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PUBLIC RELEASE DATE:
30-Nov-2001

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Contact: Donna Krupa
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American Physiological Society
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Testosterone dose-repsonse relationships in healthy young men

New study dispels belief that increasing the hormone level improves the sexual function

November 25, 2001 -- Bethesda, Md.-- The American Journal of Physiology: Endocrinology and Metabolism, one of the 14 peer-reviewed journals published by the American Physiological Society (APS), spotlights recent research findings designed to improve and understand human well-being and health. A study in the December edition examines how different doses of testosterone affect body composition, muscle size, strength, and sexual functions.

Background

Testosterone regulates many physiological processes, including muscle protein metabolism, some aspects of sexual and cognitive functions, secondary sex characteristics, erythropoiesis, plasma lipids, and bone metabolism. However, testosterone dose dependency of various hormonal dependent functions has not been well understood in the scientific community. Previous studies reveal that administration of replacement doses of testosterone to hypogonadal men and of supraphysiological doses to eugonadal men increases fat-free mass, muscle size, and strength. Conversely, suppression of endogenous testosterone concentrations is associated with loss of fat-free mass and a decrease in fractional muscle protein synthesis.

What is not known is whether testosterone effects on the muscle are dose dependent, or the nature of the testosterone dose-response relationships. Animal studies suggest that different androgen-dependent processes have different androgen dose-response relationships. Sexual function in male mammals is maintained at serum testosterone concentrations that are at the lower end of the male range. However, it is not known whether the low normal testosterone levels that normalize sexual function are sufficient to maintain muscle mass and strength, or whether the higher testosterone concentrations required to maintain muscle mass and strength might adversely affect plasma lipids, hemoglobin levels, and the prostate.

The Study

The primary objective of this study was to determine the dose dependency of testosterone's effects on fat-free mass and muscle performance. The authors hypothesized that changes in circulating testosterone concentrations would be associated with dose-dependent changes in fat-free mass, muscle strength, and power in conformity with a single linear dose-response relationship, and that the dose requirements for maintaining other androgen-dependent processes would be different.

Young men were treated with a long-acting gonadotropin-releasing hormone (GnRH) agonist to suppress endogenous testosterone secretion, and concomitantly also with one of five testosterone-dose regimens to create different levels of serum testosterone concentrations extending from subphysiological to the supraphysiological range. The lowest testosterone dose, 25 mg weekly, was selected because this dose had been shown to maintain sexual function in GnRH antagonist-treated men. The selection of the 600-mg weekly dose was based on the consideration that this was the highest dose that had been safely administered to men in controlled studies.

The authors of the study, "Testosterone Dose-Response Relationships in Healthy Young Men" are Shalender Bhasin, Linda Woodhouse, Connie Dzekov, Jeanne Dzekov, Indrani Sinha-Hikim, Ruoquing Shen, and Atam B. Singh, all from the Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA; Richard Casaburi, Dimple Bhasin, Nancy Berman, Rachelle Bross and Jeffrey Phillips, from the Harbor-University of California Los Angeles Medical Center, Torrance, CA; Xianghong Chen and Kevin E. Yarasheski at the Biomedical Mass Spectrometric Research Resource, Department of Internal Medicine, Washington University, School of Medicine, St. Louis, Missouri, Lynne Magliano and Thomas W. Storer, from the Laboratory for Exercise Sciences, El Camino College, El Camino, CA.

Protocol

This was a double-blind, randomized study consisting of a four-week control period, a 20-week treatment period, and a 16-week recovery period. The participants were healthy men, 18-35 years of age, with prior weight-lifting experience and normal testosterone levels. These men had not used any anabolic agents and had not participated in competitive sports events in the preceding year, and they were not planning to participate in competitive events in the following year. The participants were asked not to undertake strength training or moderate-to-heavy endurance exercise during the study. These instructions were reinforced every four weeks.

Sixty-one eligible men were randomly assigned to one of five groups. All received monthly injections of a long-acting GnRH agonist to suppress endogenous testosterone production. In addition, group 1 received 25 mg of testosterone enanthate intramuscularly weekly; group 2, 50 mg testosterone enanthate; group 3, 125 mg testosterone enanthate; group 4, 300 mg testosterone enanthate; and group 5, 600 mg testosterone enanthate. Twelve men were assigned to group 1, 12 to group 2, 12 to group 3, 12 to group 4, and 13 to group 5.

