Cytadren — aminoglutethimide

Aminoglutethimide is mainly identified as an inhibitor of adrenocortical steroid synthesis. Its primary function is to block the conversion of cholesterol to pregnenolone, which is required for the biosynthesis of adrenal glucocorticoids, mineralocorticoids, estrogens, and androgens. Aminoglutethimide is a nonspecific inhibitor, and also blocks several other steps in steroid synthesis including hydroxylation at C-11, C-18, and C-21, and the aromatization of androgens to estrogens. The drug may be used clinically to treat estrogen dependent breast cancer, and to treat Cushing's syndrome, which is a condition where the body overproduces the hormone cortisol. The effect that aminogluthethimide can have on cortisol and estrogen production is what makes this a drug of interest to athletes and bodybuilders.

Cortisol Inhibition

While cortisol is an essential hormone for life, its levels may also vary greatly within “normal” ranges depending on the individual, their training and dietary status, and many other personal metabolic factors. It has been a common pursuit in the sports community to find ways to control (limit) cortisol production. This is because while androgens give your muscle cells a message to increase protein synthesis, cortisol (a catabolic hormone) imparts a message to breakdown and release amino acids. If one can limit this catabolic message, net protein synthesis should, in theory, be increased. Aminoglutethimide has been used by a number of athletes and bodybuilders for this purpose, usually in combination with anabolic/androgenic steroids because it has a low level of androgen inhibition. Together with even a relatively small dose, it was thought one could shift the ratio of anabolic to catabolic hormones in favor of the former, the goal being new muscle growth. The results for this use have been mixed.

When first looked at in the realm of athletics, however, research was bare as to the best way to use aminoglutethimide as a cortisol lowering anti-catabolic. Dubbed the “adrenal escape phenomenon”, it has been noted that after a short period of regular use your body often reacts to lowered cortisol levels by increasing the release of another hormone, ACTH (adrenocorticotropic hormone). Increased ACTH could overcome the activity of aminoglutethimide, resulting in your body resuming its original levels of cortisol production (negating the benefits of cortisol inhibition). A moderate amount of hydrocortisone (20-30 mg daily) is given to patients when this occurs. This can keep glucocorticoid activity from completely diminishing, preventing the ACTH response and allowing the drug to retain its effect. For athletes, however, supplementing glucocorticoids would probably be counterproductive given the desired goal. A 2-day-on 2-day-off regime of administration was, therefore, implemented as a way to delay or even avoid the adrenal escape phenomenon. This strategy is based on theory and experimentation, however, and no clinical studies have evaluated aminiglutethimide as an anti-catabolic agent.

It is important to note that while many people believe they have used this drug as an anticatabolic, few have actually taken the correct dosage. Four tablets per day, or 1,000 mg, appears necessary to significantly inhibit the demolase enzyme (the enzyme responsible for converting cholesterol to pregnenolone, and the target when reduced cortisol is desired). Those who do venture this high commonly report fatigue and discomfort, stating that the drug is intolerable for any type of prolonged use. Today, many athletes and bodybuilders are accepting that the original proposed use of aminogluthethimide as a non-steroidal musclebuilding agent does not seem to be a plausible one. The only instances this author has really heard of this drug ever being used at such doses consistently with any type of positive response were competitive bodybuilders partaking in high-dosed Cytadren shortly before a contest. They claimed the short-term rise in androgen to corticosteroid ratio greatly aided their abilities to bring out a show-ready hard and dense physique, and credit the drug as genuinely being a very effective pre-contest agent. In speaking with the late Paul Borresen he summed up the pre-contest use of Cytadren by stating, “I have had considerable experience with the high dose use. It makes athletes sleepy and weak. It seems to help the last ten days before a show, and this is tried and tested.”

Aromatase Inhibition

Aminoglutethimide is an efficient aromatase inhibitor, and tends to inhibit the activity of this enzyme at a much lower dosage from that what is required for inhibition of corticosteroid production. While a daily dosage of 1000 mg is typically needed to inhibit cortisol, maximum suppression of aromatase and estrogen levels is typically achieved at a dosage between 250 mg and 500 mg, a point where strong adrenal steroid blockage is not noted. There also seems to be no added benefit by adding cortisol in terms of survival/response rate among breast cancer patients, pointing to the fact that the “adrenal escape phenomenon” bears little relation to its abilities as an aromatase inhibitor. Ultimately, it appears that not only do we need a higher dose (1,000 mg or 4 tablets per day minimum) to really inhibit cortisol production, but also that there is no need for an athlete to implement a rotating dose schedule if the drug is being used as an anti-estrogen.

