Doses Of Testosterone Enanthate Research Articles

Testosterone Enanthate: An In Vitro Study of the Effects Triggered in MG-63 Cells.

The aim of this study was to investigate the effects of the androgenic hormone testosterone enanthate (TE) on human MG-63 cells. MG-63 were cultured for 24 h in the presence of TE at increasing concentrations to assess its lethal dose. Therefore, the suitable concentration for a prolonged use of TE in vitro was assessed by viability assay over 9 days. Finally, MG-63 were exposed to TE for 14 days and assayed for differentiation by qPCR and Alizarin Red S staining. TE in the amount of 100 µM resulted as the maximum dose tolerated by MG-63 cells after 24 h. However, a prolonged exposure in culture TE in the amount of 100 µM showed a cytostatic effect on cell proliferation. On the contrary, TE 10 µM was tolerated by the cells and did not boost cell proliferation, but did enhance new bone formation, as revealed by COL1A1, ALPL, BGLAP, and IBSP gene expression after 3, 7, and 14 days, and calcium deposition by Alizarin Red S staining after 14 days. Based on the current study, 10 µM is the critical dose of TE that should be used in vitro to support bone differentiation of MG-63 cells.

Long-term outcomes of testosterone replacement therapy for patients with late-onset hypogonadism syndrome

ABSTRACT Introduction and Objective Testosterone replacement therapy (TRT) is effective for patients with late onset hypogonadism (LOH) syndrome. However, treatment compliance of long-term TRT for LOH syndrome patients remains unclear. We investigated the long-term outcomes of TRT for patients with LOH syndrome. Methods Forty-two patients (age: mean 55.9, SD 10.2) were diagnosed and then underwent TRT using testosterone enanthate between January 2010 and December 2014 at our hospital. We investigated long-term compliance of TRT, changes of subjective data, i.e. aging male symptom (AMS score) and, international index of erectile function (IIEF5), and objective data, i.e. free testosterone level and, serum PSA level, retrospectively. This study was approved by the Ethics Committee of our facility (Approval No.3043). Results At the time of TRT initiation, AMS score (mean, as mentioned below) was 55.1 (SD 10.1) points, IIEF5 was 7.9 (SD 3.8) points, free testosterone level was 5.8 (SD 1.9) pg/ml, and serum PSA level was 1.3 (SD 1.6) ng/ml. The duration of TRT was 27.7 (SD 29.4) months. Dose of testosterone enanthate was 183.1 (SD 69.2) mg/4weeks. AMS score and IIEF5 were significantly improved after TRT. Adverse events (AE) occurred in 9.6% of the patients, but these were no severe AE. TRT continuation rate was 50.0% at 12 months, 40.5% at 24 months, 35.7% at 36 months, and 33.3% at 48 months. In addition, there was a significantly higher rate in the group with severe AMS scores than in mild-moderate groups. In the discontinuation group of 25 patients (59.5%), the duration of treatment was significantly longer in the improvement group than in the ineffective group. Conclusions Testosterone replacement therapy for late onset hypogonadism syndrome is a safe and effective long-term treatment. The treatment continuation analysis showed that patients with severe AMS scores and better effect of TRT requested long-term treatment. Disclosure Work supported by industry: no.

Subcutaneous Testosterone Enanthate and the Effect of Body Mass Index on Serum Testosterone in Men with Testosterone Deficiency

