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Effects of nandrolone decanoate on forearm mineral density and calcium metabolism in osteoporotic postmenopausal women.

Although anabolic steroids have been used for many years to treat osteoporosis there is little available evidence about their efficacy or mode of action. These agents have recently been shown to produce an increase in total body calcium and bone density and it has been suggested that they stimulate bone formation. In this study 27 osteoporotic postmenopausal women were given 50 mg of nandrolone decanoate intramuscularly, every 2 or 3 weeks for 3 months, and the changes in forearm mineral density, fasting plasma, and urinary calcium, urinary hydroxyproline, and radiocalcium absorption were measured. Associated with a rise in forearm mineral density was a significant fall in fasting urinary calcium, but no significant change in fasting urinary hydroxyproline. The plasma calcium and phosphate fell significantly and there was a significant rise in the renal tubular reabsorption of calcium and a fall in the renal tubular reabsorption of phosphate. In a subset of 22 patients there was a significant rise in radiocalcium absorption. The results are consistent with the concept that nandrolone exerts a significant positive effect on bone formation and that this results in a fall in the fasting plasma calcium level, and consequently calcium excretion.

Absorption↗

The effects of nandrolone decanoate on bone mass and metabolism in ovariectomized rats with osteopenia.

The effects of nandrolone decanoate (ND) treatment on bone mass and metabolism were studied in ovariectomized (OVX) rats with osteopenia. The 6-month-old rats were divided into Sham (n = 12) and OVX (n = 24). The OVX rats were allowed to lose bone for 6 weeks. At 6 weeks post ovariectomy, the OVX rats were divided into two groups: (1) OVX + Vehicle and (2) OVX + ND. The effects of ND on bone mineral density (BMD), bone mineral content (BMC), and bone metabolism were studied by dual-energy X-ray absorptiometry (DXA) and biochemical markers including urinary pyridinoline (Pyr), deoxypyridinoline (Dpyr), and serum osteocalcin. After 24 weeks of treatment, histomorphometry of the right tibiae and the wet weight of the gastrocnemius and soleus skeletal muscles were also examined. Ovariectomy resulted in a significant increase in biochemical markers and a significant decrease in spine BMD (0.221+/-0.016g/cm2 in OVX group vs 0.239+/-0.008g/cm2 in Sham group) and BMC (0.550+/-0.055g in OVX group vs 0.605+/-0.042g in Sham group) at 6 weeks post ovariectomy. Spine BMD (0.227+/-0.017g/cm2), femoral BMD (0.263+/-0.012g/ cm2), and bone density of femur (1.035+/-0.036g/cm3) in the OVX + ND group were significantly greater than those in the OVX + Vehicle group (0.204+/-0.013g/cm2 for spine BMD, 0.243+/-0.009g/cm2 for femoral BMD, 0.938+/-0.06g/cm3 for bone density of femur) after 24 weeks of treatment. ND treatment decreased urinary Pyr and Dpyr significantly in OVX rats. Histomorphometric findings indicated that ND-treated rats had greater cancellous bone volume, greater trabecular number, greater trabecular thickness, and less trabecular separation than vehicle-treated OVX rats. OVX rats had greater wet weight of the gastrocnemius and soleus muscles than rats treated with ND. The data suggest that the effect of ND on bone mass is not influenced by the condition of the muscles in OVX rats. Our findings indicate that ND blocks further bone loss by inhibition of bone resorption in OVX rats with osteopenia.

Amino Acids↗

RhoA induction by functional overload and nandrolone decanoate administration in rat skeletal muscle.

