Oral Testosterone, Long Acting
Sometimes, genius is seeing something others miss; sometimes, geniuses see things that aren’t there. No, this isn’t an article about deficit spending by the federal government; it is about a testosterone delivery product investigated in the laboratories of pharmaceutical giant GlaxoSmithKline (GSK).
The history of androgen physiology is well over a century old. To understand the more modern history of androgen pharmacology, one needs to read the seminal work by Charles D. Kochakian, “How It Was; Anabolic Action of Steroids and Remembrances.”1 With this foundation in the genesis of androgenic-anabolic steroids (AAS), later developments along the AAS timeline are readily grasped.
The earliest attempts to manipulate the androgenic environ likely predate written history. In patriarchal societies and cultures, male characteristics are seen as a measure of power and dominance, as well as sexual potency and desirability. Warriors in primitive cultures consumed organs representing the vitality and virility of conquered prey or enemies, such as the liver, heart, and testes. Though some believe in the animistic powers of these organs, the soulless analysis of modern science suggests that any benefits are the product of expectation, similar to the placebo effect.
Even today, hope persists due to tradition, optimism, or just good humor. Attempts to bolster libido, erectile function, or physical strength through the consumption of phallic-shaped plants, oysters, or the testes of sheep and cattle are common. Many small towns hold an annual “testicle festival,” to the dismay of local bulls. “Fight Club” author Chuck Palahniuk chronicles his observations and the hedonistic experiences of gonad gobblers at the Rock Creek Lodge (Montana) event with his signature style in Stranger than Fiction: True Stories.2 Tables of testicles notwithstanding, the debaucheries are a result of momentary moral breakdown and prolonged intoxication, not dietary testosterone.
Testosterone and other androgens that were initially isolated have been given in experiments, demonstrating the ability of naturally produced steroids to restore male traits to castrated animals.3 Yet, as men attempted to use these natural hormones, it was soon discovered that the effects of these chemicals were very short lived, whether injected or ingested (swallowed). Current AAS are altered forms of testosterone, designed to prolong the androgenic and anabolic effects; some are also more specific in providing anabolic actions (muscle building), rather than androgenic effects (sexual function or characteristics).4,5
Most recreational AAS users gravitate toward injectable versions, as the effects are longer lasting and do not have the liver toxicity that is inherent with nearly all oral forms. Yet, there is no denying the desirable features of oral AAS, as oral AAS provide quicker results, are much more convenient, and painless. However, without certain protections, AAS are rapidly degraded by enzymes in the small intestine and liver.6-8 Thus, chemists created a library of oral AAS by attaching side chains or creating new bonds to the steroid molecule (i.e., testosterone, nortestosterone).
As it is known that the chemical modification applied to most oral AAS, called 17 alpha-alkylation, places great metabolic strain on the liver and is associated with benign and malignant tumors, clinical medicine has long avoided prescribing these agents.9 An oral AAS that bypasses the enzymatic deactivation of the liver, called “first-pass clearance,” is Andriol (testosterone undecanoate). This drug attaches a long-chain ester group, exactly as is done with injectable AAS. The ester chain used in Andriol is 11 carbons long, nearly twice that of common testosterone esters (e.g., cypionate, enanthate). By attaching testosterone to the undecanoate chain, Andriol enters the lymphatic circulation, much like sneaking through the sewers, before being dumped directly into the systemic circulation. Despite reported clinical effectiveness, recreational AAS users have little regard for Andriol, due to its curiously limited anabolic effect.
The direction in oral anabolic drug development appears to be toward selective androgen receptor modulators (SARMs).10 Yet, one lab in the complex that is GSK is taking a step backward (actually two skips and a hop) in attempting to deliver unmodified testosterone orally. Rather than protecting the steroid molecule, allowing a small dose to provide a clinically effective androgenic/anabolic response (i.e., 5 mg methandrostenolone, 2-4 mg stanozolol, 2.5-5 mg oxandrolone), GSK is considering forcing a huge dose of testosterone into the system (300 mg twice a day). The method that GSK is attempting to profit from is delayed or prolonged-release delivery.