ABSTRACT Introduction Obesity (body mass index [BMI] ≥30 kg/m^2) in men is associated with low testosterone (T) levels, and the prevalence of testosterone deficiency (TD) is greater in obese men. Information is limited regarding how BMI affects the pharmacokinetic (PK) profile or dosing of testosterone therapies (TTh) in men with TD. Serum total testosterone (TT) trough concentration (C-trough)-guided dosing achieved physiological serum TT levels (300-1100 ng/dL) in a Phase 3 trial of subcutaneous (SC) testosterone enanthate (TE) administered weekly. Objective This post-hoc analysis evaluated the association between BMI and serum TT to assess PK parameters of weekly SC TE treatment in men with TD and varying BMIs. Methods Concentration-controlled SC TE was evaluated in a single-arm Phase 3 trial. The primary endpoint was the percentage of patients who received ≥1 dose of SC TE (Safety Population) achieving an average serum TT concentration of 300-1100 ng/dL over the 7-day dosing interval, C-avg (0-168h), at Week 12. The PK Population (n=142) included all patients in the Safety Population with ≥1 blood sample drawn post-dose. Patients in the PK Population who completed the study through Week 12 (n=137) were categorized into tertiles based on baseline BMI: Tertile 1 (BMI ≤29 kg/m^2; n=45), Tertile 2 (BMI >29-32 kg/m^2; n=33), and Tertile 3 (BMI >32 kg/m^2; n=59). Assessed PK parameters included C-trough, AUC-(0-168h), C-avg (0-168h), and C-max. Weeks 6 and 12 C-trough and C-avg (0-168h) were assessed by BMI tertiles. C-trough and C-avg (0-168h) were calculated according to their Week 12 treatment doses, and an overall dose-normalized linear regression model at Week 12 was used. Results At baseline, mean (SD) serum TT levels for patients in Tertiles 1-3 were 250.7 (101.3), 235.3 (91.2), and 226.4 (81.1) ng/dL, respectively. Prior to dosing adjustments at Week 6, Tertiles 2 and 3 mean (SD) C-trough (459.2 [157.0] and 453.2 [133.0] ng/dL) were lower than Tertile 1 (616.9 [181.6] ng/dL). At Week 6, 21.2% of the total variance in C-trough levels could be predicted from BMI (P<0.001). At Week 12, patients in Tertiles 2 and 3 had lower TT C-trough (494.8 [137.6] and 469.0 [146.2] ng/dL) compared to 517.7 (153.5) ng/dL in Tertile 1. Mean (SD) C-avg (0-168h) values were 585.2 (148.1), 554.2 (104.5), and 528.5 (118.0) ng/dL in Tertiles 1-3, respectively. Mean doses at Week 12 for Tertiles 1-3 were 65.0 (13.48), 78.0 (12.12), and 78.4 (12.68) mg, respectively. Thus, the patients in Tertiles 2 and 3 require higher final doses of SC TE compared to patients in Tertile 1. Using an overall dose-normalized linear regression model at Week 12, 9.36% (P<0.001) and 16.96% (P<0.001) of the total variance in C-trough and C-avg (0-168h), respectively, can be predicted from independent BMI and dose variables. Overall, 98.5% of Week 12 completers achieved C-avg (0-168h) of 300-1100 ng/dL. Conclusions Week 12 TT C-trough, C-avg (0-168h), and C-max were inversely related to BMI, suggesting an important role for BMI and final dose selection in SC TE exposure. Patients with higher BMI tertiles may require higher testosterone dosing to replete physiologic levels. Disclosure Yes, this is sponsored by industry/sponsor: Antares Pharma, Inc. Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Antares Pharma, Inc.

SAT-037 Effect of Weight on Serum Testosterone with Subcutaneous Testosterone Enanthate in Men with Testosterone Deficiency

BACKGROUND: In men, obesity is often associated with low testosterone (T) levels, but information is limited as to how body weight affects the pharmacokinetic profile or dosing of testosterone therapy (TTh) in men with T deficiency. Historically, men with body mass index (BMI) >32.4 kg/m2 required higher doses of T 2% gel to achieve physiological T levels than men with BMI ≤29.1 or 29.2–32.4 kg/m2.(1) In a phase 3 trial (N=150) of subcutaneous (SC) testosterone enanthate (TE) administered weekly, concentration-guided dosing raised T levels to within physiological range in 92.7% of patients.(2) Here, we report a post hoc analysis evaluating the association between body weight and serum T levels attained with SC TE. Methods: SC TE was evaluated in an open-label, single-arm, dose-blinded, 52-week phase 3 trial (NCT02159469). Patients self-administered 75 mg SC TE weekly during the titration phase; blinded dose-adjustments in 25 mg increments occurred at pre-defined time points beyond the sixth dose. The primary endpoint of this study was the percentage of patients achieving an average serum T concentration (Cavg0-168h) of 300 to 1,100 ng/dL at week 12. For this post hoc analysis, a linear regression model with weight and dose as independent variables was used to assess differences in mean minimum T concentration (Cmin) and Cavg0-168h at week 12. Results: For this analysis, 137 patients were included. Doses were 50 mg (n=25), 75 mg (n=93), and 100 mg (n=19). The mean weight was 84.4 kg, 102.2 kg, and 112.0 kg for the 50 mg, 75 mg, and 100 mg dose groups, respectively (range, 49.9–146.5 kg). The dose-normalized T Cmin was 9.2 ng/dL, 5.7 ng/dL, and 4.3 ng/dL per 1 mg of SC TE for the 50 mg, 75 mg, and 100 mg groups, respectively. The dose-normalized T Cavg0-168h was 12.0 ng/dL, 7.2 ng/dL, and 5.7 ng/dL per 1 mg of SC TE. In an overall linear regression model, 48.2% (P<0.0001) and 55.0% (P<0.0001) of the total variance in Cmin and Cavg0-168h, respectively, can be predicted from the independent weight and dose variables. Conclusion: Our results show an inverse relationship between body weight and T exposure. Men with higher mean body weights required higher doses of SC TE to achieve physiologic T levels compared with men with lower mean body weights. The available doses provide effective options to reach target exposures. These findings highlight the impact of weight and dose selection on SC TE exposure.

