Exogenous Testosterone Replacement Research Articles

Exogenous Testosterone Replacement Therapy Is Associated with Increased Risk for Vascular Graft Infections Among Hypogonadal Men

/Objective: Vascular graft infections (VGIs) are a major source of morbidity following vascular bypass surgery. Hypogonadal men may be at increased risk for impaired wound healing and infections, but it is unclear if testosterone replacement therapy (TRT) mitigates this risk. We designed this study to evaluate the relationship between hypogonadism and the use of testosterone replacement therapy (TRT) with subsequent risk for developing a VGI. We performed a retrospective analysis of claims in the MarketScan database identifying men greater than 18 years of age who underwent placement of a prosthetic graft in the peripheral arterial circulation from January 2009 to December 2020. Patients were stratified based on diagnosis of hypogonadism and use of TRT within 180-days prior to surgery. The primary outcome was VGI and the need for surgical excision. The association between hypogonadism and TRT use on risk of VGI was analyzed using Kaplan-Meier plots and multivariate Cox proportional hazards models. We identified 18,312 men who underwent a prosthetic bypass graft procedure in the upper and lower extremity during the study period, of which 802 (5%) had diagnosis of hypogonadism. Among men with hypogonadism, 251 (31%) were receiving TRT. Patients on TRT were younger, more likely to be diabetic, and more likely develop a VGI during follow-up (14% vs. 8%; P<.001) that was in the lower extremity. At 5-years, freedom from VGI was significantly lower for hypogonadal men on TRT than patients not on TRT or without hypogonadism (Log rank P<.001). In Cox regression models adjusted for age, diabetes, obesity, smoking, corticosteroid use, and procedure type, hypogonadal men on TRT were at a significantly increased risk of graft infection (HR:1.94, 95%CI:1.4-2.7; P<.001) compared to controls. This study demonstrates TRT among hypogonadal men is associated with an increased risk of prosthetic VGIs. Temporary cessation of TRT should be considered for men undergoing prosthetic graft implants, particularly those in the lower extremity.

MP27-05 ANDROGEN RECEPTOR SIGNALING IN THE HUMAN PENIS IS SIMILAR REGARDLESS OF SERUM TESTOSTERONE LEVEL

You have accessJournal of UrologyCME1 Apr 2023MP27-05 ANDROGEN RECEPTOR SIGNALING IN THE HUMAN PENIS IS SIMILAR REGARDLESS OF SERUM TESTOSTERONE LEVEL Katherine Campbell, Alexandra Dullea, Braian Ledesma, Kajal Khodamoradi, Himanshu Arora, and Ranjith Ramasamy Katherine CampbellKatherine Campbell More articles by this author , Alexandra DulleaAlexandra Dullea More articles by this author , Braian LedesmaBraian Ledesma More articles by this author , Kajal KhodamoradiKajal Khodamoradi More articles by this author , Himanshu AroraHimanshu Arora More articles by this author , and Ranjith RamasamyRanjith Ramasamy More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003255.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Testosterone (T) plays an important role in the proper development and maintenance of male reproductive tissues. The normal serum testosterone levels can vary between 300 to 1000 ng/dL. However, it is unclear whether androgen receptor (AR) signaling varies based on serum T levels. The aim of this study was to assess the impact of varied serum testosterone levels on AR signaling in Human Corpus Cavernosum tissue. Based on our previous work on the Androgen Saturation hypothesis, we hypothesized that above 200 ng/dL, AR signaling would not vary. METHODS: We obtained corpus spongiosum biopsies from men undergoing inflatable penile prosthesis placement for high grade erectile dysfunction. After mechanical dispersion of tissue with a homogenizer, the total protein was extracted using RIPA buffer. Quantitative detection of VEGF (Vascular endothelial growth factor), an androgen receptor marker, and AR (Androgen Receptor) expression was evaluated by western blot. The density of the bands in all the blots was quantified using densitometry analysis with ImageJ software. RESULTS: The median age of participants was 60.7 (57.6, 65.9) years. The median serum testosterone level was 378 (257, 419) ng/dl. The western blot results (Figure 1) showed no association in the expression level of VEGF or AR regardless of the serum testosterone level. CONCLUSIONS: Even with a wide range of serum testosterone levels (209-1478 ng/dl), androgen receptor signaling was similar in penile tissue. The results of this study support our previous work to demonstrate that AR signaling may be similar regardless of T level above 200 ng/dL. This suggests that serum testosterone levels might not reflect downstream androgen receptor signaling within the penile tissue. Understanding the AR saturation hypothesis provides important context necessary for appropriate prescribing of exogenous testosterone replacement therapy to optimize patient outcomes. Markers of androgen receptor signaling in tissue could be similar regardless of serum testosterone levels. Therefore, the utility of only serum testosterone levels in considering the effect of testosterone therapy needs to be re-evaluated. Source of Funding: This work was supported by: NIH Grant R01 DK130991 and Clinician Scientist Development Grant from the ACS to Ranjith Ramasamy, SMSNA Sexual Medicine Grant to Kajal Khodamoradi © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e363 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Katherine Campbell More articles by this author Alexandra Dullea More articles by this author Braian Ledesma More articles by this author Kajal Khodamoradi More articles by this author Himanshu Arora More articles by this author Ranjith Ramasamy More articles by this author Expand All Advertisement PDF downloadLoading ...

