Supraphysiological Doses Of Testosterone Research Articles

A Study on The effect of Testosterone on Liver and Kidney functions of Male Rabbits

The purpose of this study was to examine the effect of two supraphysiological doses of testosterone on the liver and kidney functions of male rabbits. Fifteen (15) adult male rabbits were divided into 3 groups: a control group (received 100 µl sesame oil), a low dose group (received 6 mg testosterone/kg body weight), and a high dose group (received 12 mg testosterone/kg body weight). The rabbits were injected intramuscularly once a week for 6 weeks. After the end of the treatment period, the rabbits were sacrificed and blood samples were collected for analysis. Injection of testosterone resulted in a significant increase in the level of this hormone in the sera of the treated rabbits. The hormone caused increases in the levels of the liver function enzymes with the increase in dose; however, only the high dose caused statistically significant increases. Similar trend was observed with the effect of the hormone on the concentrations of creatinine and urea, where only the high dose had a statistically significant effect. These results clearly indicate that the use of this hormone with high doses for long periods could cause damage to the liver and kidney.

The effects of gonadal hormones on heroin Self-Administration in male gonadectomized rats.

Previous studies have shown that gonadal hormones influence opioid self-administration in female rodents, but very few studies have examined these effects in male rodents. The purpose of this study was to examine the effects of chronic hormone treatment on intravenous heroin self-administration in gonadectomized male rats using both physiological and supraphysiological doses of testosterone, estradiol, or progesterone. Gonadectomized male rats were surgically implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement.Using a between-subjects design, rats were treated daily with testosterone (0.175 or 1.75mg, sc), estradiol (0.0005 or 0.005mg, sc), progesterone, (0.0125 or 0.125mg, sc), or their vehicles. After 14days of chronic treatment, a dose-effect curve was determined for heroin (0.0003-0.03mg/kg/infusion) over the course of one week. Neither testosterone nor estradiol altered responding maintained by heroin. In contrast, the high dose of progesterone (0.125mg) reduced responding maintained by all doses of heroin to saline-control levels. This dose of progesterone did not reduce responding maintained by food on a progressive ratio schedule in either food-restricted or food-sated rats. These data indicate that exogenous progesterone or a pharmacologically active metabolite selectively decreases heroin intake in male rodents, which may have therapeutic implications for men with opioid use disorder.

Supraphysiological levels of testosterone induces endothelial injury via increasing generation of reactive oxygen species and ERK1/2 activation

