Why Formestane is needed.

This helps show its efficiacy at preventing estrogen and prolactin. http://www.ncbi.nlm.nih.gov/pubmed/20491779
“In cells which expressed ERalpha, formestane/herceptin combination suppressed the mRNA expression of aromatase and HER2 and decreased cyclin D1 expression”
So you know HER2 is to do with prolactin expression. Formastat(tm) contains the suicide aromatase inhibitor formestane (4-hydroxyandrostenedione), a clinically proven anti-estrogen exceedingly more potent than any supplement to come before it. 6-oxo-androstenedione, chrysin, indole-3-carbinol, calcium d-glucarate, trihydroxystilbene, not even our old Viratase (5-alpha-androstanedione) can come close. All of them combined in one capsule still wouldn’t even have a shot. Formastat(tm) is such a revolutionary advance in the area of estrogen suppression because it contains the only agent backed by not one but numerous placebo-controlled human medical studies, and so effective it is actually a prescription breast cancer drug in other countries.

Formestane (4-hydroxyandrostenedione)
Suicide Aromatase Inhibitor
Formastat is in many regards similar to a competitive steroidal aromatase inhibitor like Viratase. Both are steroidal compounds that work by attaching to the active binding site of the aromatase enzyme, preventing it from interacting with other steroids (such as testosterone) that are capable of being converted to estrogen. With the enzyme binding site occupied, it is for all intents and purposes inactive. If the inhibitor is present in a high enough level it will dramatically suppress estrogen concentrations in the blood. The difference between a competitive inhibitor like Viratase, and Formastat, is that the former will detach after some time, rendering the enzyme active again. Formastat on the other hand binds permanently with the aromatase enzyme, making it useless until the body actually replaces it through the normal metabolic attrition of enzymes. This type of compound is called a suicide or irreversible aromatase inhibitor, and has the benefit of being both highly selective in its action on estrogen and long-lasting in effect.
Because of its potent estrogen-suppressing action, 4-hydroxyandrostenedione has been successfully used on breast cancer patients in many other countries including England, Germany, Switzerland, Spain, Australia, New Zealand, Italy and Malaysia12345678 It has been shown to be an effective option as a second line of defense after tamoxifen, an estrogen receptor antagonist, has failed to elicit a positive response with patients, and to produce an overall response statistically similar to tamoxifen when administered as the first-line therapy . Those of us in the bodybuilding world looking to mitigate the physiological effects of estrogen for other purposes have likewise been confronted for the first time with a legal supplement that has all the actions and potency of a pharmaceutical agent, which would normally be obtained only with a doctor’s prescription! .
Dose and Pharmacokinetics
After oral administration peak levels of 4-hydroxyandrostenedione are reached in the blood at approximately 1.5 hours , and the drug is cleared from the body with a half-life of approximately 3 hours . Due to its nature as an irreversible inhibitor, its estrogen-suppressing activity outlives it actual active lifespan in the bloodstream. Studies have demonstrated that maximum estrogen suppression is achieved with an oral dose of only 250mg per day12 . Doubling this dose to 500mg, or even quadrupling it to 1000mg, was shown to have no effect on aromatase inhibition or estrogen levels appreciably different from the 250mg dose.
The Need for Estrogen Maintenance
Estrogen has both positive and negative effects that you should be aware of. On the positive it supports good high density cholesterol, increases muscle glucose utilization for tissue growth and repair, and even increases androgen receptor concentrations in various tissues. It is now understood that estrogen serves many useful purposes in men, particularly if we are looking for rapid muscle mass gain. If bulk is the goal it is therefore usually advised to hold off on estrogen maintenance compounds until there is a clear need for them. This brings us to the negative side of estrogen, namely that it can work to hide muscle definition by increasing water retention and fat buildup. It can also promote gynecomastia (the development of female breast tissue) in men if levels get too high. Since androgens and estrogens playing opposing roles on the disposition of body fat and the growth of mammary tissues, maximizing the ratio between these two hormones is often an important objective, particularly at times when dieting and cutting are key goals or gynecomastia is a worry because strongly aromatized hormones such as testosterone are being supplemented.
Testosterone Stimulation
To spite that fact that 4-hydroxyandrostenedione is also a weak prohormone to the anabolic steroid 4-hydroxytestosterone, as an aromatase inhibitor it also possesses notable testosterone stimulating properties. Whatever weak androgenic activity it may have is more than compensated for by its strong ability to lower estrogen levels. This action of course reduces the suppressive signal estrogen sends to your brain (estrogen is a main feedback signal to control the release of testosterone), increasing the testicular output of testosterone. In-vivo human studies show clearly that 4-hydroxyandrostenedione will suppress estrogen concentrations at levels that were not high enough to suppress gonadotropins13 . Even studies using 250mg to 500mg of 4-hydroxyandrostenedione injected every 2 weeks, or oral doses as high as 1000mg daily, have failed to show any notable suppressive effect towards testosterone concentrations14 . When the drug was given to men, including oral doses as high as 500mg (double the maximum recommended dose), we have seen measurable increases in serum testosterone concentrations 15 16 17. Due to the theoretical potential for androgenic feedback inhibition at high doses we do recommend, however, keeping within the recommended dosage range, and perhaps even limiting the dose to 2-3 caps per day, at times when increasing testosterone levels is a primary focus of use.