Exogenous Testosterone Replacement Therapy Is Associated With Increased Risk For Arterial Graft Infections

Prosthetic graft infections are a major source of morbidity following vascular bypass surgery. Recent urologic data suggests that hypogonadal men and low testosterone may infer an increased risk for infection of prosthetic implants. We designed this study to evaluate the relationship between hypogonadism, testosterone replacement therapy (TRT) and vascular graft infections.

PD47-03 LOW TESTOSTERONE LEVELS AND THE RISK OF ANEMIA IN MIDDLE-AGED MEN: A PROPENSITY SCORE–MATCHED ANALYSIS

You have accessJournal of UrologyCME1 May 2022PD47-03 LOW TESTOSTERONE LEVELS AND THE RISK OF ANEMIA IN MIDDLE-AGED MEN: A PROPENSITY SCORE–MATCHED ANALYSIS Jun Ho Lee, and Dong-Gi Lee Jun Ho LeeJun Ho Lee More articles by this author , and Dong-Gi LeeDong-Gi Lee More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002615.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Anemia is a common disease, as it affects 12.7% of men in an age-dependent manner. It has been reported that anemia is related to cardiovascular disease and increased mortality. In approximately one-third of anemia cases among older people, the cause of anemia is unexplained. Clinical data that reported that exogenous testosterone replacement in men with testosterone deficiency could induce polycythemia would be indirect evidence that shows low testosterone levels are a risk factor for anemia in men. However, there are few data concerning the endogenous testosterone effect on Hb or hematocrit (Hct) in men. Additionally, scant data are available concerning the relationship between anemia and low testosterone levels. Moreover, the aforementioned clinical data are limited by a cross-sectional study design, including a small number of men with low total testosterone levels, no adjustment for confounding factors, and an inappropriate sampling time of testosterone. Therefore, we conducted the present study to address the aforementioned limitations of previous studies using a large dataset and propensity score matched case-control study method. METHODS: Data from 8727 middle-aged men who had undergone health checkups were analyzed. Hb, Hct, testosterone, basic blood chemistry, blood pressure, and body mass index (BMI) were assessed. We estimated the glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease equation. Of the 8727 men considered, 8368 formed the cohort for propensity score matching, including 966 men with low testosterone (testosterone level <3.5 ng/mL, case) and 7402 men with normal testosterone levels (testosterone level ≥3.5 ng/mL, control); ultimately, however, members of the case and control groups were matched at a 1:2 ratio by propensity score. RESULTS: After matching, the groups were evenly distributed with respect to age, BMI, estimated GFR, hypertension, and diabetes. After matching, the mean Hb and Hct of the case group were significantly lower than those of the control group (15.0±1.1 g/dL vs. 15.3±1.0 g/dL, P <0.001; 43.5±2.9% vs. 44.4±2.8%, P<0.001, respectively). Additionally, the incidence of anemia (Hb <13 g/dL) was significantly greater in the case group (1.2% vs. 3.0%, P=0.001). Finally, the relative risk of anemia in the case was 2.4 compared to the control. CONCLUSIONS: Low testosterone is significantly and independently related to low Hb, low Hct, and anemia in middle-aged men. Our data suggest the need for screening for anemia in middle-aged patients with testosterone deficiency and vice versa. Source of Funding:- © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e794 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jun Ho Lee More articles by this author Dong-Gi Lee More articles by this author Expand All Advertisement PDF DownloadLoading ...

