The Marathon Man Of Testosterone Esters
Dan Gwartney, MD
Put aside the questions of ethics, as well as any arguments of health benefits or health concerns; in the end, steroid use is a pain in the rear- literally. Most anabolic steroid (AAS) users include injectable versions of testosterone, nandrolone and/or some other AAS in their stacks, as injectables are more consistent in maintaining androgenic concentrations, generally less expensive and less toxic.1 AAS are made suitable for injection through a variety of chemical modifications- the most commonly encountered being 17£]-esterification. Esterification is a chemical term that describes the bonding (chemical attachment) of an acid to an alcohol group. In the case of AAS, the esterification describes the attachment of a fatty acid to the hydroxyl (alcohol) group on the 17th carbon.
Was that confusing? It should have been to anyone without some exposure to organic chemistry or those self-educated in the structure of AAS. Many users take AAS chemistry for granted without realizing the drugs are elegantly designed and each has characteristics that make it better or worse for certain uses. In more basic terms, injectable AAS are chemically changed in order to develop a drug that is better suited for clinical use. Most are esterified, which is the term used when a long-chain fatty acid is attached. Pharmaceutical chemists esterify AAS so they release more slowly, allowing the drug to be active for a longer period. In general, the longer the fatty acid attached, the slower the release.2
Esterification has proven to be very beneficial in therapeutic use, as testosterone and related drugs would otherwise be cleared from the system within hours if injected in their normal form. Of course, some athletes competing in drug-tested organizations use this fact to their advantage in order to defeat certain drug screens- they use nonesterified or short-chain testosterone esters (like testosterone acetate), which are quickly flushed from the system. Anti-doping agencies have managed to catch up to this strategy by analyzing testosterone at the atomic level, looking at isotope ratios.3 Again, this is a very sophisticated technique that very few people understand unless they have been fortunate enough to have studied chemistry. For the noncompetitive athlete, or those who compete in organizations that do not test for or ban AAS, longer acting esters offer a number of advantages, including: less fluctuation (highs and lows) of serum (blood) testosterone concentrations, longer intervals between injections and more reliable anabolic response. Of course, there are some disadvantages to long-acting esters, as chemical karma always seems to require some tradeoff. Longer acting esters take longer to reach an anabolic concentration, are slower to clear the system, suppress natural testosterone production longer and contain less active component (testosterone) than short-chain esters by weight- for example, testosterone acetate is 87 percent testosterone, testosterone enanthate is 72 percent testosterone and testosterone undecanoate is 61 percent testosterone. Thus, 200mg of testosterone acetate provides 42 percent more testosterone (174mg) than the same amount of testosterone undecanoate (122mg).
Clearly, use of long-chain esters needs to be limited to long-term use in order to allow therapeutic (or anabolic) levels to accumulate. This is similar to the situation encountered with some familiar with AAS, such as nandrolone decanoate (Deca) and boldenone undecanoate (Equipoise). These AAS do not provide the rapid mass gains seen with orals or short-chain esters (acetate, propionate, etc.), in part because they are long-chain esters. Many users, accustomed to short six-to-eight-week cycles will report dissatisfaction with Deca or Equipoise, especially if they taper, due to the slow release. Post-cycle recovery is also much different with these drugs, as their suppressive effect persists for months in some cases, making it important to properly time hCG, Clomid or other drugs to restore natural testosterone production. Similar experiences can be expected with testosterone undecanoate. Finally, there is also greater difficulty in managing any adverse effect that might arise (irritability, hypomania, anger, aggression, gynecomastia, acne, hair loss, obstruction of the urine stream due to prostate growth, etc.), as elevated androgen levels will persist for weeks.
