|
61. Transdermal dihydrotestosterone treatment of
'andropause'.
de Lignieres B
Departement d'endocrinologie et medecine de la reproduction,
Hopital Necker, Paris, France.
Ann Med 1993 Jun;25(3):235-41
Male ageing coincides on average with progressive
impairment of testicular function. The most striking plasma
changes are an increase in sex hormone binding globulin (SHBG)
and a decrease in non SHBG-bound testosterone, which is the
only testosterone subfraction effectively bioavailable for
target tissues. In healthy subjects the bioavailable
testosterone declines by approximately 1% per year between 40
and 70 years but a more pronounced decline has been observed
in non-healthy groups, especially in high cardiovascular risks
groups. Relative androgen deficiency is likely to have
unfavourable consequences on muscle, adipose tissue, bone,
haematopoiesis, fibrinolysis, insulin sensitivity, central
nervous system, mood and sexual function and might be treated
by an appropriate androgen supplementation. The
potential risk for prostate has been the main reason for
limiting indications of such treatment. Testosterone (T) and
dihydrotestosterone (DHT) are two potent androgens which have
opposite effects regarding aromatase activity, an enzyme
present in prostate stroma and suspected to have a pathogenic
influence through local oestradiol synthesis.
T is the main substrate for aromatase and oestradiol synthesis
while DHT is not aromatizable and, at sufficient
concentration, decreases T and oestradiol levels. A 1.8 years
survey of 37 men aged 55-70 years treated with daily
percutaneous DHT treatment suggested that high plasma levels
of DHT (> 8.5 nmol/l) effectively induced clinical benefits
while slightly but significantly reducing prostate size. Early
stages of prostate hypertrophy require synergic stimulation by
both DHT and oestradiol, and suppressing oestradiol instead of
DHT seems easier and better adapted to the specific situation
of aged hypogonadic men.
62. Testosterone replacement therapy.
Velazquez E, Bellabarba Arata G
Department of Medicine, Medical School, University of the
Andes, Merida, Venezuela.
Arch Androl 1998 Sep-Oct;41(2):79-90
The benefits conferred by testosterone replacement therapy
are substantial, both in the short term for the
eradication of symptoms of androgen deficiency, and in the
long term for the prevention of osteoporosis. As with
any long-term treatment there are risks that must be
considered, but overall the benefits achieved far outweigh
potential risk. Ideally, androgen replacement therapy should
provide physiological serum testosterone levels, as well as
DHT and estradiol levels, and correct the clinical symptoms of
androgen deficiency in hypogonadal men. This goal is difficult
to achieve because the dose dependency of androgen-dependent
physiological processes is not known. Androgen preparations
that are currently available do not fulfill all criteria for
an ideal androgen replacement therapy. Parenteral testosterone
esters are effective, safe, practical, and inexpensive.
The transdermal testosterone systems provide an
alternative to testosterone esters in selected patients but
these preparations are expensive. Ongoing studies are
showing the benefits of testosterone replacement therapy in
aging men, but there is concern about side effects on
cardiovascular system and prostate. Thus, clinical decision
regarding testosterone therapy in older men should be better
defined.
63. Effect of androgens on the brain and other
organs during development and aging.
Swerdloff RS, Wang C, Hines M, Gorski R
Harbor-UCLA Medical Center, Torrance 90502.
Psychoneuroendocrinology 1992 Aug;17(4):375-83
Androgens have important biological effects on accessory
sexual organs and have a broad range of effects on metabolic
processes. Male hormones have been shown to have important
organizational and activational effects on morphological,
behavioral, and cognitive activity in
experimental animals. Sexual dimorphic effects on
cognitive and behavioral activities in animals have been
linked to androgens during the fetal period. The
effects of testosterone on sexual drive are well established
in humans, although the threshold for such activity appears to
be lower than that required for many of the other and organic
effects of testosterone. There are suggestive data to
link fetal androgen levels to cognitive and behavioral
activities in children and adults, but the behavioral
activities may be modified by social and other learning
processes. Androgen levels fall in older men at a
time when impaired sexual function, osteopenia, and decreased
muscle mass can be identified. The relative importance of
androgen deficiency in these disorders requires further study,
since they are likely to be multifactorial in pathogenesis.
Replacement therapy of elderly men who have lowered
testosterone levels has been proposed to decrease bone
and muscle loss as well as to improve sexual function and
general well-being. Careful studies will be required
to assess the risk-to-reward ratio of such treatment, since
theoretical adverse effects on prostate and cardiovascular
diseases may occur. While conservation in management
has its virtues, we should be reminded that several decades
ago estrogen replacement of postmenopausal women was highly
criticized until data supporting its favorable therapeutic
ratio were demonstrated.
64. Endogenous sex steroids and bone mineral
density in older women and men: the Rancho Bernardo
Study.
Greendale GA, Edelstein S, Barrett-Connor E
Division of Geriatrics, UCLA School of Medicine, USA.
J Bone Miner Res 1997 Nov;12(11):1833-43
This study examines the associations between endogenous sex
steroids and bone mineral density (BMD), using data from a
geographically defined cohort in Rancho Bernardo, California.
Participants were community-dwelling women and men aged 50-89
years who took part in a study of endogenous sex steroid
measurement between 1984-1987 and who had BMD measured in
1988-1991. Those taking corticosteroids or estrogen at the
time of sex steroid determination were excluded. The main
study outcomes were BMD of the ultradistal radius, midshaft
radius, lumbar spine, and total hip by sex steroid level,
adjusted for age, body mass index, cigarette smoking, alcohol
consumption, leisure exercise, use of thiazides, thyroid
hormones, and former estrogen use (women only). At the time of
the hormone measurements, the mean age of the 457 women was
72.1 years and that of the 534 men was 68.6 years. A
statistically significant positive relation was seen between
bioavailable estradiol and BMD at all sites in women and men.
Total estradiol was significantly associated with BMD at all
sites in women and at all but the ultradistal radius in men.
