Letrozole~femara

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Letrozole (Femara) is the chemical name of Novartis? selective third generation Aromatase Inhibitor (AI). This drug was developed to fight breast cancer by inhibiting the aromatization. It is usually used as a part of an aggressive treatment in post-menopausal women, to fight and reverse the spread of breast cancer after other treatments (such as Tamoxifen therapy) has failed. It?s probably the most efficient product on the market for this purpose currently (5) It is very similar in structure and action to it?s predecessor Arimidex.

Letrozole (Femara) also does quite a few things which would be of interest to both bodybuilders and athletes. Firstly, it has been shown to reduce estrogen levels by 98% or greater (1). In at least one documented incidence, Letrozole (Femara) reduced estrogen in the test subject to undetectable levels, and increased LH, FSH and SHBG (4). Clearly this is all of interest to bodybuilders, as less estrogen in the body means less chance of certain side effects such as water-retention, Gynocomastia, and acne. This makes Letrozole (Femara) an appropriate choice for even the heaviest bulking or cutting cycles including harsh androgens. Also, if you are a competitive bodybuilder, Letrozole (Femara) is a must have product for contest prep; no other Ancillary compound will produce a dry and tight look like Letro will.

An effective dose of Letrozole (Femara) is .25-.5mg/day (I use .25mgs/day), but be forewarned, if you go over that amount, it can kill your sex drive. Also worth noting is that there?s a rebound effect on your estrogen when you come off Letrozol. Maximum inhibition of the aromatase enzyme has been found to happen at doses as low as 100mcg! (2)

Letrozole (Femara)?s effects on serum lipids (cholesterol, both HDL and LDL) are, in the words of one researcher: "inconsistent. " Clearly, however, you?ll eventually suffer an impaired lipid profile and immune system if you keep your estrogen levels too low for too long. Your sex drive will also probably suffer from extraordinarily low levels of estrogen present.

As previously mentioned, Letrozole (Femara) can be used to raise LH and FSH (which are hormones which signal your testes to produce more testosterone). It also, of course, will raise your testosterone levels (6) via this mechanism. Again, this is of interest to athletes and bodybuilders for obvious reasons. Letrozole (Femara), of course, can be used for post-cycle-therapy (PCT) to raise test levels, but for various reasons, Tamoxifen may be a better choice. Still, I have successfully used Letrozole (Femara) for this purpose.

How good is this compared with Aromasin and Arimidex, it?s too other main rivals? Well, In non-cellular systems, Letrozole (Femara) is 2-5 times more potent than anastrozole and exemestane in its inhibition of the aromatase enzyme and activity, and in cellular systems it is 10-20x more potent! It also lasts quite a long time in your body,but takes awhile to get going. Letrozole (Femara) has a whopping 2-4 day (!) ? life, and you need to take Letrozole (Femara) for 60 days to get a steady blood plasma level (8).

Those are impressive numbers, but here?s one of the most interesting things about Letrozole (Femara):

It may reduce/eliminate/reverse existing gynocomastia!

In a study conducted on mice (*no, I know it?s not perfect), gyno-like-changes in the mammary gland were totally destroyed! Here?s a direct quote from that study:

"Our results also indicate aromatase overexpression-induced changes in mammary glands can be abrogated [destroyed] with very low concentrations of the aromatase inhibitor, Letrozole (Femara)."(7)

In addition, I?ve used Letro to get rid of my own gyno, as has a friend of mine, and we both used it at a dose of 2.5mgs/day, tapering down to .25mgs/day, and then finally off..the gyno never returned in both our cases.

I?d say that this stuff is pretty great, considering its availability and cost (when you consider the fact that .25mgs/day is more than enough protection from estrogen-related sides on most cycles), not to mention it?s overall utility for a variety of functions (destroying gyno, preventing estrogenic sides, and for PCT).

