By Dan Gwartney, M.D.
Testosterone Undecanoate: Big Gains or Big Pain?
Nearly every recreational user of anabolic steroids (AAS) accepts the legal and health risks in order to improve his quality of life— a more impressive physique, greater confidence, or a competitive edge. Yet, despite the tangible benefits conferred by AAS, there are a number of pains that users face.
In the practice of pharmacy, compliance is a major issue that determines the success of a drug treatment. Compliance means the patient following directions. To combat the habit of noncompliance, drug therapies are designed to be as effortless as possible. Thus, most oral drugs are once-daily; imagine the consequences of failing to take birth control as scheduled.
Most women follow a once-daily birth control pill schedule, but it is inconvenient. Thus, long-acting birth control options have been developed that allow for the placement of hormone-infused silicone implants lasting five years, or an intramuscular injection lasting 12 weeks. The same delivery systems used to provide long-acting female sex steroid hormones can also be applied to male sex steroid hormones, such as AAS.
AAS users already depend upon injectable AAS rather than orals, due to their higher potency, convenience, and to avoid the liver toxicity inherent in 17alpha-alkyated steroids. The health and legal risks are abstractions to most recreational users; the most concrete pain associated with injectable AAS use is pain.
Ask a type 1 diabetic about the impact of the condition on his life. Most become comfortable with dietary restrictions; it is the repeated injections and finger-pricks that are the least tolerable burdens. While recreational AAS users don’t prick fingers to monitor testosterone, many follow a frequent injection schedule. Contrary to insulin which is injected under the skin, AAS are injected deep into muscle tissue; typically the gluteus (butt muscle), but also shoulder or outer thigh. Some have a spouse/partner perform the injection, but most learn to self-inject.
A highly desirable advance in testosterone/AAS therapy would be to provide long-term sustainable release, avoiding dramatic peaks and troughs. Even the longest-acting esters currently available in the U.S. require bi-weekly injections; testosterone concentration fluctuates wildly with a three-fold difference between the highest and lowest concentrations experienced between shots. Bodybuilders avoid AAS lows by injecting more frequently, maintaining an anabolic concentration. During an AAS-only cycle, bodybuilders endure two or more intramuscular injections weekly, depending upon the dosing schedule and number of AAS stacked. Competitive bodybuilders and athletes may compound this number with injections of insulin, growth hormone, inflammatory agents, prostaglandins, etc.
A testosterone ester has been developed and used clinically in many countries possessing the desired profile. Testosterone undecanoate (TU), marketed under the brand name Aveed®, Nebido®, and others, has a decade-plus history of research and use in treating male hypogonadism (low testosterone).1-23 It is the preferred mode of hormone replacement for many men’s health specialists, due to its pharmacokinetic properties. TU is capable of maintaining a steady concentration of testosterone for 12 weeks in most users, up to 14 weeks in some.5-7 To reach a steady state, a 4 ml depot of TU in castor oil is injected, with a follow-up injection six weeks later; from then on, testosterone concentration is typically maintained with a 4 ml depot injected every 12 weeks. For American AAS users, or men receiving testosterone therapy, this sounds like nirvana— one shot every three months, rather than 12 or more.
Unfortunately, the FDA is being uncharacteristically slow in approving TU, due to the rare report of transient (short-term, like five minutes) shortness of breath that has occurred when the depot is improperly injected.24 Proper intramuscular injection technique requires that the plunger of the syringe be pulled back slightly to ensure that the drug is not being injected into a blood vessel, as this could allow the large globule to enter the bloodstream. If injected into a large vein, the globule could enter the pulmonary circulation (lungs) fairly intact, causing the sensation noted, until it is dispersed in the general circulation. Most AAS injections are limited to 2 ml or less.
One issue with TU that may affect compliance is a greater frequency or severity of injection-related pain. Four ml may not seem like a large volume, a teaspoon has 5 ml. However, when injected into the glute, 4 ml of an oil-filled depot can feel like one is sitting on a [FONT=tahoma, verdana, geneva, lucida, lucida grande, arial, helvetica, sans-serif]golf ball[/FONT]. Recently, a study was performed measuring relative pain associated with a 4 ml TU injection, and how long the pain lasts.25 This will likely be of interest to many men, as TU could quickly become the hormone replacement of choice in the U.S. when approved.