Introduction: High levels of testosterone (Testo) is associated with higher cardiovascular risk by positively modulate the generation of reactive oxygen species (ROS) and inflammatory response. Excessive ROS generation by NADPH oxidases (NOX, major source of ROS in the vasculature) leads to endothelial dysfunction, apoptosis, and inflammation. However, the intracellular mechanisms whereby supraphysiological levels of Testo promote cardiovascular damage are still ill defined. We sought to determine whether supraphysiological levels of Testo induces endothelial cell dysfunction via ROS generation and ERK1/2 activation. Methods: To study whether Testo present the same effects independent on endothelial cell type, we used Primary Human Mesenteric vascular Endothelial Cells (HMEC) and Human Umbilical Vein Endothelial Cells (HUVEC). Cells were stimulated with Testo (10 −7 M, for different time points) in the presence or absence of superoxide dismutase mimetic (Tempol, 10 -4 M, for 30 min). NOX activity, gene expression, and protein expression were determined pharmacological assays and immunoblotting, respectively. Results: Testo increased superoxide anion (O 2 − ) generation in HMEC and HUVEC at short (10 min) stimulation times, which was abolished by superoxide dismutase (SOD) mimetic [(% of control) Ctrl: 100.0 ± 0.0 n=5 vs Testo: 363.2 ± 19.77 n=6 vs. Tempol+Testo: 156.7 ± 12.12 n=6, *P<0.05]. Furthermore, long-term treatment (24 h) of endothelial cells with Testo increased Nox4 expression at gene (2.44-Fold change) and protein levels [(% of control) Ctrl: 100.0 ± 0.0 n=4 vs. Testo: 157.3 ± 4.49 n=4, *P<0.05]. Testo did not affect Nox1, Nox2, and Nox5 expressions. Furthermore, Testo increased ERK1/2 phosphorylation at 10 minutes and promoted endothelial cell inflammation at 8h, characterized by increased ICAM-1(6.49-Fold changes) and VCAM-1 [(1.42-Fold changes) gene expressions. To confirm that Testo-induced ROS production is leading to endothelial injury via ERK1/2, we treated endothelial cells with Tempol prior Testo treatment. Interestingly, superoxide dismutase mimetic prevented ERK1/2 phosphorylation induced by Testo [(% of control) Testo: 161.2 ± 11.39 n=5 vs. Tempol+Testo: 91.45 ± 9.61 n=5, *P<0.05]. Conclusion: These data indicate that supraphysiological levels of testosterone induce endothelial dysfunction via ROS generation and inflammatory response. Our data helps understanding the intracellular mechanisms that justify the cardiovascular damage caused by supraphysiological doses of testosterone and places antioxidant therapy as a possible pharmacological approach to treat patients with dysregulated testosterone levels. 2022/00103-3, São Paulo Research Foundation (FAPESP). NHLBI-R00 (R00HL14013903), AHA-CDA (CDA857268), Vascular Medicine Institute, the Hemophilia Center of Western Pennsylvania Vitalant, and Children's Hospital of Pittsburgh of the UPMC Health System. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Consumption of avocado oil (Persea americana) improves the biochemical profile of rats submitted to long-term androgenic stimulation.

Introduction: indiscriminate use of anabolic steroids is associated with cardiovascular diseases, renal damage, and hepatic toxicity. Contrastingly, nutraceutical foods such as avocados prevent and control several diseases, as they can reduce the effects of oxidative stress. Objective: this study evaluates the benefits of consuming an avocado oil-based diet to attenuate the systemic damage caused by supraphysiological doses of testosterone, by analyzing the biochemical profile of 28 42-day-old male Wistar rats. Methods: silicone pellets containing testosterone were surgically implanted, and they received control or avocado oil-based feed. After 20 weeks, all the male rats were anesthetized and their blood samples collected. Results: although the high hormone concentration had a negative influence on the biochemical profile of these animals, the groups that consumed avocado oil exhibited a reduction in serum triacylglycerols (-21 %; p = 0.0001), VLDL (-20 %; p = 0.0085), LDL (-78 %; p < 0.0001), and total cholesterol (-12 %; p < 0.0001), along with positive changes in their HDL concentrations (+7 %; p = 0.001). The avocado oil groups also manifested a reduction in the total concentration of serum proteins (-24 %; p = 0.0357), albumin (-26 %; p = 0.0015), urea (-14 %; p = 0.04), and creatinine (-33 %; p < 0.0001). The concentration of liver transaminases was found to be higher in the animals included in the induced group (ALT, +66 %; p = 0.0005, and AST, +23 %; p = 0.0021), whereas they remained stable in the avocado oil group. Conclusion: from the above, it may be concluded that supraphysiological doses of testosterone are related to increased risk factors for cardiovascular, renal, and hepatic diseases, and that the consumption of avocado oil shields the biochemical profile, thus reducing the associated risk factors.

A Study on The effect of Testosterone on Liver and Kidney functions of Male Rabbits

The purpose of this study was to examine the effect of two supraphysiological doses of testosterone on the liver and kidney functions of male rabbits. Fifteen (15) adult male rabbits were divided into 3 groups: a control group (received 100 µl sesame oil), a low dose group (received 6 mg testosterone/kg body weight), and a high dose group (received 12 mg testosterone/kg body weight). The rabbits were injected intramuscularly once a week for 6 weeks. After the end of the treatment period, the rabbits were sacrificed and blood samples were collected for analysis. Injection of testosterone resulted in a significant increase in the level of this hormone in the sera of the treated rabbits. The hormone caused increases in the levels of the liver function enzymes with the increase in dose; however, only the high dose caused statistically significant increases. Similar trend was observed with the effect of the hormone on the concentrations of creatinine and urea, where only the high dose had a statistically significant effect. These results clearly indicate that the use of this hormone with high doses for long periods could cause damage to the liver and kidney.