Safety of Human Chorionic Gonadotropin Monotherapy for Men with Previous Exogenous Testosterone Use or Replacement Therapy

ABSTRACT Introduction Human chorionic gonadotropin (hCG) is homologous to luteinizing hormone (LH) and stimulates endogenous testosterone (T) production and may be an option for testosterone replacement therapy (TRT). Currently, hCG is recommended for hypogonadal men with fertility concern as it prevents azoospermia seen with exogenous testosterone use. It is unknown if hCG is as efficacious as T in improving symptoms. We hypothesized that hCG is an effective and safe treatment in males with a history of exogenous T use or TRT. Objective Our objective was to evaluate for changes in symptoms and side effects to assess hCG monotherapy as a possible method of TRT in adult males with a history of previous exogenous T use or TRT. Methods We retrospectively reviewed 50 charts using exogenous T (including testosterone cypionate, clomid, anastrozole, methandienone, and testosterone gel) and were switched to hCG monotherapy for at least 1 month with follow-up labs. We evaluated changes in hormones [T, LH, follicle stimulating hormone (FSH), and estradiol], hematocrit (HCT), glycated hemoglobin (A1c), and prostate specific antigen (PSA). Results presented as means standard deviation. Student t-test was used to compare pre- and post-treatment values, significance was set at p=0.05. We also evaluated for incidence of thromboembolic events, including stroke, deep vein thrombosis, and myocardial infarction. Results The average age was 43.3±10.2 years with a BMI of 29.4±3.9 kg/m2. Of the patient's reviewed, 46% had used clomid, 18% T cypionate, 15% anabolic steroids, 13% T gel, 4% T pellets, and 4% methandienone. Average follow-up after starting hCG therapy was 163 days, range 28 to 583 days. Average weekly hCG dosage was 2435 IU. Serum T experienced no significant change, from 402.54±281.34 ng/dL to 404.29 ±259.64 ng/dL (p=0.58, n=50). No change was seen in FSH (4.82±6.21 to 3.71±3.24 mIU/mL, n=25), LH (3.12±4.18 to 1.98±1.86 mIU/mL, n=25), PSA (0.79±0.39 to 0.64±0.25 ng/mL, n=6), estradiol (27.84±14.82 to 27.96±13.18 pg/mL, n=31), or A1c (5.51±0.41 to 5.41±0.0.43 %, n=8). There was a statistically significant decrease of HCT (45.05±4.87 to 43.91±4.48 %, n=15). When evaluated for improvement of erectile dysfunction (ED, n=30), low libido (n=30), and low energy (n=32), 57%, 63%, and 66% of patients reported improvement of each symptom, respectively. Only 41% of patients with ED were noted to be on another medication or therapy specifically for ED. No thromboembolic events were observed. Conclusions Weekly hCG dosing appears to have no significant effect on T levels in men with a history of exogenous T use or TRT. The majority of patients reported an improvement in their hypogonadal symptoms. No changes were noted in PSA and A1c. HCT was noted to have a small, but statistically significant decrease and no thromboembolic events were recorded. Disclosure No

Testosterone and cardiovascular disease - a literature review

The effects of testosterone on the cardiovascular (CV) system make it a matter of scientific interest. Disturbances in endogenous steroid concentrations are some of the factors involved in the pathogenesis of atherosclerosis and ischemic heart disease. The aim of this article is to summarize the role of hypogonadism in the context of ischemic heart disease development and to review the current evidence on the CV benefits of testosterone replacement. Its low endogenous level is associated with worsened lipid profile, accelerated development of atherosclerotic plaques, high body mass index, metabolic syndrome and, type 2 diabetes mellitus. In light of these facts, some studies look into the benefits of exogenous testosterone replacement in patients with coronary heart disease and heart failure. The results are divergent and a large randomized trial is required to define the link between testosterone replacement therapy and CV risk. New clues present the recent data on the possible adaptive role of hypogonadism in acute coronary syndrome. This has the potential to expand the knowledge on the link between the CV system and gonadal function in men. The role of sex steroids in the pathogenesis of atherosclerotic heart disease and adaptation to acute coronary syndrome is a subject of increasing scientific interest as a result of accumulating evidence in this field.

Are SERMs safe and effective for the treatment of hypogonadism in men?

YES. For both normal-weight and obese men with low testosterone levels and hypogonadal symptoms, selective estrogen receptor modulators (SERMs), such as clomiphene citrate (CC) and enclomiphene citrate (EC), appear to be effective and safe for improving serum testosterone levels (strength of recommendation [SOR]: C, disease-oriented outcomes from randomized controlled trials [RCTs] and cohort studies). Studies also show that symptom improvement is comparable to that with exogenous testosterone replacement and similar to eugonadal men (SOR: B, patient-oriented outcomes from retrospective cohort studies).