The regulation of skeletal muscle regeneration and growth in response to functional overload is a coordinated interaction of mechanical and endocrine signaling pathways. This study's purpose was to determine if RhoA expression and activity in rat plantaris muscle was induced by functional overload with or without anabolic steroid administration. Male Sprague Dawley (125 g) rats were subjected to bilateral ablation of the gastrocnemius muscle for 3 and 21 days and treated with nandrolone decanoate (ND, 6 mg/kg b.w.) or sesame seed oil injections. Western blot analysis revealed that RhoA protein expression was induced 2.1-fold by overload and 1.9-fold by ND at 3 days. RhoA protein remained elevated by overload after 21 days (3.8-fold). In addition, RhoA protein expression in C2C12 myotubes was induced after 18 h of 1% (1.8-fold) or 2% (2.2-fold) chronic radial stretch. Competitive RT PCR revealed that RhoA mRNA concentration increased 1.9-fold with ND, 2.9-fold with overload, and 11.8-fold with overload and ND administration when compared to sham at 3 days, indicating pre-translational control of RhoA by ND and a synergism between ND and overload to up-regulate RhoA mRNA. The ratio of RhoA protein associated with the muscle membrane fraction, an indicator of RhoA activity, increased 3.7-fold after 3 days of overload compared to controls. Although ND with overload (3.8-fold) produced a larger induction of RhoA protein than overload alone, the ratio of RhoA protein associated with the membrane fraction was not altered by ND treatment at 3 days. In conclusion, RhoA is an integrator of both mechanical and growth factor signaling whose expression and activity are increased by the combination of anabolic steroid and functional overload treatments in rat plantaris muscle.

Animals↗

Relative fluorescence of normal and acid lipase-deficient cultured fibroblasts following administration of pyrene decanoic acid.

Skin fibroblasts, derived from normal individuals or patients with Wolman's disease (an autosomal recessive disorder due to acid lysosomal lipase deficiency) were incubated with the fluorescent fatty acid, pyrene-decanoic acid (P10). Measurements of the fluorescence intensities of the total lipid extracts indicated that equal quantities of P10 were incorporated into both cell types. The fluorescence emitted by the intact cells was subsequently recorded in a fluorescence microscope equipped with a microdetector unit, which permitted determination of the fluorescence emitted by the intact cell or by specific regions thereof. The fluorescence intensities emitted by the lipidotic cells exceeded those of their normal counterparts 2- and 5-fold when comparing the entire cells or the perinuclear region, respectively. The cells were then subjected to subcellular fractionation and an analysis of the fractions revealed that up to 85-90% of the fluorescence of the lysosome-mitochondrial pellet was derived from free pyrenedecanoic acid; the latter contributed only 15-18% to the fluorescence of the homogenate or the cytosol. There was no difference in the fluorescence of the lipid extracts from the respective fractions of the lipidotic or normal cells. However, the fluorescence emitted by the intact lysosome-mitochondrial fraction of the lipidotic cells exceeded that of its normal counterpart 2.5-fold. These data suggest that the increased fluorescence intensity of the intact lipidotic cells resulted from a higher quantum yield of free P10 molecules solubilized in the hydrophobic environment of their neutral lipid-containing storage granules.

Cell Compartmentation↗

Changes in soft tissue body composition and plasma lipid metabolism during nandrolone decanoate therapy in postmenopausal osteoporotic women.

Thirty-nine osteoporotic (prior spine or Colles' fracture) but otherwise healthy postmenopausal women were allocated to receive blindly either 50 mg nandrolone decanoate (ND) intramuscularly or placebo injections every 3 weeks for 1 year. Thirty-six women (92%) completed the study. ND treatment resulted in an increase in non-osseous lean weight and a corresponding decrease in fat mass (measured by dual photon absorptiometry). A 20% increase in the 24-hour urinary creatinine excretion indicated that the increase in non-osseous lean weight was caused mainly by an increase in muscle mass. With regard to serum lipids and lipoproteins, ND treatment slightly decreased high density lipoprotein (HDL) cholesterol without significantly affecting total cholesterol, low density lipoprotein (LDL) cholesterol or triglycerides. In conclusion, treatment with ND changes the soft tissue composition in osteoporotic postmenopausal women towards a leaner and more muscular body.

Adipose Tissue↗

The carboxy-terminal propeptide of type I procollagen in serum as a marker of bone formation: the effect of nandrolone decanoate and female sex hormones.