Those considering high-volume injections of other AAS, or hoping to acquire TU for recreational purposes, will likely find this worthy of note as well. Certain AAS, particularly veterinary preparations, are administered in low concentrations. In the study, recently published in the Asian Journal of Andrology, Australian clinicians followed 125 hypogonadal men receiving TU, administered as a single 4 ml intramuscular injection every 12 weeks; 43 returned during the study period for a scheduled injection, and their data were included in the analysis.25
In reviewing these results, it is important to consider that the injections were provided in the clinic, by experienced nurses using proper injection protocol. The injections were provided slowly, over 3-5 minutes, through a 1½-inch, 21-gauge needle— the standard needle size used by doctors and bodybuilders for intramuscular injections. These results likely represent “best-case scenario” as a legitimate drug, properly injected, in a clinical setting by experienced practitioners. In the “real world,” the outcome is likely to be worse, with increased risk of other injection-related complications (e.g., bleeding, infection, injecting into a vein, tissue damage, and scarring).
Rating the Pain
The men were given a color-scale to represent the injection-related pain they experienced. They scored pain at the site just prior to the injection, immediately following, three more times that day approximately four hours apart, then each morning for eight days. All of these men had received TU previously, so they all were aware of the nature of the procedure.
As these men were all otherwise healthy, the pain score just prior to the injection was zero for nearly all subjects (96 percent), showing they were pain-free at the site of the injection. Nearly all subjects felt some degree of pain immediately post-injection (80 percent), ranging from annoying (2 on a scale of 10) to moderately-severe (pain score of 7). For most, the pain was worst immediately post-injection (58 percent), and resolved fairly quickly. In fact, none of the subjects reported that pain interfered with normal activities; in all cases, the pain resolved in three days or less.26
The authors compared this to an earlier study examining pain associated with a 1 ml intramuscular injection of testosterone enanthate (TE). In this, most men did not experience reportable pain; only 29 percent noted any injection-related discomfort.27 The difference between the TE and TU experience is likely related to the volume of the injection (1 ml versus 4 ml).
Two traits were noted that were associated with less pain— age and obesity. Older men reported less pain than their younger counterparts; this may be due to reduced pain sensitivity that occurs with aging, or they may just be more stoic.28 Obese men have a much thicker subdermal (under the skin) fat pad. In some men, this may be thicker than the length of the needle, causing the 4 ml depot to be dispersed among the less reactive adipose tissue (fat), as opposed to the acutely sensitive muscle. Though this has been noted to be an issue, it appears drug delivery may be equally effective when injected as an oil depot into fat or muscle.29,30 Most normal-weight or lean men would not find the visible bulge from the injection comfortable or tolerable cosmetically.
One reasonable question is, “Why not divide the shot into two injections of 2 ml, one into each butt cheek?” After all, if pain is this common and can be severe for some, why not make the process more tolerable? Most bodybuilders who have used injectables for many cycles can share the hassles: left-handed injections for right-handers; cheap needles with blunt tips; accidentally flexing the glute while the needle is embedded; trying to inject more than 2 ml at once; and the formation of a lipoma (oil mass in the muscle from frequent injections into the same space). Some bodybuilders have had surgery to remove an abscess caused by the injection.
The advantage of injecting a single large bolus, rather than two or more smaller depots, is that a large globule releases the drug much more slowly.31 Within muscle cells, fat or oil tends to form a spherical globule. One large globule better protects the drug inside, insulating TU from esterases— enzymes that release testosterone from the pro-drug ester. TU increases testosterone concentration only after it is released from its attached ester. It appears as though the U.S. version will be administered as a 3 ml injection, every 10weeks.22,24
Therapeutically, TU offers a very convenient and reliable means of keeping testosterone levels at a suitable concentration. The only requirement will be to attend a clinic for an unusually voluminous injection; some people may be able to administer this at home. For the recreational user, if one is not willing to undergo a 4 ml injection, the time course of dispersion will not be the 12-week window seen with clinical use. The kinetics of this drug given as a 1 ml injection would likely be similar to Deca-Durabolin (nandrolone decanoate), which is esterified to a 10-carbon tail, as opposed the 11-carbon tail used in TU.