Impact of Short-Acting vs Long-Acting Testosterone Therapy on Intratesticular Testosterone Using Data From Two Open-Label Randomized Clinical Trials of Testosterone Pellets, Injections, and Intranasal Gel in Hypogonadal Men

Introduction & Objective: Exogenous testosterone (T) replacement therapy (TRT) is typically long-acting and can potentially cause infertility in a majority of men due to suppression of HPG axis. Intratesticular testosterone is vital for spermatogenesis and can be reliably evaluated with serum 17-hydroxyprogesterone (17-OHP). Based on this observation, we hypothesized that we used serum 17-OHP as a serum biomarker for evaluating intratesticular T in men receiving TRT. We hypothesized that long-acting TRT will have a significant impact on suppressing HPG axis as compared to short-acting preparations. We evaluated data from two simultaneous open-label, randomized, two-arm clinical trials amongst different treatment preparations (Trial I) subcutaneous T pellets and (Trial II) Intranasal Testosterone (Natesto) or Intramuscular Testosterone cypionate (TC).Subject & Methods: Hypogonadal men (2 AM serum T < 300 ng/dL assayed by LC-MS/MS) aged 18-65 years were randomized into open-label randomized clinical trials. Eligible subjects received: 800mg subcutaneous Testopel T pellets (n=47); or 11mg TID Intranasal testosterone (Natesto) (n=10) or 200mg x 2 weeks TC (n=10) for 2 months. Serum T and 17-OHP were collected at baseline and after 2 months of therapy. Data are presented as a post-hoc analysis of the two randomized clinical trials and reported as the median and interquartile range [25th-75th], paired sample analysis (baseline versus follow-up) was performed with the Wilcoxon test to determine change during time within the different TRT modalities, with p<0.05 considered significant. Results: Median change for serum T between baseline and 2mo follow-up to subcutaneous T pellets was 542 [454-757] ng/dL, Intranasal Testosterone 706 [517-1010] ng/dL, and TC 525 [280-712]ng/dL.; 96% of subjects in each trial achieved mean T concentrations in the eugonadal range. We demonstrated that serum T levels were within normal range among men receiving the various therapies. As expected, we found a statistically significant decrease amongst the different T preparations in serum 17-OHP. Longer acting T preparations such as T pellets and TC demonstrated the greatest decrease in 17-OHP, from 41 [20.3-65.6] to 14 [10.3-20.8] ng/dL and 80 [48-121] ng/dL to 20 [17-36] ng/dL (p<0.001), respectively. Shorter acting T preparations such as Natesto demonstrated a statistically significant decrease in 17-OHP, from 52.5 [26-67] ng/dL to 26.5 [18-39.8]ng/dL (p=0.007), but to a lesser extent as compared to the longer-acting preparations.Conclusions: Natesto, and other short acting forms of TRT may help hyogonadal men maintain Intratesticular T that is critical for maintaining spermatogenesis. The differential effects of TRT on intratesticular T based on their half-lives is novel and should be considered during the decision making for hypogondal men who wish to preserve fertility and / or testis size.

Hypogonadal hypertension in male Sprague-Dawley rats is renin-angiotensin system-dependent: role of endogenous androgens