Summative Usability Evaluation of the SCTE-AI Device: A Novel Prefilled Autoinjector for Subcutaneous Testosterone Administration

BackgroundThe subcutaneous testosterone enanthate (TE) autoinjector (SCTE-AI) is a single-use, pre-filled, disposable autoinjector intended for testosterone (T) self-administration in adult males with T deficiency. AimTo evaluate the usability of the market configuration of the SCTE-AI, including packaging and instructions for use (IFU), in order to identify and mitigate any preventable patterns of use errors that could result in harm. Methods4 groups of participants (injection-naïve or injection-experienced patients or caregivers) were randomized to 1 of 3 doses (50, 75, and 100 mg) of TE and either trained (ie, reviewed the IFU and shown how to properly inject) or not trained (only given the IFU). After simulated at-home use, participants were asked questions regarding the comprehensibility of the IFU and the intuitiveness/usability of the device. All tasks were measured as success, use error, or close call (participant initiated an error but recovered in time). Main Outcome MeasureUsability (success rates, errors, and close calls) of the drug/device combination by adult males with T deficiency or their caregivers. Results65 patients received 1 dose of TE, and 59 patients received 2 doses. Overall, 99 of 123 (80.5%) attempted injections resulted in administration of 1 full dose. Injection success rates were high and comparable among the various user groups. The most common use error (21 of 24) was due to not holding the autoinjector on the abdomen long enough (at least 8 seconds). Few critical drug delivery and safety errors or close calls were observed. No unmitigated use errors by patients or caregivers were apparent that could result in harm or have a negative impact on treatment. SCTE-AI was well tolerated. Clinical ImplicationsThe SCTE-AI development process resulted in a subcutaneous, TE autoinjection device that is intuitive to use, with clear labeling and packaging and an easy-to-understand IFU, providing an option for T-deficient adult males to self-inject subcutaneously at home. Strength & LimitationsThe strengths of the study include use of a patient-ready drug/device combination for self-administration and inclusion of both injection-naïve and injection-experienced patients and caregivers. The main limitation of the study is the presence of observers/cameras that may have distracted or created performance anxiety, potentially contributing to errors. ConclusionResults of this usability validation study indicate that the SCTE-AI device is safe and intuitive to use, with a low potential for harm and is associated with a high rate of injection success, regardless of prior training or experience.Arora S, Moclair B, Murphy K, et al. Summative Usability Evaluation of the SCTE-AI Device: A Novel Prefilled Autoinjector for Subcutaneous Testosterone Administration. J Sex Med 2018;15:1707–1715.

Effects of TNF-α on penile structure alteration in rats with hyperprolactinemia.

This study aimed to investigate the effects of anti-tumor necrosis factor (TNF)-α antibody (Ab) on alteration of penile structure in the hyperprolactinemia (hyperPRL) rat model. HyperPRL was induced in 8-week-old male Sprague-Dawley rats by allografting anterior pituitary (AP) glands under the renal capsule (+AP rats). Rats implanted with cerebral cortex (CX) were used as sham control (+CX rats). At 6 weeks post implantation, rats received either a single intra-testicular dose of TNF-α Ab (12.5 μg/kg) or testosterone replacement (2 doses of testosterone enanthate [TE], 3 mg/kg), and they were sacrificed 1 week later. Blood and penile tissue was collected for analysis. Compared to +CX rats, the +AP group had lower serum testosterone concentration and neuronal nitric oxide synthase (nNOS) expression, but exhibited a higher ratio of collagen III/I in the corpus cavernosum. Smooth muscle content exhibited no significant changes. At 1 week post TNF-α Ab injection, the collagen III/I ratio in the +AP group was decreased, and the smooth muscle content and nNOS expression increased significantly. These findings were comparable to those observed in +AP rats receiving TE. Testicular TNF-α suppresses testosterone release, which in turn results in the erectile dysfunction (ED) seen in hyperPRL. Intra-testicular TNF-α Ab treatment is as effective as testosterone supplementation on penile structure normalization in the hyperPRL model.