Estrone had a global effect on BMD in women and was not
measured in men. Higher bioavailable (but not total)
testosterone levels were associated with higher BMD of the
ultradistal radius, spine, and hip in men and the ultradistal
radius in women. Dehydroepiandrosterone was
positively associated with BMD of the midradius, spine, and
hip in women and was not associated with BMD at any site in
men. Of the sex steroids tested, bioavailable estrogen was
most strongly associated with BMD in both women and men. We
conclude that endogenous sex steroid levels are significantly
related to bone density in older women and men. Individual
variation in age-related bone loss may be partially accounted
for by alterations in sex steroid levels with aging. Further
study to elucidate safe environmental and medical methods to
maintain optimal sex steroid levels in old age is needed.
65. Endocrine aspects of ageing in the male.
Gooren LJ
Department of Endocrinology, Hospital of the Vrije
Universiteit, Amsterdam, The Netherlands.
lgooren@inter.nl.net
Mol Cell Endocrinol 1998 Oct 25;145(1-2):153-9
There is a statistical decline of testosterone
levels in ageing men, most manifest in free
testosterone. While this fall is only moderate,
ageing men show clinical signs of hypogonadism (loss of muscle
mass/strength, reduction in bone mass and an increase in
visceral fat). This might represent not only a fall but
(also) an impairment of the biological action of androgens in
target organs. The first small scale studies of androgen
supplement administration in ageing men were not
disappointing. Anticipated risks lie with the prostate and the
cardiovascular system. The risks with regard to
prostate disease are often over-rated. The question
remains how the segment of the ageing male population possibly
benefiting from androgen supplements, can be identified. For
the treatment of postmenopausal women 'designer oestrogens'
are being developed; similarly, designer androgens
retaining beneficial anabolic effects with elimination of
harmful effects on the prostate and cardiovascular system,
could be devised.
66. The effects of testosterone treatment on body
composition and metabolism in middle-aged obese men.
Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G,
Lindstedt G, Bjorntorp P
Department of Medicine I, Sahlgren's Hospital, University of
Goteborg, Sweden.
Int J Obes Relat Metab Disord 1992
Dec;16(12):991-7
Twenty-three middle-aged abdominally obese men were treated
for eight months with testosterone or with placebo.
Testosterone treatment was followed by a decrease of visceral
fat mass, measured by computerized tomography, without a
change in body mass, subcutaneous fat mass or lean body mass.
Insulin resistance, measured by the
euglycemic/hyperinsulinemic glucose clamp method, improved and
blood glucose, diastolic blood pressure and serum cholesterol
decreased with testosterone treatment. A small increase in
prostate volume was noted, but serum prostate specific antigen
concentrations were unchanged and no adverse functional
side-effects were found. Insulin sensitivity improved more
in men with relatively low testosterone values at the outset.
The mechanisms involved in these changes might act either via
effects on visceral fat accumulation, followed by metabolic
improvements, and/or via direct effects on muscle insulin
sensitivity, as suggested by results of other recent studies.
It is concluded that testosterone treatment of
middle-aged abdominally obese men gives beneficial effects on
well-being and the cardiovascular and diabetes risk profile,
results similar to those observed after hormonal replacement
therapy in postmenopausal women.
67. Effects of testosterone supplementation in the
aging male.
Tenover JS
Division of Gerontology and Geriatric Medicine, University of
Washington, Seattle 98104.
J Clin Endocrinol Metab 1992 Oct;75(4):1092-8
Serum androgen levels decline with aging in normal males,
such that a significant number of men over 60 yr of age will
have a mean serum total testosterone (T) level near the low
end of the normal adult range. It is not known whether lower T
levels in older men have an effect on androgen-responsive
organ systems, such as muscle, bone, bone marrow, and
prostate, nor are there data to evaluate the relative benefits
and risks of T supplementation in older men. We assessed the
physiological and biochemical effects of T therapy in 13
healthy men, 57-76 yr old, who had low or borderline low serum
T levels (< or = 13.9 nmol/L). Intramuscular testosterone
enanthate (TE; 100 mg weekly) and placebo injections were
given for 3 months each. Before treatment and at the end of
both 3-month treatment regimens, lean body mass, body fat,
biochemical parameters of bone turnover, hematological
parameters, lipoprotein profiles, and prostate parameters
[such as prostate-specific antigen (PSA)] were evaluated.
Serum T levels rose in all subjects with TE treatment, such
that the lowest level of T during a week's period was 19.7 +/-
0.7 nmol/L (mean +/- SE). After 3 months of TE treatment, lean
body mass was significantly increased, and urinary
hydroxyproline excretion was significantly depressed.
With TE treatment, there was a significant increase in
hematocrit, a decline in total cholesterol and low density
lipoprotein cholesterol, and a sustained increase in serum PSA
levels. Placebo treatment led to no significant
changes in any of these parameters. We conclude that short
term (3 months) TE supplementation to healthy older
men who have serum T levels near or below the lower limit of
normal for young adult men results in an increase in lean body
mass and possibly a decline in bone resorption, as
assessed by urinary hydroxyproline excretion, with some effect
on serum lipoproteins, hematological parameters, and PSA.
The sustained stimulation of PSA and the increase in
hematocrit that occur with physiological TE supplementation
suggest that older men should be screened carefully and
followed periodically throughout T therapy.
68. Predictors of skeletal muscle mass in elderly
men and women.
Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry
PJ
Clinical Nutrition Program, The University of New Mexico
School of Medicine, Albuquerque, USA.
Mech Ageing Dev 1999 Mar 1;107(2):123-36
BACKGROUND: Elderly men and women lose muscle mass and
strength with increasing age. Decreased physical activity,
hormones, malnutrition and chronic disease have been
identified as factors contributing to this loss. There are few
data, however, for their multivariate associations with muscle
mass and strength. This study analyzes these associations in a
cross-sectional sample of elderly people from the New Mexico
Aging Process Study.
