Novel progestogenic androgens for male contraception: design, synthesis, and activity of C7 α-substituted testosterone†.

Male contraceptive development has included use of testosterone (T) with or without a progestin or the use of a single molecule such as progestogenic androgens (PA) for suppression of testicular T production. Expanding upon the vast amount of data accumulated from nortestosterone (NT), NT analogs, and their prodrugs, a new series of PA, the C7 methyl, and ethyl α-substituted T analogs 7α-Methyltestosterone (7α-MT) and 7α-Ethyltestosterone (7α-ET), respectively, were hypothesized and designed to have superior androgenic and progestogenic activities when compared with parent T. Results from androgen receptor and progesterone receptor competitive binding and transcriptional activation assays showed favorable activities for these T analogs. Additionally, 7α-MT and 7α-ET were shown to be active substrates for aromatase in vitro, mitigating a potential negative impact on bone mineral density with long-term use. In conjunction with this observation, the diminished metabolism of these T analogs by 5α-reductase may reduce potential concerns for prostatic growth. In the Hershberger in vivo rat bioassay, 7α-MT and 7α-ET showed superior androgenic and anabolic activities as compared with T. These C7 α-substituted T analogs also showed clear progestogenic activity in the McPhail bioassay which evaluated endometrial glandular arborization in a rabbit model. The discovery of aromatizable molecules with reduced metabolism by 5α-reductase that have androgenic, anabolic, and progestogenic properties indicates that the core and/or prodrugs of 7α-MT and 7α-ET are promising molecules for further development as male contraceptive PAs.

Dienogest alone or dienogest combined with estrogens in the treatment of ovarian endometriomas, that is the question. A retrospective cohort study.

PURPOSE: to compare the effects of Dienogest 2 mg (D) alone or combined with estrogens (D + ethinylestradiol 0.03 mg, D + EE; D + estradiol valerate 1-3 mg, D + EV) in terms of symptoms and endometriotic lesions variations. METHODS: This retrospective study included symptomatic patients in reproductive age with ultrasound diagnosis of ovarian endometriomas. Medical therapy for at least 12 months with D, D + EE or D + EV was required. Women were evaluated at baseline visit (V1) and after 6 (V2) and 12 months (V3) of therapy. RESULTS: 297 patients were enrolled (156 in the D group, 58 in the D + EE group, 83 in the D + EV group). Medical treatment leaded to a significant reduction in size of endometriomas after 12 months, with no differences between the three groups. When comparing D and D + EE/D + EV groups, a significant decrease of dysmenorrhea was detected in the D group than in D + EE/D + EV group. Conversely, the reduction of dysuria was more significative in the D + EE/D + EV groups rather than in the D group. Regarding tolerability, treatment associated side effects were reported by 16.2% patients. The most frequent one was uterine bleeding/spotting, significantly higher in the D + EV group. CONCLUSION: Dienogest alone or associated with estrogens (EE/EV) seems to be equally effective in reducing endometriotic lesions mean diameter. The reduction of dysmenorrhea was more significative when D was administered alone, while dysuria seems to improve more when D is associated with estrogens.

A review of current chemistry, pharmacology, and regulation of endogenous anabolic steroids testosterone, boldenone, and nandrolone in horses.

Anabolic androgenic steroids are synthetic substances related to the male sex hormones (androgens). These agents promote the growth of skeletal muscle (anabolic effects) and the development of male sexual characteristics (androgenic effects). Anabolic steroids have been illegally used for many years as performance-enhancing drugs in human, equine, and canine sports and as growth promoters in livestock reared to provide meat for human consumption. The analytical challenge to developing effective means of control within these fields has been exacerbated by the reported endogenous nature of some of these steroids. Anabolic steroids have been employed extensively in equine practice over the past 50 years. Their usefulness is largely dependent on subjective opinions, as only minimal studies investigating pharmacodynamics have been carried out in horses. Therefore, their use will vary markedly between practitioners depending on their personal experiences and pressures by trainers to use them. They form part of rational therapy in a variety of conditions. In addition to their use for increasing muscle mass, they are used to varying extents in the raising of yearlings and in the training and racing of horses with the view of improving performance. The use of these agents is prohibited in the horseracing industry by the Association of Racing Commissioners International (ARCI), International Federation of Horseracing Authorities (IFHA), and Fédération Equestre Internationale (FEI).