Dose-dependent testosterone sensitivity of the steroidal passport and GC-C-IRMS analysis in relation to the UGT2B17 deletion polymorphism.

The newly implemented Steroid Module of the Athlete Biological Passport has improved doping tests for steroids. A biomarker included in this passport is the urinary testosterone glucuronide to epitestosterone glucuronide (T/E) ratio, a ratio greatly affected by a deletion polymorphism in UGT2B17. Suspect urine doping tests are further analyzed with gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) to determine the origin of the androgen. In this study, we investigated the sensitivity of the steroidal module and the IRMS analysis, in subjects administered with three doses of testosterone enanthate (500, 250, and 125 mg), in relation to the UGT2B17 polymorphism. All subjects carrying the UGT2B17 enzyme reached the traditionally used threshold, a T/E ratio of 4, after all three administered doses, whereas none of the subjects devoid of this enzyme reached a T/E of 4. On the other hand, using the athlete biological passport and IRMS analysis, all three doses could be detected to a high degree of sensitivity. The concentrations of all steroids included in the steroidal module were dose dependently increased, except for epitestosterone which decreased independent of dose. The decrease in epitestosterone was significantly associated with circulatory levels of testosterone post dose (rs =0.60 and p=0.007). In conclusion, these results demonstrate that administration of a single dose of 125-500 mg testosterone enanthate could be detected using the athlete biological passport, together with IRMS. Since IRMS is sensitive to testosterone doping independent of UGT2B17 genotype, also very small changes in the steroidal passport should be investigated with IRMS.

GABA&amp;lt;sub&amp;gt;b&amp;lt;/sub&amp;gt; Receptor Antagonist (CGP&amp;lt;sub&amp;gt;35348&amp;lt;/sub&amp;gt;) Improves Testosterone Induced Spatial Acquisition Impairment in Adult Male Rat

The high density of the androgen receptors in fundamental centers of learning and memory, such as hippocampus, shows that there must be some relationship between the androgen receptors and cognitive aspects. On the other hand, Gama Amino Butric Acid (GABA) plays a controlling role in the balance of excitability and inhibitory states in the cortex and hippocampus; a number of reports suggest that removal of the influence of inhibitory GABA receptors lead to memory enhancement and conversely the activation lead to memory inhibition. Sex steroids can rapidly influence neural activity by increasing the binding affinity of neurotransmitters such as GABAergic. To determine the effect of Testosterone on learning and memory in CA1 region of hippocampus, male albino Wistar rats (200 - 250 g) are bilaterally cannulated into CA1 of hippocampus then different doses of Testosterone enanthate or CGP35348 are injected through the cannulae for assessing of acquisition, consolidation and retrieval in a single-day testing protocol of Morris water maze task. After hippocampal microinjection with Testosterone (T), acquisition is significantly impaired, while after treatment with CGP35348, acquisition impairment caused by T can be significantly improved. Also T and CGP35348 have no significant effect on consolidation and retrieval stages of spatial memory. These results suggest that CGP35348 may have therapeutic value in the treatment of Testosterone-induced acquisition impairment.

Effects of different doses of testosterone on gonadotropins, 25-hydroxyvitamin D3, and blood lipids in healthy men.

AimsTo study the effect and time profile of different doses of testosterone enanthate on the blood lipid profile and gonadotropins.Experimental designTwenty-five healthy male volunteers aged 27–43 years were given 500 mg, 250 mg, and 125 mg of testosterone enanthate as single intramuscular doses of Testoviron® Depot. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), blood lipid profile (total cholesterol, plasma [p-] low-density lipoprotein, p-high-density lipoprotein [HDL], p-apolipoprotein A1 [ApoA1], p-apolipoprotein B, p-triglycerides, p-lipoprotein(a), serum [s-] testosterone, and 25-hydroxyvitamin D3) were analyzed prior to, and 4 and 14 days after dosing. Testosterone and epitestosterone in urine (testosterone/epitestosterone ratio) were analyzed prior to each dose after a washout period of 6–8 weeks.Results and discussionAll doses investigated suppressed the LH and FSH concentrations in serum. LH remained suppressed 6 weeks after the 500 mg dose. These results indicate that testosterone has a more profound endocrine effect on the hypothalamic–pituitary–gonadal axis than was previously thought. There was no alteration in 25-hydroxyvitamin D3 levels after testosterone administration compared to baseline levels. The 250 and 500 mg doses induced decreased concentrations of ApoA1 and HDL, whereas the lowest dose (125 mg) did not have any effect on the lipid profile.ConclusionThe single doses of testosterone produced a dose-dependent increase in serum testosterone concentrations together with suppression of s-LH and s-FSH. Alterations in ApoA1 and HDL were observed after the two highest single doses. It is possible that long-time abuse of anabolic androgenic steroids will lead to alteration in vitamin D status. Knowledge and understanding of the side effects of anabolic androgenic steroids are important to the treatment and care of abusers of testosterone.

