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PubMed2003

Salivary testosterone and EEG spectra of 9- to 11-year-old male children.

Although most investigators agree that there are electroencephalogram (EEG) changes with chronological age around puberty, no one has remarked on why this is so. As the increase in testosterone at the end of prepubertal childhood is a biomarker for the on-set of a period of accelerated growth and development, we searched for an association between testosterone level and the spectral power and topography of EEG. We tested 60 children between 9- and 11-years-old, each demonstrating normal neurological examination and Wechsler intelligence scale over 90. Salivary testosterone was measured using immunoenzymatic chemiluminescent assay. Children were divided into 3 groups according to measured testosterone level. EEG was processed with a Fast Fourier Transform; average of relative power spectral analyses were calculated and data divided into delta, theta, alpha, and beta bands. The principal finding was the highly significant interaction between EEG band and testosterone group, F(6, 171) = 4.54, Huynh-Feldt epsilon = 0.853, p =.001. Delta relative power decreased significantly and Alpha relative power increased significantly in the 2 groups with higher salivary testosterone concentration when compared to the lowest testosterone group. This work suggests that increased testosterone in prepubertal children can predict some of the same EEG changes that are usually associated with increased chronological age.

Age Factors↗

PubMed2004

Testosterone down-regulates ornithine aminotransferase gene and up-regulates arginase II and ornithine decarboxylase genes for polyamines synthesis in the murine kidney.

The enzymes ornithine aminotransferase (OAT) and ornithine decarboxylase (ODC) share L-ornithine as a common substrate and arginase II produces this amino acid. In the murine kidney, testosterone induced ODC gene expression and polyamine production, but it is unknown how OAT gene is expressed under androgen treatment. These experiments were designed to study the influence of testosterone on the renal expression of OAT gene. Pharmacological and physiological doses of testosterone were injected into female and castrated male mice. Total RNA and soluble proteins extracted from whole kidneys were analyzed by Northern and Western blots, respectively. The results clearly indicate that pharmacological doses of testosterone simultaneously down-regulated the level of OAT protein and up-regulated the expression of arginase II and ODC genes. Variations of the levels of OAT protein and arginase II mRNA and protein were strongly correlated with testosteronemia. Orchidectomy increased the renal level of OAT protein and decreased that of ODC and arginase II. These effects were reversed by injecting a physiological dose of testosterone into castrated male mice. In conclusion, OAT and ODC genes are inversely regulated by testosterone in the mouse kidney. Consequently, in kidneys of testosterone-treated mice, L-arginine-derived ornithine produced by arginase II might be preferentially used by ODC for putrescine production rather than by OAT. This metabolic fate of L-ornithine was facilitated by decreasing OAT gene expression. In contrast, in female and castrated male mice devoided of testosterone, OAT gene is highly expressed and L-ornithine is converted into L-glutamate.

Androgens↗

PubMed2006

Testosterone is required for delayed cardioprotection and enhanced heat shock protein 70 expression induced by preconditioning.

Ischemic preconditioning fails to confer immediate cardioprotection in the absence of testosterone, indicating that the hormone is required for the process. Here we set out to determine whether testosterone is also necessary for delayed cardioprotection and, if so, how it acts. Male Sprague Dawley rats (7-8 wk) underwent sham operation or gonadectomy without (G) or with testosterone replacement (GT) for 8 wk. Isolated ventricular myocytes were preconditioned either by metabolic inhibition or with U50,488H, a kappa-opioid receptor agonist. In intact rats, U50,488H was administered systemically and 24 h later the hearts were removed. Ventricular myocytes were then subjected to metabolic inhibition and anoxia and isolated hearts to regional ischemia, followed by reperfusion to induce injury. Both types of preconditioning significantly increased the viability and decreased the lactate dehydrogenase release in ventricular myocytes from sham rats. They also activated heat shock transcription factor-1 and increased heat shock protein 70 expression. In contrast, all these effects were absent in myocytes from G rats and were restored by testosterone replacement. Parallel results were found in isolated hearts. In addition, preconditioning improved contractile functions impaired by ischemic insults in sham and rats gonadectomized with testosterone replacement but not G rats. The effects of testosterone replacement in ventricular myocytes were abolished by androgen receptor blockade. In conclusion, preconditioning requires testosterone to increase heat shock protein 70 synthesis, which mediates delayed cardioprotection in the male. These effects of testosterone are mediated by the androgen receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1985

Androgen aromatization and 5 alpha-reduction in ferret brain during perinatal development: effects of sex and testosterone manipulation.