METHODS: Data collected in 1994 for 121 male and 180 female
volunteers aged 65-97 years of age enrolled in The New Mexico
Aging Process Study were analyzed. Body composition was
measured using dual energy X-ray absorptiometry; dietary
intake from 3 day food records; usual physical activity by
questionnaire; health status from annual physical
examinations; and serum testosterone, estrone, sex-hormone
binding globulin (SHBG), and insulin-like growth factor (IGF1)
from radioimmunoassays of fasting blood samples. Statistical
analyses included partial correlation and stepwise multiple
regression.
RESULTS: The muscle mass and strength (adjusted for knee
height) decreased with increasing age in both sexes.
The muscle mass was significantly associated with
serum free-testosterone, physical activity, cardiovascular
disease, and IGF1 in the men. In the women, the
muscle mass was significantly associated with total fat mass
and physical activity. Age was not associated significantly
with muscle mass after controlling for these variables. Grip
strength was associated with age independent of muscle mass in
both sexes. Estrogen (endogenous and exogenous) was not
associated with muscle mass or strength in women.
CONCLUSIONS: Age-related loss of muscle mass and strength
occurs in relatively healthy, well-nourished elderly men and
women and has a multifactorial basis. Sex hormone
status is an important factor in men but not in
women. Physical activity is an important predictor of
muscle mass in both sexes.
69. Testosterone injection stimulates net protein
synthesis but not tissue amino acid transport.
Ferrando AA; Tipton KD; Doyle D; Phillips SM; Cortiella J;
Wolfe RR
Department of Surgery, University of Texas Medical Branch,
Galveston, Texas 77550, USA.
Am J Physiol 1998 Nov;275(5 Pt 1):E864-71
Testosterone administration (T) increases lean body
mass and muscle protein synthesis. We investigated
the effects of short-term T on leg muscle protein kinetics and
transport of selected amino acids by use of a model based on
arteriovenous sampling and muscle biopsy. Fractional synthesis
(FSR) and breakdown (FBR) rates of skeletal muscle protein
were also directly calculated. Seven healthy men were studied
before and 5 days after intramuscular injection of 200 mg of
testosterone enanthate. Protein synthesis increased
twofold after injection (P < 0.05), whereas protein
breakdown was unchanged. FSR and FBR calculations
were in accordance, because FSR increased twofold (P <
0.05) without a concomitant change in FBR. Net balance between
synthesis and breakdown became more positive with both
methodologies (P < 0.05) and was not different from zero. T
injection increased arteriovenous essential and nonessential
nitrogen balance across the leg (P < 0.05) in the fasted
state, without increasing amino acid transport. Thus T
administration leads to an increased net protein synthesis and
reutilization of intracellular amino acids in skeletal
muscle.
70. Testosterone administration to elderly men
increases skeletal muscle strength and protein
synthesis.
Urban RJ; Bodenburg YH; Gilkison C; Foxworth J; Coggan AR;
Wolfe RR; Ferrando A
Department of Internal Medicine, University of Texas Medical
Branch Galveston 77555-1060, USA.
Am J Physiol 1995 Nov;269(5 Pt 1):E820-6
Aging men develop a significant loss of muscle strength
that occurs in conjunction with a decline in serum
testosterone concentrations. We investigated the effects of
testosterone administration to six healthy men [67 +/- 2 (SE)
yr] on skeletal muscle protein synthesis, strength, and the
intramuscular insulin-like growth factor I (IGF-I) system.
Elderly men with serum testosterone concentrations of 480
ng/dl or less were given testosterone injections for 4 wk to
produce serum concentrations equal to those of younger men.
During testosterone administration muscle strength
(isokinetic dynamometer) increased in both right and left
hamstring and quadricep muscles as did the fractional
synthetic rate of muscle protein (stable-isotope
infusion). Ribonuclease protection assays done on
total RNA from muscle showed that testosterone administration
increased mRNA concentrations of IGF-I and decreased mRNA
concentrations of insulin-like growth factor binding
protein-4. We conclude that increasing testosterone
concentrations in elderly men increases skeletal muscle
protein synthesis and strength. This increase may be mediated
by stimulation of the intramuscular IGF-I system.
71. Testosterone deficiency in young men: marked
alterations in whole body protein kinetics, strength, and
adiposity.
Mauras N; Hayes V; Welch S; Rini A; Helgeson K; Dokler M;
Veldhuis JD; Urban RJ
Nemours Children's Clinic, Jacksonville, Florida 32207,
USA.
nmauras@nemours.org.
J Clin Endocrinol Metab 1998 Jun;83(6):1886-92
To investigate specific effects of androgens on whole body
metabolism, we studied six healthy lean men (mean +/- SEM age,
23.2 +/- 0.5 yr) before and after gonadal steroid suppression
with a GnRH analog (Lupron), given twice, 3 weeks apart.
Primed infusions of [13C]leucine, indirect calorimetry,
isokinetic dynamometry, growth factor measurements, and
percutaneous muscle biopsies were performed at baseline (D1)
and after 10 weeks of treatment (D2); each subject served as
his own control. Testosterone concentrations were markedly
suppressed after 10 weeks of treatment (D1, 535 +/- 141 ng/dL;
D2, 31 +/- 9). Leucine's rate of appearance (index of
proteolysis) was markedly suppressed after 10 weeks of
hypogonadism (-13%; P = 0.01) as well as the nonoxidative
leucine disposal, an index of whole body protein synthesis
(-13%; P = 0.01) without any changes in plasma amino acid
concentrations. All subjects studied after 10 weeks showed a
decrease in fat-free mass, as measured by skinfold calipers
and dual emission x-ray absortiometry scans (D1, 56.5 +/- 2.9
kg; D2, 54.4 +/- 2.5; P = 0.005), and an increase in percent
fat mass (D1, 19.2 +/- 2.5%; D2, 22.2 +/- 2.5; P = 0.001).