Testosterone Dose Dependently Prevents Bone and Muscle Loss in Rodents after Spinal Cord Injury

Androgen administration protects against musculoskeletal deficits in models of sex-steroid deficiency and injury/disuse. It remains unknown, however, whether testosterone prevents bone loss accompanying spinal cord injury (SCI), a condition that results in a near universal occurrence of osteoporosis. Our primary purpose was to determine whether testosterone-enanthate (TE) attenuates hindlimb bone loss in a rodent moderate/severe contusion SCI model. Forty (n=10/group), 14 week old male Sprague-Dawley rats were randomized to receive: (1) Sham surgery (T9 laminectomy), (2) moderate/severe (250 kdyne) SCI, (3) SCI+Low-dose TE (2.0 mg/week), or (4) SCI+High-dose TE (7.0 mg/week). Twenty-one days post-injury, SCI animals exhibited a 77-85% reduction in hindlimb cancellous bone volume at the distal femur (measured via μCT) and proximal tibia (measured via histomorphometry), characterized by a >70% reduction in trabecular number, 13-27% reduction in trabecular thickness, and increased trabecular separation. A 57% reduction in cancellous volumetric bone mineral density (vBMD) at the distal femur and a 20% reduction in vBMD at the femoral neck were also observed. TE dose dependently prevented hindlimb bone loss after SCI, with high-dose TE fully preserving cancellous bone structural characteristics and vBMD at all skeletal sites examined. Animals receiving SCI also exhibited a 35% reduction in hindlimb weight bearing (triceps surae) muscle mass and a 22% reduction in sublesional non-weight bearing (levator ani/bulbocavernosus [LABC]) muscle mass, and reduced prostate mass. Both TE doses fully preserved LABC mass, while only high-dose TE ameliorated hindlimb muscle losses. TE also dose dependently increased prostate mass. Our findings provide the first evidence indicating that high-dose TE fully prevents hindlimb cancellous bone loss and concomitantly ameliorates muscle loss after SCI, while low-dose TE produces much less profound musculoskeletal benefit. Testosterone-induced prostate enlargement, however, represents a potential barrier to the clinical implementation of high-dose TE as a means of preserving musculoskeletal tissue after SCI.

Calorimetric monitoring of the effect of endurance training and testosterone treatment on rat serum denaturation transition

Differential scanning calorimetry (DSC) was applied to evaluate whether endurance training and/or testosterone treatment affect thermal behavior of rat serum. Thirty-six adolescent male Wistar rats were divided into six groups: three untrained and three trained groups, receiving weekly 0, 8, or 80 mg kg −1BM of testosterone enanthate (TE) each. Total testosterone was significantly higher in both groups treated with the higher TE dose. The rats’ body mass and the levels of serum glucose, uric acid, and free fatty acids were additionally determined. The effect of TE treatment was clearly visible in DSC curves for sedentary rats and much less for trained rats. The differences between averaged endothermic denaturation transitions of serum from sedentary and physically active untreated groups were within an experimental error. A statistically significant increase of the width of peak at its half height and the ratio of excess heat capacity at 75 °C and in the temperature of peak maximum (C p75 /C pmax) were observed due to TE treatment. The same two parameters were significantly lower for physically active rats. Significantly lower values of the enthalpy of serum denaturation (∆H) and the first moment of the transition with respect to the temperature axis (M 1) were observed for endurance-trained than for sedentary rats.