Ferrets of both sexes were killed 8 or 5 days before expected parturition as well as 7, 15, 30, or 51 days after birth, and the activities of aromatase (using 19-[3H]hydroxyandrostenedione as substrate) and of 5 alpha-reductase (using [3H] testosterone as substrate) were assayed in whole homogenates of preoptic area plus anterior hypothalamus (POA), mediobasal hypothalamus (MBH), temporal lobe (TL), and cerebral cortex. Aromatase and testosterone 5 alpha-reductase activities were also measured in these regions in adult gonadectomized male and female ferrets. Compared with adults of both sexes in which aromatase activity was low in all brain regions studied, fetal ferrets had high levels of aromatase activity in POA plus MBH and in TL. At these prenatal ages, aromatase activity in POA plus MBH was significantly higher in males than in females. Aromatase activity in POA, MBH, and TL remained high in both sexes on postnatal days 7, 15, and 30, before declining by postnatal day 51. Cortical aromatase activity was uniformly low across all perinatal ages. The existence of a sex difference in aromatase activity in fetal POA plus MBH cannot be explained by a concurrent sex difference in circulating testosterone. Administration of testosterone to pregnant female ferrets over days 30-41 of gestation caused 150- to 350-fold increases in maternal plasma concentrations of testosterone and 2- to 5-fold increases in fetal plasma testosterone. However, aromatase activity was not affected in the POA and MBH of fetuses or mothers, although activity was significantly increased in the TL of mothers given testosterone. Furthermore, castration of neonatal or adult breeding males decreased plasma androgen levels by factors of 8 and 480, respectively, but resulted in only modest reductions in POA, MBH, and TL aromatase activity (a significant reduction occurred only in the adult male TL). Relatively high levels of testosterone 5 alpha-reductase activity were found in all brain regions across all perinatal ages, as well as in gonadectomized adult ferrets; there was no sex differences at any postnatal age studied. Prenatally, males had higher levels of 5 alpha-reductase activity than females only on day -8 in the POA plus MBH. The results show that estrogen and 5 alpha-reduced androgens can be synthesized in the brains of ferrets of both sexes during the perinatal period of sexual differentiation. A functional role for this neural metabolism of androgen remains to be demonstrated in this carnivorous species.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1985

Testicular blood flow, vascular permeability, and testosterone production after stimulation of unilaterally cryptorchid adult rats with human chorionic gonadotropin.

Testicular blood flow, testosterone production, and the formation of testicular interstitial fluid (IF) were studied in unilaterally cryptorchid rats, basally, 8 h and 24 h after treatment with 200 IU human CG (hCG). Testicular blood flow was lower in the abdominal testis in both control rats and hCG-treated rats than in the scrotal testis within the same treatment group. The scrotal testicular blood flow increased significantly 24 h after hCG treatment, but not after 8 h. In the abdominal testis, there was a significant increase of blood flow 8 h after hCG, but not 24 h after. The formation of IF was subnormal in the abdominal testes of control rats, but this was corrected in hCG-treated rats, where there was a significant increase of IF in both abdominal and scrotal testes. The total endothelial surface of small blood vessels was decreased in abdominal testes. Testosterone concentration in the spermatic vein was significantly lower on the abdominal side than on the scrotal side in both control and hCG-treated rats. The concentration of testosterone was lower in IF on the abdominal side in control rats, but after hCG the testosterone concentration was similar in both scrotal and abdominal testes, indicating a trapping of testosterone in the abdominal testis. The outflow of testosterone in the spermatic vein was significantly increased at both 8 and 24 h after hCG from both the scrotal and abdominal testes, although it was always smaller from the abdominal testis. The lower secretion of testosterone from the abdominal testis after hCG was mainly due to reduced blood flow and not to any disability of the Leydig cells of abdominal testes to produce testosterone.