Seventy-nine osteoporotic (prior forearm or vertebral fracture), but otherwise healthy, postmenopausal women (aged 55 to 75 years) were allocated to two double-blind trials: (1) 39 women received either nandrolone decanoate (anabolic steroid) 50 mg as an intramuscular depot injection or a placebo injection every 3 weeks for 1 year; and (2) 40 women received either 2 mg 17 beta-estradiol plus 1 mg norethisterone acetate or placebo tablets daily for 1 year. Sixty-seven (85%) completed the 1 year of treatment. Serum concentration of type I procollagen carboxy-terminal propeptide (PICP) was measured before and at 3, 6, 9, and 12 months of therapy. In addition, 32 of the women had an iliac bone biopsy taken after double tetracycline labeling. Initial serum PICP correlated significantly with histomorphometrically measured rate of bone formation (r = .4; P less than .05) and plasma bone Gla protein (r = .6; P less than .001), but not with histomorphometrically measured bone resorption or biochemical estimates of bone resorption (fasting urinary hydroxyproline and calcium). Estrogen-progestogen therapy significantly decreased (P less than .001) serum PICP by about 30%, whereas anabolic steroid therapy hardly affected it. We conclude that serum PICP may be used as a noninvasive measurement of bone formation on a group basis. Whereas bone formation is clearly decreased during estrogen-progestogen therapy, it is not affected by long-term therapy with anabolic steroids.

Aged↗

Toxic effects of nonadecafluoro-n-decanoic acid in rats.

Nonadecafluoro-n-decanoic acid (ND-FDA) has a single dose ip LD50 of 41 mg/kg and causes anorexia and a wasting syndrome. NDFDA also appears to affect lipid metabolism although the metabolic fate and mechanism of action are not known. Control rats were pair fed with rats given 50 mg/kg. Body weights and food consumption were measured daily; body and organ weights, tissue histopathology, and hematological and clinical chemistry parameters were determined at 4, 8, 12, 16, and 30 days postdosing. Liver samples were obtained for determining cholesterol, cholesterol esters, phospholipids, total lipids, fatty acid ratios, and NDFDA. The rats became anorectic within 4 days and did not resume feeding for 10-12 days, losing about 40% of their body weight. There was a decrease in serum protein; total liver protein decreased and there was an increase in measured fatty acids except for stearic. Liver to body weight ratios of dosed rats were twice those of control rats since absolute liver weights in dosed rats remained constant during the weight loss period. The most striking histopathological change was seen in the liver with a uniform persistent cellular swelling at all times. Separation of the lipids by thin layer chromatography indicated that NDFDA was present in the most polar fraction. There also were fatty changes in the proximal tubular epithelium of the kidneys.

Animals↗

The effects of perfluoro-n-decanoic acid in the rat heart.

Perfluoro-n-decanoic acid (PFDA) is a synthetic chemical resembling a 10-carbon fatty acid. Several studies have suggested that the toxic mechanism of PFDA may involve impaired lipid metabolism and/or altered cell membrane function. We examined the possibility that altered cell membrane structure in the heart might lead to changes in the functional activity of the organ. Functional characteristics were determined in the isolated perfused rat heart by measuring the ability of the heart to respond to either sympathetic nerve stimulation or infused norepinephrine. PFDA reduced the intrinsic resting heart rate and the inotropic response to a stimulus with maximal effects occurring 8 days after dosing. In addition, resting heart rate measured in vivo was found to be reduced in PFDA-treated rats 6 to 8 days after dosing. beta-Receptor binding studies conducted 8 days after a single dose of PFDA showed that the maximum binding capacity was reduced by PFDA treatment without significant changes in receptor affinity. It is concluded that the reduction in the inotropic response to catecholamines following PFDA treatment may be explained in part by lower beta-receptor density in the myocardial cell membrane. These effects may be related to the early fall in serum thyroid hormone levels as previously reported.

Animals↗

The effects of perfluoro-n-decanoic acid (PFDA) on rat heart beta-receptors, adenylate cyclase, and fatty acid composition.

Perfluoro-n-decanoic acid (PFDA) is a member of a family of surfactants with numerous industrial applications. The acute toxicity of PFDA is characterized by body wasting and delayed lethality. Recent reports have indicated that the effects of PFDA may involve an action on the structure of biological membranes which results in an alteration of function. In the present study we extend our work on the membrane actions of PFDA by examining its effects on myocardial beta-adrenoceptor binding characteristics and adenylate cyclase. Following a single injection of PFDA the apparent number of beta-receptor binding sites was reduced compared to pair-fed controls. This change in beta-receptor binding capacity was reflected in a reduced ability of norepinephrine to activate adenylate cyclase. No alterations were observed in basal adenylate cyclase activity or in the ability of NaF or guanylyl imidodiphosphate to stimulate the enzyme. The fatty acid composition of the heart was changed by PFDA treatment. Our results suggest that the toxic effects of PFDA may be due to an alteration of the membrane lipid bilayer leading to changes in the functional activity of myocardial membranes.