BackgroundAcutely, testosterone (TES) and other androgens are efficacious vasodilators, both in vitro and in vivo; however, their long-term effects on arterial blood pressure (BP) remain unclear. It was hypothesized that endogenous androgens exert long-term anti-hypertensive effects on systemic BP through a combination of genomic and nongenomic effects to enhance vasodilation of the systemic vasculature.MethodsThe long-term effects of endogenous TES and exogenous TES replacement therapy (TRT) on BP were studied in intact (InT) and castrated (CsX) male Sprague-Dawley (SD) and testicular-feminized male (Tfm, androgen receptor defective) rats (12 weeks old). Systolic BP (tail-cuff plethysmography) was determined weekly for 15 weeks in InT-control and CsX rats. Some CsX-SD rats received androgen replacement therapy at 10-15 weeks with TES-enanthate (TRT; 1.75 mg/kg, 2x/week) or DHT-enanthate (DRT; 1.00 mg/kg. 2x/week) and a separate group of CsX-SD rats received losartan-potassium in drinking water (LST, 250 mg/L) for the entire 15 week period. Expression of renin, angiotensinogen (Agt), angiotensin converting enzyme (ACE), and angiotensin II type I receptor (AT1R) mRNA in kidney and aorta were determined by real-time PCR (rt-PCR) and plasma renin levels were determined by radioimmunoassay.ResultsThere was a progressive rise in BP over 10 weeks in CsX (109 ± 3.3 vs. 143 ± 3.5 mmHg), while BP remained stable in InT-control (109 ± 3.0 vs. 113 ± 0.3). BP gradually declined to normal in CsX-TRT rats (113 ± 1.3), while BP remained elevated in CsX (140 ± 1.2) and normal in InT-control (113 ± 0.3). LST prevented the development of hypertension in CsX at 10 weeks (100 ± 1.5 in CsX + LST vs. 143 ± 3.5 in CsX). During the next 5 weeks with TES-RT, BP declined in CsX-TRT (113 ± 1.3) and remained lower in CsX + LST (99 ± 0.4). DHT-RT reduced BP in CxS to a similar extent. In Tfm, CsX resulted in a similar rise in BP (109 ± 0.7 vs. 139 ± 0.4 mmHg), but TRT reduced BP more rapidly and to a greater extent (106 ± 2.8). rt-PCR of the kidney revealed that CsX increased expression of mRNA for renin (92%), ACE (58%), and AT1R (80%) compared to InT, while TES RT normalized expression of renin, AT1R, and ACE mRNA to levels of InT rats. Plasma renin levels exhibited changes similar to those observed for renin mRNA expression.ConclusionsThis is the first study to examine the long-term effects of endogenous and exogenous androgens on BP in male SD and Tfm rats. These data reveal that endogenous androgens (TES) exert anti-hypertensive effects that appear to involve non-genomic and possibly genomic mechanism(s), resulting in reductions in RAS expression in the kidney and enhanced systemic vasodilation.

SAT-LB94 An Unusual Case of Acute Myocardial Infarction Revealing Underlying Polycythemia Secondary to Exogenous Bioidentical Testosterone Therapy

BACKGROUND: Many patients seeking testosterone therapy are turning to compound pharmacies for customized bioidentical testosterone replacement. These pharmacies market “bioidentical” hormone therapies as more effective and superior to traditional FDA-approved synthetic therapies. Bioidentical formulations are available as injections, creams, and subcutaneous pellet implants. Exogenous testosterone replacement is associated with polycythemia complicated by increased blood pressure, blood viscosity, and platelet aggregation (1). The ensuing hypercoagulable and prothrombotic changes predispose individuals to adverse cardiac events, including myocardial infarction.CLINICAL CASE: A 66-year-old male with hypertension, type 2 diabetes, and hyperlipidemia presented with chest pain and dizziness. Initial EKG was unremarkable but troponin levels were elevated and the patient was admitted to telemetry. Lexiscan indicated anterior territory ischemia and coronary angiography revealed 95% stenosis of the left anterior descending artery (LAD). He underwent percutaneous coronary intervention (PCI) with stenting of the LAD. During the patient’s workup, he was noted to have elevated hemoglobin (20) and hematocrit (60) levels and was treated with 1g hydroxyurea as phlebotomy was unavailable. JAK2 mutation and EPO level screenings were ordered and unremarkable. The patient was noted to have multiple subcutaneous testosterone pellets in his buttocks which he stated were implanted three weeks prior. Serum total testosterone was elevated at 1226 ng/dL. Hematology was consulted and the patient continued daily 1g hydroxyurea. After discharge, the patient continued outpatient follow up with hematology and received plasmapheresis for management of polycythemia.CONCLUSION: Considering polycythemia can arise secondary to exogenous testosterone use and is a known risk factor for cardiovascular events, it is likely this patient’s myocardial infarction was complicated by his use of exogenous bioidentical testosterone. Compound pharmacies providing bioidentical testosterone are not required to report adverse events, provide black box warnings, or show evidence-based safety and efficacy profiles for their products. The increasing availability and use of non-FDA-approved testosterone therapies warrants increased physician vigilance, particularly for patients with existing cardiac conditions or predisposition to hypercoagulable and prothrombotic states. The lack of regulation and research in the realm of compound pharmacy hormone products calls for further studies and reforms to protect patients from the risk of developing detrimental complications.REFERENCE: (1) Xu, L., Freeman, G., Cowling, B. et al. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med11, 108 (2013).

Serum 17-Hydroxyprogesterone is a Potential Biomarker for Evaluating Intratesticular Testosterone.