Animals↗

PubMed1989

Sexual dimorphism and testosterone-dependent regulation of somatostatin gene expression in the periventricular nucleus of the rat brain.

Gender differences in hypothalamic somatostatin (SS) secretion may account in part for the sexually dimorphic patterns of GH secretion in rats. Since males have lower baseline serum GH levels than females, and SS inhibits GH secretion, we hypothesized that the SS neurons in the periventricular nucleus (PeN) of the male rat would have greater biosynthetic activity than those of the female. We tested this hypothesis by measuring SS mRNA in cells in the PeN of intact male and proestrous female rats. Using in situ hybridization and a computerized image analysis system, we measured SS mRNA content in individual cells in the PeN and compared signal levels (autoradiographic grains per cell) between male and proestrous female animals. The signal level of SS mRNA in cells of the PeN was significantly greater in males than in proestrous females (males, 210 +/- 7 grains/cell; females, 158 +/- 5 grains/cell; P less than 0.0005), whereas no difference was observed in SS cells of the frontal cortex (males, 100 +/- 0.8 grains/cell; females, 99 +/- 5.9 grains/cell). This difference in SS mRNA levels is likely to be the result of different hormonal environments exerting an influence on neurons of the hypothalamus. To test the hypothesis that testosterone stimulates SS gene expression in neurons of the PeN, adult male rats were castrated and immediately implanted with either empty (sham; n = 3) or testosterone-containing (n = 3) Silastic implants of a size that would deliver physiological levels of testosterone (3.6 +/- 1.5 ng/ml). We observed that castrated animals had significantly lower levels of SS mRNA signal in neurons of the PeN compared with intact animals (intact, 195 +/- 3 grains/cell; castrated, 159 +/- 6 grains/cell; P less than 0.003) and that physiological levels of testosterone prevent this reduction in SS mRNA levels (castrated testosterone-replaced, 182 +/- 4 grains/cell; castrated, 159 +/- 6 grains/cell; P less than 0.003). Furthermore, testosterone-treated castrates had SS mRNA signal levels indistinguishable from those of intact controls (intact, 195 +/- 3 grains/cell; castrated testosterone-replaced, 182 +/- 4 grains/cell). There was no significant difference in SS mRNA levels in neurons of the frontal cortex (intact, 98 +/- 2 grains/cell; castrated, 98 +/- 3 grains/cell; castrated testosterone-replaced, 102 +/- 2 grains/cell).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1989

Testosterone induction of cellular proteins in cultured Sertoli cells from hypophysectomized rats and rats of different ages.

Testosterone is essential for the maintenance of spermatogenesis, and the Sertoli cell is thought to be an important target cell for the hormone in the seminiferous tubule. The direct response of Sertoli cells to testosterone in cell culture was studied by two-dimensional gel electrophoresis of radiolabeled cellular proteins. Changes in testosterone responsiveness with age and hormonal condition were studied by culturing Sertoli cells from 20- and 40-day-old normal rats and 40-day-old rats that had been hypophysectomized at 20 days of age. Two abundant proteins, numbered 1604 and 1605 for reference purposes, were consistently increased in response to testosterone treatment in all three sets of cultured Sertoli cells. Two other proteins, 1602 and 1603, were decreased with testosterone in all three Sertoli cell cultures. Densitometric scanning of the gels revealed changes in several proteins of low abundance (i.e. proteins that represent less than 0.2% of the total incorporated radioactivity on the gel) in response to testosterone. The majority of the changes in response to testosterone were in these low abundance proteins. Protein profiles from testosterone-treated cell cultures as well as control (no hormone) Sertoli cell cultures differed among the three groups of cells. This indicates that differences in Sertoli cell function in vivo due to age and hormonal condition are reflected in culture by protein profiles.

Aging↗

PubMed1990

Sources of cholesterol for testosterone biosynthesis in murine Leydig cells.