When testosterone is ingested (swallowed), it rapidly enters the portal circulation (the blood supply that drains the intestines and is immediately filtered by the liver), and may have a sharp but short-lived peak in the systemic circulation that feeds skeletal muscle and other tissues. Taking non-modified testosterone orally may have absolutely no effect on circulating testosterone concentration, as evidenced by a recent study providing up to 80 mg of oral testosterone to hypogonadal men.11 The advantage to orally delivered testosterone is that the amount of testosterone that survives first-pass clearance is immediately available, and provides a maximal, short-lived anabolic signal. Unfortunately, the wild swing up can cause certain adverse effects (e.g., mood disorders) if it results in a supraphysiologic (higher than normal) peak, and the potential rapid drop below normal induces other, equally negative changes.
To take advantage of the safe delivery of oral, non-modified testosterone, in which 17alpha-alkylation associated elevation in liver enzymes or other signs or organotoxicity is absent, yet avoid the dramatic swings in circulating testosterone concentration, GSK applied two modes of delayed-release tablets in a study accepted for publication in the Journal of Andrology.12 To compare the relative effects, they compared the changes in blood concentration over time in a group of men who had been chemically castrated.
Chemical castration is the intentional suppression of natural testosterone production by administering one of several drugs that shut down the LH signal from the pituitary. This is done in hormone studies to remove the variability of blood concentration of testosterone between subjects due to individual differences in testosterone production and timing of the blood draw.13 When all subjects are held at very low and non-varying “steady state” of testosterone, then any change in testosterone concentration can be assumed to be due to the ingested drug.
Now that the stage has been set, the subjects were chemically castrated (a kinder, gentler castration) with acyline, a drug that suppresses testosterone production for up to two weeks. They were then divided into two groups; one receiving testosterone only (T), the other receiving 1 mg finasteride daily in addition (TF). Finasteride is a type 2 5alpha-reductase inhibitor that blocks the conversion of testosterone into its more androgenic metabolite, DHT. Interestingly, use of dutasteride, a 5alpha-reductase inhibitor that inhibits both type 1 and type 2, was too potent, suppressing DHT below the physiologic range of normal.14 Another point of interest is the belief that most of the benefits and advantages of SARMs are due to their avoidance of 5alpha-reductase.15 Using finasteride, or dutasteride, essentially turns testosterone into a SARM.
Both groups were followed for two weeks. They received a 300-mg dose of testosterone on days 2, 3 and 4 that consisted of testosterone, modified-fast release testosterone, and modified-slow release testosterone, respectively. On days 8, 9, and 11, they received a 600-mg dose in the same order. The delay between day 9 and day 11 was to ensure the modified-fast testosterone dose of 600 mg had cleared the system.12
The authors reported findings that were as expected. The acyline reduced serum (blood) testosterone concentration to 2.0 nmol/L (group T) and 2.3 nmol/L (group TF), respectively (lower limit of normal in this assay is 6.8 nmol/L). All mega-doses of testosterone resulted in increased serum testosterone, with the slowly released forms giving peaks later, versus the relatively immediate response of testosterone.
By 10 hours post-dose, serum testosterone was back below the lower limit of normal, regardless of how the testosterone was delivered. When administered in the finasteride group (TF), the immediate release form of testosterone resulted in a peak concentration slightly above the upper limit of normal for approximately an hour, and the modified fast-release form produced an average concentration well above normal that lasted nearly six hours in two subjects, throwing off the results as they were weirdly high by a factor of five to 10.
The duration of effect, being able to maintain a physiologic concentration of testosterone, was extended two hours with values falling below normal by the 12-hour measurement. The 600-mg dose provided a greater peak than the 300-mg dose in all forms, with all but the slow-release testosterone-only group exceeding the normal range. The finasteride group saw elevations above the upper limit of normal last up to six hours.
As the 600-mg dose resulted in supraphysiologic elevations in all groups, the remainder of the study was limited to the 300-mg groups. The further findings reported were as expected, with the finasteride preventing a treatment related elevation in DHT (the androgenic metabolite of testosterone that causes hair loss, prostate enlargement, etc.) seen in the testosterone-only group.
Perhaps the most curious finding was that estradiol (an estrogen) concentration never fell below the normal range, despite testosterone being suppressed. Further, in the finasteride group, estradiol concentration exceeded the upper limit of normal, remaining supraphysiologic longer than testosterone remained physiologic. This places future patients at risk of potential estrogenic side effects.12
The authors seemed encouraged by the findings of this treatment format (slow-release testosterone along with finasteride). Frankly, it seems archaic and fails greatly in comparison to existing drugs and other testosterone delivery modalities. In addition to potentially exposing men to dramatic swings in peripheral testosterone concentration, as well as supraphysiologic elevations in estrogen, it would need to be individually titrated to each patient, which is time-intensive, expensive, and inconvenient.