Chronic Testosterone Increases Impulsivity and Influences the Transcriptional Activity of the Alpha-2A Adrenergic Receptor Signaling Pathway in Rat Brain

Testosterone is an anabolic androgenic steroid hormone involved in brain development, reproduction, and social behavior. Several studies have shown that testosterone can cause impulsivity in humans, which in turn, is linked with mood-related psychiatric disorders and higher risk of death by suicide. The mechanisms by which testosterone abuse influences impulsivity are unclear. The present study aims to understand how testosterone influences impulsivity in a rodent model both at behavioral and molecular levels. In this study, rats were either only gonadectomized or gonadectomized and injected with supraphysiological doses of testosterone. Their relative impulsivity levels were assessed using the go/no-go task. Serum level of testosterone was measured using ELISA. Transcript levels of alpha-2A adrenergic receptor (Adra2a), G proteins (stimulatory subunit-Gαs [Gnas], inhibitory subunit-Giα [Gnai1 and Gnai2]), and catalytic and regulatory subunits of protein kinase A (PKA) were examined using quantitative PCR (qPCR) in brain areas associated with limbic system (prefrontal cortex (PFC), hippocampus, and amygdala). The testosterone-treated (T) group showed significantly higher level of serum testosterone and displayed a lower go/no-go ratio, indicating greater impulsivity compared to the gonadectomized (GDX) group. The transcript levels Adra2a and Gαs genes and PKA subunits encoded by Prkar1a, Prkar1b, Prkar2a, and Prkaca genes were significantly upregulated in PFC of testosterone treated rats. The expression levels of these genes were not significantly altered in hippocampus. On the other hand, amygdala showed changes only in Gnas and Prkar2a. These results suggest that chronic testosterone influences impulsivity possibly via hyperactive alpha-2A adrenergic receptor-PKA signaling axis, specifically in the PFC.

Voluntary exercise and testosterone therapy caused increase in percentage of Myh6 and expression of oxidative stress marker Cybb in left ventricles of rats

Abstract Aim: The aim of this study is to identify a possible damage to heart ventricles caused by supraphysiological doses of testosterone, voluntary physical activity or their combination. Methods: In the 8-week long experiment, 10-12 weeks old male Wistar rats were administered testosterone depot in dose of 100 mg/kg (TES, n = 15) or vehiculum (CON, n = 12) once a week subcutaneously. Next groups injected with testosterone (SPOTES, n = 12) or vehiculum (SPO, n = 12) were running in exercise wheels ad libitum. Gene expressions in left and right ventricles of the heart were measured by quantitative reverse transcription polymerase chain reaction method. Results:ln left ventricles of the testosterone groups, we observed a mild but significant increase in the percentage of Myh6 myosin heavy chain isoform and higher expression of NADPH oxidase subunit Cybb (*p &lt; 0.05). Conclusions:Testosterone affected the expression of genes related to contractile apparatus and oxidative stress in the left ventricle but not in right ventricle of the heart of rats. The observed level of physical activity did not have a compelling effect on the expression of measured genes.

Development and Characterization of Uterine Glandular Epithelium Specific Androgen Receptor Knockout Mouse Model1

