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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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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