There are several options in existence that would allow for convenient delivery of testosterone and other androgens. Injectable testosterone undecanoate has been used for years in many countries with a highly favorable clinical and patient-centric experience base, allowing for consistent concentrations of testosterone over 12 weeks.16 Many AAS are SARMs, being developed to provide a greater anabolic:androgenic ratio of effect, specifically nandrolone. SARMs in development appear to be effective, apparently avoiding much of the androgenic effect by not interacting with 5alpha-reductase. Even the use of 5alpha-reductase inhibitors combined with low-dose aromatase inhibitors may hold more appeal for borderline low and hypogonadal men, particularly finasteride, as it is now available as a generic.
For the bodybuilder and other recreational users, there really isn’t much here except for confirmation that non-modified testosterone is rapidly degraded and ineffective, unless taken in mega-doses. Though it may seem like taking 1 mg of finasteride and possibly 0.5 mg of anastrozole may be a simple way to increase natural testosterone or the potency of an AAS cycle (a practice that is common among many higher-caliber bodybuilders), it is not without potential risk. Using non-modified, or even the prolonged-release form of testosterone is unlikely to provide acceptable results for illicit users. The dosing schedule will require taking the drug at least twice daily, if not three times daily, with subphysiologic trough values. As with any other AAS, this would suppress natural testosterone production. The observation noted of supraphysiologic estradiol values when finasteride is combined with testosterone would likely lead to feminizing side effects (e.g., gynecomastia), unless aromatase activity is blocked.
It is unclear why this study was performed; perhaps it was an attempt to find a drug candidate for an existing drug delivery platform. The results and methods are archaic, rather than innovative, and there is no practical advantage in this drug product over many existing options.
References:
1. Kochakian CD. How It Was; Anabolic Action of Steroids and Remembrances, Birmingham: University of Alabama School of Medicine, 1984. ASIN: B0006EF59G.
2. Palahniuk C. Stranger Than Fiction: True Stories, New York: Doubleday, 2004. ISBN-13: 978-0385504485.
3. Dorfman RI. Studies on the bioassay of hormones; the relative reactivity of the comb of various breeds of chicks to androgens. Endocrinology, 1948;42(1-6):7-14.
4. Foss GL. Some experiences with a new anabolic steroid (methandrostenolone). Br Med J, 1960 Apr 30;1(5182):1300-5.
5. Shahidi NT. A review of the chemistry, biological action, and clinical applications of anabolic-androgenic steroids. Clin Ther, 2001 Sep;23(9):1355-90.
6. Kaminsky LS, Fasco MJ. Small intestinal cytochromes P450. Crit Rev Toxicol, 1991;21(6):407-22.
7. Kato M. Intestinal first-pass metabolism of CYP3A4 substrates. Drug Metab Pharmacokinet, 2008;23(2):87-94.
8. von Richter O, Burk O, et al. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther, 2004 Mar;75(3):172-83.
9. No authors listed. Hepatic effects of 17 alpha-alkylated anaboli-androgenic steroids. HIV Hotline, 1998 Dec;8(5-6):2-5.
10. Bhasin S, Jasuja R. Selective androgen receptor modulators as function promoting therapies. Curr Opin Clin Nutr Metab Care, 2009 May;12(3):232-40.
11. Birzniece V, Meinhardt UJ, et al. Testosterone stimulates extra-hepatic but not hepatic fat oxidation (Fox): comparison of oral and transdermal testosterone administration in hypopituitary men. Clin Endocrinol, (Oxf) 2009 Nov;71(5):715-21.
12. Snyder CN, Clark RV, et al. Pharmacokinetics of Two Novel Formulations of Modified Release Oral Testosterone Alone and with Finasteride in Normal Men with Experimental Hypogonadism. J Androl, 2010 May 13. [Epub ahead of print]
13. Page ST, Lin DW, et al. Persistent intraprostatic androgen concentrations after medical castration in healthy men. J Clin Endocrinol Metab, 2006 Oct;91(10):3850-6.
14. Page ST, Bremner WJ, et al. Nanomilled oral testosterone plus dutasteride effectively normalizes serum testosterone in normal men with induced hypogonadism. J Androl, 2008 Mar-Apr;29(2):222-7.
15. Gao W, Dalton JT. Ockham's razor and selective androgen receptor modulators (SARMs): are we overlooking the role of 5alpha-reductase? Mol Interv, 2007 Feb;7(1):10-3.