Comparison of the effectiveness of Dienogest with medroxyprogesterone acetate in the treatment of pelvic pain and recurrence of endometriosis after laparoscopic surgery.

PURPOSE: The aim of this study was to compare the effects of Dienogest and medroxyprogesterone acetate (MPA) on the recurrence of endometriosis lesions and clinical symptoms in women undergoing laparoscopic surgery. METHODS: This single center clinical trial was conducted among 106 women with endometriosis undergoing laparoscopic surgery who candidate receiving post-surgery hormone therapy. Participants were allocated to two groups. The first group received Dienogest pills (2 mg) daily for the first three months and then cyclic for three months afterward. The second group received MPA pills twice daily (10 mg) for three months and then cyclic for the next three months. Six months after the intervention, the rate of endometriosis recurrence, the size of endometriosis lesions and pelvic pain were assess and compared between two groups. RESULTS: Finally, data were evaluated based on 48 and 53 women in the Dienogest and MPA groups, respectively. After 6 months follow-up assessments the pelvic pain score was significantly lower in Dienogest group than MPA group (P < 0.001). There was not statistically difference between two groups in terms of recurrence rate of endometriosis (P = 0.4). Although the size of endometriosis cyst recurrence was smaller in Dienogest group compared to MPA group (P = 0.02). CONCLUSIONS: The findings showed that Dienogest treatment has better effect in reducing pelvic pain and the mean size of the recurrent endometriosis lesions after endometriosis laparoscopic surgery when compared to MPA treatment. Although the recurrent rate of endometriosis was similar between these treatments.

Genome-Wide Gene Expression Profiling Reveals the Direct Effect of Dienogest on Ovarian Endometriotic Stromal Cells.

Endometriosis affects up to 10% of women of reproductive age, causing dysmenorrhea, chronic pelvic pain, and infertility. The current key drug for endometriosis is dienogest, a progestin with high specificity for the progesterone receptor. To reveal the direct anti-endometriotic effect of dienogest on ovarian endometriotic cells, we investigated the genome-wide gene expression profiles of ovarian endometriotic stromal cells with (Dienogest group) or without dienogest treatment (Control group) and compared the groups' gene expression profiles. We performed a gene ontology (GO) analysis and Ingenuity pathway analysis using these data. To validate the microarray data, we performed real-time RT-PCRs and immunohistochemistry for the differentially expressed genes between the two groups. Of 647 genes differentially expressed between the two groups, 314 genes were upregulated and 333 were downregulated in the Dienogest group versus the Control group. The GO analysis showed that the regulation of macrophage chemotaxis, the collagen catabolic process, and the proteoglycan biosynthetic process are the main biological processes closely associated with the differentially expressed genes. We identified 20 canonical pathways that were most significantly differentially expressed in the Dienogest group versus the Control group. We observed that matrix metalloproteinases (MMPs) are the genes in these pathways that are most closely associated with dienogest treatment. Of components involved in the regulation of macrophage chemotaxis, colony-stimulating factor 1 and macrophage-stimulating 1 are potential upstream regulators of MMPs and were observed herein to be suppressed by dienogest. Our results suggest that dienogest may thus exert its anti-endometriotic effect by directly suppressing MMPs.

Adolescence as a critical period for nandrolone-induced muscular strength in relation to abuse liability, alone and in conjunction with morphine, using accumbal dopamine efflux in freely moving rats.

