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FOR IMMEDIATE RELEASE
Contact: Donna Krupa
Phone: 703.527.7357
Cell: 703.967.2751
djkrupa1@aol.com
Testosterone Dose-Response 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.
Source: American Journal of Physiology: Endocrinology and
Metabolism, December 2001
-end-
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.
***
Editor’s Note: For the full
text of the research cited above, or to set up an interview with a member of
the research team, please contact Donna Krupa at 703.527.7357 (direct dial),
703.967.2751 (cell) or djkrupa1@aol.com.
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