The sources of cholesterol for testosterone production were investigated in freshly isolated murine Leydig cells. In vitro stimulation with human CG (hCG) (0.2 IU/ml) caused a 75-fold increase in testosterone production. Leydig cells contained approximately equal amounts of free and esterified cholesterol (7.8 vs. 8.7 micrograms/mg protein). The total cholesterol content of cells stimulated for 4 h with hCG was significantly decreased compared with unstimulated cells (8.4 vs. 17.6 micrograms/mg protein); both free and esterified cholesterol decreased by about 50%. In unstimulated Leydig cells incubated with [14C]acetate for 12 h, the majority of incorporated [14C] was found in free and esterified cholesterol, whereas, in the hCG-stimulated cells, 80% of incorporated 14C was in testosterone. The activity of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase after 4 h in hCG-stimulated cells was 20% higher than in unstimulated cells (115.5 vs. 84.4 pmol/mg protein.min). However, by 6 h, HMG-CoA reductase activity doubled in the hCG-stimulated compared with unstimulated cells. By 12 h, HMG-CoA reductase activity in hCG-stimulated cells was 4 times the preincubation level and 8 times the 12-h level in unstimulated cells. HMG-CoA reductase activity induced by hCG was blocked by aminoglutethimide, an inhibitor of the cholesterol side-chain cleavage enzyme. Lovastatin, a potent inhibitor of HMG-CoA reductase, had no effect on unstimulated or hCG-stimulated testosterone production during a 12-h incubation. Murine high density lipoproteins (mHDL) increased HMG-CoA reductase activity in both unstimulated (29%) and hCG-stimulated (20%) cells. During a 6 h incubation, mHDL increased hCG-stimulated testosterone production by 20%, but had no effect on unstimulated testosterone production. These results suggest that murine Leydig cells store enough cholesterol and cholesteryl esters to support testosterone production for at least 12 h in vitro. Although mHDL does not have a major stimulatory effect on testosterone biosynthesis, it may be involved in the regulation of de novo cholesterol synthesis.

Aminoglutethimide↗

PubMed1975

Dynamics of venous-arterial testosterone transfer in the pampiniform plexus of the rat.

The dynamics of venous-arterial testosterone transfer in the pampiniform plexus of the rat have been studied using [3-H] testosterone in controlled perfusion in the pampiniform plexus isolated from its testicle in vivo. The rate of transfer of testosterone increased in direct proportion to the testosterone concentration in spermatic vein blood over the range 0-100 ng/ml. When the venous-arterial concentration gradient was reversed by infusing [14-C] testosterone into the spermatic artery proximal to the pampiniform plexus, the label was transferred from the artery to the adjacent spermatic vein. Transfer of [3-H] methoxy-inulin infused concomitantly with the [14-C] testosterone was relatively insignificant in either direction. The testosterone transfer rate generally increased with increasing blood flow over the range 0.01-0.36 ml/min. However, transfer rate became less dependent on blood flow at the high end of the range. A comparison of transfer rates from whole blood and dextran (6% in saline) each containing 24-27 ng [1,2-3-H] testosterone/ml and flowing at 0.36 ml/min for one hour resulted in a maximum of 6.1% transfer from blood and 46% transfer from dextran. Transfer from blood reached plateau levels in less than 10 min, whereas transfers from dextran peaked between 30 and 40 min. At lower rates testosterone transfer from dextran reached equilibration levels, whereas transfer from blood rarely exceeded 5% of spermatic venous levels. We concluded that venous-arterial steroid transfer in the pampiniform plexus behaves like a passive countercurrent diffusion system that is concentration limited, depending principally on the concentration gradient of diffusible steroid between the closely juxtaposed spermatic vein and artery.

Animals↗

PubMed1993

Postreceptor events involved in the up-regulation of beta-adrenergic receptor mediated lipolysis by testosterone in rat white adipocytes.

