14 SERIOUS Nandrolone Decanoate Side Effects for Men [Warning]Most androgenic drugs are available as esters for a prolonged depot action. However, the enzymes involved in the hydrolysis nandrolone liver the esters have not been identified. There is one nadnrolone indicating that PDE7B may be involved in the activation of testosterone enanthate. The aims are to identify the nandrolone liver compartments where the hydrolysis of testosterone enanthate and nandrolone decanoate nandrolone liver, and to investigate the involvement of PDE7B in the activation. We also kiver if testosterone and nandrolone affect the expression of the PDE7B gene.
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Most androgenic drugs are available as esters for a prolonged depot action. However, the enzymes involved in the hydrolysis of the esters have not been identified. There is one study indicating that PDE7B may be involved in the activation of testosterone enanthate.
The aims are to identify the cellular compartments where the hydrolysis of testosterone enanthate and nandrolone decanoate occurs, and to investigate the involvement of PDE7B in the activation. We also determined if testosterone and nandrolone affect the expression of the PDE7B gene. The hydrolysis studies were performed in isolated human liver cytosolic and microsomal preparations with and without specific PDE7B inhibitor.
The gene expression was studied in human hepatoma cells HepG2 exposed to testosterone and nandrolone. We show that PDE7B serves as a catalyst of the hydrolysis of testosterone enanthate and nandrolone decanoate in liver cytosol. These results show that PDE7B is involved in the activation of esterified nandrolone and testosterone and that the gene expression of PDE7B is induced by supra-physiological concentrations of androgenic drugs. Testosterone has been therapeutically used for several decades, primarily for androgen replacement therapy in hypogonadal men.
Moreover these agents are commonly abused by athletes and sportsmen to improve muscle mass. The abuse of these compounds for cosmetic purposes among non-competing recreational body-builders and non-athletes is a major social concern and has become a growing health problem Pope and Katz, ; Eklof et al.
Synthetic analogs such as nandrolone may also have other therapeutic indications such as osteoporosis and aplastic anemia Frisoli et al. Most of the androgenic drugs are available as esters, e. These drugs have a prolonged depot action due to slow release of the lipophilic steroid ester from the injection site.
It is not known which enzymes catalyze the hydrolysis of the esters in order to activate these pro-drugs. We have previously demonstrated that phosphodiesterase 7B PDE7B is involved in the hydrolysis and activation of testosterone enanthate Ekstrom et al.
The mechanisms that regulate the expression of PDE genes are not well known. However, whether anabolic androgenic steroids affect the expression of PDE has not been investigated. Here we have analyzed if PDE7B is involved in the hydrolysis of nandrolone decanoate using human liver homogenates, microsomes and cytosols. Moreover we have evaluated if PDE7B gene expression is modified by therapeutic and supra-physiological doses of testosterone enanthate and nandrolone decanoate in human liver cells HepG2 using real-time PCR.
Five human liver homogenates were obtained from our liver bank approved by the Ethics Review board in Stockholm. The liver samples were homogenized in 50 mM potassium phosphate from Merck Darmstadt, Germany buffer pH 7. In order to determine the cellular compartment where the hydrolysis takes place, cytosols and microsomes were prepared and incubation assays were carried out using the same procedure as for homogenates.
The resulting supernatant was further exposed to defined speed centrifugation, whereby a microsomal pellet and a cytosolic fraction were obtained. The pellet was homogenized and mixed with buffer 50 mM potassium phosphate buffer, pH 7. The protein concentration in liver homogenates, microsomes, and cytosols were performed according to Lowry et al. The hydrolysis of nandrolone decanoate was also studied in the presence of caffeine from Sigma-Aldrich Chemie GmbH dissolved in the incubation buffer 2.
Prior to androgen treatment, the HepG2 cells were split and plated in well plates and pre-incubated for 2—3 days. Testosterone enanthate from Sigma-Aldrich Chemie GmbH and nandrolone decanoate were diluted in ethanol The non-treated controls were incubated with vehicle only. The experiments were performed in at least four independent experiments.
Each reaction was performed in triplicate and no-template controls were included in each experiment. The untreated sample was employed as a calibrator and the delta CT-formula was used as described in the literature Livak and Schmittgen, The gene expression was quantified as the yield of the target gene relative to that of Beta-actin gene. The hydrolysis activity, the inhibitory effect in liver sub-cellular fractions as well as the comparison of PDE7B mRNA expression levels between androgen-exposed and non-exposed cells were all compared nonparametric Mann Whitney test.
