% for estradiol (E2) to 95% for estrone (E1). Exemestane reaches peak plasma concentrations within 2 hours following the oral administration of a 25 mg dose. The biological life of the drug is between 24 and 30 hours, most will say 27 hours. This is significant since it has a much shorter half life than for the non-steroidal inhibitors. A single oral dose of 25 milligrams of exemestane causes a relatively long-lasting reduction in plasma and urinary estrogen levels, with maximal suppression occurring approximately 2 to 3 days after dosing and persists for about 4 to 5 days.It has been shown that 25 milligrams of exemestane is basically just as effective as 50 milligrams at suppressing estrogen, raising testosterone levels, and levels of IGF. It is therefore unnecessary to go higher in doses than 25 milligrams per day. Due to the active life of the compound exemestane should be administered roughly once every twenty-four hours. It has been documented that 2.5mgs will be sufficient for treatment but most pharmaceutical companies will only produce the AI in 25mg tablets. Most people that are not using it for breast cancer; are bodybuilders are on anabolic cycle looking to avoid gynecomastia, bloating and making drier gains. As of recently; bodybuilders are also using it as part of their post cycle therapy to avoid estrogenic rebound. A NOTE: The main difference between Type 1(suicidal) and Type 2(competitive) is that type 1 will deactivate the estrogen and the enzyme will be gone, which means a new aromatase enzyme must be created. In Type 2 AI’s, the AI will compete for the binding site and once the individual stops taking the AI, the effects will come to a hault which can be problematic if you are on or still carry metabolites of a highly aromatizing androgen in your system. Or in the words of AR “ It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as “suicide inhibition.” In other words, Exemestane, by being structurally similar to the target of the enzymes, permanently binds to those enzymes, thereby preventing them from ever completing their task of converting androgens into estrogens.” A study conducted with a group of researchers monitored 68 older women for about 2 years. All the women had already been taking 20 mgs nolvadex daily for two to three years. Half of the women continued with the nolvadex treatment and the other half started taking 25 mgs exemestane per day instead. The exemestane group gained a notable amount of lean body mass. Within the two years that the trial lasted; the women in that group gained an average of 2.2 kg lean body mass. And the same group lost an average of 0.7 kg fat. That comes out to a whopping 30 percent loss in fat from starting which is quite remarkable. American cancer researchers have given an explanation on how exemestane might produce these effects. Exemestane itself has almost no androgenic effect, but the researchers announced in 2007 that an exemestane metabolite the 17beta-hydroxy analogue is capable of interacting with the androgen receptor. [Mol Cancer Ther. 2007 Nov;6(11):2817-27.] Again this is metabolite is the one believed to responsible for many of the pro-bodybuilding effects. “Aromatase inhibitors (AI) are being evaluated as long-term adjuvant therapies and chemopreventives in breast cancer. However, there are concerns about bone mineral density loss in an estrogen-free environment. Unlike nonsteroidal AIs, the steroidal AI exemestane may exert beneficial effects on bone through its primary metabolite 17-hydroexemestane. We investigated 17-hydroexemestane and observed it bound estrogen receptor alpha (ERalpha) very weakly and androgen receptor (AR) strongly. Next, we evaluated 17-hydroexemestane in MCF-7 and T47D breast cancer cells and attributed dependency of its effects on ER or AR using the antiestrogen fulvestrant or the antiandrogen bicalutamide. 17-Hydroexemestane induced proliferation, stimulated cell cycle progression and regulated transcription at high sub-micromolar and micromolar concentrations through ER in both cell lines, but through AR at low nanomolar concentrations selectively in T47D cells. Responses of each cell type to high and low concentrations of the non-aromatizable synthetic androgen R1881 paralleled those of 17-hydroexemestane. 17-Hydroexemestane down-regulated ERalpha protein levels at high concentrations in a cell type-specific manner similarly as 17beta-estradiol, and increased AR protein accumulation at low concentrations in both cell types similarly as R1881. Computer docking indicated that the 17beta-OH group of 17-hydroexemestane relative to the 17-keto group of exemestane contributed significantly more intermolecular interaction energy toward binding AR than ERalpha. Molecular modeling also indicated that 17-hydroexemestane interacted with ERalpha and AR through selective recognition motifs employed by 17beta-estradiol and R1881, respectively. We conclude that 17-hydroexemestane exerts biological effects as an androgen. These results may have important implications for long-term maintenance of patients with AIs.” Pharmacokinetics and Dose Finding of a Potent Aromatase Inhibitor, Aromasin (Exemestane), in Young Males Nelly Mauras, John Lima, Deval Patel, Annie Rini, Enrico di Salle, Ambrose Kwok and Barbara Lippe Nemours Children’s Clinic and Research Programs (N.M., J.L., A.R.), Jacksonville, Florida 32207; and University of Florida Health Sciences Center (D.P.) and Amersham Pharmacia Biotech (E.d.S., A.K., B.L.), Peapack, New Jersey 07977 Address all correspondence and requests for reprints to: Nelly Mauras, M.D., Nemours Children’s Clinic, 807 Children’s Way, Jacksonville, Florida 32207. E-mail: [email protected]. Abstract Suppression of estrogen, via estrogen receptor or aromatase blockade, is being investigated in the treatment of different conditions. Exemestane (Aromasin) is a potent and selective irreversible aromatase