In the previous studies we have shown that testosterone increases lipolytic responsiveness to catecholamines in rat white adipocytes, and that is associated with an up-regulation of beta-adrenergic receptor density. However, the postreceptor events involved in the testosterone induced enhancement of beta-adrenergic receptor activated lipolysis in these cells have not been adequately studied, and were therefore investigated in the present study. Male Sprague Dawley rats were divided into three groups: control, castrated, and castrated treated with testosterone. The beta-adrenergic receptor-mediated cAMP accumulation, measured with RIA after isoproterenol (a beta-adrenergic agonist) stimulation was decreased in castrated rats, and reversed by testosterone treatment, suggesting a testosterone effect at or proximal to adenylate cyclase. However, no differences between the groups were found in abundance of G alpha protein messenger RNAs (G alpha s, G alpha i-1, and G alpha i-2) as analyzed by Northern blot and a solution hybridization RNase protection assay, or in G protein mass measured with a quantitative enzyme-linked immunosorbent assay in fat cell membrane preparation. Lipolysis stimulated by N6-monobutyryl-cAMP was reduced in castrated rats and recovered by testosterone treatment, suggesting that components distal to the adenylate cyclase, i.e. protein kinase A (PKA) and/or hormone sensitive lipase (HSL) also are involved in testosterone regulation of lipolysis. In conclusion, these and previous results suggest that the testosterone-induced increase in lipolytic response to catecholamines in rat white adipocytes is mediated through several events including an increased beta-adrenergic receptor density, probably an increased adenylate cyclase activity and an increased protein kinase A/hormone sensitive lipase activity at the postreceptor level with apparent absence of effect on the expression of G-proteins.

Adenylyl Cyclases↗

PubMed1994

Gender-specific, maturation-dependent effects of testosterone on chondrocytes in culture.

This study examined the effects of testosterone on chondrocytes in vitro in order to determine whether the effects of testosterone were dependent on the stage of chondrocyte maturation and gender specific. Cells derived from male or female rat costochondral growth zone and resting zone cartilage were used as the cell culture model. [3H]Thymidine incorporation, cell number, alkaline phosphatase specific activity, and percent collagen production were used as indicators. Alkaline phosphatase specific activity in matrix vesicles and plasma membranes isolated from male and female chondrocyte cultures was measured to determine which membrane fraction was targeted by the hormone. The role of fetal bovine serum in the culture medium was also addressed. The results demonstrated that testosterone decreases cell number and [3H]thymidine incorporation in male chondrocytes, suggesting that it may promote differentiation of these cells. Alkaline phosphatase specific activity is stimulated in growth zone cells, with no effect on resting zone cells. The increase in enzyme activity is targeted to the matrix vesicles. Cells cultured in serum-free medium exhibit a dose-dependent inhibition of alkaline phosphatase activity when cultured with testosterone, even in the presence of phenol red. Testosterone-dependent stimulation of enzyme activity is seen only in the presence of serum, suggesting that serum factors are also necessary. Testosterone increased the percent collagen production in male cells only, regardless of the cartilage zone of origin. The results of this study indicate that the effects of testosterone are dependent on the time of exposure, presence of serum, and sex and stage of maturation of the chondrocytes. Testosterone-dependent stimulation of alkaline phosphatase specific activity is targeted to matrix vesicles.

Alkaline Phosphatase↗

PubMed1996

Increased epidermal growth factor expression produced by testosterone in the submaxillary gland of female mice is accompanied by changes in poly-A tail length and periodicity.

The level of mature EGF messenger RNA (mRNA) in the female submaxillary salivary gland (SMG) begins to rise after 3 days' treatment with testosterone (200 micrograms sc qod), and by 5 days it reaches a plateau of approximately 5 times baseline. Testosterone can increase the transcription of other genes in the SMG rapidly, so the lag in the EGF is not due to a slow androgen receptor response, and EGF mRNA can respond rapidly to other mediators, so the lag is not an innate characteristic of EGF transcription. Immunoreactive EGF levels reach a steady-state several times greater than the plateau reached by EGF mRNA, suggesting that testosterone also enhances the efficiency of EGF mRNA translation. Because testosterone has been reported to alter poly-A polymerase activities and because the translation and stability of some mRNAs is affected by changes in their polyadenylation, we used 3' rapid amplification of complementary DNA ends (3' RACE) to determine whether testosterone affected this aspect of EGF RNA metabolism. We found that EGF transcripts in untreated female SMG occur indistinct size classes, with poly-A tails of approximately 20, 50, 70, 100, and 200 A's attached after the terminal polyadenylation signal. In contrast, EGF transcripts in male SMG have poly-A tails of less clearly defined lengths, being more heterogeneous, ranging from approximately 20-100 A's. Treating female mice with testosterone causes the poly-A pattern in the SMG to change to a more heterogeneous population ranging from approximately 20-100 A's, similar to the male pattern. This change in EGF transcript polyadenylation occurs concurrently with the changes observed in the levels of EGF mRNA. EGF transcripts from male or female kidney contain distinct poly-A tails of approximately 20, 50, 70, 100, and 200 A's: neither EGF mRNA levels nor polyadenylation was altered by testosterone. The tissue-specific increase in EGF mRNA levels and in translational efficiency produced by testosterone in the female mouse SMG could involve this posttranscriptional alteration in transcript polyadenylation.