However, in the balance of things, there is a growing support for long-chain esters, especially in the clinical world. Testosterone is actually used by some medical doctors legitimately, though the media would have the public believe quacks, rogues, madmen and medical mercenaries only prescribe the drug. A paper was recently published in the Asian Journal of Andrology describing the experiences of a group of physicians in Germany using the drug testosterone undecanoate for over eight years in men with low testosterone.4 In the article, the authors compared testosterone undecanoate to the more commonly encountered testosterone enanthate and found it to be equivalent or superior in all aspects. Numerous other reports of long-term use were referred to in the article, supporting the findings of the German clinicians.5-8
The crux of the advantage of testosterone undecanoate over all other forms of testosterone replacement relates to its ability to provide stable concentrations over an extended period of time (up to 14 weeks in some cases) without causing users to experience extreme highs and lows. Interestingly, it was noted that many patients were able to "feel" when their concentrations became low, allowing the clinicians to tailor the injection schedule to the individual.9 This is particularly interesting when one considers that testosterone levels drop so gradually when using testosterone undecanoate that day-to-day changes are very small. This suggests that individuals are able to somehow detect when a threshold minimum concentration is passed, instigating the request for additional dosing. There were no reports of patients requesting more frequent or higher dosing, which would be seen if habituation occurred. Habituation is a trait seen in addictive drug use, when a higher dose or more frequent use is required to satisfy the addict's cravings; habituation has been suggested to exist with AAS use. The absence of such behavior over eight years supports the suggestion that testosterone undecanoate can be used successfully in a properly supervised, clinical setting.
The German clinicians found that 1,000mg of testosterone undecanoate (4ml at 250mg/ml) injected six weeks apart for the first two treatments and then every 12 weeks thereafter provided most patients with satisfactory response. Certain patients did display quicker testosterone clearance and were given their maintenance doses every 10 weeks.4 Serum testosterone concentrations did tend to peak the first two weeks after injections, occasionally exceeding the upper limits of normal for a brief period, but otherwise they were maintained in the normal range for the entire course of treatment. It has been noted that larger volume injections decreases bioavailability and the article stated that a single, 4ml injection was given- so it is possible that dividing the dosing into two injections of 2ml (one shot for each glute) would provide a greater maximal concentration and prolong the effect...a consideration for a bodybuilder who would likely be seeking a supraphysiologic dose.10
An issue often raised against the use of testosterone is the risk of side effects. Testosterone undecanoate, used for testosterone replacement, was found to be safe and adverse side effects were minimal. In fact, the authors stated, "No major adverse effects were encountered in the clinical trials of testosterone undecanoate.4 This is not surprising, as the pharmaceutically active component is testosterone itself." DHT and estradiol (an estrogen) levels were normal throughout treatment; gynecomastia, breast tenderness and acne were only reported in a minority of patients. However, earlier trials did have a higher incidence of these symptoms when more frequent dosing led to supraphysiologic testosterone concentrations, as would be expected with any testosterone preparation.4 Prostate growth was noted early on in the patients, but it stabilized during treatment and remained within normal range. This was expected, as the men were selected from a group that had low testosterone to begin with and presented with undersized prostates collectively. None of the men showed a change in urine flow during treatment.4
Another side effect noted in a minority of the men was an increase in hematocrit (a measure of how much of your blood is red blood cells as opposed to fluid) above 52 percent.4 Though this does not sound threatening, and some athletes such as competitive cyclists use hyperbaric chambers, erythropoietin and steroids to increase their hematocrit (a higher hematocrit delivers more oxygen to working muscles); a high hematocrit increases the risk of blood clots that can cause strokes, heart attacks and other life-threatening conditions.11 The risk of any adverse health effect and the need to individually tailor the drug administration schedule argues strongly for testosterone undecanoate to be dispensed by a knowledgeable health practitioner.
The benefits noted during testosterone undecanoate treatment were noteworthy. Many of the subjects reported better mood, greater sexual interest and a reduction in fatigue.5,12 There was a drop in "good" cholesterol (HDL), but it was of the same or lesser magnitude of decrease seen with total cholesterol, "bad" cholesterol (LDL) and triglycerides. Similar changes were reported in another report discussing long-term treatment with testosterone undecanoate, with the exception that there was a slight increase in the "good" cholesterol.13,14 Thus, it would appear, at least when used as hormone replacement, that testosterone undecanoate does not worsen the lipid (cholesterol and fats) profile and may even improve it slightly.13 The lipid profile provides some indication of a person's risk of a future heart attack or stroke.