Rates of lipid oxidation decreased (-31%; P = 0.05) after
treatment, with parallel changes in resting energy expenditure
(-9%; P = 0.05). Mean and peak GH concentrations (measured
every 10 min for 6 h) and GH production rates did not decrease
after testosterone deficiency, with an actual increase in
basal secretion (P < 0.02). Plasma insulin-like growth
factor I (IGF-I) concentrations did not change significantly
after 10 weeks of treatment (D1, 227 +/- 44 micrograms/L; D2,
291 +/- 60; P = 0.08). Isokinetic dynamometry of leg extensors
at 60 degrees and 180 degrees/s was also decreased after 10
weeks of hypogonadism. Total ribonucleic acid (RNA) was
isolated from muscle biopsy samples, and ribonuclease
protection assays were performed using human complementary DNA
clones for IGF-I, IGF-binding protein-4, myosin, and actin.
Ten weeks after Lupron treatment, messenger RNA (mRNA)
concentrations of IGF-I decreased significantly, whereas there
was a trend toward higher IGF-binding protein-4
concentrations, with no change in myosin or actin mRNA
concentrations. In conclusion, testosterone deficiency
in young men is associated with a marked decrease in measures
of whole body protein anabolism, decreased strength, decreased
fat oxidation, and increased adiposity. These effects
of testosterone deficiency are independent of changes in
peripheral GH production and IGF-I concentrations, even though
im IGF-I mRNA concentrations decrease. These data
suggest a direct effect of androgens on whole body lipid and
protein metabolism.
72. Androgen administration to aging men.
Tenover JS
Division of Gerontology and Geriatric Medicine, Emory
University School of Medicine, Atlanta, Georgia.
Endocrinol Metab Clin North Am 1994
Dec;23(4):877-92
Normal aging in men frequently is associated with a decline
in serum testosterone levels below the normal range for young
adult men. These changes in serum testosterone with
age may impact negatively on androgen target organs such as
bone, muscle, and psychosexual functioning. Androgen
replacement therapy may be of benefit in certain older men,
but the potential benefits must be balanced with the potential
risks.
73. Endocrine aspects of ageing in the male.
Mol Cell Endocrinol 1998 Oct 25;145(1-2):153-9
Gooren LJ
Department of Endocrinology, Hospital of the Vrije
Universiteit, Amsterdam, The Netherlands.
lgooren@inter.nl.net
There is a statistical decline of testosterone levels in
ageing men, most manifest in free testosterone. While this
fall is only moderate, ageing men show clinical signs of
hypogonadism (loss of muscle mass/strength, reduction in bone
mass and an increase in visceral fat). This might represent
not only a fall but (also) an impairment of the biological
action of androgens in target organs. The first small scale
studies of androgen supplement administration in ageing men
were not disappointing. Anticipated risks lie with the
prostate and the cardiovascular system. The risks with regard
to prostate disease are often over-rated. The question remains
how the segment of the ageing male population possibly
benefiting from androgen supplements, can be identified. For
the treatment of postmenopausal women 'designer oestrogens'
are being developed; similarly, designer androgens retaining
beneficial anabolic effects with elimination of harmful
effects on the prostate and cardiovascular system, could be
devised.
74. Therapeutic role of androgens in the treatment
of osteoporosis in men.
Katznelson L
Harvard Medical School, Massachusetts General Hospital,
Boston, USA.
Baillieres Clin Endocrinol Metab 1998
Oct;12(3):453-70
There has been much recent interest in the relationship
between androgens and bone mineralization in men. Increases in
serum androgens during puberty allow for skeletal maturation
and the attainment of peak bone mass, and the persistence of
normal testosterone secretion during adulthood is important
for the maintenance of bone density. Testosterone
deficiency is associated with heightened bone turnover and is
a major risk factor for osteoporosis in men. The
administration of testosterone to androgen-deficient men leads
to an increase in bone mass, particularly in the trabecular
bone compartment, and a reduction in levels of surrogate
markers of bone turnover, suggesting that androgens have a
dampening effect on bone remodelling. In addition, the
administration of androgens to eugonadal men with idiopathic
osteoporosis, with resulting supraphysiological testosterone
concentrations, may lead to increases in bone mineral density.
The risk of osteopenia due to androgen deficiency and the
benefits of testosterone substitution therapy or
supraphysiological administration on bone will be
reviewed.
75. Clinical experience using the Androderm
testosterone transdermal system in hypogonadal adolescents and
young men with beta-thalassemia major.
De Sanctis V, Vullo C, Urso L, Rigolin F, Cavallini A,
Caramelli K, Daugherty C, Mazer N
Department of Pediatrics, Hospital S. Anna, Ferrara,
Italy.
J Pediatr Endocrinol Metab 1998;11 Suppl
3:891-900
beta-Thalassemia major is associated with a high prevalence
of hypogonadotropic hypogonadism affecting adolescents and
young men with this disease. The pharmacokinetics of
Androderm, a non-scrotal permeation-enhanced testosterone
transdermal system, was previously studied in this population
using three application regimens designed to mimic the
nocturnal secretion and circadian patterns of testosterone
production characteristics of puberty and young adulthood. In
regimen I, designed for prepubertal 14 to 16 year-olds, a
single Androderm patch (2.5 mg/day nominal delivery rate) is
applied at night and removed 12 hours later in the morning. In
regimen II, designed for partially virilized 17 to 19
year-olds, a single Androderm patch is applied nightly for 24
hours. In regimen III, intended for virilized men aged 20
years and older, two Androderm patches (total dose of 5
mg/day) are applied nightly for 24 hours. This report presents
the results of a 12-month open label study using these three
Androderm regimens to treat nine hypogonadal males with
beta-thalassemia (ages 16.8 to 31.8 yr). Our data show
that Androderm produced physiologically appropriate
testosterone levels, lowered SHBG levels, promoted growth and
virilization, increased bone mineral density, and was
generally well tolerated in this population of hypogonadal
adolescents and young men with beta-thalassemia.
76. Insulin resistance, body fat distribution, and
sex hormones in men.
Haffner SM, Karhapaa P, Mykkanen L, Laakso M
Department of Medicine, University of Texas Health Science
Center, San Antonio 78284-7873.
Diabetes 1994 Feb;43(2):212-9
Although many studies have suggested that increased
androgenicity is associated with insulin resistance and
hyperinsulinemia in both pre- and postmenopausal women,
relatively few data are available on this relationship in men.