Aminoglutethimide is usually regarded highly among athletes and bodybuilders as an estrogen maintenance agent. Studies have shown it to be capable of decreasing aromatase activity by as much as 92% after administration of 250 mg per day. Patient response rates also show aminoglutethimide to be at least as effective as tamoxifen therapy in treating estrogen dependent cancer cells, and more effective under certain conditions. Due to its discussed broad range of non-specific activity, however, including the potential inhibition of not only estrogens, but corticosteroids, aldosterone, and androgens as well, it is not regarded as highly as newer (second and third generation) aromatase inhibitors in terms of patient comfort and efficacy, and is not widely used for this purpose today. Athletes, however, still tend to consider it to be an effective remedy for estrogenic side effects like gynecomastia, increased water retention, and fat gain.

Brand name Cytadren, Aminoglutethimide, Aminoblastin, Rodazol, Mamomit, Orimeten, Orimetene

Aminoglutethimide History

Aminoglutethimide was FDA approved as an anticonvulsant drug in 1960. Side effects were common with treatment, however, including drowsiness, dizziness, and partial loss of motor control. In 1966 reports of adrenal insufficiency subsequent to aminoglutethimide use were reported. The drug was withdrawn from the U.S. market as an anticonvulsant that same year due to its recently understood effects on the adrenal gland. By 1967, however, the drug was reintroduced for a new purpose, namely inhibition of aromatase activity and the treatment of breast cancer. It was one of the first aromatase inhibitors sold, and is identified alongside testolactone as a “first-generation” agent of this type. Given its novel effects on adrenal steroid production, the U.S. FDA also granted approval for the use of aminoglutethimide for the treatment of Cushing’s syndrome.

At one time aminoglutethimide was available under numerous brand names and in more than 2-dozen countries. Ciba’s Cytadren and Orimeten preparations were by far the most common, and could be found in such nations as Argentina, Australia, Austria, Brazil, Canada, Chile, Czech Republic, France, Germany, Hong Kong, Ireland, Israel, Italy, Malaysia, Netherlands, Norway, New Zealand, Russia, South Africa, Spain, Sweden, Switzerland, United Kingdom, and the United States. Additionally, the drug could be found on occasion under other names including Aminoblastin, Rodazol, and Mamomit. The vast majority of original aminoglutethimide preparations have since been discontinued, however. Today, the drug remains available in a very small number of countries, most notably the United States (Cytadren), Russia (Mamomit), Hong Kong (Orimetene), and Australia (Cytadren).

How is Aminoglutethimide Supplied

Aminoglutethimide is most commonly supplied in tablets of 250 mg.

Structural Characteristics of Aminoglutethimide

Aminoglutethimide is an analog of glutethimide. It has the chemical designation 2-(4- Aminophenyl)-2- ethylglutarimide;3-(4-Aminophenyl)-3-ethylpiperidine- 2,6-dione.

Aminoglutethimide Side Effects

Frequent side effects associated with aminoglutethimide include fatigue, dizziness, skin rashes, fever, and nausea. Other side effects may include sleep disorder, apathy, depression, vomiting, stomach upset, thyroid dysfunction, virilization, jaundice, elevated cholesterol levels, changes in blood cell counts, and high blood pressure. Additionally, those bodybuilders and athletes taking it at a dosage high enough to promote cortisol suppression often note that reduced levels of this hormone bring about more aches and pains in the joints when trying to lift heavy weights. It seems logical that this might lead to an increased susceptibility to injury. Users should be careful not to overexert themselves during the short periods in which this drug is used in high doses. Most of the listed side effects listed here are most common with higher dosed regimens that inhibit the adrenal production of cortisol, and are less common with athletes taking one or two tablets per day as an anti-estrogen. Even in low doses aminoglutethimide may cause birth defects, and should never be taken during pregnancy.

Aminoglutethimide Administration

Aminoglutethimide is medically indicated for the treatment of Cushing’s syndrome, metastatic breast cancer in postmenopausal women, and palliative treatment in men with advanced prostate cancer. When used to treat Cushings syndrome, the dosage used may range from 1,000 mg to 2,000 mg per day, often in conjunction with 20-30 mg of hydrocortisone to avoid the aforementioned adrenal escape phenomenon.