TU is an exciting advance in testosterone replacement. However, for those looking to use it more frequently to maintain a supraphysiologic concentration over an extended period, TU may require big (or at least annoying) pains for big gains.
References:
1. Zhang GY, Gu YQ, et al. A pharmacokinetic study of injectable testosterone undecanoate in hypogonadal men. J Androl, 1998 Nov-Dec;19(6):761-8.
2. 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.
3. Nieschlag E, Büchter D, et al. Repeated intramuscular injections of testosterone undecanoate for substitution therapy in hypogonadal men. Clin Endocrinol (Oxf), 1999 Dec;51(6):757-63.
4. 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.
5. 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 Nov;89(11):5429-34.
6. Yassin AA, Saad F. Treatment of sexual dysfunction of hypogonadal patients with long-acting testosterone undecanoate (Nebido). World J Urol, 2006 Dec;24(6):639-44.
7. 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 Dec;9(4):221-7.
8. Yassin AA, Saad F. Improvement of sexual function in men with late-onset hypogonadism treated with testosterone only. J Sex Med, 2007 Mar;4(2):497-501.
9. 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 May;9(3):291-7.
10. Zitzmann M, Nieschlag E. Androgen receptor gene CAG repeat length and body mass index modulate the safety of long-term intramuscular testosterone undecanoate therapy in hypogonadal men. J Clin Endocrinol Metab, 2007 Oct;92(10):3844-53.
11. Minnemann T, Schubert M, et al. A four-year efficacy and safety study of the long-acting parenteral testosterone undecanoate. Aging Male, 2007 Sep;10(3):155-8.
12. Saad F, Gooren LJ, et al. A dose-response study of testosterone on sexual dysfunction and features of the metabolic syndrome using testosterone gel and parenteral testosterone undecanoate. J Androl, 2008 Jan-Feb;29(1):102-5.
13. Saad F, Gooren L, et al. An exploratory study of the effects of 12-month administration of the novel long-acting testosterone undecanoate on measures of sexual function and the metabolic syndrome. Arch Androl, 2007 Nov-Dec;53(6):353-7.
14. Moisey R, Swinburne J, et al. Serum testosterone and bioavailable testosterone correlate with age and body size in hypogonadal men treated with testosterone undecanoate (1000 mg IM--Nebido). Clin Endocrinol (Oxf), 2008 Oct;69(4):642-7.
15. Minnemann T, Schubert M, et al. Comparison of a new long-acting testosterone undecanoate formulation vs testosterone enanthate for intramuscular androgen therapy in male hypogonadism. J Endocrinol Invest, 2008 Aug;31(8):718-23.
16. Morgentaler A, Dobs AS, et al. Long acting testosterone undecanoate therapy in men with hypogonadism: results of a pharmacokinetic clinical study. J Urol, 2008 Dec;180(6):2307-13.
17. Jockenhövel F, Minnemann T, et al. Comparison of long-acting testosterone undecanoate formulation versus testosterone enanthate on sexual function and mood in hypogonadal men. Eur J Endocrinol, 2009 May;160(5):815-9.
18. Kornmann B, Nieschlag E, et al. Body fat content and testosterone pharmacokinetics determine gonadotropin suppression after intramuscular injections of testosterone preparations in normal men. J Androl, 2009 Sep-Oct;30(5):602-13.
19. Zhuravlev VN, Frank MA, et al. Sexual functions of men with obstructive sleep apnoea syndrome and hypogonadism may improve upon testosterone administration: a pilot study. Andrologia, 2009 Jun;41(3):193-5.
20. Haider A, Gooren LJ, et al. Improvement of the Metabolic Syndrome and of Non-alcoholic Liver Steatosis upon Treatment of Hypogonadal Elderly Men with Parenteral Testosterone Undecanoate. Exp Clin Endocrinol Diabetes, 2010 Mar;118(3):167-171.