We examined the association of body mass index (BMI),
waist-to-hip ratio (WHR), sex hormone-binding globulin (SHBG),
total and free testosterone, dehydroepiandrosterone sulfate
(DHEA-SO4), and estradiol with insulin concentrations and
whole-body glucose disposal in 87 men from a population-based
study in Kuopio, Finland. BMI was significantly correlated
with fasting insulin (r = 0.46), total whole-body glucose
disposal (r = -0.30), glucose oxidation (r = -0.21), and
nonoxidative glucose disposal (r = -0.25). WHR also was
significantly associated with fasting insulin (r = 0.61),
total whole-body glucose disposal (r = -0.54), glucose
oxidation (r = -0.23), and nonoxidative whole-body glucose
disposal (r = -0.50). SHBG and total and free
testosterone were significantly associated with insulin
concentrations and total and nonoxidative glucose disposal but
not with glucose oxidation. DHEA-SO4 and estradiol
were not associated with insulin, glucose concentrations, or
whole-body glucose disposal in univariate analysis. In
multivariate analysis, total whole-body glucose disposal was
associated negatively with WHR and positively associated with
total testosterone and SHBG; nonoxidative whole-body glucose
disposal was associated negatively with WHR and positively
associated with total and free testosterone. Glucose oxidation
was significantly associated only with WHR. In conclusion,
higher WHR and lower testosterone were strongly associated
with a decrease in total and nonoxidative whole-body glucose
disposal in men.
77. Decreased testosterone and
dehydroepiandrosterone sulfate concentrations are associated
with increased insulin and glucose concentrations in
nondiabetic men.
Haffner SM, Valdez RA, Mykkanen L, Stern MP, Katz MS
Department of Medicine, University of Texas Health Science
Center, San Antonio 78284.
Metabolism 1994 May;43(5):599-603
Although many studies indicate that increased androgenicity
is associated with insulin resistance and hyperinsulinemia in
both premenopausal and postmenopausal women, relatively few
data are available on this relationship in men. We examined
the association of sex hormone-binding globulin (SHBG), total
and free testosterone, dehydroepiandrosterone sulfate
(DHEA-SO4), and estradiol to glucose and insulin
concentrations before and during an oral glucose tolerance
test in 178 men from the San Antonio Heart Study, a
population-based study of diabetes and cardiovascular disease.
Total and free testosterone and DHEA-SO4 were
significantly inversely associated with insulin
concentrations. Free testosterone and DHEA-SO4 were
also significantly inversely correlated with glucose
concentrations. SHBG was weakly positively associated with
glucose concentrations. Estradiol was not related to glucose
or insulin concentrations. After adjustment for age,
obesity, and body fat distribution, insulin concentrations
remained significantly inversely correlated with free
testosterone (r = -.23), total testosterone (r = -.21), and
DHEA-SO4 (r = -.21; all P < .01). In conclusion,
we observed that increased testosterone and DHEA-SO4 are
associated with lower insulin concentrations in men. This is
in striking contrast to women, where increased androgenicity
is associated with insulin resistance and
hyperinsulinemia.
78. Effects of acute hyperinsulinemia on
testosterone serum concentrations in adult obese and
normal-weight men.
Pasquali R, Macor C, Vicennati V, Novo F, De lasio R, Mesini
P, Boschi S, Casimirri F, Vettor R
Dipartimento di Medicina Interna e Gastroenterologia, and
Istituto di Farmacologia Clinica, University Alma Mater,
Bologna, Italy.
Metabolism 1997 May;46(5):526-9
In a previous study performed in adult obese and
normal-weight male subjects, we found that suppression of
insulin levels by diazoxide reduced testosterone and increased
sex hormone-binding globulin (SHBG) blood concentrations.
These and other data suggested that insulin may have a
regulatory capacity in testosterone secretion and/or
metabolism in men, similar to what has already been
demonstrated in women. In this study, we investigated the
effects of acute hyperinsulinemia on major androgen levels,
including testosterone, in two groups of normal-weight in =
11) and obese (n = 9) men. Acute hyperinsulinemia was obtained
by the euglycemic-hyperinsulinemic clamp technique.
Relationships between the degree of insulin resistance (ie,
total glucose disposal [M value]) and testosterone levels were
also evaluated. Basal testosterone levels in obese
subjects (10.40 +/- 3.02 nmol/L) were significantly lower than
in normal-weight controls (15.50 +/- 4.65 nmol/L, P
<.01), whereas no difference was present in androstenedione
and dehydroepiandrosterone sulfate (DHEA-S) concentrations.
During the clamp study, testosterone was significantly
increased in the obese group (11.79 +/- 3.64 nmol/L, P <
.05) but not in the control group (15.81 +/- 4.54 nmol/L, P =
NS). The other two androgens did not significantly change in
either the obese or control group. There was a highly
significant correlation between baseline testosterone
concentrations, with M values suggesting a relationship
between impaired peripheral insulin sensitivity and reduced
plasma testosterone concentrations. It should be pointed out
that there was a certain discrepancy in the testosterone
variations, particularly in the control group, in which two
thirds of the subjects had no change or some decrease in
testosterone levels, whereas in the remainder testosterone
increased over the values of the assay variation coefficient.
These findings are consistent with the hypothesis that insulin
may regulate testosterone blood levels also in male subjects.
Whether these effects are primarily due to increased hormone
secretion or reduced clearance needs to be investigated.
79. Testosterone and regional fat
distribution.
Marin P
Department of Heart and Lung Diseases, Sahlgrenska University
Hospital, Goteborg, Sweden.