While estrogen action is the major driver of uterine development, androgens acting via the androgen receptor (AR) may also promote uterine growth as suggested by uterine phenotypes in global AR knockout (ARKO) female mice. Because AR is expressed in uterine endometrial glands, we generated (Cre/loxP) uterine gland epithelium-specific ARKO (ugeARKO) to determine the role of endometrial gland-specific androgen actions. However, AR in uterine gland epithelium may not be required for normal uterine development and function because ugeARKO females had normal uterine development and fertility. To determine if exogenous androgens acting via AR can fully support uterine growth in the absence of estrogens, the ARKO and ugeARKO females were ovariectomized and treated with supraphysiological doses of testosterone or dihydrotestosterone (nonaromatizable androgen). Both dihydrotestosterone and testosterone supported full uterine regrowth in wild-type females while ARKO females had no regrowth (comparable to ovariectomized only). These findings suggest that androgens acting via AR can promote full uterine regrowth in the absence of estrogens. The ugeARKO had 50% regrowth when compared to intact uterine glands, and histomorphologically, both the endometrial and myometrial areas were significantly (P < 0.05) reduced, suggesting glandular epithelial AR located in the endometrium may indirectly modify myometrial development. Additionally, to confirm Cre function in endometrial glands, we generated uge-specific PTEN knockout mouse model. The ugePTEN knockout females developed severe endometrial hyperplasia and therefore present a novel model for future research.

Cognitive effects of testosterone and finasteride administration in older hypogonadal men.

Serum concentrations of neuroactive androgens decline in older men and, in some studies, low testosterone is associated with decreased cognitive function and incidence of depression. Existing studies evaluating the effect of testosterone administration on cognition in older men have been largely inconclusive, with some studies reporting minor to moderate cognitive benefit, while others indicate no cognitive effect. Our objective was to assess the cognitive effects of treating older hypogonadal men for 1 year with a supraphysiological dose of testosterone, either alone or in combination with finasteride (a type II 5α-reductase inhibitor), in order to determine whether testosterone produces cognitive benefit and whether suppressed dihydrotestosterone influences cognition. Sixty men aged ≥60 years with a serum testosterone concentration of ≤300 ng/dL or bioavailable testosterone ≤70 ng/dL and no evidence of cognitive impairment received testosterone-enanthate (125 mg/week) versus vehicle, paired with finasteride (5 mg/day) versus placebo using a 2×2 factorial design. Testosterone caused a small decrease in depressive symptoms as assessed by the Geriatric Depression Scale and a moderate increase in visuospatial memory as assessed by performance on a recall trial of the Rey-Osterrieth Complex Figure Test. Finasteride caused a small increase in performance on the Benton Judgment of Line Orientation test. In total, major improvements in cognition were not observed either with testosterone or finasteride. Further studies are warranted to determine if testosterone replacement may improve cognition in other domains.

Breast Cancer in Female-to-Male Transsexuals: Two Cases With a Review of Physiology and Management

Testosterone is important for the development of secondary sexual characteristics in female-to-male (FtM) transsexuals, but it may increase breast cancer risk. To date, only one breast cancer case has been reported in the literature in a FtM transsexual after 10 years of testosterone therapy. We describe 2 cases of breast cancers diagnosed in FtM transsexuals who have been treated with supraphysiological doses of testosterone. Our 2 cases demonstrate the unique issues that concern the management of FtM transsexuals with breast cancer and examine possible roles of testosterone in the development of breast cancer.

Concerning “Effects of a supraphysiological dose of testosterone on physical function, fatigue, and mood in men with human immunodeficiency virus-associated weight loss”

to the editor: In their article on the effects of a supraphysiological dose of testosterone in HIV-infected patients with weight loss, Knapp et al. ([6][1]) found improvements in some parameters, such as fat-free mass, mood, fatigue, and certain quality of life measurements in treated compared with

Testosterone Doping: Dealing with Genetic Differences in Metabolism and Excretion