Athletes and bodybuilders using aminoglutethimide for cortisol inhibition will commonly take a dosage of 1,000 mg per day, usually for brief periods of 2-3 weeks or less (10 days of use pre-contest is reported with some bodybuilders). A schedule of 2-days on, 2-days off may be used in an attempt to extend the effectiveness of aminoglutethimide for longer periods, but such use is usually discarded in place of daily short-term administration. The dosage most commonly used for mitigating the estrogenic side effects of anabolic/androgenic steroid use ranges from 125 mg to 500 mg per day (1/2 to 2 tablets), with 1 tablet (250 mg) per day appearing to be the most common dosage selected.

Aminoglutethimide Availability

Aminoglutethimide is produced in a small number of countries, and is a fairly expensive pharmaceutical. As such, it may sell for as much as $2 per tablet on the black market.

Bodybuilders reference

Aminoglutethimide is normally prescribed for patients with breast cancer or Cushings Syndrome. In both cases patients suffer from catastrophic physiological decline. To a profound degree this is notably due to severe over production of endogenous glucocorticoids. The one glucocorticoid most readers would be familiar with is cortisol.

Bodybuilders and strength athletes have often utilized this drug as a means of inhibiting the P-450 and aromatase enzymes. This obviously refers to inhibition of the two potential pathways in which susceptible AAS are converted into estrogens. The result of administration of aminoglutethimide is partial or complete inhibition of endogenous hormone biosynthesis. When this drug is introduced into the body it blocks the conversion of cholesterol into pregnenolone. Since this is the first step in all hormone biosynthesis: By blocking the conversion of C-19 androgens into C-15 estrogens it functions as an anti-estrogen. This is one of the obvious intents reported users had in mind. But by inhibiting the conversion of cholesterol into pregnenolone it also proportionately inhibits the endogenous biosynthesis of all hormones including androgens, estrogens, aldosterone, and cortisol. This brings the discussion to the second reason this drug use was commonly reported. Cortisol is a catabolic hormone that just loves to eat muscle tissue. In fact it is a significant part of the equation that induces genetic limitations to muscular augmentation. Many authorities and athletes alike have realized on a few facts: (1) Less cortisol = less muscle catabolism (destruction) (2) Less estrogen = less fat accumulation and less gyno resulting in a leaner physique (3) Less aldosterone = less water retention and a harder appearance. But less conversion of cholesterol into pregnenolone = less endogenous testosterone. Most noted these effects were highly desirable since the absence of natural testosterone production was abundantly replace through AAS use. And it was generally acknowledged that the absence of competing hormones had a profound synergistic effect upon those the selfadministered.

According to the available returns the average reported dosages were 500-750mg daily to inhibit excessive estrogen formation from AAS aromatization and 1000-2000mg daily for the purpose of cortisol inhibition. Most reported a scaled weekly dosage increase was most effective: Week #1 250mg 2xd, week #2 250mg 3xd, week #3 & 4 500mg 2xd.

*My personal experience with this drug was that a 2 day on – 2 day off protocol worked best with fewer negative side effects.

Of the many side effects is that the drug inhibits the body's ability to react to inflammatory responses. This means it can prevent the body from inhibiting hemorrhaging (I do hope that no one cut themselves shaving!) and fight disease among other things. It can also make a bodybuilder a victim of CUSSING SYNDROME. Other side effects include: Sore joints from a reduction in glucocorticoids, reduced white/red blood cell counts, reduced platelet counts, and liver disease.

The package insert states 2-7 250-mg tabs daily for treatment of CUSHINGS SYNDROME. CUSHINGS victims have a "much" higher cortisol/cortisone production than even the most over trained athlete. For this reason 500 mg-1000 mg daily total was considered more than enough for a chemically enhanced bodybuilder for cortisol/cortisone suppression, and 250 mg -500 mg sufficient for use as an anti-estrogen and aldosterone control drug during cycles. It was also noted that Aminoglutethmide was not be utilized for more than 4-6 weeks. At that point, the body responded by increasing production of ACTH and a whole new series of catabolic effects resulted.