Nandrolone, an anabolic androgenic steroid, is included in the prohibited list of the World Anti-Doping Agency. Drugs of abuse activate brain dopamine neurons and nandrolone has been suspected of inducing dependence. Accordingly, possible critical periods for the effects of nandrolone on muscular strength and dopaminergic activity have been investigated, including the effects of chronically administered nandrolone alone and on morphine-induced increases in dopamine efflux in the nucleus accumbens. Six- or 10-week-old male Sprague-Dawley rats were used. Treatment with nandrolone was initiated in adolescent (6-week-old) and young adult (10-week-old) rats. Nandrolone (5.0 mg/kg s.c.) or sesame oil vehicle was given once daily, on six consecutive days per week, for 3 weeks and then once per day for 4 consecutive days. Nandrolone enhanced the developmental increase in grip strength of 6- but not 10-week-old rats, without altering the developmental increase in body weight of either age group. Using in vivo microdialysis in freely moving 6-week-old rats given nandrolone for 4 weeks, basal accumbal dopamine efflux was unaltered, while the increase in dopamine efflux induced by acute administration of morphine (1.0 mg/kg s.c.) was reduced. The present study provides in vivo evidence that adolescence constitutes a critical period during which repeated administration of nandrolone enhances increases in muscular strength without influencing increases in body weight. Though repeated administration of nandrolone during this period of adolescence did not stimulate in vivo mesolimbic dopaminergic activity, it disrupted stimulation by an opioid, the drug class that is most commonly coabused with nandrolone.

The effect of supraphysiological dose of nandrolone decanoate administration on the inflammatory, neurotrophin and behavioral response in adult and old male mice.

This study examined the effect of 6 weeks of supraphysiological nandrolone decanoate (ND) administration in adult mice (7 months) on cognitive function and neuroinflammation during aging. Male C57BL/6 mice were randomized into ND (10 mg·kg-1·wk-1) or control (CTL) groups. Half of the mice were tested at a young (Y) age (ND-Y and CTL-Y), 1 week following final ND administration, while the remaining mice were tested at 16 months (O) (ND-O and CTL-O). Learning and memory were better in young mice compared to older mice, regardless of treatment. ND-O displayed decreased anxiety as compared to all other groups. TNFα and IL1ß expression were higher in older mice, regardless of treatment. ND administration in young mice appeared to attenuate the neuroinflammatory response in aging mice as evidenced by decreased COX2, IL-4 and increased IL-10 expression in ND-O compared to CTL-O. BDNF AR and ER expression increased in ND-O compared to CTL-O. Results of the study indicated that supraphysiological ND administration had no negative effect on learning and memory but may attenuate anxiety in older mice. In addition, ND administration in young adult mice may attenuate the inflammatory response during aging, which may be related to elevations in both AR and ER expression.

Association between neuronal degeneration and supraphysiological doses of two types of anabolic steroids in rat brain.

The anabolic androgenic steroids (AAS) are natural compounds that are precursors or derivatives of testosterone and, as a consequence of indiscriminate use, cause irreversible neuronal effects. For this study, 70 brain samples were used from male Wistar rats, separated into 14 groups, divided into: control, sedentary, and exercise groups; in the concentrations: 5 mg, 10 mg, and 15 mg. Two different AAS were used: Testosterone Cypionate (TC) and Nandrolone Decanoate (ND). The encephali followed all the conventional histological procedures, for further analysis of the estimates of neuron bodies of the Locus coeruleus; also being carried out the techniques of the Tunnel Assay and Von Kossa staining. The results obtained show significant values different from the control group: Testosterone Cypionate (TCS): 5 mg (25,00 ± 4,47); 10 mg (23,67 ± 4,45) and 15 mg (21,93 ± 5,65), as well as for Nandrolone Decanoate (ND) in the doses: 5 mg (23,40 ± 3,81); 10 mg (22,80 ± 3,80) and 15 mg (22,80 ± 4,54) being the values of the control group (CGS) 34,27 ± 6,06. For the groups that exercised, the values were: TCT 5 mg 20,87 ± 3,23; TCT 10 mg 21,93 ± 4,91 and TCT 15 mg 21,47 ± 4,36 while, the Nandrolone Decanoate (ND) groups, in the different doses were: NDT 5 mg 21,53 ± 4,34; NDT 10 mg 23,53 ± 1,68 and NDT 15 mg 23,40 ± 2,20, also expressing significant values different from the control group. When comparing the sedentary control group with the animals that exercised, a statistically significant difference was observed being: CGS 34,27 ± 6,06; TCT 5 mg; 20,87 ± 3,23; NDT 5 mg 21,53 ± 4,34; TCT 10 mg 21,93 ± 4,91; NDT 10 mg 23,53 ± 1,68; TCT 15 mg 21,47 ± 4,36 and NDT 15 mg 23,40 ± 2,20. The results of this study, point out that both steroids drastically reduce neuronal density in the Locus coeruleus area inferring that, the possible cause of neuronal death is necrosis, caused by intracellular calcium imbalance.

Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation: A randomized clinical trial.

INTRODUCTION: Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E2 ] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin. MATERIAL AND METHODS: We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2-3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover). CLINICAL TRIAL REGISTRATION: NCT02352090. RESULTS: Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p < 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206] pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers. CONCLUSIONS: Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.

Nandrolone decanoate and testosterone undecanoate differently affect stress hormones, neurotransmitter systems, and general activity in the male rat.

Anabolic androgenic steroids (AAS) are frequently used to improve physical appearance and strength. AAS are known to affect muscle growth, but many AAS-users also experience psychiatric and behavioral changes after long-term use. The AAS-induced effects on the brain seem to depend on the type of steroid used, but the rationale behind the observed effect is still not clear. The present study investigated and compared the impact of nandrolone decanoate and testosterone undecanoate on body weight gain, levels of stress hormones, brain gene expression, and behavioral profiles in the male rat. The behavioral profile was determined using the multivariate concentric squared field test (MCSF-test). Blood plasma and brains were collected for further analysis using ELISA and qPCR. Nandrolone decanoate caused a reduction in body weight gain in comparison with both testosterone undecanoate and control. Rats receiving nandrolone decanoate also demonstrated decreased general activity in the MCSF. In addition, nandrolone decanoate reduced the plasma levels of ACTH in comparison with the control and increased the levels of corticosterone in comparison with testosterone undecanoate. The qPCR analysis revealed brain region-dependent changes in mRNA expression, where the hypothalamus was identified as the region most affected by the AAS. Alterations in neurotransmitter systems and stress hormones may contribute to the changes in behavior detected in the MCSF. In conclusion, both AAS affect the male rat, although, nandrolone decanoate has more pronounced impact on the physiological and the behavioral parameters measured.

Nandrolone Supplementation Promotes AMPK Activation and Divergent 18[FDG] PET Brain Connectivity in Adult and Aged Mice.

Decreased anabolic androgen levels are followed by impaired brain energy support and sensing with loss of neural connectivity during physiological aging, providing a neurobiological basis for hormone supplementation. Here, we investigated whether nandrolone decanoate (ND) administration mediates hypothalamic AMPK activation and glucose metabolism, thus affecting metabolic connectivity in brain areas of adult and aged mice. Metabolic interconnected brain areas of rodents can be detected by positron emission tomography using 18FDG-mPET. Albino CF1 mice at 3 and 18 months of age were separated into 4 groups that received daily subcutaneous injections of either ND (15 mg/kg) or vehicle for 15 days. At the in vivo baseline and on the 14th day, brain 18FDG-microPET scans were performed. Hypothalamic pAMPKT172/AMPK protein levels were assessed, and basal mitochondrial respiratory states were evaluated in synaptosomes. A metabolic connectivity network between brain areas was estimated based on 18FDG uptake. We found that ND increased the pAMPKT172/AMPK ratio in both adult and aged mice but increased 18FDG uptake and mitochondrial basal respiration only in adult mice. Furthermore, ND triggered rearrangement in the metabolic connectivity of adult mice and aged mice compared to age-matched controls. Altogether, our findings suggest that ND promotes hypothalamic AMPK activation, and distinct glucose metabolism and metabolic connectivity rearrangements in the brains of adult and aged mice.

Estradiol Valerate vs Ethinylestradiol in Combined Oral Contraceptives: Effects on the Pituitary-Ovarian Axis.