Lepidium meyenii (maca) consumption prevent benign prostatic hyperplasia

Lepidium meyenii (maca) is a Peruvian Andean with effects against benign prostatic hyperplasia (BPH); a disease associated with male sexual dysfunction.BPH was induced in mice with two doses of testosterone enanthate (TE) (83mg/kg, day 1 and 7), a negative control received the vehicle. Experimental groups received TE alone or TE in combination with Finasteride (FN) (0.6 mg/Kg/day), a drug used to treat BPH, red maca (RM)( 167 mg/Kg/day), or black maca (BM)( 167 mg/Kg/day) extracts during 21 days. At the end of the study, weights of body and reproductive organs (prostate, seminal vesicles (SV), testicles, preputial glands (PG), and epididymis) were recorded and compared to negative controls.Results showed that TE induced BPH increasing weights of prostate and SV to 225% and 149% of negative controls, respectively. Treatments with FN, RM and BM prevented these effects and maintained prostate weights at 71%, 44%, and 82% of TE, respectively. The SV weights were maintained at 73%, 80% and 81% of TE, respectively. Weights of testicles, and PG were also increased by TE, and treatments with RM were more effective than BM or FN in maintaining weights closer to negative controls. Overall, RM protected against changes in weights of male reproductive organs that accompanied HPB at higher extent than FN or BM. The underlying mechanisms to explain the RM protective effects are being investigated.

Effect of Testosterone and Resistance Training on Cardiac Mass and Contractility in Men with COPD

Introduction: Testosterone therapy and resistance training have been demonstrated to improve muscle mass and strength in patients with testosterone deficiency. However the effects on cardiac mass and contractility of these interventions have not been identified in prospective placebo-controlled trials. The hypothesis of this trial was that resistance training and testosterone replacement would improve cardiac mass and contractility in male COPD patients with low testosterone levels. Methods: We conducted a 10 week trial in a 2 by 2 factorial design, randomizing 53 patients to replacement doses of testosterone enanthate (100 mg weekly) or placebo, as well as to a program of lower extremity resistance training or no exercise. We performed rest and exercise cardiac computed tomography (CCT) studies before and after 10 weeks of therapy to evaluate right and left heart function. Patients were injected with 40-50 ml of non-ionic, iodinated contrast and cine CCT images were obtained at rest. Patients were exercised to 60% of their maximal work rate on a semi-supine ergometer, then re-injected with another bolus of 40-50 ml of contrast and re-imaged. We evaluated cardiac output and left ventricular (LV) and right ventricular (RV) mass, LV and RV stroke volume, ejection fractions and end-diastolic volumes at rest and exercise, before and after therapy. Results: 42 men with COPD (mean FEV1=40%pred. pre-bronchodilator) and low testosterone levels (mean=320ng/dl) completed the 10 week protocol. Factorial analysis demonstrated that testosterone, but not resistance training increased LV and RV mass (by 4.9% and 8.3%, respectively). Resistance training, but not testosterone, was associated with increased LV ejection fraction at rest and during exercise (by 5.5% and 4.4%, respectively). In the entire study group, increases in both left and right ventricular mass were correlated with increases in lean body mass (assessed by DEXA) (r=0.49 and r=0.65, respectively). Conclusions: In men with COPD, testosterone replacement and strength training are associated with distinct alterations in cardiac structure and function. Specifically, resistance training improved ejection fraction, while testosterone increased lean body mass and LV mass.

Testosterone Suppresses Hepcidin in Men: A Potential Mechanism for Testosterone-Induced Erythrocytosis

The mechanisms by which testosterone increases hemoglobin and hematocrit are unknown. The aim was to test the hypothesis that testosterone-induced increase in hematocrit is associated with suppression of the iron regulatory peptide hepcidin. Healthy younger men (ages 19-35 yr; n = 53) and older men (ages 59-75 yr; n = 56) were studied. Weekly doses of testosterone enanthate (25, 50, 125, 300, and 600 mg) were administered over 20 wk, whereas endogenous testosterone was suppressed by monthly GnRH agonist administration. Blood and serum parameters from each individual were measured at wk 0, 1, 2, 4, 8, and 20. Longitudinal analyses were performed to examine the relationship between hepcidin, hemoglobin, hematocrit, and testosterone while controlling for potential confounders. High levels of testosterone markedly suppressed serum hepcidin within 1 wk. Hepcidin suppression in response to testosterone administration was dose-dependent in older men and more pronounced than in young men, and this corresponded to a greater rise in hemoglobin in older men. Serum hepcidin levels at 4 and 8 wk were predictive of change in hematocrit from baseline to peak levels. Testosterone administration is associated with suppression of serum hepcidin. Greater increases in hematocrit in older men during testosterone therapy are related to greater suppression of hepcidin.