Adenylyl Cyclases↗

Perfluoro-N-decanoic acid effects on enzymes of fatty acid metabolism.

In vitro perfluorodecanoate (PFDA) effects on Pseudomonas acyl-CoA synthetase, Candida acyl-CoA oxidase and pigeon muscle carnitine acetyltransferase were examined. Synthetase made little PFDA-CoA from PFDA. It used palmitate, oleate, laurate and decanoate more extensively. PFDA inhibited acyl-CoA formation from these acids. Palmitoyl-CoA formation was affected most. That of decanoyl-CoA was affected least. Inhibitions appeared to be competitive. Acyl-CoA oxidase test substrates were palmitoyl-CoA, lauroyl-CoA and decanoyl-CoA. Oxidase preferred C-10 and C-12 acyl-CoAs. PFDA inhibited oxidation of C-10 and C-12 acyl-CoAs more than that of palmitoyl-CoA. Inhibitions with C-16 and C-10 acyl-CoAs were competitive, KIs 593 +/- 150 and 76 +/- 6.0 microM. Acetyl-CoA was the best acetyltransferase substrate. C-2 to C-8 transfer from acyl-CoAs was inhibited similarly by PFDA. Inhibitions of C-2 and C-8 transfer were competitive and non-competitive, respectively, KIs 111 +/- 15 and 76 +/- 28 microM.

Animals↗

Nandrolone decanoate treatment of post-menopausal osteoporosis for 2 years and effects of withdrawal.

This study investigated the effects of nandrolone decanoate (ND) therapy (50 mg i.m. every 3 or 4 wk) on bone mass and soft tissue body composition in post-menopausal women. Twenty-two (22) women were followed up over a period of 30 mth, during which they received ND therapy for 12-24 mth and were treatment-free for the other 6-18 mth. While they were receiving treatment forearm bone mineral content (BMC) and lean body mass (LBM) increased, whereas fat mass (FM) decreased. After withdrawal of ND therapy the BMC, LBM and FM values all tended to return to pretreatment levels. Serum high-density-lipoprotein cholesterol showed a non-significant decrease, while serum low-density-lipoprotein cholesterol and serum total cholesterol remained unchanged during therapy. It was concluded that ND therapy can achieve an increase in BMC in post-menopausal women, but this is maintained only for as long as therapy is continued.

Aged↗

Effects of nandrolone decanoate therapy on bone mass and calcium metabolism in women with established post-menopausal osteoporosis: a double-blind placebo-controlled study.

In many patients with involutional osteoporosis anabolic steroids may produce a rapid subjective improvement and a pronounced reduction in the frequency of complaints. Animal experiments have demonstrated that anabolic steroids can also have an objective effect on bone tissue. Twenty (20) post-menopausal osteoporotic patients were randomly assigned to 2 different treatment regimens; 10 patients were treated with 50 mg i.m. of nandrolone decanoate (ND) every 3 wk for 12 mth and 10 patients were treated with a placebo. Both groups also received an oral calcium supplement (1 g/day). Bone mineral content (BMC) was measured by dual photon absorptiometry before and after 1, 3, 6 and 12 mth of treatment. Plasma alkaline phosphatase (ALP) and urinary hydroxyproline excretion were measured at the same time. Intestinal calcium absorption was measured by the 47Ca oral test before and after treatment. A transiliac bone biopsy was performed before and after treatment in 4 patients in each group. After 1 yr there was a significant increase in lumbar spine BMC in the group receiving calcium plus ND. A progressive increase in plasma ALP was also observed in the group treated with ND but this was not significant, whereas radiocalcium absorption did increase significantly in this group. Histomorphometric study of bone samples demonstrated a significant increase in trabecular bone volume (TBV) and in active osteoid surface area in the patients treated with ND. Because plasma ALP tends to increase when a small decrease in bone resorption occurs (as measured by urinary hydroxyproline excretion) and the active osteoid surfaces also significant augment, we concluded that ND therapy increases the bone formation rate through inhibition of bone resorption. This interpretation could explain the considerable increase in lumbar spine BMC and the significant increase in TBV observed in patients treated with ND.

