Best Form of Testosterone

Injectable T is Safer than Topical

Pharmaceutical boards shout “blasphemy!” as they invest millions into lobbying government to erect barriers of entry against competitors … make that research and development to provide a safer and more effective means of treating men suffering from symptomatic testosterone deficiency. The earliest forms of androgens were unmodified metabolites extracted from urine, and finally testosterone itself, injected to provide a short burst of increased androgen exposure that was rapidly cleared. Chemists realized they would need to modify the chemical structure of the androgens to survive metabolic clearance, so they initially alkylated the anabolic-androgenic steroids (AAS) at the C17 position of the molecule. This allowed AAS to be taken orally, and provide a sustained effect for roughly a day. However, it became evident that this form of modification (17alpha-alkylation) causes toxic effects to the liver in many. Finally, long-acting injectable versions of AAS were developed that esterified varying length fatty acids, again to the C17 carbon.¹

17beta-esterification is the form of modification that accounts for most injected AAS, including the various testosterone esters: propionate, enanthate, cypionate and undecanoate. Suspended in an oil carrier, these 17beta-esters of testosterone are capable of providing a reasonably steady concentration of testosterone for periods dependent upon the length of the fatty acid ester, up to 12 weeks in the case of testosterone undecanoate. Testosterone esters are injected, typically into muscle (e.g., gluteus, deltoid, vastus lateralis) and are slowly released from the oil globule into the bloodstream. Once the testosterone ester is “floating” in the blood, it is attacked by esterase enzymes that cleave (cut) the ester bond— releasing the fatty acid from the testosterone portion of the molecule. The now-freed testosterone has a short time to work, as it is metabolized just as quickly as if it had never been esterified. The benefit of esterified testosterone is that it continuously releases testosterone at a concentration that can be titrated by adjusting the dose and frequency of the injections.

Safety of Testosterone Esters

Testosterone esters have a decades-long history of use with an admirable safety record when dispensed under the supervision of a qualified physician.^2,3 Even when misused in supraphysiologic manner, testosterone esters are generally well tolerated, though there are clear health risks that escalate considerably with abusively dosed cycles. Further, certain individuals are predisposed to clotting, psychological distress, estrogen excess, liver damage and other side effects.^4,5 This may result in significant harm, even death.

Cynics might believe that there was little clinical demand during the latter part of last century for testosterone replacement therapy (TRT) due to the campaigning of the anti-doping agencies, and absence of any financial incentive for pharmaceutical manufacturers, as patents for the esters were expired. An exception being the recently approved (after an inordinate delay) testosterone undecanoate Aveed, that has been marketed since 2003 in many other countries under the brand name Nebido.⁶ In their place, patentable topical testosterone formulations were formulated. The claimed benefits included a more physiologic release, convenience and safety compared to the injected esters.⁷ Though there was long a lack of awareness and acceptance of “testosterone deficiency” as a clinical condition, much of the demand for TRT is the result of direct-to-consumer marketing by pharmaceutical companies selling topically delivered testosterone. In fact, the Endocrine Society openly discourages screening men for testosterone deficiency, impeding physician intervention and patient care.

Little real benefit has been noted in studies comparing injected testosterone esters to topical formulations.⁷ Further, the increase in certain adverse events (increased hematocrit, gynecomastia) associated with injected testosterone are offset by distinct adverse effects caused by topical testosterone (local site irritation, transference).^8,9 Even the (highly disputed) recent studies that claim (after considerable statistical manipulation) that TRT is associated with an increase in cardiovascular risks found no increase based upon the delivery method used.^10,11 In fact, the most damning study used topical testosterone to treat older men with limited mobility, not an injected ester.¹²

Cardiovascular Risk Factors

A study analyzing the results of 35 trials using testosterone sought to determine the effect on cardiovascular risk based on how the testosterone was given— oral, injected or topical.¹³ In fact, the authors discovered that oral testosterone therapy is particularly risky, with over twice the relative risk compared to the control groups. Injected and topical testosterone were not significantly associated with risk (due to a wide statistical variation), but the results support the suggestion that topical testosterone is less safe than injected esters, as the topical relative risk was 1.27 and the injected ester relative risk was 0.66. This means that if the data were tightly clustered (which is nearly impossible in meta-analysis), that topical use would have a 27 percent GREATER risk of a cardiovascular event (e.g., heart attack, stroke, death), whereas injected esters would have a 34 percent LESSER risk. This is most clearly reported in a study following over 6,000 patients treated with intramuscular (injected) testosterone ester therapy, which showed that intramuscular testosterone therapy did not affect cardiovascular risk EXCEPT for those most at risk.¹⁴ In the men most likely to suffer a cardiovascular event (e.g., heart attack, stroke, death), intramuscular testosterone was PROTECTIVE, with a 31 percent REDUCED likelihood of these events. The next group down (third quartile, or those in the upper half of risk, as opposed to upper quarter) just missed showing a significantly protective effect of the same magnitude.

