Testosterone Undecanoate

Slow and Steady Wins the Race

There are many different anabolic steroids available. In his most recent edition of the anabolic steroid reference manual Anabolics 2004, popular author Bill Llewellyn lists over 60 steroids in addition to the myriad other anabolic or fat-reducing drugs.¹ The category of anabolic steroids is certain to expand due to new pharmaceutical developments and the reclassification of prohormones.

            This daunting number can be understood relatively easily when one considers that many of the drugs are modifications of a small number of steroid molecules. The classic example is testosterone. Testosterone is the predominant androgen produced by men. It is called a C-19 steroid, referring to the number of carbon atoms in its structure. In addition to influencing secondary sexual characteristics (penile growth, facial hair, body hair, etc.), testosterone is responsible for promoting and maintaining the greater muscle mass expressed by men in comparison to women.² Men who suffer from low levels of testosterone typically have high body fat and reduced muscle mass.^3,4 Conversely, when testosterone levels are elevated above normal, (supra-physiologic), greater amounts of muscle develop in response to exercise.⁵ Of course, bodybuilders have been aware of the latter phenomenon for decades.

            The Long and Short of It

Testosterone is not suitable for oral delivery, as enzymes in the intestines and liver quickly metabolize the steroid to an inactive form, and the metabolites are rapidly excreted.^6,7 This is true of all androgens unless they are modified to survive oral delivery, such as 17-A alkylation or 1-double bond.⁷

            The preferred method for delivering testosterone is intramuscular injection. Testosterone can be injected unmodified as a suspension, but the release is so rapid that frequent injections are required and wide fluctuations in hormone level occur.⁸ To make the injections more suitable for clinical use, fatty acids are attached to the steroid molecule using a 17-B ester bond, allowing the steroid to be dissolved in oil and to prolong the release of the steroid in a more even manner.⁹ The fatty acids vary in length. The shorter fatty acids are the fast-acting esters- acetate and propionate. Lengthier fatty acids are used in the slower- acting and longer-lasting esters- cypionate, enanthate and decanoate.

Choosing among these various esters is a matter of personal preference. Some athletes prefer the fast-acting short esters, as they allow for rapid results, short cycles and short clearance times. Counting against these short-chain esters is the need for frequent injections and the fact that mood swings are common as testosterone levels fluctuate widely.

            Most bodybuilders prefer the longer-acting esters, as they are prepared to undergo long cycles, do not need to be concerned about drug testing and prefer to minimize the number of injections. As the concentration of testosterone is released more slowly, initial gains using the longer-chain esters are slower, but long-term results are excellent. Thus, many bodybuilders will stack fast-acting orals, or use an ester blend like Sustanon, to ensure early gains.

            Better Delivery 

There haven't been many recent developments in testosterone delivery, as there is little clinical demand for the hormone. However, drug trials for treating male menopause (andropause) and male contraception are opening new areas of investigation.² Currently, testosterone cypionate and enanthate are the most commonly used forms of testosterone for treating andropause, though topical formulations are gaining acceptance.² Both the esters and gels suffer disadvantages, however. The esters have sharp peaks leading to brief spurts of supra-physiologic levels, with a short period of effectiveness before requiring a repeat injection.⁹ The gel formulations require daily application and can be removed with washing, sweating or by rubbing against clothes.

            To provide a more suitable injectable alternative, a longer-acting ester has been developed and studied for several years. Developed by JenaPharm in Germany, testosterone undecanoate is an 11-carbon-long, saturated fatty acid attached by a 17-B ester bond to testosterone (CAS registry #5949-44-0). The undecanoate ester is one carbon longer than the more familiar decanoate ester used in the steroids Deca-durabolin and Neotest 250. Only two listed injectable steroids use the undecanoate ester; a nandrolone ester, marketed under the brand name Dynabolan and a testosterone blend marketed in Mexico under the name Deposterona. There is another 11-carbon-long ester used in certain injectable formulations, similar in spelling, the undecylenate ester. This ester is used in the popular veterinary steroid Equipoise. Undecylenate differs by having a double bond at the terminal carbon.

            Astute readers and experienced steroid users may recognize testosterone undecanoate as the chemical name of the oral drug Andriol.¹⁰ Andriol is unique among oral drugs in that it uses the long-chain ester to enhance oral delivery, as opposed to 17-A alkylation. Andriol enters the circulation through the lymphatic system, avoiding the enzymatic degradation of the liver and intestines. Though clinical studies investigating the use of Andriol for hormone replacement were supportive, field reports by bodybuilders who have used Andriol have been less flattering.^4,11,12 Even when dosed above 240 milligrams per day, the anabolic effect of oral Andriol is very weak. It's unknown what accounts for the disappointing results, but at this time, it appears oral Andriol is not an effective anabolic.