Alkaline Phosphatase↗

Irreversibly inhibitory kinetics of 3,5-dihydroxyphenyl decanoate on mushroom (Agaricus bisporus) tyrosinase.

3,5-Dihydroxyphenyl decanoate (DPD) is found to inhibit the diphenolase activity of tyrosinase from mushroom (Agaricus bisporus). The effects of DPD on the diphenolase activity of mushroom tyrosinase have been studied. The results show that the enzyme activity decreases very slowly with an increase in DPD concentrations at lower concentrations of DPD (between 5 and 60 microM). But at higher concentrations of DPD, DPD can strongly inhibit the diphenolase activity of the enzyme and the inhibition is irreversible. The IC50 value was estimated to be 96.5 microM. The inhibition mechanism of DPD has been investigated and the results show that DPD can bind to the free enzyme molecule and enzyme-substrate complex and lose the enzyme activity completely. The inhibition kinetics has been studied in detail by using the kinetic method of the substrate reaction described by Tsou. The microscopic rate constants of the enzyme inhibited by DPD at higher concentrations have been determined.

Agaricus↗

The effect of sub-chronic nandrolone decanoate treatment on dopaminergic and serotonergic neuronal systems in the brains of rats.

Anabolic-androgenic steroids (AASs) are widely abused by adolescents, although persistent AAS use can cause several adverse physical and mental effects, including drug dependence. The first aim of the present study was to study the action of nandrolone decanoate on dopaminergic and serotonergic activities in the brains of rats. In order to evaluate the anabolic or toxic effects of the dosing regimens used, selected peripheral effects were monitored as well. Male Wistar rats were treated for 2 weeks. Injections containing nandrolone (5 and 20 mg/kg, i.m.) or vehicle were given once daily, 5 days a week. The levels of dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites were assayed from dissected brain regions 3 days after the last injection. Blood was collected for chemical assays before, after 1 week treatment and at decapitation. Both doses of nandrolone significantly increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC), a metabolite of DA in the cerebral cortex, and the higher dose of nandrolone increased the concentrations of 5-HT in the cerebral cortex compared with the vehicle. In addition, after nandrolone treatment, the levels of hemoglobin and erythrocytes increased, and reticulocyte levels decreased. The results suggest that nandrolone at supraphysiological doses, high enough to induce erythropoiesis, induces changes in the dopaminergic and serotonergic neuronal system in the brains of rats. These phenomena may account to some of the observed central stimulatory properties that have been reported following AAS abuse.

3,4-Dihydroxyphenylacetic Acid↗

Effects of nandrolone decanoate on the neuromuscular junction of rats submitted to swimming.

This study addressed the effects of nandrolone decanoate (ND) on contractile properties and muscle fiber characteristics of rats submitted to swimming. Male Wistar rats were grouped in sedentary (S), swimming (Sw), sedentary+ND (SND), and swimming+ND (SwND), six animals per group. ND (3 mg/kg) was injected (subcutaneously) 5 days/week, for 4 weeks. Swimming consisted of 60-min sessions (load 2%), 5 days/week, for 4 weeks. After this period, the sciatic nerve extensor digitorum longus (EDL) muscle was isolated for myographic recordings. Fatigue resistance was assessed by the percent (%) decline of 180 direct tetanic contractions (30 Hz). Safety margin of synaptic transmission was determined from the resistance to the blockade of indirectly evoked twitches (0.5 Hz) induced by pancuronium (5 to 9x10(-7) M). EDL muscles were also submitted to histological and histochemical analysis (haematoxylin-eosin (HE); nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR)). Significant differences were detected by two-way ANOVA (p<0.05). ND did not change body mass, fatigue resistance or kinetic properties of indirect twitches in either sedentary or swimming rats. In contrast, ND reduced the safety margin of synaptic transmission in sedentary animals (SND=53.3+/-4.7% vs. S=75.7+/-2.0%), but did not affect the safety margin in the swimming rats (SwND=75.81+/-3.1% vs. Sw=71.0+/-4.0%). No significant difference in fiber type proportions or diameters was observed in EDL muscle of any experimental group. These results indicate that ND does not act as an ergogenic reinforcement in rats submitted to 4 weeks of swimming. On the other hand, this study revealed an important toxic effect of ND, that it reduces the safety margin of synaptic transmission in sedentary animals. Such an effect is masked when associated with physical exercise.