21. Caminiti G, Volterrani M, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol, 2009 Sep 1;54(10):919-27.
22. Wang C, Harnett M, et al. Pharmacokinetics and Safety of Long-Acting Testosterone Undecanoate Injections in Hypogonadal Men: An 84-Week Phase III Clinical Trial. J Androl, 2010 Feb 4. [Epub ahead of print].
23. Aversa A, Bruzziches R, et al. Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. J Endocrinol Invest, 2010 Mar 10. [Epub ahead of print].
24. Drugs.com. Complete Response Letter for Aveed NDA. Available at: [FONT=tahoma, verdana, geneva, lucida, lucida grande, arial, helvetica, sans-serif]Endo Pharmaceuticals Provides Regulatory Update on Aveed (Testosterone Undecanoate) Injection[/FONT], accessed March 17, 2010.
25. Sartorius G, Fennell C, et al. Factors influencing time course of pain after depot oil intramuscular injection of testosterone undecanoate. Asian J Androl, 2010 Mar;12(2):227-33.
26. Llewellyn W. Equipoise® (boldenone undecylenate). William Llewellyn’s Anabolics, Molecular Nutrition, LLC. Jupiter, FL;2009:235-7.
27. Mackey MA, Conway AJ, et al. Tolerability of intramuscular injections of testosterone ester in oil vehicle. Hum Reprod, 1995 Apr;10(4):862-5.
28. Gagliese L. Pain and aging: the emergence of a new subfield of pain research. J Pain 2009 Apr;10(4):343-53.
29. Burbridge BE. Computed tomographic measurement of gluteal subcutaneous fat thickness in reference to failure of gluteal intramuscular injections. Can Assoc Radiol J, 2007 Apr;58(2):72-5.
30. Svendsen O, Blom L, et al. Local toxicity of different drugs after intramuscular or intralipomatous injection in pigs: serum concentrations after three different formulations of cis(Z)-clopenthixol. Acta Pharmacol Toxicol, (Copenh) 1985 Aug;57(2):78-87.
31. Fotherby K. Factors affecting the duration of action of the injectable contraceptive norethisterone enanthate. Contracept Deliv Syst, 1981 Jul;2(3):249-57.
Testosterone Undecanoate: Big Gains or Big Pain?
Nearly every recreational user of anabolic steroids (AAS) accepts the legal and health risks in order to improve his quality of life— a more impressive physique, greater confidence, or a competitive edge. Yet, despite the tangible benefits conferred by AAS, there are a number of pains that users face.
In the practice of pharmacy, compliance is a major issue that determines the success of a drug treatment. Compliance means the patient following directions. To combat the habit of noncompliance, drug therapies are designed to be as effortless as possible. Thus, most oral drugs are once-daily; imagine the consequences of failing to take birth control as scheduled.
Most women follow a once-daily birth control pill schedule, but it is inconvenient. Thus, long-acting birth control options have been developed that allow for the placement of hormone-infused silicone implants lasting five years, or an intramuscular injection lasting 12 weeks. The same delivery systems used to provide long-acting female sex steroid hormones can also be applied to male sex steroid hormones, such as AAS.
AAS users already depend upon injectable AAS rather than orals, due to their higher potency, convenience, and to avoid the liver toxicity inherent in 17alpha-alkyated steroids. The health and legal risks are abstractions to most recreational users; the most concrete pain associated with injectable AAS use is pain.
Ask a type 1 diabetic about the impact of the condition on his life. Most become comfortable with dietary restrictions; it is the repeated injections and finger-pricks that are the least tolerable burdens. While recreational AAS users don’t prick fingers to monitor testosterone, many follow a frequent injection schedule. Contrary to insulin which is injected under the skin, AAS are injected deep into muscle tissue; typically the gluteus (butt muscle), but also shoulder or outer thigh. Some have a spouse/partner perform the injection, but most learn to self-inject.
A highly desirable advance in testosterone/AAS therapy would be to provide long-term sustainable release, avoiding dramatic peaks and troughs. Even the longest-acting esters currently available in the U.S. require bi-weekly injections; testosterone concentration fluctuates wildly with a three-fold difference between the highest and lowest concentrations experienced between shots. Bodybuilders avoid AAS lows by injecting more frequently, maintaining an anabolic concentration. During an AAS-only cycle, bodybuilders endure two or more intramuscular injections weekly, depending upon the dosing schedule and number of AAS stacked. Competitive bodybuilders and athletes may compound this number with injections of insulin, growth hormone, inflammatory agents, prostaglandins, etc.