            A Marathon, Not a Sprint

This experience should not cloud the promise of injectable testosterone undecanoate. It has clearly been demonstrated that all injected testosterone esters are capable of providing impressive gains in size and strength when used in conjunction with resistance training and proper nutrition. The effectiveness of testosterone is an accepted fact, allowing this article to focus on the utility of this novel ester.

            As stated previously, many athletes prefer short-chain testosterone esters, as results are experienced rapidly and the drug clears the system quickly if testing is a concern. However, most bodybuilders plan on longer cycles, lasting 16 to 20 weeks or more. It's not unheard of for some competitive bodybuilders and powerlifters to continue steroid use uninterrupted for a year or more. Rather than seeking quick results that are prone to leave as swiftly as they were gained, bodybuilders know that lasting muscle gains require an approach that is more similar to a marathon than a sprint. Though such an approach holds significant health concerns, in addition to the legal consequences of illegal anabolic steroid use and possession, it's the best approach for realizing the benefits of a slow-releasing ester.

            To use any particular steroid to its greatest advantage, it's vital to understand the basic pharmacology of the drug, including its pharmacokinetics. Pharmacokinetics defines how rapidly a drug enters the system, elicits its effects and is cleared from the system. In the case of testosterone undecanoate, the latter two components are essentially the same as all other testosterone esters. Testosterone esters promote gains in muscle mass and strength in a dose-dependent fashion, meaning higher doses promote larger, stronger muscles.¹³ Not only does the maximal dose matter, but also the pattern of delivery. If testosterone levels are only elevated for a few days of the week, or even a few hours of each day, a sustained anabolic effect is not guaranteed. As testosterone levels rise, so, too, do the levels of testosterone metabolites (estradiol and DHT). If levels of estradiol or DHT remain elevated, related side effects will occur.⁵

            The pharmacokinetics of testosterone undecanoate were recently described in a paper published in the Journal of Clinical Endocrinology and Metabolism.¹⁴ The authors compared testosterone undecanoate to testosterone enanthate in treating men who suffered from low testosterone. Both treatments were effective in reversing clinical signs of low testosterone, though testosterone enanthate did not maintain testosterone in the normal range throughout the entire interval between injections, (250 milligrams by intramuscular injection (i.m.) every three weeks). On the contrary, the interval between injections of testosterone undecanoate (1,000 milligrams i.m.) had to be lengthened from six to 12 weeks, as testosterone levels continued to climb using the six-week interval.

            Great Promise, Potential Risk

            Reading the last paragraph closely, most bodybuilders would likely become excited, as the prospect of injecting an anabolic once every six to 12 weeks would be a prayer answered. Recall that the dose of 1,000 milligrams every 12 weeks is a replacement dose, so for an anabolic response, supra-physiologic dosing would be required. An earlier paper investigating the use of testosterone undecanoate as a male contraceptive determined that the contraceptive effect of 1,000 milligrams of testosterone undecanoate was equivalent to 200 milligrams of testosterone injected weekly.¹⁵ If the anabolic effect is consistent with the contraceptive effect, then a dosing schedule of 1,000 milligrams of testosterone undecanoate injected every two weeks would be equivalent to 600 milligrams of testosterone enanthate given weekly, an anabolic dose used by athletes and proven in several studies.¹³

            As testosterone undecanoate is prepared at a concentration of 250 milligrams per milliliter (mg/ml), each injection would have a volume of four cc, which is what was administered to the study's subjects. This would provide approximately 630 milligrams of testosterone, as the active steroid constitutes 63 percent of the esterified molecule by weight.⁹ The authors report that the volume was well tolerated, though bodybuilders would disagree, as over three cc in a single site becomes uncomfortable and may interfere with lower body training for several days. However, as the frequency of injections would drop from twice weekly to twice a month, it's likely most users would accept the discomfort or split the injection in half and inject into gluteals on both sides.

The promise of testosterone undecanoate is tremendous, but so too are the potential risks. If side effects did occur, they would be long lasting. The half- life of testosterone undecanoate has been measured at 34 days, though the pharmacokinetics suggest it may be even longer.^14,16 Estrogenic and androgenic side effect protection would need to be instituted at the onset of the cycle and health parameters monitored throughout the cycle. Blood lipids will decrease, including the good HDL cholesterol, increasing the risk of a heart attack or stroke over the long term; prostate problems can arise, as can hair loss, breast growth and emotional disorders.⁵