References:


Clin Cancer Res. 2005 Apr 15;11(8):2809-21.
J Clin Endocrinol Metab. 1995 Sep;80(9):2658-60.
Eur J Obstet Gynecol Reprod Biol. 2002 Nov 15;105(2):161-5
Epilepsy Behav. 2004 Apr;5(2):260-3
Semin Oncol. 2004 Dec;31(6 Suppl 12):3-8.
Diabetes Obes Metab. 2005 May;7(3):211-5.
J Steroid Biochem Mol Biol. 2001 Dec;79(1-5):27-34. Aromatase overexpression transgenic mice model: cell type specific expression and use of Letrozole (Femara) to abrogate mammary hyperplasia without affecting normal physiology.
(Clin Cancer Res. 2003 Jan;9(1 Pt 2):468S-72S.).

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Biological and clinical effects of aromatase inhibitors in neoadjuvant therapy.

Miller WR, Dixon JM, Cameron DA, Anderson TJ.
Department of Clinical Oncology, and Breast Unit, Western General Hospital, University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK. w.r.miller@ed.ac.uk

Postmenopausal women with large primary oestrogen receptor-rich (>20 fmol/mg protein or 80 histoscore) breast cancers have been treated neoadjuvantly with either letrozole (2.5 or 10 mg daily n=12 in each case) or anastrozole (1 or 10mg daily n=12 and 11, respectively). Tumour was available for analysis before treatment (wedge biopsy) and 3 months later at definitive surgery (wide local excision or mastectomy). Clinical response to treatment was assessed by sequential measurements of tumour volume based on caliper assessment, ultrasound and mammography. Results showed that in these selected groups of patients a reduction in tumour volume with treatment was observed in 43 of 47 cases (91%). Pathological responses, i.e. clear decrease in tumour cellularity or increased fibrosis was evident in 32 cases (68%). Furthermore, there was a decrease with therapy in immunohistochemical staining for Ki67 in all tumours. Staining for progesterone receptor (PgR) was reduced in all 21 PgR-positive cancers treated with letrozole and in 16 of 17 positive cancers treated with anastrozole. These effects are at least as great as those seen in a non-randomised group of patients treated with tamoxifen over the same time period (additionally tamoxifen treatment was often associated with an increase in PgR staining). The results suggest that potent specific aromatase inhibitors will be valuable in treating hormone-dependent cancers

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This may be a basis for using Letro to reduce mammery gland tissue (gyno).



Aromatase overexpression transgenic mice model: cell type specific expression and use of letrozole to abrogate mammary hyperplasia without affecting normal physiology.

Mandava U, Kirma N, Tekmal RR.
Department of Gynecology and Obstetrics, Emory University, 4217 Woodruff Memorial Building, 1639 Pierce Drive, Atlanta, GA 30322-4710, USA.

Our recent studies have shown that overexpression of aromatase results in increased tissue estrogenic activity and induction of hyperplastic and dysplastic lesions in female mammary glands and gynecomastia and testicular cancer in male aromatase transgenic mice. Both aromatase mRNA and protein are overexpressed in transgenic mammary glands and its expression is not limited to epithelial cells. However, it is more in epithelial than in stromal cells. Our results also indicate aromatase overexpression-induced changes in mammary glands can be abrogated with very low concentrations of the aromatase inhibitor, letrozole. Low concentration of letrozole had no effect on normal physiology as indicated by no significant change in the circulating levels of estradiol and follicle stimulating hormone as well as no change in estrogen responsive genes such as the progesterone receptor and lactoferrin in the uterine tissue. These observations indicate that the expression of aromatase in both epithelial and stromal cells can influence the complex interactions of biochemical pathways leading to mammary carcinogenesis and that the aromatase inhibitor, letrozole can be used as chemopreventive agents without affecting normal physiology.

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Use of the aromatase inhibitor letrozole to treat male infertility.