Nutritional Intake

Energy and protein intakes were standardized at 36 kcal/kg. The standardized diet was initiated two weeks before treatment started; dietary instructions were reinforced every four weeks. The nutritional intake was verified by analysis of three-day food records and 24-hour food recalls every four weeks.

Outcome Measures

Body composition and muscle performance were assessed at baseline and during week 20. Fat-free mass and fat mass were measured by underwater weighing and dual-energy X-ray absorptiometry. Total thigh muscle and quadriceps muscle volumes were measured by MRI scanning.

For estimation of total body water, the men ingested 10 g of 2H2O, and plasma samples were drawn at 0, 120, 180, and 240 min. A measurement of 2H abundance in plasma was made by nuclear magnetic resonance spectroscopy, with a correction factor of 0.985 for exchangeable hydrogen. Another measure of bilateral leg press strength was taken by use of the one-repetition maximum (1-RM) method. A seated leg press exercise with pneumatic resistance was used for this purpose. Subjects performed 5-10 min of leg cycling and stretching warm-up and received instruction and practice in lifting mechanics before performing progressive warm-up lifts leading to the 1-RM. Seat position and the ensuing knee and hip angles, as well as foot placement, were measured and recorded for use in subsequent testing. To ensure reliability in this highly effort-dependent test, the 1-RM score was reassessed within seven days, but not sooner than two days, after the first evaluation. If duplicate scores were within five percent, the higher of the two values was accepted as the strength score. If the two tests differed by greater than five percent, additional studies were conducted.

Sexual function was assessed by daily logs of sexual activity and desire that were maintained for seven consecutive days at baseline and during treatment by use of a published instrument. Spatial cognition was assessed by a computerized checkerboard test and mood by Hamilton's depression and Young's mania scales.

Adverse experiences, blood counts and chemistries, prostate-specific antigen (PSA), plasma lipids, total and free testosterone, luteinizing hormone (LH), sex steroid-binding globulin (SHBG), and insulin-like growth factor I (IGF-I) levels were measured periodically during control and treatment periods. Serum total testosterone was measured by an immunoassay.

Results

Of 61 men enrolled, 54 completed the study: 12 in group 1, 8 in group 2, 11 in group 3, 10 in group 4, and 13 in group 5. One man discontinued treatment because of acne; other subjects were unable to meet the demands of the protocol. The five groups did not significantly differ with respect to their baseline characteristics. Key findings included:

- Compliance: All evaluable subjects received 100percent of their GnRH agonist injections, and only one man in the 125-mg group missed one testosterone injection.

- Nutritional intake: Daily energy intake and proportion of calories derived from protein, carbohydrate, and fat were not significantly different among the five groups at baseline. There was no significant change in daily caloric, protein, carbohydrate, or fat intake in any group during treatment.

- Hormone levels: Serum total and free testosterone levels, measured during week 16, one week after the previous injection, were linearly dependent on the testosterone dose (P = 0.0001). Serum total and free testosterone concentrations decreased from baseline in men receiving the 25- and 50-mg doses and increased at 300- and 600-mg doses. Serum LH levels were suppressed in all groups. Serum SHBG levels decreased dose dependently at the 300- and 600-mg doses but did not change in other groups. Serum IGF-I concentrations increased dose dependently at the 300- and 600-mg doses.

- Body composition: Fat-free mass, measured by underwater weighing, did not change significantly in men receiving the 25- or 50-mg testosterone dose, but it increased dose dependently at higher doses. The changes in fat-free mass were highly dependent on testosterone dose (P = 0.0001) and correlated with log total testosterone concentrations during treatment (r = 0.73, P = 0.0001). Fat mass, measured by underwater weighing, increased significantly in men receiving the 25- and 50-mg doses, but did not change in men receiving the higher doses of testosterone. There was an inverse correlation between change in fat mass by underwater weighing and log testosterone concentrations.

- Muscle size: The thigh muscle volume and quadriceps muscle volume did not significantly change in men receiving the 25- or 50-mg doses but increased dose-dependently at higher doses of testosterone. The changes in thigh muscle and quadriceps muscle volumes correlated with log testosterone levels during treatment.