inhibitor. To characterize its suppression of estrogen and its pharmacokinetic (PK) properties in males, healthy eugonadal subjects (14–26 yr of age) were recruited. In a cross-over study, 12 were randomly assigned to 25 and 50 mg exemestane daily, orally, for 10 d with a 14-d washout period. Blood was withdrawn before and 24 h after the last dose of each treatment period. A PK study was performed (n = 10) using a 25-mg dose. Exemestane suppressed plasma estradiol comparably with either dose [25 mg, 38% (P 0.002); 50 mg, 32% (P 0.008)], with a reciprocal increase in testosterone concentrations (60% and 56%; P 0.003 for both). Plasma lipids and IGF-I concentrations were unaffected by treatment. The PK properties of the 25-mg dose showed the highest exemestane concentrations 1 h after administration, indicating rapid absorption. The terminal half-life was 8.9 h. Maximal estradiol suppression of 62 ± 14% was observed at 12 h. The drug was well tolerated. In conclusion, exemestane is a potent aromatase inhibitor in men and an alternative to the choice of available inhibitors. Long-term efficacy and safety will need further study. Exemestane induces bone cell growth Effects of aromatase inhibitors on human osteoblast and osteoblast-like cells: A possible androgenic bone protective effects induced by exemestane Yasuhiro Mikia, Takashi Suzukia, Masahito Hatorib, Katsuhide Igarashic, Ken-ich Aisakic, Jun Kannoc, Yasuhiro Nakamuraa, Miwa Uzukid, Takashi Sawaic, Hironobu Sasanoa Received 21 April 2006; received in revised form 6 November 2006; accepted 14 November 2006. published online 25 January 2007. Abstract Effects of aromatase inhibitors (AIs) on the human skeletal system due to systemic estrogen depletion are becoming clinically important due to their increasing use as an adjuvant therapy in postmenopausal women with breast cancer. However, possible effects of AIs on human bone cells have remained largely unknown. We therefore studied effects of AIs including the steroidal AI, exemestane (EXE), and non-steroidal AIs, Aromatase Inhibitor I (AI-I) and aminoglutethimide (AGM), on a human osteoblast. We employed a human osteoblast cell line, hFOB, which maintains relatively physiological status of estrogen and androgen pathways of human osteoblasts, i.e., expression of aromatase, androgen receptor (AR), and estrogen receptor (ER) ß. We also employed osteoblast-like cell lines, Saos-2 and MG-63 which expressed aromatase, AR, and ERa/ß in order to further evaluate the mechanisms of effects of AIs on osteoblasts. There was a significant increment in the number of the cells following 72 h treatment with EXE in hFOB and Saos-2 but not in MG-63, in which the level of AR mRNA was lower than that in hFOB and Saos-2. Alkaline phosphatase activity was also increased by EXE treatment in hFOB and Saos-2. Pretreatment with the AR blocker, flutamide, partially inhibited the effect of EXE. AI-I exerted no effects on osteoblast cell proliferation and AGM diminished the number of the cells. hFOB converted androstenedione into E2 and testosterone (TST). Both EXE and AI-I decreased E2 level and increased TST level. In a microarray analysis, gene profile patterns following treatment with EXE demonstrated similar patterns as with DHT but not with E2 treatment. The genes induced by EXE treatment were related to cell proliferation, differentiation which includes genes encoding cytoskeleton proteins. We also examined the expression levels of these genes using quantitative RT-PCR in hFOB and Saos-2 treated with EXE and DHT and with/without flutamide. HOXD11 gene known as bone morphogenesis factor and osteoblast growth-related genes were induced by EXE treatment as well as DHT treatment in both hFOB and Saos-2. These results indicated that the steroidal aromatase inhibitor, EXE, stimulated hFOB cell proliferation via both AR dependent and independent pathways. Aromasin’s study showing positive effects on IGF The point of this random study I came across was to compare the effects of progestins and aromatase inactivators on bone remodelling markers and the components of insulin-like growth factor in patients with metastatic breast cancer. Within the structure of over 700 patients; including a double-blind clinical trial comparing exemestane (EXE) with megestrol acetate (MA), serum 17 beta-estradiol (E2), estrone (E1), estrone sulphate (E1S), bone alkaline phosphatase (BAP), carboxy-terminal cross-linking telopeptide of type I collagen (ICTP) and the components of insulin-like growth factor (IGF) family (IGF-1, IGF-2 and IGFBP-3) were determined in 53 patients (24 random to EXE and 29 ramdom to MA). After eight weeks of treatment, both ICTP and BAP increased (p < 0.01) in the EXE group, but only ICTP in the MA group (p < 0.03). The 8-week suppression of E2 and E1S was more pronounced in the EXE group (to, respectively, 11.2% and 9.9% of baseline values) than in the MA group (33.1% and 29.7%). IGF-1 increased (p < 0.01) in both groups, but more so in the patients treated with MA. Estrogen levels negatively correlated with ICTP in both groups, but were not related to BAP in either. IGF-1 negatively correlated with estrogens in both groups. The results of this study indicate that anti-aromatase therapy is associated with INCREASED osteoclast activity, and suggest the existence of possible differential effects of different hormonal therapies on bone remodeling markers regardless of the estrogen suppression induced by EXE. (Anticancer Res. 2003 Jul-Aug;23(4):3485-91.) Dosage: One should start off with 12.5mgs to assess tolerance, if more is needed then try 25mg. It’s suggested that for one week the individual take it daily, but then after that initial week can take it every other day at one’s preferred dosage. There is no need to taper this specific Aromatase Inhibitor.
Posted on: Tue, 24 Jun 2014 13:01:42 +0000
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