A testosterone ester has been developed and used clinically in many countries possessing the desired profile. Testosterone undecanoate (TU), marketed under the brand name Aveed®, Nebido®, and others, has a decade-plus history of research and use in treating male hypogonadism (low testosterone).1-23 It is the preferred mode of hormone replacement for many men’s health specialists, due to its pharmacokinetic properties. TU is capable of maintaining a steady concentration of testosterone for 12 weeks in most users, up to 14 weeks in some.5-7 To reach a steady state, a 4 ml depot of TU in castor oil is injected, with a follow-up injection six weeks later; from then on, testosterone concentration is typically maintained with a 4 ml depot injected every 12 weeks. For American AAS users, or men receiving testosterone therapy, this sounds like nirvana— one shot every three months, rather than 12 or more.
Unfortunately, the FDA is being uncharacteristically slow in approving TU, due to the rare report of transient (short-term, like five minutes) shortness of breath that has occurred when the depot is improperly injected.24 Proper intramuscular injection technique requires that the plunger of the syringe be pulled back slightly to ensure that the drug is not being injected into a blood vessel, as this could allow the large globule to enter the bloodstream. If injected into a large vein, the globule could enter the pulmonary circulation (lungs) fairly intact, causing the sensation noted, until it is dispersed in the general circulation. Most AAS injections are limited to 2 ml or less.
One issue with TU that may affect compliance is a greater frequency or severity of injection-related pain. Four ml may not seem like a large volume, a teaspoon has 5 ml. However, when injected into the glute, 4 ml of an oil-filled depot can feel like one is sitting on a [FONT=tahoma, verdana, geneva, lucida, lucida grande, arial, helvetica, sans-serif]golf ball[/FONT]. Recently, a study was performed measuring relative pain associated with a 4 ml TU injection, and how long the pain lasts.25 This will likely be of interest to many men, as TU could quickly become the hormone replacement of choice in the U.S. when approved.
Those considering high-volume injections of other AAS, or hoping to acquire TU for recreational purposes, will likely find this worthy of note as well. Certain AAS, particularly veterinary preparations, are administered in low concentrations. In the study, recently published in the Asian Journal of Andrology, Australian clinicians followed 125 hypogonadal men receiving TU, administered as a single 4 ml intramuscular injection every 12 weeks; 43 returned during the study period for a scheduled injection, and their data were included in the analysis.25
In reviewing these results, it is important to consider that the injections were provided in the clinic, by experienced nurses using proper injection protocol. The injections were provided slowly, over 3-5 minutes, through a 1½-inch, 21-gauge needle— the standard needle size used by doctors and bodybuilders for intramuscular injections. These results likely represent “best-case scenario” as a legitimate drug, properly injected, in a clinical setting by experienced practitioners. In the “real world,” the outcome is likely to be worse, with increased risk of other injection-related complications (e.g., bleeding, infection, injecting into a vein, tissue damage, and scarring).
Rating the Pain
The men were given a color-scale to represent the injection-related pain they experienced. They scored pain at the site just prior to the injection, immediately following, three more times that day approximately four hours apart, then each morning for eight days. All of these men had received TU previously, so they all were aware of the nature of the procedure.
As these men were all otherwise healthy, the pain score just prior to the injection was zero for nearly all subjects (96 percent), showing they were pain-free at the site of the injection. Nearly all subjects felt some degree of pain immediately post-injection (80 percent), ranging from annoying (2 on a scale of 10) to moderately-severe (pain score of 7). For most, the pain was worst immediately post-injection (58 percent), and resolved fairly quickly. In fact, none of the subjects reported that pain interfered with normal activities; in all cases, the pain resolved in three days or less.26
The authors compared this to an earlier study examining pain associated with a 1 ml intramuscular injection of testosterone enanthate (TE). In this, most men did not experience reportable pain; only 29 percent noted any injection-related discomfort.27 The difference between the TE and TU experience is likely related to the volume of the injection (1 ml versus 4 ml).