16. 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]
Sometimes, genius is seeing something others miss; sometimes, geniuses see things that aren’t there. No, this isn’t an article about deficit spending by the federal government; it is about a testosterone delivery product investigated in the laboratories of pharmaceutical giant GlaxoSmithKline (GSK).
The history of androgen physiology is well over a century old. To understand the more modern history of androgen pharmacology, one needs to read the seminal work by Charles D. Kochakian, “How It Was; Anabolic Action of Steroids and Remembrances.”1 With this foundation in the genesis of androgenic-anabolic steroids (AAS), later developments along the AAS timeline are readily grasped.
The earliest attempts to manipulate the androgenic environ likely predate written history. In patriarchal societies and cultures, male characteristics are seen as a measure of power and dominance, as well as sexual potency and desirability. Warriors in primitive cultures consumed organs representing the vitality and virility of conquered prey or enemies, such as the liver, heart, and testes. Though some believe in the animistic powers of these organs, the soulless analysis of modern science suggests that any benefits are the product of expectation, similar to the placebo effect.
Even today, hope persists due to tradition, optimism, or just good humor. Attempts to bolster libido, erectile function, or physical strength through the consumption of phallic-shaped plants, oysters, or the testes of sheep and cattle are common. Many small towns hold an annual “testicle festival,” to the dismay of local bulls. “Fight Club” author Chuck Palahniuk chronicles his observations and the hedonistic experiences of gonad gobblers at the Rock Creek Lodge (Montana) event with his signature style in Stranger than Fiction: True Stories.2 Tables of testicles notwithstanding, the debaucheries are a result of momentary moral breakdown and prolonged intoxication, not dietary testosterone.
Testosterone and other androgens that were initially isolated have been given in experiments, demonstrating the ability of naturally produced steroids to restore male traits to castrated animals.3 Yet, as men attempted to use these natural hormones, it was soon discovered that the effects of these chemicals were very short lived, whether injected or ingested (swallowed). Current AAS are altered forms of testosterone, designed to prolong the androgenic and anabolic effects; some are also more specific in providing anabolic actions (muscle building), rather than androgenic effects (sexual function or characteristics).4,5
Most recreational AAS users gravitate toward injectable versions, as the effects are longer lasting and do not have the liver toxicity that is inherent with nearly all oral forms. Yet, there is no denying the desirable features of oral AAS, as oral AAS provide quicker results, are much more convenient, and painless. However, without certain protections, AAS are rapidly degraded by enzymes in the small intestine and liver.6-8 Thus, chemists created a library of oral AAS by attaching side chains or creating new bonds to the steroid molecule (i.e., testosterone, nortestosterone).
As it is known that the chemical modification applied to most oral AAS, called 17 alpha-alkylation, places great metabolic strain on the liver and is associated with benign and malignant tumors, clinical medicine has long avoided prescribing these agents.9 An oral AAS that bypasses the enzymatic deactivation of the liver, called “first-pass clearance,” is Andriol (testosterone undecanoate). This drug attaches a long-chain ester group, exactly as is done with injectable AAS. The ester chain used in Andriol is 11 carbons long, nearly twice that of common testosterone esters (e.g., cypionate, enanthate). By attaching testosterone to the undecanoate chain, Andriol enters the lymphatic circulation, much like sneaking through the sewers, before being dumped directly into the systemic circulation. Despite reported clinical effectiveness, recreational AAS users have little regard for Andriol, due to its curiously limited anabolic effect.
The direction in oral anabolic drug development appears to be toward selective androgen receptor modulators (SARMs).10 Yet, one lab in the complex that is GSK is taking a step backward (actually two skips and a hop) in attempting to deliver unmodified testosterone orally. Rather than protecting the steroid molecule, allowing a small dose to provide a clinically effective androgenic/anabolic response (i.e., 5 mg methandrostenolone, 2-4 mg stanozolol, 2.5-5 mg oxandrolone), GSK is considering forcing a huge dose of testosterone into the system (300 mg twice a day). The method that GSK is attempting to profit from is delayed or prolonged-release delivery.
When testosterone is ingested (swallowed), it rapidly enters the portal circulation (the blood supply that drains the intestines and is immediately filtered by the liver), and may have a sharp but short-lived peak in the systemic circulation that feeds skeletal muscle and other tissues. Taking non-modified testosterone orally may have absolutely no effect on circulating testosterone concentration, as evidenced by a recent study providing up to 80 mg of oral testosterone to hypogonadal men.11 The advantage to orally delivered testosterone is that the amount of testosterone that survives first-pass clearance is immediately available, and provides a maximal, short-lived anabolic signal. Unfortunately, the wild swing up can cause certain adverse effects (e.g., mood disorders) if it results in a supraphysiologic (higher than normal) peak, and the potential rapid drop below normal induces other, equally negative changes.