Effects of Graded Doses of Testosterone on Erythropoiesis in Healthy Young and Older Men

Erythrocytosis is a dose-limiting adverse effect of testosterone therapy, especially in older men. Our objective was to compare the dose-related changes in hemoglobin and hematocrit in young and older men and determine whether age-related differences in erythropoietic response to testosterone can be explained by changes in erythropoietin and soluble transferrin receptor (sTfR) levels. We conducted a secondary analysis of data from a testosterone dose-response study in young and older men who received long-acting GnRH agonist monthly plus one of five weekly doses of testosterone enanthate (25, 50, 125, 300, or 600 mg im) for 20 wk. The study took place at a General Clinical Research Center. Participants included 60 older men aged 60-75 yr and 61 young men aged 19-35 yr. Outcome measures included hematocrit and hemoglobin and serum erythropoietin and sTfR levels. Hemoglobin and hematocrit increased significantly in a linear, dose-dependent fashion in both young and older men in response to graded doses of testosterone (P<0.0001). The increases in hemoglobin and hematocrit were significantly greater in older than young men. There was no significant difference in percent change from baseline in erythropoietin or sTfR levels across groups in either young or older men. Changes in erythropoietin or sTfR levels were not significantly correlated with changes in total or free testosterone levels. Testosterone has a dose-dependent stimulatory effect on erythropoiesis in men that is more pronounced in older men. The testosterone-induced rise in hemoglobin and hematocrit and age-related differences in response to testosterone therapy may be mediated by factors other than erythropoietin and sTfR.

Anastrozole improved testosterone-induced impairment acquisition of spatial learning and memory in the hippocampal CA1 region in adult male rats

Neurohormones like testosterone and estrogen have an important role in learning and memory. Many biological effects of androgens in the brain require the local conversion of these steroids to an estrogen. The current research has conducted to assess the effect of testosterone, estrogen and aromatase inhibitor (anastrozole) on spatial discrimination of rats, using Morris water maze and also the pathway of the effect of testosterone by using anastrozole. Adult male rats were bilaterally cannulated into CA1 region of hippocampus and divided into 15 groups. Different groups received DMSO 0.5 μl and DMSO 0.5 μl + DMSO 0.5 μl as control groups and different doses of testosterone enanthate (TE) (20, 40 and 80 μg/0.5 μl), estradiol valerat (EV) (1, 2.5, 5, 10, and 15 μg/0.5 μl), anastrozole (An) (0.25, 0.5, 1 μg/0.5 μl), TE 80 μg/0.5 μl + anastrozole 0.5 μg/0.5 μl and EV 15 μg/0.5 μl + anastrozole 0.5 μg/0.5 μl all days before training. TE and EV were injected 30–35 min before training and anastrozole was injected 25–30 min before training. Our results have shown both TE 80 μg/0.5 μl and EV 15 μg/0.5 μl groups increase in escape latency and traveled distance to find invisible platform. Also we have shown that anastrozole dose dependently decreases escape latency and traveled distance. We resulted that both TE and EN impaired acquisition of spatial learning and memory but anastrozole improved it. Anastrozole also could be buffered TE-induced impairment effect but not EV.

Differences in the Apparent Metabolic Clearance Rate of Testosterone in Young and Older Men with Gonadotropin Suppression Receiving Graded Doses of Testosterone