Anabolic Steroid Guide reference

Cytadren is not an anabolic/androgenic steroid. Cytadren inhibits the buildup of androgens, estrogens, and the suprarenal cortical hormones (glucocorticoids and mineralocor-ticoids). Cytadren has a highly antiestrogenic effect since, on the one hand, it inhibits the body's own estrogen production and, on the other hand, it obviates the conversion of androgens into estrogens. This is especially encouraging since it helps to keep the estrogen level of bodybuilders low. The second highly interesting point is that Cytadren prohibits the buildup of adrenocortical hormones. It obviates the production of endogenous cortisone like no other compound by inhibiting the conversion of cholesterol into cortisone. For this reason, Cytadren, in school medicine, is used for the treatment of Cushing's syndrome, a hyperfunction of the adrenal glands which causes the body to overproduce cortisone. Consequently, it reduces the cortisone level, which has several advantages for the athlete. Cortisone is a cata-bolic hormone and catabolic is the exact opposite of anabolic. Cortisone prevents the protein synthesis in the muscle cell, resulting in a muscular atrophy by breaking down amino acids in the muscle cell.

The human body constantly releases cortisone and reacts to stress situations such as intense training by increasing its cortisone release. Natural bodybuilders, therefore, after a short time, experience a stagnation in their development since the release of the body's cortisone is higher than the anabolic effect of working out. The more advanced the athlete and the harder his workout, the more his cortisone level will increase.

If the release of cortisone can be successfully obviated or at least considerably reduced the ratio of anabolic hormones to catabolic hormones in the body shifts in favor of the former. This results in an increase in muscle mass and body strength. And Cytadren achieves exactly these results; however, there is one problem. Cytadren reduces the cortisone level so effectively that the body tries to balance this by hypophysially producing more ACTH (adenocorticotropic hormone), thus stimulating the secretion of cortisone by the adrenal glands. Thus in school medicine, when treating Cushing's syndrome, a low dose of oral hydrocortisone is used to prevent the hypophysis from producing ACTH. The dose is so low that the cortisone level in the blood does not rise substantially. And this is exactly the problem. Cytadren reduces the cortisone level which the body balances by producing ACTH, thus neutralizing the effect of Cytadren. If exogenous hydrocortisone is taken no ACTH is produced; however, this also reduces the effect of Cytadren. It is therefore necessary to find an administration schedule that prevents or delays the body's own production of ACTH. Since the body does not show abrupt reactions when the cortisone level is lowered by the intake of Cytadren, the compound must be taken over several days before the body begins reacting. If Cytadren is only taken for a period of two days and then discontinued for two entire days, it seems logical that the body will not have enough time to react accordingly, thus interrupting the production of ACTH in the hypophysis. Similar to Clenbuterol, an alternating administration schedule with two days of administration and two days of abstinence is created. Another problem needs to be solved since Cytadren, as mentioned earlier, inhibits the body's own production of androgen. Cytadren, therefore, should not be used by natural bodybuilders. The solution to this problem is to take a long-term effective testosterone such as Testosterone enanthate simultaneously. Testoviron Depot 250, for example, can be considered as one such possible compound.

As for the question of dosage, we have arrived at a very interesting point. In school medicine the dosage for the treatment of Cushing's syndrome is between 2 and 7 tablets per day. Since not enough athletes have used this compound so far, we do not have enough experimental data. Due to the fact that the cortisone level of athletes is not as high as in persons who suffer from a hyperfunction of the adrenal glands, it is probable that lower dosages are sufficient. A dose of mor than 250mg/day is not recommended and should be taken very carefully. A good example of dose is: half a tab 125mg in the morning and 62.5mg (quarter tab) every six hours. Make sure to not abruptly discontinure as cortisol rebound may occur. The tablets are always taken individually, in regular intervals throughout the day, and taken best during meals. How long should it be taken? This question is difficult to answer but, considering that the body can some-times increase the production of ACTH, it is advised that the compound is not used longer than 4-6 weeks. (We must also consider potential side effects, which we will discuss in a minute.) Another interesting aspect: Cytadren is (as of yet) not on any doping list. We have heard from reliable informants that a combination of Cytadren, growth hormones, and a low quantity of injectable testosterone is the new hit among athletes of any field, since it allows the athlete to pass any doping test.