To take advantage of the safe delivery of oral, non-modified testosterone, in which 17alpha-alkylation associated elevation in liver enzymes or other signs or organotoxicity is absent, yet avoid the dramatic swings in circulating testosterone concentration, GSK applied two modes of delayed-release tablets in a study accepted for publication in the Journal of Andrology.12 To compare the relative effects, they compared the changes in blood concentration over time in a group of men who had been chemically castrated.
Chemical castration is the intentional suppression of natural testosterone production by administering one of several drugs that shut down the LH signal from the pituitary. This is done in hormone studies to remove the variability of blood concentration of testosterone between subjects due to individual differences in testosterone production and timing of the blood draw.13 When all subjects are held at very low and non-varying “steady state” of testosterone, then any change in testosterone concentration can be assumed to be due to the ingested drug.
Now that the stage has been set, the subjects were chemically castrated (a kinder, gentler castration) with acyline, a drug that suppresses testosterone production for up to two weeks. They were then divided into two groups; one receiving testosterone only (T), the other receiving 1 mg finasteride daily in addition (TF). Finasteride is a type 2 5alpha-reductase inhibitor that blocks the conversion of testosterone into its more androgenic metabolite, DHT. Interestingly, use of dutasteride, a 5alpha-reductase inhibitor that inhibits both type 1 and type 2, was too potent, suppressing DHT below the physiologic range of normal.14 Another point of interest is the belief that most of the benefits and advantages of SARMs are due to their avoidance of 5alpha-reductase.15 Using finasteride, or dutasteride, essentially turns testosterone into a SARM.
Both groups were followed for two weeks. They received a 300-mg dose of testosterone on days 2, 3 and 4 that consisted of testosterone, modified-fast release testosterone, and modified-slow release testosterone, respectively. On days 8, 9, and 11, they received a 600-mg dose in the same order. The delay between day 9 and day 11 was to ensure the modified-fast testosterone dose of 600 mg had cleared the system.12
The authors reported findings that were as expected. The acyline reduced serum (blood) testosterone concentration to 2.0 nmol/L (group T) and 2.3 nmol/L (group TF), respectively (lower limit of normal in this assay is 6.8 nmol/L). All mega-doses of testosterone resulted in increased serum testosterone, with the slowly released forms giving peaks later, versus the relatively immediate response of testosterone.
By 10 hours post-dose, serum testosterone was back below the lower limit of normal, regardless of how the testosterone was delivered. When administered in the finasteride group (TF), the immediate release form of testosterone resulted in a peak concentration slightly above the upper limit of normal for approximately an hour, and the modified fast-release form produced an average concentration well above normal that lasted nearly six hours in two subjects, throwing off the results as they were weirdly high by a factor of five to 10.
The duration of effect, being able to maintain a physiologic concentration of testosterone, was extended two hours with values falling below normal by the 12-hour measurement. The 600-mg dose provided a greater peak than the 300-mg dose in all forms, with all but the slow-release testosterone-only group exceeding the normal range. The finasteride group saw elevations above the upper limit of normal last up to six hours.
As the 600-mg dose resulted in supraphysiologic elevations in all groups, the remainder of the study was limited to the 300-mg groups. The further findings reported were as expected, with the finasteride preventing a treatment related elevation in DHT (the androgenic metabolite of testosterone that causes hair loss, prostate enlargement, etc.) seen in the testosterone-only group.
Perhaps the most curious finding was that estradiol (an estrogen) concentration never fell below the normal range, despite testosterone being suppressed. Further, in the finasteride group, estradiol concentration exceeded the upper limit of normal, remaining supraphysiologic longer than testosterone remained physiologic. This places future patients at risk of potential estrogenic side effects.12
The authors seemed encouraged by the findings of this treatment format (slow-release testosterone along with finasteride). Frankly, it seems archaic and fails greatly in comparison to existing drugs and other testosterone delivery modalities. In addition to potentially exposing men to dramatic swings in peripheral testosterone concentration, as well as supraphysiologic elevations in estrogen, it would need to be individually titrated to each patient, which is time-intensive, expensive, and inconvenient.