Two traits were noted that were associated with less pain— age and obesity. Older men reported less pain than their younger counterparts; this may be due to reduced pain sensitivity that occurs with aging, or they may just be more stoic.28 Obese men have a much thicker subdermal (under the skin) fat pad. In some men, this may be thicker than the length of the needle, causing the 4 ml depot to be dispersed among the less reactive adipose tissue (fat), as opposed to the acutely sensitive muscle. Though this has been noted to be an issue, it appears drug delivery may be equally effective when injected as an oil depot into fat or muscle.29,30 Most normal-weight or lean men would not find the visible bulge from the injection comfortable or tolerable cosmetically.
One reasonable question is, “Why not divide the shot into two injections of 2 ml, one into each butt cheek?” After all, if pain is this common and can be severe for some, why not make the process more tolerable? Most bodybuilders who have used injectables for many cycles can share the hassles: left-handed injections for right-handers; cheap needles with blunt tips; accidentally flexing the glute while the needle is embedded; trying to inject more than 2 ml at once; and the formation of a lipoma (oil mass in the muscle from frequent injections into the same space). Some bodybuilders have had surgery to remove an abscess caused by the injection.
The advantage of injecting a single large bolus, rather than two or more smaller depots, is that a large globule releases the drug much more slowly.31 Within muscle cells, fat or oil tends to form a spherical globule. One large globule better protects the drug inside, insulating TU from esterases— enzymes that release testosterone from the pro-drug ester. TU increases testosterone concentration only after it is released from its attached ester. It appears as though the U.S. version will be administered as a 3 ml injection, every 10weeks.22,24
Therapeutically, TU offers a very convenient and reliable means of keeping testosterone levels at a suitable concentration. The only requirement will be to attend a clinic for an unusually voluminous injection; some people may be able to administer this at home. For the recreational user, if one is not willing to undergo a 4 ml injection, the time course of dispersion will not be the 12-week window seen with clinical use. The kinetics of this drug given as a 1 ml injection would likely be similar to Deca-Durabolin (nandrolone decanoate), which is esterified to a 10-carbon tail, as opposed the 11-carbon tail used in TU.
TU is an exciting advance in testosterone replacement. However, for those looking to use it more frequently to maintain a supraphysiologic concentration over an extended period, TU may require big (or at least annoying) pains for big gains.
References:
1. Zhang GY, Gu YQ, et al. A pharmacokinetic study of injectable testosterone undecanoate in hypogonadal men. J Androl, 1998 Nov-Dec;19(6):761-8.
2. 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.
3. Nieschlag E, Büchter D, et al. Repeated intramuscular injections of testosterone undecanoate for substitution therapy in hypogonadal men. Clin Endocrinol (Oxf), 1999 Dec;51(6):757-63.
4. 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.
5. 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 Nov;89(11):5429-34.
6. Yassin AA, Saad F. Treatment of sexual dysfunction of hypogonadal patients with long-acting testosterone undecanoate (Nebido). World J Urol, 2006 Dec;24(6):639-44.
7. 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 Dec;9(4):221-7.
8. Yassin AA, Saad F. Improvement of sexual function in men with late-onset hypogonadism treated with testosterone only. J Sex Med, 2007 Mar;4(2):497-501.
9. 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 May;9(3):291-7.
10. Zitzmann M, Nieschlag E. Androgen receptor gene CAG repeat length and body mass index modulate the safety of long-term intramuscular testosterone undecanoate therapy in hypogonadal men. J Clin Endocrinol Metab, 2007 Oct;92(10):3844-53.
11. Minnemann T, Schubert M, et al. A four-year efficacy and safety study of the long-acting parenteral testosterone undecanoate. Aging Male, 2007 Sep;10(3):155-8.
12. Saad F, Gooren LJ, et al. A dose-response study of testosterone on sexual dysfunction and features of the metabolic syndrome using testosterone gel and parenteral testosterone undecanoate. J Androl, 2008 Jan-Feb;29(1):102-5.
