lunes, 28 de diciembre de 2015

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 golf ball. 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 10 weeks.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.

By Dan Gwartney, M.D. 


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