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Testosterone Thresholds and Muscle Mass Gains Needed to Enhance Muscle Strength and Function

In a previous article "Combined Testosterone and GH therapy for best results on body composition and safety profiles" I covered a study showing that testosterone replacement therapy alone produced significant gains in total lean body mass, leg/arm muscle mass, strength and aerobic endurance, together with significant reductions in whole-body and trunk fat. [1] 
In the same study, addition of GH (growth hormone) further enhanced these beneficial results. 
In a follow-up to that that study, the researchers looked deeper into the data with the following analyses: [20] 
- Pathway analysis to test the hypothesis that testosterone and GH affected muscle mass directly and that a threshold change in lean tissue (muscle) mass was needed to generate significant improvements in muscle performance and physical function. 
- Bootstrap analysis to determine threshold hormone levels associated with threshold changes in whole-body and appendicular lean mass that would be necessary for improving muscle performance and functional outcomes.
Here I report on the results of this insighful analysis...
Threshold gain in lean tissue and muscle mass needed for improvements in muscle performance and physical function
The pathway analysis confirmed the hypothesis that increases in testosterone and IGF-1 concentrations in older men were robustly associated with gains in total lean body mass and leg/arm muscle mass but were not directly related to the demonstrable improvements in muscle performance or physical function. In contrast, the global enhancements in maximal strength of the major muscle groups of the upper and lower body along with significant increases in stair climbing power were directly related to increases in lean tissue mass.[20] 
Independently, increases in testosterone levels were directly related to increases in physical activity levels (assessed by the Physical Activity Scale of the Elderly, PASE), but the pathway analysis indicated that the increase in physical activity levels was not related to increases in muscle mass or performance per se.[20] 
It may be speculated that the increase in physical activity levels seen with testosterone replacement therapy may be more related to an improved state of mood and well-being, or a feeling of being more “energized” and less fatigued, which is commonly reported by men who are treated with testosterone replacement therapy. [2-7] Androgens, by improving mitochondrial function, control the sense of energy and vitality, and the “pick-up-and-go” mentality (as well as possibly influences the pathogenesis of insulin resistance, type 2 diabetes and cardiovascular disease).[8] 
Increases in total lean body mass (LBM) of 3.3 lb (1.5 kg) and leg/arm muscle mass (appendicular skeletal muscle mass, ASMM) of 1.8 lb (0.8 kg) were needed to achieve significant improvements in maximal strength (mean 31%) as determined by 1-RM testing, with maximal changes in some subjects exceeding 115%. Physical function (assessed by the Margaria stair climbing power) improvements were correlated with increases in 1-RM strength. 
Because threshold increases in lean body mass (+3.3 lb) and leg/arm muscle mass (+1.8 lb) were associated with significant improvements in muscle performance and physical function, they study researchers deemed these changes in body composition to represent threshold targets for testosterone replacement therapy, alone or in combination with GH. In line with this, improvements in muscle performance have been demonstrated in studies that achieved increases in lean body mass that exceeded the threshold of 3.3 lb.[1, 9-12]
Threshold hormone levels associated with threshold changes in whole-body and appendicular lean mass
For subjects receiving only testosterone replacement therapy (without GH) bootstrap analysis found that achievement of a total testosterone threshold level of 1046 ng/dL was necessary in order to reach the threshold improvements in total lean body mass and leg/arm muscle mass. This corresponded to a free testosterone threshold level of 477 pg/mL.[20] 
This can explain why some testosterone replacement studies, which used relatively low fixed doses of testosterone and achieved small increments in testosterone levels, reported relatively small lean body  mass gains and little or no change in muscle strength or physical function.[13-17]
Addition of GH to testosterone therapy lowers testosterone thresholds needed to reach threshold gains lean body mass and leg/arm muscle mass gains.[20] 
The addition of GH at a dose of either 0.009 or 0.015 IU per lb body weight per day (0.003 or 0.005 mg/kg/d) to transdermal testosterone lowered the threshold levels of total and free testosterone needed to achieve the threshold gains of +3.3 lb increase in lean body mass and +1.8 lb increase in leg/arm muscle mass:
Testosterone only - required threshold:
Total testosterone:   1046 ng/dL
Free testosterone:    477ng/dL
Testosterone + GH - required threshold:
Free testosterone:    944 pg/mL
Free testosterone:    303 pg/mL
Elevations in free testosterone performed comparable to elevations in total testosterone in their ability to predict gains in total lean body mass and leg/arm muscle mass.