There are several options in existence that would allow for convenient delivery of testosterone and other androgens. Injectable testosterone undecanoate has been used for years in many countries with a highly favorable clinical and patient-centric experience base, allowing for consistent concentrations of testosterone over 12 weeks.16 Many AAS are SARMs, being developed to provide a greater anabolic:androgenic ratio of effect, specifically nandrolone. SARMs in development appear to be effective, apparently avoiding much of the androgenic effect by not interacting with 5alpha-reductase. Even the use of 5alpha-reductase inhibitors combined with low-dose aromatase inhibitors may hold more appeal for borderline low and hypogonadal men, particularly finasteride, as it is now available as a generic.
For the bodybuilder and other recreational users, there really isn’t much here except for confirmation that non-modified testosterone is rapidly degraded and ineffective, unless taken in mega-doses. Though it may seem like taking 1 mg of finasteride and possibly 0.5 mg of anastrozole may be a simple way to increase natural testosterone or the potency of an AAS cycle (a practice that is common among many higher-caliber bodybuilders), it is not without potential risk. Using non-modified, or even the prolonged-release form of testosterone is unlikely to provide acceptable results for illicit users. The dosing schedule will require taking the drug at least twice daily, if not three times daily, with subphysiologic trough values. As with any other AAS, this would suppress natural testosterone production. The observation noted of supraphysiologic estradiol values when finasteride is combined with testosterone would likely lead to feminizing side effects (e.g., gynecomastia), unless aromatase activity is blocked.
It is unclear why this study was performed; perhaps it was an attempt to find a drug candidate for an existing drug delivery platform. The results and methods are archaic, rather than innovative, and there is no practical advantage in this drug product over many existing options.
References:
1. Kochakian CD. How It Was; Anabolic Action of Steroids and Remembrances, Birmingham: University of Alabama School of Medicine, 1984. ASIN: B0006EF59G.
2. Palahniuk C. Stranger Than Fiction: True Stories, New York: Doubleday, 2004. ISBN-13: 978-0385504485.
3. Dorfman RI. Studies on the bioassay of hormones; the relative reactivity of the comb of various breeds of chicks to androgens. Endocrinology, 1948;42(1-6):7-14.
4. Foss GL. Some experiences with a new anabolic steroid (methandrostenolone). Br Med J, 1960 Apr 30;1(5182):1300-5.
5. Shahidi NT. A review of the chemistry, biological action, and clinical applications of anabolic-androgenic steroids. Clin Ther, 2001 Sep;23(9):1355-90.
6. Kaminsky LS, Fasco MJ. Small intestinal cytochromes P450. Crit Rev Toxicol, 1991;21(6):407-22.
7. Kato M. Intestinal first-pass metabolism of CYP3A4 substrates. Drug Metab Pharmacokinet, 2008;23(2):87-94.
8. von Richter O, Burk O, et al. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther, 2004 Mar;75(3):172-83.
9. No authors listed. Hepatic effects of 17 alpha-alkylated anaboli-androgenic steroids. HIV Hotline, 1998 Dec;8(5-6):2-5.
10. Bhasin S, Jasuja R. Selective androgen receptor modulators as function promoting therapies. Curr Opin Clin Nutr Metab Care, 2009 May;12(3):232-40.
11. Birzniece V, Meinhardt UJ, et al. Testosterone stimulates extra-hepatic but not hepatic fat oxidation (Fox): comparison of oral and transdermal testosterone administration in hypopituitary men. Clin Endocrinol, (Oxf) 2009 Nov;71(5):715-21.
12. Snyder CN, Clark RV, et al. Pharmacokinetics of Two Novel Formulations of Modified Release Oral Testosterone Alone and with Finasteride in Normal Men with Experimental Hypogonadism. J Androl, 2010 May 13. [Epub ahead of print]
13. Page ST, Lin DW, et al. Persistent intraprostatic androgen concentrations after medical castration in healthy men. J Clin Endocrinol Metab, 2006 Oct;91(10):3850-6.
14. Page ST, Bremner WJ, et al. Nanomilled oral testosterone plus dutasteride effectively normalizes serum testosterone in normal men with induced hypogonadism. J Androl, 2008 Mar-Apr;29(2):222-7.
15. Gao W, Dalton JT. Ockham's razor and selective androgen receptor modulators (SARMs): are we overlooking the role of 5alpha-reductase? Mol Interv, 2007 Feb;7(1):10-3.
16. 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]