The statistical analyses were performed using GraphPrism Software version 4. To assess the cellular compartment where the nandrolone decanoate hydrolysis takes place, we measured the esterase activity in human liver homogenates, microsomes, and cytosols.
The hydrolysis of nandrolone decanoate was similar in homogenates 0. The hydrolysis of nandrolone decanoate was lower in the cytosols as compared to homogenate and microsome fractions. In a previous study we showed that the hydrolysis of testosterone enanthate in human liver homogenates was inhibited by specific PDE7 inhibitor BRL In the microsomes, there was no inhibition in esterase activity Figure 1B.
To further assess if other PDEs may be involved in the hydrolysis of nandrolone decanoate the non-specific PDE7B inhibitor caffeine was tested.
There was no significant difference between caffeine and BRL inhibition indicating that caffeine inhibits hydrolysis to the same extent as BRL Caffeine did not inhibit the nandrolone decanoate hydrolysis in microsomes. These results indicate that no other PDEs are involved in the cleavage of steroid esters.
In order to study if androgen drugs affect the transcriptional activity of PDE7B, testosterone enanthate and nandrolone decanoate, were added at different concentrations 0. There was no induction at the lowest concentration 0. Nandrolone decanoate significantly increased PDE7B expression approximately 4-fold at 0. The PDE7B gene expression was induced after 2 h exposure. In order to see if testosterone and nandrolone themselves would induce the transcription of PDE7B, free testosterone and nandrolone were added to the cells.
The androgens but not the estrogens induced the PDE7B gene expression. Moreover, when estradiol or estradiol cypionate was added to the cells no induction in PDE7B expression was observed Figure 3.
In a previous in vitro study we showed that PDE7B is involved in the hydrolysis of testosterone enanthate. Here we show that PDE7B also activates nandrolone decanoate. Our inhibition studies indicate that the hydrolyze rate of nandrolone decanoate is higher in microsomes than in cytosols. Our results indicate that PDE7B is active in the cytosol compartment.
Since we did not find any inhibition in the microsomes, our results further supports that PDE7B and not PDE7A is involved in the hydrolysis of nandrolone decanoate. Even though only a minor part of the androgen hydrolysis may be catalyzed by PDE7B in vitro , PDE7B activity may be of clinical interest since a genetic variation in PDE7B has been shown to be associatied with bioavailibilty of testosterone in vivo Ekstrom et al.
The PDEs are all, to different degree, inhibited by the drugs caffeine and theophylline. These results indicate that no other PDEs are involved in the hydrolysis of nandrolone decanoate. The induction was observed using androgen concentrations that are in the range of those observed in healthy volunteers after the administration of testosterone enanthate mg and nandrolone decanoate mg Bagchus et al. Our results indicate that the transcriptional activation of PDE7B may be of importance after administration of supra-physiological doses of androgens.
Moreover, testosterone and nandrolone are both known to be inactivated by UDP-glucuronosyltransferases 2B enzymes Kuuranne et al. So it is possible that the bioactive concentration of the androgens rapidly decreases after entering the cells and therefore the effect is diminished.
Testosterone are aromatized to estrogenic metabolites by CYP19 resulting in estrogenic effects in testosterone abusers e. For nandrolone, the estrogenic effects are mitigated as a result of the drug being a progestin, but nevertheless, effects such as gynaecomastia may still occur at larger doses.
In order to confirm that the up-regulation of PDE7B is due to an androgenic effect, rather than an estrogenic effect, we used R, a synthetic androgen receptor agonist, free estradiol and estradiol cypionate in our cell experiments. Since R, but neither free estradiol nor estradiol cypionate, was shown to increase the transcription of PDE7B we conclude that the induction in PDE7B gene expression is indeed an androgenic effect.
Moreover, the activated AR may interact with other transcription factors without direct binding to DNA. PDE7B has been discussed to play a role in various diseases including asthma, chronic lymphocytic leukemia, Alzheimer, schizophrenia Perez-Torres et al.
PDE7B has also been discussed as an interesting pharmacological target. For example, PDE7B has been proposed as a candidate gene for treatment response to risperidone Ikeda et al. Our result indicates that PDE7B may have additional pharmacological roles, i. In conclusion here we provide data indicating that PDE7B plays a role in the activation of esterified androgen drugs.
Moreover, the expression of PDE7B is induced by supra-physiological concentrations of androgen drugs. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Dexamethasone down-regulates cAMP-phosphodiesterase in human osteosarcoma cells.
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