It is essential that anyone considering such use enlist the supervision of a physician to monitor the potential consequences of prolonged, supra-physiologic androgen administration. Users should have access to an aromatase inhibitor, like Arimidex. An inhibitor of 5-A reductase (finasteride, duasteride) is also desirable to offset hair loss or prostate problems. As mentioned earlier, testosterone undecanoate is being investigated as a contraceptive. Use of this drug at supra-physiologic levels is certain to impair fertility and low sperm counts may persist for months or years after the drug is discontinued. Restoration of fertility has been achieved in bodybuilders using human chorionic gonadotrophin, Clomid and Femara.^17,18

            Summing Up

Testosterone undecanoate is an 11-carbon-long ester that promises a comfortable means of sustaining supra-physiologic testosterone levels.^19,20 Bodybuilders may be able to benefit from anabolic levels of testosterone with twice monthly injections, or fewer. However, as the pharmacokinetics of this ester have not been determined for anabolic use in humans versus replacement or contraceptive dosing, levels should be closely monitored, along with possible health consequences, at regularly scheduled intervals. The possibility of escalating doses (meaning the drug builds up with frequent dosing) makes it impossible to determine the optimal anabolic schedule for this drug. Individuals subject to drug testing should realize this steroid will likely remain in the system, in detectable amounts, for at least six months and possibly in excess of one year.

            Cycles using testosterone undecanoate would likely depend upon the use of a short-acting ester or orals at the onset, as the initial results would be slower than experienced with current testosterone esters. This is likely the reasoning behind the formulation of Deposterona, though at a concentration of 60 mg/ml, the injection volume would be considerable and uncomfortable.

            It is a positive note to see the further development of testosterone delivery. And well-written papers, such as the pharmacokinetic study, are extremely useful in better understanding the use of such drugs. Testosterone undecanoate offers the promise of a useful tool should supra-physiologic anabolic steroid therapy become approved. For those who choose to use this or other long-acting drugs illicitly, be aware of the health and legal consequences. Close monitoring is essential, as once problems arise, they hold the potential of persisting for a long time.

References 

1. Llewellyn W. Anabolics 2004. Molecular Nutrition Press, Jupiter, FL;2004.
2. Hayes F. Androgen replacement in the male: recent studies. Curr Opin Endocrin Diabetes, 2001 Dec;8(6):301-6.
3. Wang C, Swedloff RS, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Testosterone gel study group. J Clin Endocrinol Metab, 2000 Aug;85(8):2839-53.
4. Wittert GA, Chapman IM, et al. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci, 2003 Jul;58(7):618-25.
5. Hartgens F, Kuipers H. Effects of androgenic-anabolic steroids in athletes. Sports Med, 2004;34(8):513-54.
6. Shackleford DM, Faassen WA, et al. Contribution of lymphatically transported testosterone undecanoate to the systemic exposure of testosterone after oral administration of two andriol formulations in conscious lymph duct-cannulated dogs. J Pharmacol Exp Ther, 2003 Sep;306(3):925-33.
7. Hameed A, Brothwood T, et al. Delivery of testosterone replacement therapy. Curr Opin Investig Drugs, 2003 Oct;4(10):1213-9.
8. Llewellyn W. Testosterone suspension. Anabolics 2004. Molecular Nutrition Press, Jupiter, FL;2004:163-5.
9. Partsch CJ, Weinbauer GF, et al. Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate. Eur J Endocrinol, 1995 Apr;132(4):514-9.
10. Gooren LJ. A ten-year safety study of the oral androgen testosterone undecanoate. J Androl, 1994 May-Jun;15(3):212-5.
11. Llewellyn W. Andriol (testosterone undecanoate). Anabolics 2004. Molecular Nutrition Press, Jupiter, FL;2004:80-1.
12. Kohn FM, Schill WB. A new oral testosterone undecanoate formulation. World J Urol, 2003 Nov;21(5):311-5.
13. Bhasin S, Woodhouse L, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab, 2001 Dec;281(6):E1172-81.
14. Schubert M, Minnemann D, 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 Nov;89(11):5429-34.
15. Kamischke A, Ploger D, et al. Intramuscular testosterone undecanoate with or without oral levonorgestrel: a randomized placebo-controlled feasibility study for male contraception. Clin Endocrinol, 2000 Jul;53(1):43-52.
16. Behre HM, Abshagen K, et al. Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies. Eur J Endocrinol, 1999 May;140(5):414-9.
17. Menon DK. Successful treatment of anabolic steroid-induced azoospermia with human chorionic gonadotropin and human menopausal gonadotropin. Fertil Steril, 2003 Jun;79 Suppl 3:1659-61.
18. Tan RS, Vasudevan D. Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse. Fertil Steril, 2003 Jan;79(1):203-5.
19. 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 May-Jun;23(3):419-25.
20. Callies F, Kollenkirchen U, et al. Testosterone undecanoate: a useful tool for testosterone administration in rats. Exp Clin Endocrinol Diabetes, 2003 Jun;111(4):203-8.