CONTEXT: Limited studies have compared the effects of combined oral contraceptives (COCs) containing natural estrogens and synthetic ethinylestradiol (EE) on reproductive hormones. OBJECTIVE: To compare estradiol valerate (EV) + dienogest (DNG), EE + DNG, and DNG alone (active control) on levels of follicle stimulating hormone (FSH), luteinizing hormone, anti-Müllerian hormone (AMH), ovarian steroids, sex hormone binding globulin (SHBG), and the free androgen index (FAI). METHODS: This spin-off study from a randomized trial enrolled 59 healthy, 18 to 35-year-old ovulatory women, outpatients at Helsinki and Oulu University Hospitals, Finland, who were randomized to EV 2 mg + DNG 2-3 mg (n = 20); EE 0.03 mg + DNG 2 mg (n = 20); and DNG 2 mg (n = 19) for 9 weeks. Blood samples were drawn at baseline, and at 5 and 9 weeks. Age and BMI were comparable between groups; 3 women discontinued. RESULTS: EV + DNG suppressed FSH by -27% (-51% to -3%) (median [95% CI]) vs EE + DNG, -64% (-78 to -51), P = 0.04, but AMH levels decreased similarly by -9% (-18 to -0.1) vs -13% (-28 to 0.2), P = 0.38, respectively. EV + DNG increased SHBG levels by 56% (30% to 82%) and EE + DNG by 385% (313% to 423%), P < 0.001. Total testosterone decreased by 16% (-27% to -5%) in the EV + DNG group but it did not decrease in the EE + DNG group, whereas the FAI decreased by -39% (-54% to -25%) vs -72% (-78% to -67%), P < 0.001. DNG alone did not induce changes in any of these parameters. CONCLUSION: Compared with EE + DNG, treatment with EV + DNG resulted in milder pituitary downregulation and reduced induction of hepatic SHBG synthesis-potentially carrying more beneficial health effects.

Nandrolone supplementation does not improve functional recovery in an aged animal model of volumetric muscle loss injury.

Aging hinders the effectiveness of regenerative medicine strategies targeting the repair of volumetric muscle loss (VML) injury. Anabolic steroids have been shown to improve several factors which contribute to the age-related decline in muscle's regenerative capacity. In this study, the impact of exogenous nandrolone decanoate (ND) administration on the effectiveness of a VML regenerative repair strategy was explored using an aged animal model. Unilateral tibialis anterior VML injuries were repaired in 18-month-aged animal models (male Fischer 344 rat) using decellularized human skeletal muscle scaffolds supplemented with autologous minced muscle. The contralateral limb was left untreated/uninjured. Following repair, ND(+) or a carrier control (ND-) was delivered via weekly injection for a period of 8 weeks. At 8 weeks, muscle isometric torque, gene expression, and tissue structure were assessed. ND(+) treatment did not improve contractile torque recovery following VML repair when compared to carrier only ND(-) injection controls. Peak isometric torque in the ND(+) VML repair group remained significantly below contralateral uninjured control values (4.69 ± 1.18vs. 7.46 ± 1.53 N mm/kg) and was statistically indistinguishable from carrier only ND(-) VML repair controls (4.47 ± 1.18 N mm/kg). Gene expression for key myogenic genes (Pax7, MyoD, MyoG, IGF-1) were not significantly elevated in response to ND injection, suggesting continued age related myogenic impairment even in the presence of ND(+) treatment. ND injection did reduce the histological appearance of fibrosis at the site of VML repair, and increased expression of the collagen III gene, suggesting some positive effects on repair site matrix regulation. Overall, the results presented in this study suggest that a decline in regenerative capacity with aging may present an obstacle to regenerative medicine strategies targeting VML injury and that the delivery of anabolic stimuli via ND administration was unable to overcome this decline.

Anabolic Steroids-Driven Regulation of Porcine Ovarian Putative Stem Cells Favors the Onset of Their Neoplastic Transformation.