The first documented use of testosterone as a performanceenhancing substance in sport began in the 1950s. The success of Russian weightlifters during this era led Dr. John B. Zeigler to surreptitiously obtain information from their trainers that they were using testosterone. Later, Zeigler would use Dianabol to enhance the performance of weightlifters at the York Barbell Club beginning in 1958. Once Pandora’s Box was open, it was impossible to close. The growth and widespread use of anabolic steroids in many competitive sports eventually led the U.S. Congress to schedule testosterone and other anabolic agents under the Anabolic Steroids Control Act in 1990 (Public Law 101647). For many years, the medical community argued that there was no proof that testosterone enhanced athletic performance. Finally, in 1996, Bhasin and co-workers showed that supraphysiological doses of testosterone indeed produced performance benefits (1), something the athletes had known for four decades. The urinary testosterone to epitestosterone (T/E) ratio was the first test to be used for evaluation of abuse of a natural (or endogenous) substance such as testosterone to enhance performance in sport. The production of reliable quadrupole gas chromatograph/mass spectrometers in the mid-1970s allowed more widespread study of urinary steroid profiles. Donike and coworkers (2) observed an unusual distribution of testosterone concentrations in samples collected at the Moscow Olympics in 1980. In 1982, Donike proposed the use of the urinary T/E ratio based on the observation that epitestosterone was excreted in the urine in a relatively constant amount and as such constituted a way to compensate for the variability in testosterone concentration that occurred as a function of the diluteness of the urine (2). Because the primary metabolite of testosterone is testosterone glucuronide, the procedure developed by Donike used -glucuronidase in the preparation of the samples for analysis. In 1983, the International Olympic Committee accepted a T/E ratio of greater than 6:1 as evidence of testosterone doping, based on the 99th percentile of the log normal distribution of ratio values established by Donike and his co-workers. It was soon clear that the T/E ratio based on population reference ranges had limitations. For example, it had been noted in 1970 that genetic make-up could have a significant effect on urinary testosterone excretion, whereas epitestosterone excretion was unaffected (3). As population T/E ratio data accumulated in the anti-doping laboratories, it was clear that there were two distributions of urinary T/E ratios in both men and women, one with a maximum frequency at a T/E ratio of about 0.1 and a much larger population with a maximum frequency at a T/E ratio of about 1. Within the anti-doping community, the smaller population was referred to as low mode, and it was known that administration of testosterone to low-mode individuals did not result in a T/E ratio above the population threshold (4). Jakobsson and her colleagues (5) provided the mechanism for lowmode excretion in 2006 when they demonstrated that the UGT2B17 gene deletion was the cause of significant differences in testosterone glucuronide excretion between Korean and Swedish men. In their current paper in this issue, JakobssonSchulze et al. (6) report that when subjects deficient in the UGT2B17 gene (del/del) receive exogenous testosterone, their T/E ratio does not rise above the current population-based threshold of 4:1. One potential route of excretion of testosterone in UGT2B17 del/del genotypes is through other phase II metabolites such as testosterone sulfate. Borts and Bowers (7) directly measured the concentrations of testosterone and epitestosterone sulfate and glucuronide using HPLC/tandem mass spectrometry. Low-mode excretors did not produce larger than normal amounts of testosterone or epitestosterone sulfate. There was also no change in the relative production of sulfate conjugates. Because phase II metabolism does not explain the difference in testosterone handling in these individuals, it would be interesting to know what phase I metabolism products are increased in individuals with the UGT2B17 del/del polymorphism. This information may help develop a more sensitive test for testosterone

Effects of testosterone administration on fat distribution, insulin sensitivity, and atherosclerosis progression.

In spite of the widespread belief that testosterone supplementation increases the risk of atherosclerotic heart disease, evidence to support this premise is lacking. Although supraphysiological doses of testosterone, such as those used by athletes and recreational body builders, decrease plasma high-density lipoprotein (HDL) cholesterol concentrations, replacement doses of testosterone have had only a modest or no effect on plasma HDL in placebo-controlled trials. In epidemiological studies, serum total and free testosterone concentrations have been inversely correlated with intra-abdominal fat mass, risk of coronary artery disease, and type 2 diabetes mellitus. Testosterone administration to middle-aged men is associated with decreased visceral fat and glucose concentrations and increased insulin sensitivity. Testosterone infusion increases coronary blood flow. Similarly, testosterone replacement retards atherogenesis in experimental models of atherosclerosis. However, the long-term risks and benefits of testosterone administration in human immunodeficiency virus-infected men with fat redistribution syndrome have not been studied in randomized clinical trials.