Obes Res 1995 Nov;3 Suppl 4:609S-612S
The effects of testosterone treatment of abdominally obese
men have been assessed by evaluating the following parameters:
The metabolic activity of different adipose tissue regions in
vivo (using lipid label as a tracer) and in vitro (measuring
lipoprotein lipase (LPL) activity), the total and visceral
adipose tissue mass, insulin sensitivity, fasting blood
glucose, blood lipids, and blood pressure as well as prostate
volume. Middle-aged men with abdominal obesity were treated
with transdermal administration of testosterone (T),
dihydrotestosterone (DHT) or placebo (P) during 9 months. The
study was double-blind. Treatment with T was followed by an
inhibited uptake of lipid label in adipose tissue
triglycerides, a decreased LPL-activity and an increased
turn-over rate of lipid label in the abdominal adipose tissue
region in comparisons with the DHT and P groups. These effects
on adipose tissue metabolism were not detected in the femoral
adipose tissue region in any of the groups. T
treatment was also followed by a specific decrease of visceral
fat mass (measured by CT-scan), by increased insulin
sensitivity (measured with the euglycemic glucose clamp), by a
decrease in fasting blood glucose, plasma cholesterol and
triglycerides as well as a decrease in diastolic blood
pressure. In the DHT group an increased visceral mass
was detected. No other changes in these variables were found
in the DHT and P groups. There were no detectable changes in
prostate volume (measured by ultra-sound), prostate specific
antigen concentration, genito-urinary history or urinary flow
measurements in any of the groups. It is suggested that T
substitution to a selected group of men results in general
metabolic and circulatory improvements. The prostate area
needs further careful attention.
80. Androgen treatment of middle-aged, obese men:
effects on metabolism, muscle and adipose tissues.
Marin P, Krotkiewski M, Bjorntorp P
Department of Medicine I, Sahlgren's Hospital, University of
Goteborg, Sweden.
Eur J Med 1992 Oct;1(6):329-36
OBJECTIVES: This pilot investigation was conducted to
explore the relationship between androgens and glucose
tolerance in obese men and to select an optimal mode for
androgen treatment.
METHODS: For exploratory purposes, testosterone (T) or
dihydrotestosterone (DHT) were given in different doses and
preparations for different periods of time to obese,
middle-aged men. The administration forms were selected in
order to by-pass the liver. In the first two studies T was
given as a single intramuscular injection of 250 or 500 mg and
the results evaluated after 1 week. In two subsequent studies
testosterone was administered in moderate doses either as oral
T undecanoate or a T and DHT in preparations applied on the
skin for transdermal absorption for 6 weeks and 3 months
respectively. Before and after treatment the following
examinations were performed: glucose tolerance tests with
insulin determinations or euglycemic clamps at submaximal
insulin levels. Anthropometric measurements including the
waist/hip circumference ratio and estimations of body fat and
lean body mass (from measurements of whole body potassium
content) were performed. Plasma triglyceride and cholesterol
concentrations, liver function tests and blood pressure were
followed. Physical examination including the prostate was
performed before and after study. Muscle function, glycogen
synthase and morphology were examined in the 3-month
study.
RESULTS: Administration of T was followed by moderate
increases of circulating T concentrations in all studies,
except after injection of 500 mg, where large increases were
seen. Follicle stimulating hormone and luteinizing hormone
levels decreased consistently. Injection of 500 mg T resulted
in a decreased glucose tolerance. In the other
treatment groups, plasma insulin decreased or glucose
disappearance rate increased in clamp measurements, suggesting
improved insulin sensitivity. This was most
pronounced in men with relative hypogonadism from the outset.
In the study of 3 months duration, a decrease in the waist/hip
ratio, without a change in body fat mass, was also seen.
Plasma lipids, liver function tests and blood pressure did not
change. Muscle strength, the fractional velocity of glycogen
synthase as well as the percentage and diameter of type IIB
fibres increased after T treatment. No adverse effects were
seen. 17 -beta oestradiol concentrations were unaltered and
DHT administration was less effective than T, suggesting that
T rather than derivatives of this hormone was mainly
responsible for the effects observed.
CONCLUSION: The results suggest that T
administration to middle-aged, obese man may have beneficial
effects.
81. Androgen and estrogen-androgen hormone
replacement therapy: a review of the safety literature, 1941
to 1996.
Gelfand MM, Wiita B
Department of Obstetrics and Gynecology, Sir Mortimer B.
Davis Jewish General Hospital, Montreal, Quebec, Canada.
Clin Ther 1997 May-Jun;19(3):383-404; discussion
367-8
The endocrine physiology of the climacteric supports a
rationale for the concomitant replacement of androgen and
estrogen following menopause. Clinical and research experience
with estrogen-androgen hormone replacement therapy, as well as
androgen-only therapy, suggests that the health benefit
offered by androgen replacement exceeds the potential risk
when treatment is properly managed. In this review, we
concentrate on the effects of oral alkylated androgens. The
virilizing effects (e.g., hirsutism, acne, voice change, and
alopecia) of oral androgens are typically dose and duration
dependent; androgen replacement at doses < or = 10 mg once
daily administered for prolonged periods (> 6 months)
produces masculinization effects that generally abate with
dose reduction or discontinuation of treatment. No clinical
sequelae or irreversible pathophysiologic effects have been
associated with any virilization that may occur.
Changes in lipoprotein metabolism associated with oral
estrogen-androgen use include reduced total cholesterol levels
and reduced high-density lipoprotein cholesterol levels which
may reduce the long-term risk of cardiovascular disease. No
clinically identifiable risk with respect to other
cardiovascular variables, such as blood pressure, has been
associated with the longterm administration of low doses of
oral androgen. With regard to liver toxicity, reports
of jaundice, peliosis hepatis, and hepatocellular carcinoma
are extremely rare at the dose levels of androgen used in
hormone replacement therapy, although individual sensitivity
to the potential hepatotoxic effects of oral alkylated and
nonalkylated androgen may vary considerably. Daily dosing with
oral alkylated androgen in combination with estrogen is well
tolerated. Retrospective and prospective studies involving the
use of androgens alone and in combination with estrogens
demonstrate that concerns about the adverse effects of
androgen use associated with supraphysiologic, self-escalated
doses in men do not apply to the much lower doses combined
with estrogens for hormone replacement in postmenopausal
women.
82. Testosterone inhibits the immunostimulant
effect of thymosin fraction 5 on secondary immune response in
mice.
Catanzano-Troutaud D; Ardail D; Deschaux PA
Laboratory of General and Comparative Immunophysiology,
Limoges, France.