Patry G, Jarvi K, Grober ED, Lo KC.
Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. kochman@hadassah.org.il

OBJECTIVE: Report the case of induction of spermatogenesis with the aromatase inhibitor letrozole. DESIGN: Case report. SETTING: University Infertility center. PATIENT(S): A 31-year-old man with primary infertility, normal volume azoospermia, normal follicle stimulating hormone (FSH) levels and pattern of nonobstructive azoospermia (NOA) on a testicular biopsy. INTERVENTION(S): The patient was given the aromatase inhibitor letrozole for 4 months and had repeated FSH, testosterone, LH levels, semen analyses, and finally a testicular biopsy. MAIN OUTCOME MEASURE(S): Results of a testis biopsy. RESULT(S): Testis biopsy showed normal spermatogenesis following 4 months of letrozole therapy. CONCLUSION(S): This is the first case report on the use of letrozole to treat male infertility and the first case report on the induction of spermatogenesis in a man with NOA using any aromatase inhibitor

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Use of ultrasensitive recombinant cell bioassay to measure estrogen levels in women with breast cancer receiving the aromatase inhibitor, letrozole.

Klein KO, Demers LM, Santner SJ, Baron J, Cutler GB Jr, Santen RJ.
Children's Hospital of Orange County, California 92668, USA.

The development of well tolerated, potent, specific, and nontoxic aromatase inhibitors for the treatment of postmenopausal women with estrogen-dependent breast cancer has been a major goal of recent studies. The third generation inhibitors now under investigation are nearly 10,000-fold more potent than first generation compounds. Currently available RIAs for plasma estradiol lack sufficient sensitivity to measure levels during aromatase inhibition and, thus, to assess drug potency precisely. The availability of an ultrasensitive bioassay for estradiol provided the opportunity to accurately assess the potency of a new third generation triazole aromatase inhibitor, letrozole (CGS 20267). We used this assay to measure estradiol levels in 14 women with metastatic breast cancer given letrozole at doses of 100 micrograms to 5.0 mg/day over a 12-week period. The lack of differences between doses and sampling times allowed pooling of data. Basal estradiol levels of 7.2 +/- 1.9 pmol/L (mean +/- SEM, 1.95 +/- 0.52 pg/mL) fell to 0.26 +/- 0.11 pmol/L (0.07 +/- 0.03 pg/mL) during the first 6 weeks of therapy and to 0.48 +/- 0.18 pmol/L (0.13 +/- 0.05 pg/mL) during the second 6 weeks of therapy. Although plasma estradiol levels measured by RIA were significantly correlated with levels measured by bioassay (r = 0.79; P < 0.01), the degree of suppression assessed by the bioassay (95 +/- 2% after 6 weeks) was greater than that determined by the RIA (81 +/- 4%), presumably due to improved ability to measure very low estradiol levels. We conclude that plasma estradiol is suppressed by letrozole to lower levels than previously observed, with equivalent suppression at all doses studied. A slight, although not statistically significant, rebound in estradiol levels occurs during the second 6 weeks of therapy compared to the first 6 weeks. Maximum inhibition of aromatase is achieved at letrozole doses as low as 100 micrograms.

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Pharmacology and pharmacokinetics of the newer generation aromatase inhibitors.

Buzdar AU.
Department of Breast Medical Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA. abuzdar@mdanderson.org

The newer generation aromatase inhibitors (AIs) as a class show efficacy and tolerability benefits over previously established treatments in postmenopausal women with advanced breast cancer. At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) are 41-48 h, 2-4 days, and 27 h, respectively. Time to steady-state plasma levels is 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have only been reported with exemestane. Anastrozole treatment has no impact on plasma lipid levels, whereas both letrozole and exemestane have an unfavorable effect. From indirect comparisons, anastrozole shows the highest degree of selectivity compared with letrozole and exemestane, in terms of a lack of effect on adrenosteroidogenesis. To date, there are no data suggesting any major differences in clinical efficacy between the newer generation AIs anastrozole and letrozole. Based on the observed pharmacological profiles, however, it cannot be assumed that the AIs will display the same tolerability and safety profiles when given for extended periods of time in the adjuvant setting. The effects of anastrozole, letrozole, and exemestane are being investigated in the adjuvant setting, and these data will elucidate the possible long-term consequences of the pharmacological effects reported after short-term exposure