The first thing to bear in mind when talking about testosterone level thresholds is that these are assay dependent. The thresholds in this study are derived from the gold standard steroid hormone assay liquid chromatography–tandem mass spectrometry (LC-MS). In clinical practice automated platform immunoassays are more common. It this study it was stated that total testosterone levels by LC-MS are on average approx. 100 ng/dL higher than those obtained by the automated platform immunoassays. 
Regardless the assay used, this analysis highlights the need for individual dose titration in order to induce threshold gains in muscle mass that improve strength and performance.
The studies reported here derived testosterone and muscle mass thresholds for relatively healthy men aged 65 years or older. It is likely that these thresholds required to achieve improvements in muscle function and performance in intermediate-frail and frail elderly men are lower, as has been shown in another study.[18]
Previous studies have shown that there are greater gains in muscle mass and protein synthesis when both hormones are co-administered.[9, 15, 19] in this study, when subjects were partitioned according to whether they had high or low elevations in testosterone and IGF-1 levels, there was a clear hormone level-dependent response for the combinations in relation to improvements in total lean body mass and leg/arm muscle mass.[20] Subjects who experiences increases in both total testosterone and IGF-1 above the median had greatest gains in total lean mass and leg/arm muscle mass.[20] However, it should be pointed out that this dose-response curve may be different at supra-physiological levels. The analysis was conducted on testosterone and IGF-1 levels within the healthy physiological range.
Using combinations of hormones with different but complementary anabolic actions may more effectively enhance muscle mass gains. As combined testosterone + GH therapy allows for achievement of significant benefits at lower doses of each, compared to using either alone, this strategy is likely also safer in the long-term.


Ageless Forever does not offer multiple anabolic therapy for athletic enhancement or bodybuilding gains. This practice is considered illegal and unethical.

The studies we report on GH were conducted in subjects with established sub-optimal hormone levels.

Our goal at Ageless Forever is to replace (within the pysiological range) and balance sub-optimal hormone levels, as identified by comprehensive blood testing and clinical evaluation, for prevention of metabolic deterioration and health promotion.


1.            Sattler, F.R., et al., Testosterone and growth hormone improve body composition and muscle performance in older men. J Clin Endocrinol Metab, 2009. 94(6): p. 1991-2001.

2.            Amanatkar, H.R., et al., Impact of exogenous testosterone on mood: a systematic review and meta-analysis of randomized placebo-controlled trials. Ann Clin Psychiatry, 2014. 26(1): p. 19-32.

3.            Spitzer, M., et al., The effect of testosterone on mood and well-being in men with erectile dysfunction in a randomized, placebo-controlled trial. Andrology, 2013. 1(3): p. 475-82.

4.            Wang, C., et al., Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study. J Clin Endocrinol Metab, 1996. 81(10): p. 3578-83.

5.            Jockenhovel, F., et al., Comparison of long-acting testosterone undecanoate formulation versus testosterone enanthate on sexual function and mood in hypogonadal men. Eur J Endocrinol, 2009. 160(5): p. 815-9.

6.            Jockenhovel, F., et al., Timetable of effects of testosterone administration to hypogonadal men on variables of sex and mood. Aging Male, 2009. 12(4): p. 113-8.

7.            Saad, F., et al., Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Curr Diabetes Rev, 2012. 8(2): p. 131-43.

8.            Traish, A., B. Abdallah, and G. Yu, Androgen deficiency and mitochondrial dysfunction: implications for fatigue, muscle dysfunction, insulin resistance, diabetes, and cardiovascular disease. . Horm Mol Biol Clin Invest 2011. 8: p. 431–444.

9.            Blackman, M.R., et al., Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA, 2002. 288(18): p. 2282-92.

10.          Ferrando, A.A., et al., Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am J Physiol Endocrinol Metab, 2002. 282(3): p. E601-7.

11.          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, 2005. 90(2): p. 678-88.

12.          Page, S.T., et al., Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab, 2005. 90(3): p. 1502-10.

13.          Nair, K.S., et al., DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med, 2006. 355(16): p. 1647-59.

14.          Emmelot-Vonk, M.H., et al., Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA, 2008. 299(1): p. 39-52.

15.          Giannoulis, M.G., et al., The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial. J Clin Endocrinol Metab, 2006. 91(2): p. 477-84.

16.          Hildreth, K.L., et al., Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low-normal testosterone levels. J Clin Endocrinol Metab, 2013. 98(5): p. 1891-900.

17.          Kenny, A.M., et al., Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. J Am Geriatr Soc, 2010. 58(6): p. 1134-43.

18.          Srinivas-Shankar, U., et al., Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab, 2010. 95(2): p. 639-50.

19.          Huang, X., et al., Effects of growth hormone and/or sex steroid administration on whole-body protein turnover in healthy aged women and men. Metabolism, 2005. 54(9): p. 1162-7.

20.          Sattler, F., et al., Testosterone threshold levels and lean tissue mass targets needed to enhance skeletal muscle strength and function: the HORMA trial. J Gerontol A Biol Sci Med Sci, 2011. 66(1): p. 122-9.

Last modified on Wednesday, 10 December 2014 21:51

Medical Writer & Nutritionist

MSc Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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