Int J Immunopharmacol (ENGLAND) Feb 1992, 14 (2)
p263-8
The purpose of the present investigation was to examine the
in vivo influence of testosterone on the immune properties of
a thymic factor (thymosin fraction 5, TF5) a partially
purified thymic preparation in male Swiss IOPS/OF1 mice (5-10
weeks old). Testosterone administration (100 micrograms/ml)
significantly inhibited the enhanced anti-sheep red blood cell
antibody response induced by TF5 (100 micrograms/ml); this
inhibition was only observed on the secondary antibody
response and not on the primary. These results suggest
that gonadal steroids can affect the immune response by
modulating the activity of thymic factors.
83. Testosterone inhibits immunoglobulin production
by human peripheral blood mononuclear cells.
Kanda N; Tsuchida T; Tamaki K
Department of Dermatology, Faculty of Medicine, University of
Tokyo, Japan.
Clin Exp Immunol (ENGLAND) Nov 1996, 106 (2)
p410-5
We studied the in vitro effect of testosterone on
spontaneous immunoglobulin production by human peripheral
blood mononuclear cells (PBMC). Testosterone inhibited IgG and
IgM production by PBMC both from males and females. The
inhibitory effect of testosterone was revealed at doses more
than 1 nM, increased dose-dependently, and reached a plateau
at 100 nM. At doses < 1000 nM, testosterone did not reduce
cell viability. Testosterone treatment reduced IgG
production by 59.0% and that of IgM by 61.3% compared with
control. Immunoglobulin production by B cells was
also suppressed by testosterone, though the magnitude of the
suppressive effect on B cells was lower than that on whole
PBMC; testosterone-induced decrease of IgG production compared
with control was 26.9% and that of IgM was 24.9%. Exogenous
IL-6 partially restored the impaired immunoglobulin production
of testosterone-treated PBMC; IgG production in testosterone
culture was increased by IL-6 from 35.6% to 66.5% of control
and that of IgM was also increased from 38.9% to 71.2%,
respectively. Testosterone treatment reduced IL-6 production
of monocytes by 78.4% compared with control, but neither
affected that of T cells or B cells. These results
suggest that testosterone may suppress immunoglobulin
production of human PBMC directly by inhibiting B cell
activity and indirectly by reducing IL-6 production of
monocytes. It is thus indicated that this hormone may have
protective and therapeutic effects on human autoimmune
diseases.
84. Sex hormones and bone mineral density in
elderly men.
Murphy S, Khaw KT, Cassidy A, Compston JE
Clinical Gerontology Unit, Addenbrooke's Hospital, Cambridge,
UK.
Bone Miner 1993 Feb;20(2):133-40
The aim of this study was to determine the relationships
between sex hormones and bone mineral density (BMD) in older
men. Community-dwelling men (n = 134, mean age (SD) 69.5 (3.1)
years) were recruited from two general practices in Cambridge,
UK. Plasma total testosterone and sex hormone binding globulin
(SHBG) were assayed and a free androgen index (FAI) was
derived as the ratio of total testosterone to SHBG (x 100).
Spine and hip BMD were measured by dual energy x-ray
absorptiometry using the Hologic QDR-1000. After adjusting for
age and body mass index (BMI), the FAI correlated with femoral
neck (r = 0.20, P = 0 0.03), intertrochanteric, trochanteric
and Ward's Triangle BMD (r = 0.22, P = 0.01). Analysis of
variance, with adjustment for age and BMI, showed a
progressive upward trend of hip BMD with increasing quartiles
of FAI. The findings suggest that free testosterone plays a
role in determining bone mineral density in older men.
85. Does hypogonadism contribute to the occurrence
of a minimal trauma hip fracture in elderly men?
Stanley HL, Schmitt BP, Poses RM, Deiss WP
Division of Geriatric Medicine, McGuire VAMC, Richmond, VA
23249.
J Am Geriatr Soc 1991 Aug;39(8):766-71
The risk of MTHF in hypogonadal elderly men was
investigated with a case-control model. Cases and controls
were selected from males age 65 years and older residing in
the 120-bed McGuire Veterans Affairs Medical Center Nursing
Home Care Unit over a 5-day interval. Historical data and
serum free testosterone (fTe) were available on 17 subjects
with MTHF and 61 controls. When groups were compared for
differences in age, race, alcohol abuse, cigarette abuse, and
diseases or drugs that may be associated with MTHF, only race
was significantly different. Although 25.6% of residents were
black, 100% of MTHF subjects were white (P = 0.004).
Hypogonadism was defined as a random fTe less than 9 pg/mL
(normal 9 to 46 pg/mL) and was found in 21 subjects (26.9%).
Of cases with a MTHF, 58.8% were hypogonadal compared with
only 18.0% of controls. Utilizing logistic regression, a
highly significant association was found between hypogonadism
and MTHF (P = 0.008), and using the odds ratio, subjects with
hypogonadism were 6.5 times more likely to have a MTHF (95% CI
2.0 to 20.6). To adjust for race, the odds ratio was repeated
excluding black subjects, and the results remained highly
significant (4.6, 95% CI 1.3 to 16.2). We conclude that
hypogonadal elderly white men may be at increased risk for
MTHF.
86. Relations of endogenous anabolic hormones and
physical activity to bone mineral density and lean body mass
in elderly men.
Rudman D, Drinka PJ, Wilson CR, Mattson DE, Scherman F,
Cuisinier MC, Schultz S
Department of Medicine, Medical College of Wisconsin,
Milwaukee 53295-1000.
Clin Endocrinol (Oxf) 1994 May;40(5):653-61
OBJECTIVE: It has been proposed that declining activities
of the somatotrophic or gonadotrophic axes, or sedentary life
style, are partial causes for geriatric losses of bone mineral
density (BMD) and of lean body mass (LBM). The present study
tested these hypotheses by determining, in both free-living
and institutionalized elderly men, the correlations of bone
mineral density (BMD), total body bone mineral content (TBBMC)
and lean body mass (LBM) with the following predictor
variables: age, body mass index, body weight, serum
insulin-like growth factor I (IGF-I), serum testosterone,
habitual physical activity and mobility.