Measures of Aggression and Mood Changes in Male Weightlifters With and Without Androgenic Anabolic Steroid Use

Supraphysiologic doses of testosterone are associated with increased aggression that is hypothesized to be a function of testosterone serum concentrations, mood, and personality. The study attempted to characterize this relationship among weightlifters who were users (n = 10) and nonusers (n = 18) of anabolic steroids. Participants were interviewed using the Modified Mania Rating Scale and Hamilton Rating Scale for Depression to assess mood, the Buss-Durkee Hostility Inventory (BDHI) and Point Subtraction Aggression Paradigm (PSAP) to assess aggression, and the Personality Disorder Questionnaire (PDQ-R) to assess personality. Blood samples were obtained for the determination of total, free, and weakly bound testosterone. Comparisons of continuous variables between testosterone users and non-users were performed with a parametric (unpaired t-test) or non-parametric (Mann-Whitney) test where appropriate. Correlations with testosterone were examined separately for testosterone users and non-users, using Spearman rank correlation. The subjective (BDHI) and objective (PSAP) assessments of aggression found that supranormal testosterone concentrations were associated with increased aggression. However, the PDQ-R results suggest that this finding was confounded by the personality disorder profile of the steroid users, because steroid users demonstrated Cluster B personality disorder traits for antisocial, borderline, and histrionic personality disorder.

Altered molecular dynamics and antioxidant status in the spermatozoa in testosterone-induced oligospermia in mouse.

Though supraphysiological doses testosterone (T) and its derivatives are known to suppress spermatogenesis in mammals by interfering with the hypothalamus-pituitary axis leading to oligozoospermia, no study has been performed to evaluate the integrity of the sperm cells produced by such individuals. In T-induced oligozoospermia in the mouse, the spermatozoa showed suppressed zona-binding ability though the motility and viability remained unchanged. In order to assess whether this decreased zona-binding ability is due to perturbations in the mechanical properties of the sperm membranes, we attempted to examine the molecular dynamics employing a lipophilic spin label (16-doxyl stearate) and a protein-binding label (Mal-Net) in two sets of independent experiments. The results showed that the rotational freedom of lipophilic molecules reduced significantly within the first week of T-treatment. During weeks 1 through 4, the protein rotation was found to be retarded significantly. We observed a sharp increase in the ascorbyl radical associated with the cauda epididymal spermatozoa and epididymal fluid of testosterone-treated mice. Moreover, the glutathione (GSH) content in the spermatozoa and the epididymal fluid increased significantly after testosterone-treatment. Further, there was a elevation in the superoxide dismutase (SOD) activity and suppression in the superoxide anion radical generated by the cauda epididymal spermatozoa of testosterone-treated animals. A change in the mechanical properties of a bilayer could modify both the mechanical properties and the function of incorporated proteins. In many instances, a liquid-crystalline bilayer is necessary for protein function. It is likely that the change in the physical properties of sperm membranes might cause the inhibition of enzymes associated with spermatozoa after T-treatment. The alterations in the sperm membrane structure and the antioxidant potentials of both the spermatozoa and the cauda epididymal fluid could also account for the decrease in the zona-binding index of the spermatozoa in T-treated animals. Thus, this study demonstrates for the first time that supraphysiological doses of testosterone could modify the mechano-dynamic properties of sperm membranes and could perturb the redox status of both spermatozoa and the epididymal fluid.

The effect of testosterone on androgen receptors and human penile growth.