Thus the side effects of Cytadren need to be looked at and they are, unfortunately, numerous and sometimes very severe. The most common side effects are fatigue and dizziness. Lack of concentration, restlessness, depression, apathy, and sleeping disorder are less common but possible. Even rarer and mostly depending on the doses are nausea, vomiting, gastrointestinal pain, diarrhea, and headaches. A possible rash and the already mentioned fatigue and dizziness are usually initial symptoms and these can be minimized by taking slowly increasing dosages, or they may simply disappear. The package insert of Ciba-Geigy GmbH Germany also states that in some cases there is an inadequate thyroid function which requires treatment. It is therefore recommended that the thyroid gland be supervised by a physician during intake of Cytadren. Another problem that can occur is liver disease. Cases of reduced counts of the white blood cells, the blood platelets, and even of all blood cells have been reported. Those who plan to try Cytadren should carefully read the package insert. It has been our experience that athletes, due to the reduced cortisone level, complain about joint pain and are also exposed to a higher risk of getting injured. There is no question that Cytadren is effective when taken according to the two-day alternating administration schedule; however, the athlete should carefully consider the cost/benefit factor prior to taking the compound. Cytadren is in U.S. pharmacies only available by prescription. A package with 100 tablets of 250 mg each costs $190, so that Cytadren is not a budget-priced compound. Each package contains 10 push-through strips of 10 tablets each. The tablets are indented on one side with an imprinted "G" on both the right and left of the breakage line. On the other side of the tablet the letters "CG" are punched in. Cytadren is rarely found on the black market.

Newbies Research Guide reference

Aminoglutethimide is another of the earliest to be developed aromatase inhibitors, and was also the first drug to gain widespread acceptance for this purpose. Like testolactone, it was also made available as a prescription drug long before its mechanism of action was fully understood. In fact it has quite an interesting history. This compound, a derivative of the hypnotic glutethimide, was first sold in the United States as an anticonvulsant medication in 1960. By 1966 howev- er, adrenal insufficiency was being reported in patients taking the drug and it was soon taken off of the market. Studies began looking at this compound in a new light not long after though, eventually warranting its return to the market. Aminoglutethimide ultimately came to be of the most prescribed and researched aromatase inhibitors available. Its effect on cortisol secretion also makes it an effective treatment for an illness such as Cushing’s syndrome, where the body over produces cortisol.

Developing a proper dosage regimen for aminoglutethimide has also proven to be a confusing process. When first being applied to patients it was shown to be only transiently effective at lowering inhibiting adrenal steroid secretion (typically lasting for only for 3-7 days). Dubbed the adrenal escape phenomenon, it was shown that the body would notice the lowered output of cortisol, and triggers the heightened release of ACTH (adrenocorticotropic hormone) in response. This restores the normal release of adrenal steroids and nullifies the effect of aminoglutethimide. Clinically a small dose of hydrocortisone (40mg) is used to avoid this response, which for some time had also been the accepted practice for use in breast cancer treatment.

In later studies however, we find that the main mechanism in which this drug benefits breast cancer patients (inhibition of peripheral aromatase activity) is differ- ent from that which interferes with adrenal hormones. We also see that the dosage was important in triggering each particular response. It appears that aro- matase inhibition is achieved at a much lower dose than is needed to block steroid production by the adrenal gland. While a daily dosage of 1000mg is typi- cally needed to inhibit the demolase enzyme (the enzyme responsible for converting cholesterol to pregnenolone, and the target when reduced adrenal output is needed), maximum suppression of aromatase and estrogen levels is achieved at a dosage between 250 and 500mg (a point where adrenal steroid block- age should not be noted). There also seems to be no added benefit by adding cortisol in terms of survival/response rate among patients, and subsequently there is need to supplement cortisol when taking this drug for the purposes of inhibiting aromatase (nor for the athlete to implement a rotating dose schedule). Another suggested athletic use however remains to be that of an anti-catabolic, which is discussion in of itself.

In effectiveness this compound rates highly, with aromatase activity shown to decrease as much as 92% after administration of only 250mg. Patient response studies also show aminoglutethimide to be at least as effective as tamoxifen therapy in treating estrogen dependent cancer cells, more so under certain condi- tions. However, due to its discussed broad range of activity, including the potential inhibition of not only cortisol and estrogens but also aldosterone and andro- gens as well, it is not regarded as highly in terms of patient comfort. This is not to give the impression that complaints are very common though, as aminog- lutethimide still has an extremely good safety record. Athletes can likewise consider it to be an extremely effective remedy for estrogenic side effects should it be available on the black market, at least as much so as Nolvadex.

References

Wlliam Llewellyn (2011) - Anabolics
L. Rea (2002) - Chemical Muscle Enhancement Bodybuilders Desk Reference
Anabolic Steroid Guide
Newbies Research Guide

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