Animals↗

PubMed2001

Caspase-3 and caspase-activated deoxyribonuclease are associated with testicular germ cell apoptosis resulting from reduced intratesticular testosterone.

The purpose of the present study was to examine the possible involvement of caspase-3 and caspase-activated deoxyribonuclease in rat testicular germ cell apoptosis resulting from reduced intratesticular testosterone concentration. Adult Sprague Dawley rats received LH-suppressive testosterone- and estradiol-filled SILASTIC capsules of 2.5 and 0.1 cm, respectively, a regimen known to rapidly reduce testosterone production by the testes and to produce azoospermia within 8 wk. Germ cell internucleosomal DNA cleavage increased compared with control levels by 1 wk postimplantation and increased further through 4 wk. In situ terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling revealed that spermatocytes represented the predominant apoptotic cell type. Modest immunoreactivity for active caspase-3 was localized to the cytoplasm or perinuclear region of the germ cells of control testes. After testosterone and estradiol administration, however, intense staining for caspase-3 was localized to the nuclei of spermatocytes. Western blotting revealed significantly increased caspase-3 cleavage (activation) in nuclei isolated from germ cells after rats were administered testosterone and estradiol. Cleavage of the caspase-3 substrate protein, poly(ADP-ribose) polymerase, was seen after testosterone and estradiol treatment. Additionally, the caspase-activated deoxyribonuclease protein content was significantly increased in germ cells after rats were administered testosterone and estradiol, and caspase-activated deoxyribonuclease immunoreactivity was localized to the nuclei of apoptotic spermatocytes. Taken together, these results indicate that germ cell apoptosis resulting from a reduced intratesticular testosterone concentration is caspase-3 activation dependent and suggest that the translocation of active caspase-3 and caspase-activated deoxyribonuclease to the nucleus may be involved in the induction of germ cell apoptosis.

Animals↗

PubMed2002

Effects of oral androstenedione administration on serum testosterone and estradiol levels in postmenopausal women.

Androstenedione is a steroid hormone and an intermediate in the synthetic pathway of both testosterone and estradiol in men and women. It is available without prescription and taken with the expectation that it may have beneficial effects on strength, general well-being, libido, and quality of life. Although studies have shown that oral androstenedione increases serum testosterone and estradiol levels in men, the hormonal effects of androstenedione in postmenopausal women are unknown. We randomly assigned 30 healthy postmenopausal women to receive 0, 50, or 100 mg androstenedione as a single oral dose. After androstenedione administration, we made hourly measurements of serum androstenedione, estrone, estradiol, and testosterone concentrations during 12 h of frequent blood sampling. The mean change (+/-SD) in serum androstenedione area under the curve (AUC) was greater in both the 50-mg (79 +/- 39%) and 100-mg dose groups (242 +/- 184%) than in the control group (-29 +/- 28%) (P < 0.0001 for controls vs. 50-mg group and controls vs. 100-mg group). The mean change in serum androstenedione AUC was also greater in the 100-mg than 50-mg dose group (P = 0.0026). The mean change in serum estrone AUC was greater in both the 50-mg (108 +/- 72%) and 100-mg dose groups (116 +/- 119%) than in the control group (-5 +/- 19%), although the control vs. 100-mg group comparison did not quite meet statistical significance (P < 0.0001 for controls vs. 50-mg group, P = 0.0631 controls vs. 100-mg group). The mean change in serum estradiol AUC remained stable after supplementation in all groups without any between-group differences observed (-11 +/- 17%, 2.8 +/- 34%, -11 +/- 27%, for the control, 50-mg, and 100-mg groups, respectively). The mean change in serum testosterone AUC was greater in both the 50-mg (185 +/- 146%) and 100-mg dose groups (457 +/- 601%) than in the control group (-27 +/- 13%) (P < 0.0001 for controls vs. 50-mg group and for controls vs. 100-mg group). The mean change in testosterone AUC was also greater in the 100-mg dose group than 50-mg dose group (P = 0.0257). There was considerable individual variability in the changes of serum androstenedione, estrone, and testosterone levels in the treated groups with peak serum testosterone levels exceeding the upper limit of normal in 4 of 10 women in the 50-mg dose group and 6 of 10 in the 100-mg dose group. We concluded that the acute administration of both 50-mg and 100-mg of androstenedione increases serum testosterone and estrone levels, but not estradiol levels, in postmenopausal women. If these hormonal effects are sustained during long-term administration, regular use of this supplement by postmenopausal women could thus cause both beneficial and adverse effects.