Recent rat studies suggest that early exposure to exogenous testosterone accelerates the loss of androgen receptors and compromises eventual penile length. In humans we hypothesize that down regulation of the androgen receptor is not the mechanism that stops penile growth. To test this hypothesis we investigated the effects of androgen deprivation and supplementation on the developing human penis. A total of 15 normal human fetal penises at 7 to 19 weeks of gestation (mean plus or minus standard deviation 12 +/- 4.5) was divided in half sagittally. Specimens were grafted beneath the renal capsule of male athymic nude mice or nude rats. Three groups of host animals were prepared, including 10 with no testosterone that were castrated at grafting, 15 with testosterone and 5 with super testosterone in which 50 mg. testosterone propionate pellets were implanted subcutaneously at grafting. Each fetal penile specimen was its own control, since half was implanted into an intact animal and the other into a castrated or super testosterone host. Six weeks after grafting the specimens were analyzed for gross size (length), histology and expression of androgen receptors. All human fetal penile specimens grew from the nadir size and appeared as white exophytic growths on the surface of the host kidneys. Normal grafts were larger than castrate specimens (mean 6.9 +/- 2.1 versus 3.9 +/- 2.1 mm., p = 0.014). Mean length of the super testosterone specimens (7.3 +/- 2.3 mm.) was not significantly greater than that of normal specimens (p = 0.797). Histological analysis revealed that all specimens were composed of viable penile tissue. Cellular density of the castrate penises was approximately 2 times greater than that of the normal and super testosterone specimens (40.6 +/- 5.9 versus 25.1 +/- 2.8 cells per cm.2, p > 0.001), as calculated on enlarged micrographs. Supraphysiological doses of testosterone did not change the histology compared to controls. Immunohistochemical localization revealed androgen receptors expressed throughout the corporeal bodies, surrounding stroma and penile skin with intracellular localization to nucleus. The mean proportion of cells expressing androgen receptors was higher in the castrate (29.4 +/- 5.2 cells per cm.2) than in the normal (24.0 +/- 3.7) and super testosterone (24.7 +/- 4.5) grafts (p = 0.005). However, in regard to growth there was no change in the proportion of androgen receptor positive cells among the groups. Testosterone influences penile growth, possibly as a result of extracellular stromal expansion. The number of androgen receptor positive cells in the human fetal penis did not change among the castrate, normal and super testosterone hosts. These experiments support the hypothesis that penile growth cessation is mediated by mechanisms other than down regulation of the androgen receptor. Furthermore, these data support the hypothesis that early administration of androgen to prepubertal male individuals does not result in a shorter phallus in adulthood.

The Effect of Testosterone on Androgen Receptors and Human Penile Growth

Purpose Recent rat studies suggest that early exposure to exogenous testosterone accelerates the loss of androgen receptors and compromises eventual penile length. In humans we hypothesize that down regulation of the androgen receptor is not the mechanism that stops penile growth. To test this hypothesis we investigated the effects of androgen deprivation and supplementation on the developing human penis. Materials and Methods A total of 15 normal human fetal penises at 7 to 19 weeks of gestation (mean plus or minus standard deviation 12 −/− 4.5) was divided in half sagittally. Specimens were grafted beneath the renal capsule of male athymic nude mice or nude rats. Three groups of host animals were prepared, including 10 with no testosterone that were castrated at grafting, 15 with testosterone and 5 with super testosterone in which 50 mg. testosterone propionate pellets were implanted subcutaneously at grafting. Each fetal penile specimen was its own control, since half was implanted into an intact animal and the other into a castrated or super testosterone host. Six weeks after grafting the specimens were analyzed for gross size (length), histology and expression of androgen receptors. Results All human fetal penile specimens grew from the nadir size and appeared as white exophytic growths on the surface of the host kidneys. Normal grafts were larger than castrate specimens (mean 6.9 −/− 2.1 versus 3.9 −/− 2.1 mm., p = 0.014). Mean length of the super testosterone specimens (7.3 −/− 2.3 mm.) was not significantly greater than that of normal specimens (p = 0.797). Histological analysis revealed that all specimens were composed of viable penile tissue. Cellular density of the castrate penises was approximately 2 times greater than that of the normal and super testosterone specimens (40.6 −/− 5.9 versus 25.1 −/− 2.8 cells per cm. [2], p >0.001), as calculated on enlarged micrographs. Supraphysiological doses of testosterone did not change the histology compared to controls. Immunohistochemical localization revealed androgen receptors expressed throughout the corporeal bodies, surrounding stroma and penile skin with intracellular localization to nucleus. The mean proportion of cells expressing androgen receptors was higher in the castrate (29.4 −/− 5.2 cells per cm. [2]) than in the normal (24.0 −/− 3.7) and super testosterone (24.7 −/− 4.5) grafts (p = 0.005). However, in regard to growth there was no change in the proportion of androgen receptor positive cells among the groups. Conclusions Testosterone influences penile growth, possibly as a result of extracellular stromal expansion. The number of androgen receptor positive cells in the human fetal penis did not change among the castrate, normal and super testosterone hosts. These experiments support the hypothesis that penile growth cessation is mediated by mechanisms other than down regulation of the androgen receptor. Furthermore, these data support the hypothesis that early administration of androgen to prepubertal male individuals does not result in a shorter phallus in adulthood.