Some of the most successful new drugs, relative to market sales, have been those treating erectile dysfunction, such as Viagra and Levitra. Yet, the positive effect testosterone has on erectile function has long been ignored. In part, this may be due to the fact that it would be difficult to profit from testosterone-based drugs, since there would be no patent protection; the politico-legal environment also discourages developing uses of this inexpensive treatment. However, it is still worthwhile to note that not only does testosterone improve erectile function in hypogonadal men- thankfully, since sexual desire and arousal is increased with testosterone use- but it works in many men who cannot achieve an erection with Viagra or similar drugs.15 Studies report that approximately half of all men with erectile dysfunction achieve normal erectile function within 12-24 weeks when treated with testosterone.16
Of course, this increase in sexual urges and ability could restore the hope for parenting for some, or increase the risk of an unplanned pregnancy for others. Depending upon one's outlook, testosterone undecanoate may hold an additional side effect or benefit. Studies among East Asian men showed testosterone undecanoate to be more effective than condom use in preventing unplanned pregnancies due to the suppression of spermatogenesis (creation of sperm).17 However, men should be cautioned that condom use is still necessary to reduce the transmission of most sexually transmitted diseases.
Unfortunately, the ability of testosterone undecanoate to induce infertility (no sperm produced, or azoospermia) is weaker among Caucasian men, with only 60 percent achieving azoospermia when dosed every six weeks.18 Companies are developing combination products, using long-acting testosterone preparation along with progestins (a type of hormone found in women's birth control pills) to make a suitable, long-acting contraceptive for men.18 Though many AAS users may become sterile while using testosterone undecanoate, it is not certain enough to guarantee against an unplanned pregnancy.
The question remains then, what about testosterone undecanoate as an AAS, not a contraceptive or hormone replacement? One study looked at the effect of testosterone undecanoate in healthy, normal, young men. As noted before, testosterone concentrations peaked the first two weeks after injection (reaching supraphysiologic levels in many subjects), increasing anger/hostility slightly, but with no increase in violence, aggressive or sexual behavior.12 Within four weeks, testosterone levels had returned to normal values in the test subjects. LH, the pituitary hormone that signals testosterone production by the testes, was quickly suppressed after the injection but rose gradually to maintain testosterone values near normal throughout the 12-week study. Thus, it appears that testosterone undecanoate may clear gradually enough that most users may be able to cycle off without requiring the use of Clomid or hCG. Being able to avoid the near-inevitable loss of muscle mass and onset of fatigue and mild depression that often accompanies AAS withdrawal at the end of a cycle would be very valuable.
The use of testosterone has been shamed into the shadows due to the ostracization by the media and its affiliation with sports doping. This has impeded research severely, to the detriment of AAS users and society who could benefit from many of the positive effects of testosterone treatment. Testosterone undecanoate appears to offer many benefits over traditional forms of testosterone by providing more reliable and sustained concentrations. Despite being used safely for nearly a decade in many patients receiving the drug for replacement, testosterone undecanoate is not without risk. However, most of the risks are dose-related, occurring most frequently when testosterone concentrations exceed the normal range. Unfortunately, this is exactly where many users would prefer to dose the drug. Though it is unlikely that clinicians will have the latitude to provide any AAS for anabolic purposes in healthy men, the authors of the German report agreed with earlier comments that testosterone therapy must be tailored to the needs and expectations of the individual. Considering the broad range of "normal" for serum testosterone concentrations, it is possible that many men may benefit from maintaining testosterone concentrations nearer to the upper limit of normal.