Figure 1. Mean testosterone increase in 6 normal men given 500mg of oral 4-hydroxyandrostenedione. Source: Comparison of the pharmacokinetics and pharmacodynamics of unformulated and formulated 4-hydroxyandrostenedione taken orally by healthy men. Cancer Chemother Pharmacol 1990;27(1):67-71
Post-Cycle Use
When used during the recovery window after a cycle of prohormones, or even steroids for that matter, Formastat can offer a very unique additional benefit. The main focus at this time is of course minimizing the post-cycle hypoandrogenic (low androgen) state, mainly by trying to restore the natural production of testosterone, which in many cases has been suppressed by the cycle of hormones. In most cases some type of anti-estrogen is incorporated into an athlete’s recovery program, due to the effect they can have on testosterone release (discussed above). Because Formastat is also a prohormone to 4-hydroxytestosterone, however, it allows for some small level of continued supplementation of exogenous androgen during this window. Normally this would be considered a very bad idea, as androgens are usually suppressive towards testosterone release. But with this product its weak androgenic activity is compensated for by its estrogen suppressing action, so provided reasonable doses are used it can essentially serve as a small bridge to full testosterone recovery. Regular aromatase-inhibitors, of course, cannot offer this benefit.
searl and bell formestat research Cancer Chemother Pharmacol 1990;27(1):99-130
DHT Inhibition
This compound has also demonstrated some ability to inhibit the 5-alpha reductase enzyme in certain in-vitro studies , which would seem to suggest it could offer some benefit by reducing androgenic activity in sensitive target tissues with high concentrations of 5-alpha reductase. At least one study in Scotland, however, suggests that this trait of 4-hydroxyandrostenedione is not strong enough to offer much of a physiological effect . Another makes note of both testosterone and DHT increases in some male patients taking the compound, not testosterone alone, which clearly does not support a strong DHT inhibiting role . We therefore at this time do not have enough evidence to conclude that 4-hydroxyandrostenedione is a potent 5-alpha-reductase inhibiting compound, however will continue to investigate this possible activity.
The Need for Estrogen Maintenance
Estrogen has both positive and negative effects that you should be aware of. On the positive it supports good high density cholesterol, enhances growth hormone output, increases muscle glucose utilization for tissue growth and repair, and even increases androgen receptor concentrations in various tissues. It is now understood that estrogen serves many useful purposes in men, particularly if we are looking for rapid muscle mass gain. If bulk is the goal it is therefore usually advised to hold off on estrogen maintenance compounds until there is a clear need for them. This brings us to the negative side of estrogen, namely that it can work to hide muscle definition by increasing water retention and fat buildup. It can also promote gynecomastia (the development of female breast tissue) in men if levels get too high. Since androgens and estrogens playing opposing roles on the disposition of body fat and the growth of mammary tissues, maximizing the ratio between these two hormones is often an important objective, particularly at times when dieting and cutting are key goals or gynecomastia is a worry because strongly aromatized hormones such as testosterone are being supplemented.
A Naturally Occurring Hormone
4-hydroxylated androgens such as 4-hydroxyandrostenedione have been shown to be naturally occurring, and therefore can be legally sold as nutritional supplements.
REFERENCES:
1 Treatment of advanced breast cancer with formestane. Murray R, Pitt P. Ann Oncol 1994;5 Suppl 7:S11-3
2 Pilot study of formestane in postmenopausal women with breast cancer. Joseph JK, Lim AK. Med J Malaysia 1998 Mar;53(1):37-41