Recently we found that testosterone levels are higher in older men than young men receiving exogenous testosterone. We hypothesized that older men have lower apparent testosterone metabolic clearance rates (aMCR-T) that contribute to higher testosterone levels. The objective of the study was to compare aMCR-T in older and young men and identify predictors of aMCR-T. Sixty-one younger (19-35 yr) and 60 older (59-75 yr) men were given a monthly GnRH agonist and weekly testosterone enanthate (TE) (25, 50, 125, 300, or 600 mg) for 5 months. Estimated aMCR-T was calculated from the amount of TE delivered weekly and trough serum testosterone concentrations, corrected for real-time absorption kinetics from the im testosterone depot. Older men had lower total (316 +/- 13 vs. 585 +/- 26 ng/dl, P < 0.00001) and free testosterone (4 +/- 0.1 vs. 6 +/- 0.3 ng/dl, P < 0.00001) and higher SHBG (52 +/- 3 vs. 33 +/- 2 nmol/liter, P < 0.00001) than younger men at baseline. Total and free testosterones increased with TE dose and were higher in older men than young men in the 125-, 300-, and 600-mg dose groups. aMCR-T was lower in older men than young men (1390 +/- 69 vs. 1821 +/- 102 liter/d, P = 0.006). aMCR-T correlated negatively with age (P = 0.0007), SHBG (P = 0.046), and total testosterone during treatment (P = 0.02) and percent body fat at baseline (P = 0.01) and during treatment (P = 0.004). aMCR-T correlated positively with lean body mass at baseline (P = 0.03) and during treatment (P = 0.01). In multiple regression models, significant predictors of aMCR-T included lean body mass (P = 0.008), percent fat mass (P = 0.009), and SHBG (P = 0.001). Higher testosterone levels in older men receiving TE were associated with an age-related decrease in apparent testosterone metabolic clearance rates. Body composition and SHBG were significant predictors of aMCR-T.

Genomic and nongenomic effects of intrahippocampal microinjection of testosterone on long-term memory in male adult rats

In addition to their well-known genomic effects via intracellular receptors, androgens rapidly alter neuronal excitability through a nongenomic pathway. The nongenomic effect of testosterone, as the main androgen, apart from its traditional effects, was assessed in one of the fundamental centers of learning and memory, the hippocampus, on long-term memory (LTM) in passive avoidance conditioning. Different doses of testosterone enanthate (T) or testosterone-BSA (T-BSA) bilaterally were injected into the CA1 region of the hippocampus 15 min before shock delivery (1 mA during 5 s) in a two-compartment passive avoidance apparatus. After 24 h, animals were tested for passive avoidance retrieval. Bilateral injection of 20 μg T or 55 μg T-BSA into the CA1 significantly decreases step-through latency. Therefore, it seems that testosterone can impair LTM in passive avoidance conditioning both via intracellular receptors and through nongenomic pathway.

Regulation of caltrin mRNA expression by androgens in the murine prostate.

Testicular androgens induce the proliferation and differentiation of prostatic epithelial cells by regulating the expression of androgen target genes. The use of subtractive hybridization to isolate genes that are differentially expressed during the early phase of androgen-induced prostatic regrowth in castrated mice resulted in identification of the murine caltrin gene. Caltrin messenger RNA (mRNA) was highly expressed in the prostates of intact mice. Five weeks following castration of mice, steady state caltrin mRNA levels were reduced by 70%. Within 12 hours of administration of pharmacological doses of testosterone enanthate, steady state caltrin mRNA levels were elevated and increased to 90% of levels found in intact mice by 24 hours. Reverse transcriptase-polymerase chain reaction analysis of prostate tissue localized caltrin mRNA transcripts to the dorsal but not the ventral or lateral prostate. Within the dorsal prostate, in situ hybridization always localized caltrin mRNAs to the prostatic epithelial cells. Testosterone-induced increases in caltrin mRNA levels were detected prior to S-phase progression and initiation of proliferation in this cell population. Caltrin has been demonstrated previously to function as a calcium transport inhibitor at the plasma membrane. Findings of this study indicate that caltrin is highly expressed and androgen-regulated in the murine prostate, where it is associated with androgen-induced proliferation and differentiation of epithelial cells.

TRANSILLUMINATION TO EVALUATE SPERMATOGENESIS: EFFECT OF TESTOSTERONE ENANTHATE IN ADULT MALE RATS

The present study has been designed to determine which stages of seminiferous cycle were modified by in vivo intramuscular administration of one or two doses of 25 mg of testosterone enanthate. Testicular weight was significantly reduced after treatment with two doses of testosterone enanthate (p < .05). Assessment of total lengths of stages per 100 mm of seminiferous tubules scored by transillumination showed that testosterone enanthate increased significantly the length of stages VI-VII, but it reduced total lengths of stages I, XII, and XIII-XIV. A dose-dependent reduction in the absolute and relative frequency of stage I was observed with testosterone enanthate treatment, whereas stages VI-VII were significantly increased. Analysis of relative frequencies of stages showed that stages XIII-XIV and stages I-V were significantly below the control value (1), whereas stages VI-VIII were over 1. In summary, results of the present study showed that transillumination is an adequate technique to assess the effect of drugs on spermatogenesis, and that testosterone enanthate modifies the pattern of the stages of the seminiferous epithelium cycle, before testicular weight is affected.