Nandrolone (Ndn) and boldenone (Bdn), the synthetic testosterone analogues with strong anabolic effects, despite being recognized as potentially carcinogenic compounds, are commonly abused by athletes and bodybuilders, which includes women, worldwide. This study tested the hypothesis that different doses of Ndn and Bdn can initiate neoplastic transformation of porcine ovarian putative stem cells (poPSCs). Immunomagnetically isolated poPSCs were expanded ex vivo in the presence of Ndn or Bdn, for 7 and 14 days. Results show that pharmacological doses of both Ndn and Bdn, already after 7 days of poPSCs culture, caused a significant increase of selected, stemness-related markers of cancer cells: CD44 and CD133. Notably, Ndn also negatively affected poPSCs growth not only by suppressing their proliferation and mitochondrial respiration but also by inducing apoptosis. This observation shows, for the first time, that chronic exposure to Ndn or Bdn represents a precondition that might enhance risk of poPSCs neoplastic transformation. These studies carried out to accomplish detailed molecular characterization of the ex vivo expanded poPSCs and their potentially cancerous derivatives (PCDs) might be helpful to determine their suitability as nuclear donor cells (NDCs) for further investigations focused on cloning by somatic cell nuclear transfer (SCNT). Such investigations might also be indispensable to estimate the capabilities of nuclear genomes inherited from poPSCs and their PCDs to be epigenetically reprogrammed (dedifferentiated) in cloned pig embryos generated by SCNT. This might open up new possibilities for biomedical research aimed at more comprehensively recognizing genetic and epigenetic mechanisms underlying not only tumorigenesis but also reversal/retardation of pro-tumorigenic intracellular events.

Interaction of high-intensity endurance exercise and nandrolone on cardiac remodeling: role of adipo-cardiac axis.

OBJECTIVES: Given the cardiac pathological remodeling following to anabolic androgenic steroids (AASs) consumption, we examined the effect of chronic administration of nandrolone decanoate with high-intensity endurance exercise on the left ventricular hypertrophy index, levels of hydroxyproline, tumor necrosis factor-alpha (TNF-α), adiponectin (APN) and its receptors (AdipoR1 and AdipoR2) expression in rats' hearts. METHODS: The male Wistar rats randomly divided to six groups included the control (CTL), exercise (Ex), nandrolone (Nan), vehicle (Arach), trained vehicle (Ex + Arach), and trained nandrolone (Ex + Nan) groups that were treated for eight weeks. RESULTS: Nandrolone consumption significantly enhanced the hypertrophy index (p<0.05) and exercise intensified this effect. It also increased the level of cardiac hydroxyproline (p<0.001), however exercise completely masked this effect. The values of TNF-α protein and AdipoR1 protein significantly increased in trained nandrolone-treated (Ex + Nan) group in comparison with CTL group (p<0.05), however, did not show significant alteration in Nan or Ex groups. High-intensity endurance exercise significantly enhanced the AdipoR2 protein (p<0.05), but, co-administration of nandrolone with exercise prevented this effect. The mRNA expression of AdipoR1 significantly reduced in the animals that received nandrolone for eight weeks and exercise recovered this effect (p<0.001). CONCLUSIONS: Despite an additive effect of high-intensity endurance exercise plus nandrolone on TNF-α level, their effects on hydroxyproline and APN receptors expression is incompatible in heart of rat. It is suggests a part of beneficial regulatory role of endurance exercise against nandrolone induced heart remodeling may apply through modulation of APN system.

Effects of nandrolone decanoate on femur morphology. Experimental study.

PURPOSE: To evaluate the immediate and late effects of nandrolone on femur morphology of rats. METHODS: Twenty-eight animals with 20 weeks of age were divided into four groups: C28, control animals that were euthanized eight weeks after the experiment started; C40, control animals euthanized 20 weeks after the experiment started; T28, treated animals receiving nandrolone during eight weeks and euthanized immediately after the treatment period; and T40, animals treated during eight weeks and euthanized 12 weeks after the end of the treatment. Treated animals received nandrolone decanoate during eight weeks and control groups received peanut oil by intramuscular injection. After euthanasia, femurs were removed, dissected, weighted and measured by digital pachymeter. RESULTS: The T40 group presented an increase on distal epiphysis diameter when compared to C40 group. There was no difference between treated and control groups in relation to body and femur absolute weight, relative weight and length of femur. There was also no difference in relation to diameter of proximal epiphysis and diameter of diaphysis among the groups. CONCLUSIONS: Nandrolone decanoate does not produce significant effect on femur, exception on its distal extremity at late period. The effects of such drug may depend on the time after administration.

Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11ß-MNTDC in healthy men.