Anabolic Agents↗

Administration of the anabolic androgenic steroid nandrolone decanoate to female rats causes alterations in the morphology of their uterus and a reduction in reproductive capacity.

OBJECTIVE: The aim of the present investigation was to characterize the effects of supraphysiological doses of the anabolic androgenic steroid nandrolone decanoate (ND) on the fertility of female rats, as well as on the morphology of their uterus. STUDY DESIGN: Female Wistar rats (n=15) received a subcutaneous injection of ND (15 mg/kg) once daily during a 2-week period, while the control animals (n=10) were administered vehicle alone (arachidis oleum) in the same manner. Estrus behavior was evaluated 4 weeks after termination of this treatment and in cases where signs of receptivity were present, the female rat was given the opportunity to copulate with a male. After breeding, the female animals were sacrificed and their uteri examined histomorphologically. RESULTS: All ND-treated animals exhibited abnormal vaginal smears, whereas all of the control smears were normal. Most (73%) of the treated females demonstrated normal estrus behavior (i.e., willingness) on the day of mating, but none got pregnant; whereas all of the control rats became pregnant. The female rats receiving the ND showed an enhanced rate of weight gain and the myometrium thickness of their uteri was significantly increased, while the endometrium was significantly thinner. Furthermore, ND caused a significant proportion of the treated animals to display tortuous and irregularly branching endometrial glands, as well as a lack of the physiologically normal infiltration of eosinophilic leukocytes into the endometrium (endometrial eosinophilic homing), a finding that has not been reported previously. CONCLUSION: The present findings indicate that high doses of ND cause morphological and physiological alterations in the uterus of female rats that are associated with a suppression of their reproductive capacity.

Anabolic Agents↗

Nandrolone decanoate impairs exercise-induced cardioprotection: role of antioxidant enzymes.

The beneficial effects of exercise in reducing the incidence of cardiovascular diseases are well known and the abuse of anabolic androgenic steroids (AAS) has been associated to cardiovascular disorders. Previous studies showed that heart protection to ischemic events would be mediated by increasing the antioxidant enzyme activities. Here, we investigated the impact of exercise and high doses of the AAS nandrolone decanoate (DECA), 10 mgkg(-1) body weight during 8 weeks, in cardiac tolerance to ischemic events as well as on the activity of antioxidant enzymes in rats. After a global ischemic event, hearts of control trained (CT) group recovered about 70% of left ventricular developed pressure, whereas DECA trained (DT), control sedentary (CS) and DECA sedentary (DS) animals recovered only about 20%. Similarly, heart infarct size was significantly lower in the CT group compared to animals of the three other groups. The activities of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) were significantly higher in CT animals than in the other three groups, whereas catalase activity was not affected in any group. Together, these results indicate that chronic treatment with DECA cause an impairment of exercise induction of antioxidant enzyme activities, leading to a reduced cardioprotection upon ischemic events.

Anabolic Agents↗

Nandrolone decanoate has long-term effects on dominance in a competitive situation in male rats.

The aim of the present study was to examine possible long-term effects of the anabolic androgenic steroid (AAS), nandrolone decanoate (ND), on dominance in a provoking and competitive situation in sexually matured male rats. The experimental group (n=10) received daily injections of ND [15 mg/kg in a volume of 1 ml/kg subcutaneous (s.c.) injection for 14 days]. During the corresponding period, the controls (n=10) were given daily injections of an oil vehicle (1 ml/kg s.c.). All animals were tested in a competitive situation at four occasions after the end of the treatment period (week 5, 8, 11 and 14). Water-deprived pairs of rats, consisting of one ND-treated rat and one control, had to compete for access to water. The results showed that the ND-treated rats approached the water spout significantly more often compared to the controls. During the competition tests, the ND-treated rats spent more time drinking, an effect that was prominent for 11 weeks after the end of the treatment period. The ND-treated rats also displayed more frequently piloerection than the controls. The results indicate that ND has long-term effect on dominance in a provoking and competitive situation.

Anabolic Agents↗