Administration, Oral↗

PubMed2004

The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men.

Testosterone has immune-modulating properties, and current in vitro evidence suggests that testosterone may suppress the expression of the proinflammatory cytokines TNFalpha, IL-1beta, and IL-6 and potentiate the expression of the antiinflammatory cytokine IL-10. We report a randomized, single-blind, placebo-controlled, crossover study of testosterone replacement (Sustanon 100) vs. placebo in 27 men (age, 62 +/- 9 yr) with symptomatic androgen deficiency (total testosterone, 4.4 +/- 1.2 nmol/liter; bioavailable testosterone, 2.4 +/- 1.1 nmol/liter). Compared with placebo, testosterone induced reductions in TNFalpha (-3.1 +/- 8.3 vs. 1.3 +/- 5.2 pg/ml; P = 0.01) and IL-1beta (-0.14 +/- 0.32 vs. 0.18 +/- 0.55 pg/ml; P = 0.08) and an increase in IL-10 (0.33 +/- 1.8 vs. -1.1 +/- 3.0 pg/ml; P = 0.01); the reductions of TNFalpha and IL-1beta were positively correlated (r(S) = 0.588; P = 0.003). In addition, a significant reduction in total cholesterol was recorded with testosterone therapy (-0.25 +/- 0.4 vs. -0.004 +/- 0.4 mmol/liter; P = 0.04). In conclusion, testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol. Twenty of these men had established coronary disease, and because total cholesterol is a cardiovascular risk factor, and proinflammatory cytokines mediate the development and complications associated with atheromatous plaque, these properties may have particular relevance in men with overt vascular disease.

Adult↗

PubMed2005

Testosterone and estradiol among older men.

CONTEXT: Testosterone and estradiol levels decline with age in men. This change may affect multiple clinical outcomes, but there have been few reports of the distribution and correlates of testosterone and estradiol concentrations in elderly men. OBJECTIVE: The purpose of these studies was to assess sex steroid levels in a large cohort of older men. DESIGN: We conducted a cross-sectional cohort evaluation. SETTING: Community-dwelling men were studied at six academic medical centers in the United States. PARTICIPANTS: The Osteoporotic Fractures in Men Study is a prospective cohort of men aged at least 65 yr. In these studies, a randomly selected stratified subsample of 2623 participants was analyzed. MAIN OUTCOME MEASURES: We assessed levels of total and free testosterone and estradiol and SHBG. RESULTS: Age was inversely associated with free testosterone and free estradiol levels (P for trend = 0.001 for both). Notably, at any age, there was substantial variation in levels of each hormone. Free testosterone levels were lower in men with greater body mass index, lower SHBG, and poorer self-reported health status and in those of Asian race. Free estradiol concentrations were lower in men with lower body mass index and higher SHBG levels. Free estradiol and free testosterone were modestly correlated (r = 0.20; P < 0.001), but at any level of free testosterone, there was considerable variation in free estradiol levels. CONCLUSIONS: This is the largest cohort of older men in which sex steroid levels are available, and it demonstrates that testosterone and estradiol, and their free fractions, tend to decline with age even among older men. However, substantial variation is also present. The relationships between sex steroid levels and their consequences in aging are likely to be complex.