Haemostatic Effects of Supraphysiological Levels of Testosterone in Normal Men

The effects of exogenous testosterone on the haemostatic system were studied in a group of 32 healthy men undergoing a clinical trial of hormonal male contraception. The men received 200 mg testosterone oenanthate (TE) weekly i.m., and plasma samples were taken pretreatment, at defined time points up to 52 weeks of treatment, and 4 and 8 weeks after discontinuing TE. This dose of TE caused a 2-fold increase in trough plasma testosterone levels. TE caused a fall in plasma fibrinogen concentration after 16 weeks of treatment. This was sustained for the duration of TE treatment and recovered to pretreatment levels during the recovery phase. There was also a sustained fall in the level of C4b binding protein which showed a rebound to levels above pretreatment during recovery. Levels of antithrombin III and prothrombin fragment F1.2 rose initially during TE treatment, and levels of protein C, protein S (free) and plasminogen activator inhibitor fell, but the concentrations of these factors all returned to pretreatment levels during continued treatment. There was no change in the plasma concentrations of beta-thromboglobulin, tissue plasminogen activator, protein S (total), or D-dimer. There was a sustained increase in haemoglobin concentration and haematocrit, without any change in platelet count. The observed changes were consistent with mild activation of the haemostatic system during initial treatment with testosterone. After several months the raised activation markers had returned to pretreatment levels indicating that a new equilibrium had been established which did not appear to be prothrombotic.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of sex steroids on cocaine lethality in male and female mice

1. Endogenous sex steroid levels were altered in mice via gonadectomy, via physiological or supraphysiological doses of testosterone and/or estradiol, and via tamoxifen dosing to antagonize estrogens. 2. The role of sex hormones in susceptibility to cocaine lethality was examined via the response of mice after endocrine alterations to an intraperitoneal (i.p.) cocaine HCl (75 mg/kg). Incidence of deaths was significantly decreased only in sham-operated males receiving estradiol or tamoxifen and in ovariectomized or sham-operated females receiving doses of estradiol. 3. The levels of estradiol in both sexes appeared to be more influential than were levels of testosterone as a determinant of susceptibility to cocaine.

120 TESTICULAR FUNCTION AFTER TESTIOSTERONE TREATMENT IN TALL ADOLESCENTS

Testosterone treatment in tall boys is widely used to reduce predicted adult height. But there are only few data on testicular function after discontinuation of therapy. We studied 21 young men (22 ± 2.8 yrs. of age) by LH-RH-test and analysis of spermatic fluid 1-12 yrs. after therapy. LH (1.79 ± 0.72 μg/l and FSH (0.78 ± 0.9μg/l) could be stimulated by LH-RH-test up to peak levels of 8.54 ± 3.83 and 1.7 ± 1.59 μg/l, respectively. 5 of 21 men showed pathological results. Mean testicular volume was 25.3 ± 7.6 ml but ranged from 10 to 40 ml. Results of spermatic fluid analysis are shown in the table. 4 of 19 sperm counts were below a normal limit of 20 mio./ml. Further criteria applied for evaluation of sperm quality increased the percentage of pathological conditions up to 50 %. These findings suggest consequences for testicular function and reproduction, if supraphysiological doses of testosterone are administered to pubertal boys for reduction of predicted height.