SUBJECTS: Forty-nine independent, community-dwelling older
men, and 49 men of similar age residing in two Veterans
Administration extended care facilities. The age range was
58-95 years.
MEASUREMENTS: Serum IGF-I and testosterone were measured by
radioimmunoassay. Habitual physical activity in the
independent men and mobility in the institutionalized men were
estimated by standard instruments. LBM and bone status at nine
skeletal sites were determined by dual X-ray
absorptiometry.
RESULTS: The BMD and TBBMC values of the free living men
were 4-20% higher than those of the institutionalized men. In
the independent old men, serum testosterone was the strongest
predictor of BMD and TBBMC, while age was the only predictor
of LBM. In the chronically institutionalized men, age, body
weight and immobility were the strongest predictors of body
composition, and testosterone was correlated only with femoral
neck BMD.
CONCLUSIONS: In aging independent men, low levels
of testosterone are associated with demineralization of the
skeleton. Immobility and under-weight are associated
with the osteopenia of old men residing in nursing homes. In
this cross-sectional study of elderly men, there was no
evidence of a relation of the
87. Effect of castration on the morphology of the
motor end-plates of the rat levator ani muscle.
Tobin C, Pecot-Dechavassine M
Eur J Cell Biol 1982 Feb;26(2):284-8
The levator ani (L. A.) muscle, part of the genital
apparatus of rodents, atrophies after castration. Changes in
end-plate structure in the L. A. muscle of castrated male rats
were examined with correlated light and electron microscopic
methods. Four months after castration acetylcholinesterase
staining reveals, in some muscle fibres, the presence of
subneural gutters composed of a succession of cuplets whereas
the subneural gutters are continuous and ramified in control
muscles. Six months after castration most of the end-plates
are further modified. Their terminal arborization, as revealed
by silver nitrate staining, is more tortuous and irregular
than in controls. At the ultrastructural level, reduced
sole-plate and superimposed axonal endings are seen in some
end-plates three months after castration. Our findings
demonstrate that the changes (reduction of muscular activity
and atrophy of muscle) are accompanied by adaptations of the
neuromuscular junctions. As receptors for testosterone
are known to be present in these motoneurons and muscle
fibres, the observed morphological changes might be under the
control of testosterone acting on both muscle and
motoneurons.
88. Electrophysiological and contractile properties
of the levator ani muscle after castration and testosterone
administration.
Vyskocil F, Gutmann E
Pflugers Arch 1977 Mar 11;368(1-2):105-9
Electrical and contractile properties of the levator ani
muscle were studied in normal rats, in castrated rats and in
castrated rats treated with testosterone. 2. No significant
changes in the frequency of miniature end-plate potentials
were found 6 months after castration. The frequency increased
already 6 h after testosterone treatment; an increase of about
100% was observed after 7 days of testosterone treatment. 3.
Castration led to a 2-fold increase of the input resistance of
the muscle fibres. After 7 days of testosterone treatment the
input resistance was only slightly higher than normal. 4. The
weight of the muscle was decreased to 18% of the control value
after 6 months castration. It increased to 46% after 7 days of
testosterone treatment. 5. The muscles of castrated animals
revealed a prolongation of contraction time and marked changes
in maximal rate of tension development and half relaxation
time. Partial recovery of these parameters was found after 7
days of testosterone treatment. 6. Long-term castration did
not induce any denervation-like changes of action potential
parameters, and no tetrodotoxin resistance was found in spite
of marked muscle atrophy.
89. The influence of testosterone on neuromuscular
transmission in hormone sensitive mammalian skeletal
muscles.
Souccar C, Lapa AJ, do Valle JRU
Muscle Nerve 1982 Mar;5(3):232-7
The influence of testosterone on neuromuscular transmission
was studied in levator ani (LA) and extensor digitorum longus
(EDL) muscles taken from normal rats, castrated rats, and
castrated rats treated with testosterone. Thirty days after
castration LA muscle weights were reduced by 60%, but the
frequency and amplitude of the miniature end-plate potentials
(mepps) were increased by 40% and 50%, respectively. The
weights and mepp frequencies of the EDL muscles were not
altered after castration, but the mepp amplitudes increased by
30%. The quantal content of the endplate potentials was not
affected in either muscle. Administration of testosterone to
the castrated rats prevented such changes in the LA muscles.
The results indicate that castration of adult rats
affects the spontaneous transmitter release in both muscles,
but the changes are more pronounced in the levator ani, which
is a target muscle for testosterone.
90. Role of striated penile muscles in penile
reflexes, copulation, and induction of pregnancy in the
rat.
Sachs BD
J Reprod Fertil 1982 Nov;66(2):433-43
In 4 experiments, various striated penile muscles of the
rat were excised. Without the ischiocavernosus (IC) muscles no
dorsiflexions ('flips') of the glans penis occurred during ex
copula reflex tests, but erections were unaffected. In
attempted copulation, males lacking the IC muscles rarely
gained intromission, apparently because dorsiflexion of the
glans penis is necessary for penetration of the vagina.
Nonetheless some males lacking the IC muscles displayed the
gross motor pattern of intromission and ejaculated, but rarely
within the vagina. Males lacking the bulbocavernosus (BC) and
levator ani (LA) muscles were incapable of developing intense
erections ('cups') in ex copula tests, but they did have
lesser erections, probably due to vascular action. Males with
excised BC and LA muscles displayed normal copulatory
behaviour, including intromission and intravaginal
ejaculation, but only 1/15 females mated to these males became
pregnant. The infertility of the males was attributed in part
to their inability to form the penile cup, which caused them
to withdraw a larger portion of the seminal plug from the
vagina and, presumably, prevented the plug from being tightly
lodged against the cervix. In male rats copulation apparently
requires co-ordination of the penile vasculature with the
contraction of separate groups of striated penile muscles,
each having a distinct contribution to the integrated pattern
of copulation and, ultimately, to the male's fertility.
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