For the purpose of hormone replacement, testosterone undecanoate seems nearly ideal, allowing the patient to be dosed just four times a year, which would allow his physician to perform a brief physical and some lab tests to ensure that no adverse effects are being experienced. For the athlete or bodybuilder, it also holds a great deal of value. Considering that above-normal levels were experienced in healthy young men for four weeks after being injected with 1,000mg of testosterone undecanoate, it is conceivable that an anabolic cycle could be achieved with monthly, or less frequent, injections. Indeed, a separate study performed in Italy showed that men who received 1,000mg of testosterone undecanoate (for the purpose of contraception) every eight weeks experienced a linear increase in testosterone concentration over time.18 This means that testosterone concentration accumulated, as each "booster" shot was given before the full amount of the previous dose had cleared. Not only would this relieve a user from twice-weekly injections, as is standard with most AAS, but the prolonged release may allow a user to return to normal testicular function without relying upon Clomid or hCG.
Clearly, there is much yet to be learned about the use of testosterone undecanoate in healthy young men. However, as research continues in its use as a contraceptive and possibly as adjunct therapy in erectile dysfunction, common knowledge about this drug is certain to grow.
What About The Beans?
Many people became aware of a relatively new steroid during the BALCO scandal and media coverage related to Major League Baseball star Barry Bonds. They are called "beans," "beanies" or "Mexican beans" in gym slang because of their appearance- small, brown gelcaps containing the steroid Andriol (testosterone undecanoate)- and have reportedly been used by many athletes. However, real-world encounters with individuals who have used Andriol or other brands of testosterone undecanoate gelcaps are very limited. The reasons for this are high cost and low effectiveness.
Certainly, for a professional athlete, the cost is marginal and the addition of a quickly clearing oral steroid to stack with products like the "Clear" and the "Cream" might be enticing in such a situation. However, the average user finds Andriol offers very little bang for the buck. Bill Llewellyn reports in his book Anabolics 2005 that users find no anabolic effect using doses less than 240mg per day and gains are modest, even with higher doses. This compares very poorly to classic orals, which are mildly effective in the 10-20mg/day range and many are quite potent at doses less than 60mg/day.
At first, this is quite confusing, because the active ingredient in Andriol is testosterone. The long-chain ester undecanoate allows the drug to be absorbed through the lymphatic system, which is a separate circulation that does not pass through the liver. This preserves the steroid, as the enzymes that normally detoxify drugs before they enter the circulating bloodstream do not metabolize it. Thus, one would think that getting approximately 150+ mg of testosterone daily would lead to tremendous gains. After all, many recreational bodybuilders are quite satisfied with the gains achieved using 400mg per week of injectable testosterone esters. The problem, it appears, is that oral delivery of testosterone undecanoate is very inefficient.
Early studies showed that only trace amounts of testosterone undecanoate were absorbed after a single oral dose. Approximately 5 percent of the dose was considered to be bioavailable, meaning that each capsule is the equivalent of 2mg of testosterone. This would be in keeping with the observations many men report of seeing no results with less than six capsules (240mg), as this would basically replace the normal daily production of testosterone from the testes. Also, the clearance of the drug is quite rapid, so it is likely that if the dose is taken all at once, that mental and emotional effects might be noted, but anabolic effects may not be sustained, as the elevation in testosterone is not maintained.
A study in 2003 demonstrated that taking the gelcaps with a meal greatly increased absorption. In fact, compared to taking the drug on an empty stomach, nearly 10 times as much testosterone was delivered. Just recently, another study reported that the composition of the meal makes a difference as well. Higher fat meals increase the absorption of testosterone undecanoate, allowing nearly five times as much to become bioavailable. Thus, compared to taking the drug on an empty stomach, it would appear that taking testosterone undecanoate gelcaps with a fatty meal (19 grams of fat or greater) increases the effectiveness of the drug greatly.
Clinically, this would be very important, but most sophisticated bodybuilders were already aware of this and still found the effectiveness of this drug to be lacking. While the design of the drug is quite elegant and allows for the oral delivery of testosterone without resorting to 17Éø-alkylation, which is known to cause liver stress and subsequent damage, it provides little for the purposes of enhancing muscular size or strength.
References:
Llewellyn W. Andriol (testosterone undecanoate). Anabolics 2005. Body of Science Press, Jupiter, FL, 2005:100-2.
