Written by Jose Antonio, Ph.D.
06 April 2007

You’ve heard the hype.  Take supplement xyz and regulate nitric oxide levels in your body.  You’re 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 (esp. testosterone) acts 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 termed Y-27632.   In a recent animal study, castration reduced the maximal erectile response by 33%, 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.[1]T Dose of 125 mg Ideal for OldiesLiving on the anabolic edge; what happens of you give 60 healthy, older men (60-75 yr of age) a long-acting GnRH (gonadotropic-releasing hormone) agonist to suppress endogenous testosterone production and either 25, 50, 125, 300, or 600 mg testosterone enanthate weekly for 20 weeks.  They measured a gamut of things including fat free (FFM) and fat mass, muscle strength, sexual function, mood, visuospatial cognition, hormone levels, and safety measures were evaluated before, during and after treatment. Of 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 mg per week (the minimal dose required to even get a slight increase) to 600 mg per week you have a FFM gain that ranged from 3.7 pounds to 16.1 pounds.  Not too shabby.     

Also fat mass decreased more so as doses of T went up.  Oddly enough, young men receiving 25 and 50 mg 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 >54%, 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 supraphysiological testosterone doses, these high doses are associated with high frequency of adverse effects. The best trade-off was achieved with a testosterone dose (125 mg) that was associated with high normal testosterone levels, low frequency of adverse events and significant gains in fat-free mass and muscle strength.”[2]  Thus, if you are looking for an ideal dose, at least in older men, 125 mg of T enanthate per week might be your best bet.

Andro works in the gonadally challenged
In general, you’ll find that past studies of delta4-androstene-3,17-dione (4-androstenedione) administration in men have shown little 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 in vitro. Furthermore, they determined the effects of a high dose of 4-androstenedione on testosterone levels, FFM, and muscle strength in hypogonadal men. Okay, so keep in mind these are in the parlance of the governor of California, ‘girlie-men.’

High dose androstenedione (500 mg 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 (the formation of skeletal muscle) in vitro (in test tubes), with substantially lower potency than DHT or dihydrotestosterone.  So it’s a weak androgen.

On the practical side of things, taking 1500 mg 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 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 2 weeks of a lead-in, well-balanced diet followed by 10 days of an experimental diet containing either moderate (1.0 g/kg) or high (2.1 g/kg) protein. Thirteen healthy women received both levels of protein in random order. And 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.