- Muscle performance: The leg press strength did not change significantly in the 25- and 125-mg-dose groups but increased significantly in those receiving the 50-, 300-, and 600-mg doses. Leg power did not change significantly in men receiving the 25-, 50-, and 125-mg doses of testosterone weekly, but it increased significantly in those receiving the 300- and 600-mg doses. The increase in leg power correlated with log testosterone concentrations and changes in fat-free mass and muscle strength.

- Behavioral measures: The scores for sexual activity and sexual desire measured by daily logs did not change significantly at any dose. Similarly, visual-spatial cognition and did not change significantly in any group.

- Adverse experiences and safety measures: Hemoglobin levels decreased significantly in men receiving the 50-mg dose but increased at the 600-mg dose; the changes in hemoglobin were positively correlated with testosterone concentrations. Changes in plasma HDL cholesterol, in contrast, were negatively dependent on testosterone dose and correlated with testosterone concentrations. Total cholesterol, plasma low-density lipoprotein cholesterol, and triglyceride levels did not change significantly at any dose. Serum PSA, creatinine, bilirubin, alanine aminotransferase, and alkaline phosphatase did not change significantly in any group, but aspartate aminotransferase decreased significantly in the 25-mg group. Two men in the 25-mg group, five in the 50-mg group, three in the 125-mg group, seven in the 300-mg group, and two in the 600-mg group developed acne. One man receiving the 50-mg dose reported decreased ability to achieve erections.

Discussion

The researchers found that GnRH agonist administration suppressed endogenous LH and testosterone secretion. Therefore, circulating testosterone concentrations during treatment were proportional to the administered dose of testosterone enanthate. This strategy of combined administration of GnRH agonist and graded doses of testosterone enanthate was effective in establishing different levels of serum testosterone concentrations among the five treatment groups. The different levels of circulating testosterone concentrations created by this regimen were associated with dose- and concentration-dependent changes in fat-free mass, fat mass, thigh and quadriceps muscle volume, muscle strength, leg power, hemoglobin, circulating IGF-I, and plasma HDL cholesterol.

Serum PSA levels, sexual desire and activity, and spatial cognition did not change significantly at any dose. The changes in fat-free mass, muscle volume, leg press strength and power, hemoglobin, and IGF-I were positively correlated, whereas changes in plasma HDL cholesterol and fat mass were negatively correlated with testosterone dose and total and free testosterone concentrations during treatment.

There were no significant changes in overall sexual activity or sexual desire in any group, including those receiving the 25-mg dose. Testosterone replacement of hypogonadal men improves frequency of sexual acts and fantasies, sexual desire, and response to visual erotic stimuli. The data demonstrate that serum testosterone concentrations at the lower end of male range can maintain some aspects of sexual function.

Conclusions

This study demonstrates that an increase in circulating testosterone concentrations results in dose-dependent increases in fat-free mass, muscle size, strength, and power. The relationships between circulating testosterone concentrations and changes in fat-free mass and muscle size conform to a single log-linear dose-response curve. The data do not support the notion of two separate dose-response curves reflecting two independent mechanisms of testosterone action on the muscle.

In addition, the study could not determine if responsiveness to testosterone is attenuated in older men. Testosterone dose-response relationships might be modulated by other muscle growth regulators, such as nutritional status, exercise and activity level, glucocorticoids, thyroid hormones, and endogenous growth hormone secretory status. Serum PSA levels decrease after androgen withdrawal, and testosterone replacement of hypogonadal men increases PSA levels into the normal range.

The data demonstrate that different androgen-dependent body functions respond differently to different testosterone dose-response relationships. Some aspects of sexual function and spatial cognition, and PSA levels, were maintained by relatively low doses of testosterone in GnRH agonist-treated men and did not increase further with administration of higher doses of testosterone. In contrast, graded doses of testosterone were associated with dose and testosterone concentration-dependent changes in fat-free mass, fat mass, muscle volume, leg press strength and power, hemoglobin, IGF-I, and plasma HDL cholesterol.

Testosterone doses associated with significant gains in fat-free mass, muscle size, and strength were associated with significant reductions in plasma HDL concentrations. Further studies are needed to determine whether clinically significant anabolic effects of testosterone can be achieved without adversely affecting cardiovascular risk. Selective androgen receptor modulators that preferentially augment muscle mass and strength, but only minimally affect prostate and cardiovascular risk factors, are desirable.

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Source: American Journal of Physiology: Endocrinology and Metabolism, December 2001

The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.


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