A second arm of the 35-trial meta-analysis involved looking at how the body handles testosterone delivered topically versus injected.¹³ Testosterone is a prohormone in many tissues, as it can be converted into estradiol or dihydrotestosterone (DHT). Elevated DHT is thought to have an association with increased cardiovascular risk, and the skin is a site with significant 5alpha-reductase activity— the enzyme that converts testosterone to DHT.^15,16 Again, topical testosterone (you know, the supposedly newer, safer and industry-friendly testosterone) increased DHT considerably more than injected testosterone. The increase was over twice as great.

Who Said Topicals Are Safer?

Finally, a study accepted for publication in the American Journal of Physiology - Endocrinology & Metabolism reports on direct comparison of injected testosterone and topical, as it relates to three areas of extreme interest to all men— but more specifically, athletes.¹⁷ These areas are 1) increase in muscle mass and strength; 2) skeletal benefits (i.e., bone density and fracture risk); and 3) safety, with an emphasis on cardiovascular safety.

This meta-analysis deserves to be read by all, but its length and relative complexity may be intimidating to most laymen. It is worthy to note its finding, though, in a thorough manner— as this directly contrasts two of the main arguments that have been directed against the use of testosterone esters: that topical formulations are equivalent therapies and carry less risk. FALSE! … if the findings of this meta-analysis are confirmed in future studies.

It is important to acknowledge that these studies investigated the use of replacement doses, with rare exception. Yet, ask any athlete or bodybuilder who has misused/abused anabolic steroids for the purpose of gaining muscle size and/or strength if they have any affection for the topical agents. Men who have prior exposure to AAS are frequently dissatisfied with topical-based TRT, preferring injections, based upon conversations with several health care providers and patients on TRT. Certainly, many have tried AndroGel, Androderm or Testim, as these drugs are readily prescribed (either directly to the patient or to a third party who diverts the drug to the athlete/bodybuilder). Further, to facilitate access to the topical testosterone products, these specific drugs are commonly the approved product for hospital and insurance provider formularies. One such product, Testoderm, is even exempt from the controlled substance list.¹⁸ It would not be surprising to see others seek the same status.

Returning to the comparative study, the authors note that a loss of muscle mass is a component of aging, affecting primarily the type II (fast-twitch) muscles. This loss is also accompanied by a loss of motor neurons, the nerves that signal muscle action. Muscle mass is restored, even increased during TRT (or AAS misuse) in a dose-dependent manner, as has been noted in several studies and pretty much every gym except for Planet Fitness.^3,19 Interestingly, both type I and type II fibers respond positively to increasing testosterone concentration.

The increase in muscle is most disparate comparing low-dose TRT versus higher-dose protocols. In other words, low-dose TRT combats muscle loss by reducing protein degradation in the muscle; higher-dose TRT not only reduces protein degradation, but also increases muscle protein synthesis through mTOR activation, increasing intracellular IGF-1 and increasing satellite cell proliferation.^20,21 The separate effects of higher-dose TRT not only increase muscle mass, but also raise the ceiling for continued growth.

Modest vs. Moderate Strength Gains

A criticism often voiced in clinical circles regarding injected TRT is that the pattern of release produces a short-lived period of supraphysiologic testosterone concentration in the blood, whereas for topical formulation, the peaks and valleys stay within the normal range. However, it may be that this period of elevated testosterone created by the pharmacokinetics of injected esters (i.e., how they are released into the bloodstream) is actually a benefit that is absent in transdermal (i.e., topical) formulations. Bodybuilders design their muscle-building cycles to avoid allowing the AAS concentration to remain in the supraphysiologic range, avoiding any drop into the normal range. In fact, this observation was made, that strength increases while on TRT were “modest” to insignificant with topical TRT, whereas injected TRT resulted in “moderate” strength gains.^17,22

Bone strength is nowhere near as “sexy” as muscle mass and strength. However, it is a legitimate target for TRT. Aging men suffer osteopenia, much like menopausal women, which can lead to an increased risk of fracture (broken bone). It is interesting again, that low-dose TRT requires testosterone to aromatize (convert into estradiol, the female sex steroid) in bone to provide full protection, whereas higher-dose TRT does not. Again, in comparing the results of numerous studies, injected TRT produced an increase in bone mineral density (a measure of bone strength) of upward to 10 percent, whereas topical TRT provided no benefit.²³

Lastly, the safety of a therapy is always of paramount importance. Testosterone replacement therapy, occurring primarily in late middle-aged and elderly men, carries three confirmed adverse events (i.e., side effects): increase in red blood cell concentration, or hematocrit; prostate events; and a small reduction in HDL, or good cholesterol. Briefly, TRT does not increase the risk of prostate cancer, despite the decades-long belief.²⁴ The relative effect between injected TRT and topical TRT on red blood cell production, prostate effects and natural testosterone production have not been studied.¹⁷

The advent of topically delivered TRT is a welcome option for most clinicians. However, the advantage lies primarily in convenience, and avoiding the discomfort of an intramuscular injection. Further, it appears that the advocates of topical TRT may have misspoken in regard to equivalent benefits, and greater safety based upon these reviews. There has been enough time for post-marketing surveillance to determine any advantages or safety risks associated with the various products on the market. At this time, there appears to be distinct advantages to the “tried-and-true” injectable esters.

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