Tauber U, Schroder K, et al. Absolute bioavailability of testosterone after oral administration of testosterone-undecanoate and testosterone. Eur J Drug Metab Pharmacokinet, 1986;11:145-9.
Bagchus WM, Hust R, et al. Important effect of food on the bioavailability of oral testosterone undecanoate. Pharmacotherapy, 2003;23:319-25.
Schnabel PG, Bagchus W, et al. The effect of food composition on serum testosterone levels after oral administration of Andriol Testocaps. Clin Endocrinol, 2007;66:579-85.
References:
1. Parkinson AB, Evans N. Anabolic androgenic steroids: a survey of 500 users. Med Sci Sports Exerc, 2006;38:644-51.
2. Llewellyn W. Synthetic AAS Development. Anabolics 2005. Body of Science Press, Jupiter, FL;2005:20-24.
3. Cawley AT, Kazlauskas R, et al. Isotopic fractionation of endogenous anabolic androgenic steroids and its relationship to doping control in sports. J Chromatagr Sci, 2005;43:32-8.
4. Saad F, Kamischke A, et al. More than eight years' hands-on experience with the novel long-acting parenteral testosterone undecanoate. Asian J Androl, 2007;9:291-7.
5. Von Eckardstein S, Nieschlag E. Treatment of male hypogonadism with testosterone undecanoate injected at extended intervals of 12 weeks: a phase II study. J Androl, 2002;23:419-25.
6. Morales A, Nieschlag E, et al. Clinical experience with the new long-acting injectable testosterone undecanoate. Report on the educational symposium on the occasion of the 5th World Congress on the Aging Male, 9-12 February 2006, Salzburg, Austria. Aging Male, 2006;9:221-7.
7. Zitzmann M, Nieschlag E. Long term experience of more than 8 years with a novel formulation of testosterone undecanoate (Nebido) in substitution therapy of hypogonadal men. Aging Male, 2006;9:5 (abstract).
8. Schubert M, Minnemann T, et al. Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism. J Clin Endocrinol Metab, 2004:89:5429-34.
9. Zitzmann M, Faber S, et al. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab, 2006;90:4335-43.
10. Minto CF, Howe C, et al. Pharmacokinetics and pharmacodynamics of nandrolone esters in oil vehicle: effects of ester, injection site and injection volume. J Pharm Exp Ther, 1997;281:93-102.
11. Barbui T, Finazzi G. Therapy for polycythemia vera and essential thrombocythemia is driven by the cardiovascular risk. Semin Thromb Hemost, 2007;33:321-9.
12. O'Connor DB, Archer J, et al. Effects of testosterone on mood, aggression and sexual behavior in young men: a double-blind, placebo-controlled, cross-over study. J Clin Endocrinol Metab, 2004;89:2837-45.
13. Zitzmann M, von Eckardstein S, et al. Long-term experience with injections of testosterone undecanoate for substitution therapy in hypgonadal men. In: 87th Annual Meeting of the Endocrine Society; 2005 June 4 - 7; San Diego, CA; p. 306.
14. Schubert M, Zitzmann M, et al. Innovation in testosterone therapy for the treatment of male hypogonadism. J Men's Health & Gender, 2006;3:356-62.
15. Yassin AA, Saad F, et al. Testosterone undecanoate restores erectile function in a subset of patients with venous leakage: a series of case reports. J Sex Med, 2006;3:727-35.
16. Yassin AS, Saad F. Treatment of sexual dysfunctions in men with late onset hypogonadism treated with testosterone only. World J Urol, 2006;24:639-44.
17. Gui YL, He CH, et al. Male hormonal contraception: suppression of spermatogenesis by injectable testosterone undecanoate alone or with levonorgestrel implants in Chinese men. J Androl, 2004;25:720-7.
18. Qoubaitary A, Meriggiola C, et al. Pharmacokinetics of testosterone undecanoate injected alone or in combination with norethisterone enanthate in health men. J Androl, 2006;27:853-67.