BACKGROUND: Dimethandrolone (DMA) and 11ß-methyl-19-nortestosterone (11ß-MNT) are two novel compounds with both androgenic and progestational activity that are under investigation as potential male hormonal contraceptives. Their metabolic effects have never been compared in men. OBJECTIVE: Assess for changes in insulin sensitivity and adiponectin and compare the metabolic effects of these two novel androgens. MATERIALS/METHODS: In two clinical trials of DMA undecanoate (DMAU) and 11ß-MNT dodecylcarbonate (11ß-MNTDC), oral prodrugs of DMA and 11ß-MNT, healthy men received drug, or placebo for 28 days. Insulin and adiponectin assays were performed on stored samples. Mixed model analyses were performed to compare the effects of the two drugs. Student's t test, or the non-parametric Kruskal-Wallis test as appropriate, was used to evaluate for an effect of active drug versus placebo. RESULTS: Class effects were seen, with decrease in HDL-C and SHBG, and increase in weight and hematocrit, with no statistically significant differences between the two compounds. No changes in fasting glucose, fasting insulin, or HOMA-IR were seen with either compound. There was a slight decrease in adiponectin with DMAU that was not seen with 11ß-MNTDC. An increase in LDL-C was seen with 11ß-MNTDC but not with DMAU. DISCUSSION: There were no significant changes in insulin resistance after 28 days of oral administration of these novel androgens despite a mild increase in weight. There may be subtle differences in their metabolic impacts that should be explored in future studies. CONCLUSION: Changes in metabolic parameters should be carefully monitored when investigating androgenic compounds.

Structurally different anabolic androgenic steroids reduce neurite outgrowth and neuronal viability in primary rat cortical cell cultures.

The illicit use of anabolic androgenic steroids (AAS) among adolescents and young adults is a major concern due to the unknown and unpredictable impact of AAS on the developing brain and the consequences of this on mental health, cognitive function and behaviour. The present study aimed to investigate the effects of supra-physiological doses of four structurally different AAS (testosterone, nandrolone, stanozolol and trenbolone) on neurite development and cell viability using an in vitro model of immature primary rat cortical cell cultures. A high-throughput screening image-based approach, measuring the neurite length and number of neurons, was used for the analysis of neurite outgrowth. In addition, cell viability and expression of the Tubb3 gene (encoding the protein beta-III tubulin) were investigated. Testosterone, nandrolone, and trenbolone elicited adverse effects on neurite outgrowth as deduced from an observed reduced neurite length per neuron. Trenbolone was the only AAS that reduced the cell viability as indicated by a decreased number of neurons and declined mitochondrial function. Moreover, trenbolone downregulated the Tubb3 mRNA expression. The adverse impact on neurite development was neither inhibited nor supressed by the selective androgen receptor (AR) antagonist, flutamide, suggesting that the observed effects result from another mechanism or mechanisms of action that are operating apart from AR activation. The results demonstrate a possible AAS-induced detrimental effect on neuronal development and regenerative functions. An impact on these events, that are essential mechanisms for maintaining normal brain function, could possibly contribute to behavioural alterations seen in AAS users.

Identification of biomarkers for drug-resistant endometriosis using clinical proteomics.

Dienogest (DNG), is an effective and widely used progestin used in the treatment of endometriosis, yet clinically, a subset of cases show resistance to DNG treatment. During a previous investigation on the effect of DNG of cytokines and growth factor production, we incidentally found that endometriotic cyst fluid did not demonstrate inhibitory effects to DNG in a subset of cases. To clarify the mechanisms of this resistance to DNG, we performed proteomics analysis to compare the protein expression between DNG-sensitive and resistant cases. Based upon our results, several proteins were extracted that relate to neutrophil granulocyte activation marker (myeloperoxidase, lactotransferrin), inflammation (azurocidin, neutrophil gelatinase-associated lipocalin, etc.), and others biological processes reflecting the clinical environment of the endometriotic cyst. Among these proteins, azurocidin (AZU) is perhaps most interesting one as azurocidin is a protease that cleaves insulin-like growth factor-1 (IGFBP-1) associated with clear cell carcinoma of the ovary. We propose that the proteins extracted in the present study warrant further investigation in their relationship to carcinogenesis of endometrioma.