13. Saad F, Gooren L, et al. An exploratory study of the effects of 12-month administration of the novel long-acting testosterone undecanoate on measures of sexual function and the metabolic syndrome. Arch Androl, 2007 Nov-Dec;53(6):353-7.
14. Moisey R, Swinburne J, et al. Serum testosterone and bioavailable testosterone correlate with age and body size in hypogonadal men treated with testosterone undecanoate (1000 mg IM--Nebido). Clin Endocrinol (Oxf), 2008 Oct;69(4):642-7.
15. Minnemann T, Schubert M, et al. Comparison of a new long-acting testosterone undecanoate formulation vs testosterone enanthate for intramuscular androgen therapy in male hypogonadism. J Endocrinol Invest, 2008 Aug;31(8):718-23.
16. Morgentaler A, Dobs AS, et al. Long acting testosterone undecanoate therapy in men with hypogonadism: results of a pharmacokinetic clinical study. J Urol, 2008 Dec;180(6):2307-13.
17. Jockenhövel F, Minnemann T, et al. Comparison of long-acting testosterone undecanoate formulation versus testosterone enanthate on sexual function and mood in hypogonadal men. Eur J Endocrinol, 2009 May;160(5):815-9.
18. Kornmann B, Nieschlag E, et al. Body fat content and testosterone pharmacokinetics determine gonadotropin suppression after intramuscular injections of testosterone preparations in normal men. J Androl, 2009 Sep-Oct;30(5):602-13.
19. Zhuravlev VN, Frank MA, et al. Sexual functions of men with obstructive sleep apnoea syndrome and hypogonadism may improve upon testosterone administration: a pilot study. Andrologia, 2009 Jun;41(3):193-5.
20. Haider A, Gooren LJ, et al. Improvement of the Metabolic Syndrome and of Non-alcoholic Liver Steatosis upon Treatment of Hypogonadal Elderly Men with Parenteral Testosterone Undecanoate. Exp Clin Endocrinol Diabetes, 2010 Mar;118(3):167-171.
21. Caminiti G, Volterrani M, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol, 2009 Sep 1;54(10):919-27.
22. Wang C, Harnett M, et al. Pharmacokinetics and Safety of Long-Acting Testosterone Undecanoate Injections in Hypogonadal Men: An 84-Week Phase III Clinical Trial. J Androl, 2010 Feb 4. [Epub ahead of print].
23. Aversa A, Bruzziches R, et al. Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. J Endocrinol Invest, 2010 Mar 10. [Epub ahead of print].
24. Drugs.com. Complete Response Letter for Aveed NDA. Available at: [FONT=tahoma, verdana, geneva, lucida, lucida grande, arial, helvetica, sans-serif]Endo Pharmaceuticals Provides Regulatory Update on Aveed (Testosterone Undecanoate) Injection[/FONT], accessed March 17, 2010.
25. Sartorius G, Fennell C, et al. Factors influencing time course of pain after depot oil intramuscular injection of testosterone undecanoate. Asian J Androl, 2010 Mar;12(2):227-33.
26. Llewellyn W. Equipoise® (boldenone undecylenate). William Llewellyn’s Anabolics, Molecular Nutrition, LLC. Jupiter, FL;2009:235-7.
27. Mackey MA, Conway AJ, et al. Tolerability of intramuscular injections of testosterone ester in oil vehicle. Hum Reprod, 1995 Apr;10(4):862-5.
28. Gagliese L. Pain and aging: the emergence of a new subfield of pain research. J Pain 2009 Apr;10(4):343-53.
29. Burbridge BE. Computed tomographic measurement of gluteal subcutaneous fat thickness in reference to failure of gluteal intramuscular injections. Can Assoc Radiol J, 2007 Apr;58(2):72-5.
30. Svendsen O, Blom L, et al. Local toxicity of different drugs after intramuscular or intralipomatous injection in pigs: serum concentrations after three different formulations of cis(Z)-clopenthixol. Acta Pharmacol Toxicol, (Copenh) 1985 Aug;57(2):78-87.
31. Fotherby K. Factors affecting the duration of action of the injectable contraceptive norethisterone enanthate. Contracept Deliv Syst, 1981 Jul;2(3):249-57.