Aged↗

PubMed2006

Relationship among serum testosterone, sexual function, and response to treatment in men receiving dutasteride for benign prostatic hyperplasia.

CONTEXT: Although benign prostatic hyperplasia (BPH) is an androgen-dependent disorder, little is known regarding the influence of serum testosterone levels on sexual or prostate function or clinical response to dutasteride. OBJECTIVE: The objective of the study was to explore these relationships in a large cohort of men treated with dutasteride for BPH. DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: Among 4254 men with BPH participating in 2-yr placebo-controlled dutasteride trials, 27% had a pretreatment serum testosterone less than 300 ng/dl. These 1162 men were divided into seven groups based on their serum testosterone level (<150, 150-174, 175-199, 200-224, 225-249, 250-274, and 275-299 ng/dl) and compared with men with normal baseline serum testosterone (BST; > or = 300 ng/dl). Questionnaires were used to assess sexual function, prostate-specific antigen (PSA), and prostate volume to assess androgenic stimulation of the prostate and the American Urological Association Symptom Index to assess clinical responses. RESULTS: Although lower BST was associated with increased sexual dysfunction, this increase was not seen until BST was less than 225 ng/dl. There was no decrease in baseline PSA and prostate volume at low BST levels. Dutasteride was effective at decreasing PSA and prostate volume and improving BPH symptoms at all BST levels. CONCLUSIONS: In men with BPH, the frequency of sexual dysfunction increases at serum testosterone concentrations less than 225 ng/dl. However, PSA and prostate volume were similar at all testosterone levels, explaining why BPH can occur in men that would otherwise be considered hypogonadal. The fact that dutasteride is also effective in men with normal and low testosterone levels suggests that the high levels of 5alpha-reductase and dihydrotestosterone in the prostate allow the development and progression of prostatic hyperplasia, even at low circulating testosterone levels.

Aged↗

PubMed2006

Effects of testosterone replacement in androgen-deficient women with hypopituitarism: a randomized, double-blind, placebo-controlled study.

CONTEXT: Hypopituitarism in women is characterized by profound androgen deficiency due to a loss of adrenal and/or ovarian function. The effects of testosterone replacement in this population have not been reported. OBJECTIVE: The objective of the study was to determine whether physiologic testosterone replacement improves bone density, body composition, and/or neurobehavioral function in women with severe androgen deficiency secondary to hypopituitarism. DESIGN: This was a 12-month randomized, placebo-controlled study. SETTING: The study was conducted at a general clinical research center. STUDY PARTICIPANTS: Fifty-one women of reproductive age with androgen deficiency due to hypopituitarism participated. INTERVENTION: Physiologic testosterone administration using a patch that delivers 300 microg daily or placebo was administered. MAIN OUTCOME MEASURES: Bone density, fat-free mass, and fat mass were measured by dual x-ray absorptiometry. Thigh muscle and abdominal cross-sectional area were measured by computed tomography scan. Mood, sexual function, quality of life, and cognitive function were assessed using self-administered questionnaires. RESULTS: Mean free testosterone increased into the normal range during testosterone administration. Mean hip (P = 0.023) and radius (P = 0.007), but not posteroanterior spine, bone mineral density increased in the group receiving testosterone, compared with placebo, as did mean fat-free mass (P = 0.040) and thigh muscle area (P = 0.038), but there was no change in fat mass. Mood (P = 0.029) and sexual function (P = 0.044) improved, as did some aspects of quality of life, but not cognitive function. Testosterone at physiologic replacement levels was well tolerated, with few side effects. CONCLUSIONS: This is the first randomized, double-blind, placebo-controlled study to show a positive effect of testosterone on bone density, body composition, and neurobehavioral function in women with severe androgen deficiency due to hypopituitarism.

Adrenal Insufficiency↗