Written by Dr. Jose Antonio, MD
30 October 2006

  Anabolic Alphabet Soup: NO, T, FFM and AR

 

Rho-kinase Inhibitor Real Deal for NO

You've heard the hype. Take supplement xyz and regulate nitric oxide (NO) levels in your body. Your muscles will grow, your private parts will grow, your mother-in-law will like you, your pet beagle... blah blah... it'll just do everything.  Well, back to reality Spock. However, there are substances that do actually modulate NO and do it quite significantly. For instance, androgens (especially testosterone) act as strong modulators of erectile function influencing both nitric oxide and vasoconstrictor signaling. What happens if you cut off your testicles (hypothetically speaking)?

It results in a depressed erectile response; this is due in part to a loss of nitric oxide production and increased responsiveness to constrictive agents.  The mechanism for this is related to what scientists call the RhoA/Rho-kinase signaling pathway. Guess what happens if you inhibit the Rho-kinase pathway? 

Scientists have discovered a Rho-kinase inhibitor that they've termed Y-27632. In a recent animal study, castration reduced the maximal erectile response by 33 percent and testosterone replacement restored the response.  Injection of Y-27632 increased the erectile response in all experimental groups; the active Rho/Rho-kinase pathway contributes to the reduced erectile response after castration due to an upregulation of RhoA/Rho-kinase protein levels. Furthermore, giving T or better yet, giving Y-27632, was an effective treatment resulting in a robust erectile response. 

 

Ideal T Dose for Oldies

            This is about living on the anabolic edge. What happens if you give 60 healthy, older men (60-75 years of age) a long-acting GnRH (gonadotropic-releasing hormone) agonist to suppress endogenous testosterone production and either 25, 50, 125, 300, or 600 milligrams of testosterone enanthate weekly for 20 weeks? Researchers measured a gamut of things including fat free (FFM) and fat mass, muscle strength, sexual function, mood, visuospatial cognition, hormone levels and safety measures; these were evaluated before, during and after treatment.

Of the 60 older men who were randomized, 52 completed the study. After adjusting for testosterone dose, changes in serum total testosterone (change

-6.8, -1.9, +16.1, +49.5, and +101.9 nmol/L, at 25, 50, 125, 300 at 600 mg* per week, respectively) and hemoglobin (change -3.6, +9.9, +20.9, +12.6, +29.4 g/L at 25, 50, 125, 300, and 600 mg*wk(-1), respectively) levels were dose-related in older men and significantly greater in older men than young men. The changes in FFM (-0.3, +1.7, +4.2, +5.6, +7.3 kg, respectively in five ascending dose groups) and muscle strength in older men were correlated with testosterone dose and concentrations, and were not significantly different in young and older men. So, basically, starting at the low dose of 50 milligrams per week (minimal dose required to even get a slight increase) to 600 milligrams per week, you have an FFM gain that ranged from 3.7 pounds to 16.1 pounds. Not too shabby. 

            Also fat mass decreased more as doses of T went up. Oddly enough, young men receiving 25- and 50-milligram doses gained more fat mass than older men. Sexual function, mood and visuospatial cognition did not change significantly in either group. However, side effects were higher in older men.  For instance, frequency of hematocrit greater than 54 percent, leg edema and prostate events was numerically higher in older men than in young men. So, what's the bottom line?

According to the study's authors, "Older men are as responsive as young men to testosterone's anabolic effects; however, older men have lower testosterone clearance rates, higher increments in hemoglobin and a higher frequency of adverse effects. Although substantial gains in muscle mass and strength can be realized in older men with supra-physiological testosterone doses, these high doses are associated with high frequency of adverse effects. The best trade-off was achieved with a testosterone dose (125 milligrams) that was associated with high normal testosterone levels, low frequency of adverse events and significant gains in fat-free mass and muscle strength."Thus, if you are looking for an ideal dose, at least in older men, 125 milligrams of T enanthate per week might be your best bet.

 

Andro for the Gonadally Challenged

In general, you'll find that past studies of delta4-androstene-3,17-dione (4-androstenedione) administration in men have shown few significant effects on testosterone levels, fat-free mass (FFM) and muscle strength. To determine whether 4-androstenedione has androgenic/anabolic properties, scientists evaluated its association with androgen receptor (AR) and its effects on myogenesis (the formation of skeletal muscle) in vitro (in test tubes). Furthermore, they determined the effects of a high dose of 4-androstenedione on testosterone levels, FFM and muscle strength in hypogonadal men. OK, so keep in mind that in the parlance of the Governor of California these are "girlie-men."

 High dose androstenedione (500 milligrams thrice daily) was given for 12 weeks; scientists measured FFM, muscle strength and hormone levels in nine healthy, hypogonadal men. What happened? At the cellular level, "andro" definitely "acts" like an androgen. They fund that it binds to the androgen receptor, or AR, induces AR-nuclear translocation and promotes myogenesis in vitro with substantially lower potency than DHT or dihydrotestosterone. So, it's a weak androgen.

On the practical side, taking 1,500 milligrams of 4-androstenedione daily significantly increased serum androstenedione, total and free testosterone, estradiol and estrone levels, and suppressed SHBG and HDL cholesterol levels. 4-Androstenedione administration was associated with significant gains in fat-free mass (3.7 pounds) and muscle strength in the bench press (9.5 pounds) and leg press exercises (41.4 pounds).3 

Similar to what I have personally observed in young athletic women, andro does work. It's not the best androgen out there (and it's pretty much useless if your ‘nads are in working order), but for older men and for women, andro can exert anabolic properties.

 

            Protein and Bones

Scientists ascertained the effect of a high-protein diet on calcium kinetics in women. The study consisted of two weeks of a lead-in, well-balanced diet followed by 10 days of an experimental diet containing either moderate (1.0 grams per kilogram of bodyweight [g/kg]) or high (2.1 g/kg) protein. Thirteen healthy women received both levels of protein in random order. What did they find?

Intestinal calcium absorption increased during the high-protein diet in comparison to the moderate as did urinary calcium. So, basically, more protein equals more calcium absorbed and more calcium excreted. Basically, there were no protein induced effects on net bone balance. So, at least in the short term, according to this study, high protein diets are not detrimental to bone.4  

 

References

1.         Wingard, C.J., et al., Improved erectile function after Rho-kinase inhibition in a rat castrate model of erectile dysfunction. Am J Physiol Regul Integr Comp Physiol, 2003. 284(6): p. R1572-9.

2.         Bhasin, S., et al., Older Men are as Responsive as Young Men to the Anabolic Effects of Graded Doses of Testosterone on the Skeletal Muscle. J Clin Endocrinol Metab, 2004.

3.         Jasuja, R., et al., Delta-4-androstene-3,17-dione (4-androstenedione) Binds Androgen Receptor, Promotes Myogenesis in Vitro, and Increases Serum Testosterone Levels, Fat-Free Mass, and Muscle Strength in Hypogonadal Men. J Clin Endocrinol Metab, 2004.

4.         Kerstetter, J.E., et al., The impact of dietary protein on calcium absorption and kinetic measures of bone turnover in women. J Clin Endocrinol Metab, 2004.

 

STEPHEN: THIS MAY BE A NEW BIO.

Jose Antonio, PhD, is the CEO of the International Society of Sports Nutrition (http://www.sportsnutritionsociety.org/) as well as the Chief Science Officer of Javalution Coffee Company (http://www.javafit.com/).