3 Formestane is feasible and effective in elderly breast cancer patients with comorbidity and disability. Venturino A, Comandini D. Breast Cancer Res Treat 2000 Aug;62(3):217-22
4 Formestane versus megestrol acetate in postmenopausal breast cancer patients after failure of tamoxifen: a phase III prospective randomised cross over trial of second-line hormonal treatment (SAKK 20/90). Swiss Group for Clinical Cancer Research (SAKK). Thurlimann B, Castiglione M. Eur J Cancer 1997 Jun;33(7):1017-24
5 Formestane in the treatment of advanced postmenopausal breast cancer. Possinger K, Jonat W, Hoffken K. Ann Oncol 1994;5 Suppl 7:S7-10
6 Comparison of the selective aromatase inhibitor formestane with tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer. Perez Carrion R, Alberola Candel V. Ann Oncol 1994;5 Suppl 7:S19-24
7 An endocrine and pharmacokinetic study of four oral doses of formestane in postmenopausal breast cancer patients. Dowsett M, Mehta A. et al. Eur J Cancer 1992;28(2-3):415-20
8 Formestane is feasible and effective in elderly breast cancer patients with comorbidity and disability. Venturino A, Comandini D. et al. Breast Cancer Res Treat 2000 Aug;62(3):217-22
9 Formestane. A review of its pharmacological properties and clinical efficacy in the treatment of postmenopausal breast cancer. Wiseman LR, Goa KL. Drugs Aging 1996 Oct;9(4):292-306
10 Comparison of the pharmacokinetics and pharmacodynamics of unformulated and formulated 4-hydroxyandrostenedione taken orally by healthy men. Dowsett M, Lloyd P. Cancer Chemother Pharmacol 1990;27(1):67-71
11 Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients. Dowsett M, Cunningham DC et al. Cancer Res 1989 Mar 1;49(5):1306-12
12 An endocrine and pharmacokinetic study of four oral doses of formestane in postmenopausal breast cancer patients. Dowsett M, Mehta A, King N, Smith IE, Powles TJ, Stein RC, Coombes RC. Eur J Cancer 1992;28(2-3):415-20
13 Aromatase inhibitors and hormone-dependent cancers. Brodie AM, Banks PK, Inkster SE, Dowsett M, Coombes RC. J Steroid Biochem Mol Biol 1990 Nov 20;37(3):327-33
14 Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients. Dowsett M, Cunningham DC et al. Cancer Res 1989 Mar 1;49(5):1306-12
15 Aromatase inhibition: 4-hydroxyandrostenedione (4-OHA, CGP 32349) in advanced prostatic cancer. Davies JH, Dowsett M, Jacobs S, Coombes RC, Hedley A, Shearer RJ. Br J Cancer 1992 Jul;66(1):139-42
16 Comparison of the pharmacokinetics and pharmacodynamics of unformulated and formulated 4-hydroxyandrostenedione taken orally by healthy men. Dowsett M, Lloyd P. Cancer Chemother Pharmacol 1990;27(1):67-71
17 Pharmacokinetics of 4-hydroxyandrostenedione in man after intramuscular injection of different formulations and the effect of this drug on plasma aromatizable androgens and 17beta-estradiol concentrations. Danza G, Muratori M, Guarna A, Occhiato EG, Sadri R, Serio M. J Steroid Biochem Mol Biol 1993 Sep;46(3):373-9
18 Aromatase and other inhibitors in breast and prostatic cancer. Brodie AM, Banks PK, Inkster SE, Son C, Koos RD. Steroid Biochem Mol Biol 1990 Dec 20;37(6):1043-8
19 Effects of 4-hydroxyandrost-4-ene-3,17-dione and its metabolites on 5 alpha-reductase activity and the androgen receptor. Davies JH, Shearer RJ et al. J Enzyme Inhib 1992;6(2):141-7
20 A kinetic analysis of the inhibition of human prostatic 5 alpha-reductase by 4-hydroxyandrostenedione and related steroids. Houston B, Habib FK Steroids 1988 Sep;52(3):237-47
21 Aromatase inhibition: 4-hydroxyandrostenedione (4-OHA, CGP 32349) in advanced prostatic cancer. Davies JH, Dowsett M. Br J Cancer 1992 Jul;66(1):139-42
22 Sexual specific C-4 hydroxylation of 5 -androstane-3,17-dione in rats and the influence of the antiandrogen cyproteron acetate. Wenzel M, Pitzel L, Bollert B. Hoppe Seylers Z Physiol Chem 1972 Jun;353(6):861-8

Relative Potency of Type 1 and Type 2 Aromatase Inhibitors

Product

Aromatase Inhibition (%)

Residual Aromatase (%)

Formestane/

4-Androstenoldione

91.9

8.1

Aromasin/Exemestane

97.9

2.1

Cytadren/

Aminoglutethimide

90.6

9.4

Arimidex/Anastrozole

96.7

3.1

Femara/Letrozole

98.7

1.3

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