Intratesticular testosterone is essential for spermatogenesis and can only be reliably measured with invasive testicular sampling. Previous studies have demonstrated good correlation between intratesticular testosterone and serum 17-hydroxyprogesterone (17-OHP) in men treated with human chorionic gonadotropin. Based on this observation we hypothesized that we can use serum 17-OHP as a serum biomarker for evaluating intratesticular testosterone in men receiving medications that alter serum testosterone. Initially, we conducted a cross-sectional analysis of men with a single serum 17-OHP evaluation from July 2018 to March 2019. We followed this with a prospective analysis from July 2018 to October 2019 with evaluation of 140 men including fertile controls, and those receiving treatments that alter serum testosterone at baseline and after 3 months of therapy. According to the data distribution, we reported the median and interquartile ranges, and used the Mann Whitney U or Wilcoxon tests. In the initial cross-sectional analysis of 93 men, a total of 30 men received treatments that increase or maintain intratesticular testosterone concentrations, such as clomiphene citrate and/or human chorionic gonadotropin; 21 men received treatments that suppress intratesticular testosterone concentrations (various exogenous testosterone replacement therapy formulations) and 42 fertile men with normal serum testosterone (greater than 300 ng/dl) were used as control. We demonstrated that serum testosterone levels were within normal range among men receiving the various therapies. In contrast, we found that serum 17-OHP was undetectable in men who received exogenous testosterone replacement therapy, as opposed to men receiving human chorionic gonadotropin and/or clomiphene citrate or fertile controls (p <0.05). In the prospective evaluation that ensued, 17-OHP values decreased in the 21 men who received testosterone replacement therapy (47.5 [21-70] to 13.5 [10-23] ng/dl, p <0.05). Conversely, 17-OHP increased in the 55 men who received human chorionic gonadotropin and/or clomiphene citrate when compared to their baseline levels (42 [24-72] to 88 [61-135] ng/dl, p <0.05). Serum 17-OHP appears to be a reliable serum marker for intratesticular testosterone levels and could potentially be used to titrate or change medications that alter intratesticular testosterone.

The Possible Effect of DHEA on Hepatic and Metabolic Dysfunction in a Rat Model of Male Hypogonadism

Abstract Background: Male hypogonadism is characterized by androgen deficiency in the body. Several studies have shown that testosterone deficiency is inducing a metabolic syndrome and insulin resistance. Although of the unwanted effects of exogenous testosterone replacement therapy, it is the main treatment of male hypogonadism. One of the safe treatment options is Dehydroepiandrosterone (DHEA) replacement therapy which is the precursor of testosterone. Up to date and to the best of our knowledge, no one investigates the effect of DHEA on glucose-6-phosphatase enzyme in a rat model of male hypogonadism and its impact on the metabolic dys-function. Aim of Study: The aim of the research is to investigate the possible protective effect of DHEA on hepatic and meta-bolic dysfunction in a rate model of male hypogonadism through examining its effect on glucose-6-phosphatase enzyme. Moreover, it studies the possible therapeutic effects of the male androgen (DHEA) on the hepatic steatosis and insulin resistance triggered by testosterone deficiency. Material and Methods: Thirty-two Wistar Kyoto rats were divided into 4 groups as follows (I) Untreated controls, (II) Untreated orchidectomized, (III) Control, treated with DHEA and (IV) Orchidectomized, treated with DHEA. Treatment was carried three times per week for 12 weeks. Cobas c111, Roche diagnostic, USA machine was used to measure the level of the glucose, liver enzymes and lipid profile. Enzyme-Linked Immunosorbent Assay (ELISA) was used to measure the plasma level of testosterone hormone, insulin and glucose-6-phosphatase enzyme. Results: As expected, the plasma testosterone decreased significantly in ORCH rats, with significant increase in glucose, lipid profile as well as significant decrease in insulin as compared to control rats. Moreover, our data revealed insig-nificant increases in plasma testosterone in ORCH + DHEA with significant increase in ORCH + DHEA compared to control + DHEA. DHEA did not significantly affect G-6-Pase enzyme. Also, ORCH shows significant increase in triglyceride and cholesterol as well as the ORCH + DHEA.Conclusion: Testosterone deficiency and DHEA replace-ment therapy have no effects on glucose 6-phosphatase enzyme. Male hypogonadism is a risk factor for metabolic syndrome and NAFLD that could not be treated effectively with DHEA.

37-Year-Old Man With Fatigue and Erectile Dysfunction

37-Year-Old Man With Fatigue and Erectile Dysfunction

MP59-17 COMPARISON OF SHORT-ACTING VS. LONG-ACTING TESTOSTERONE GELS ON FSH

INTRODUCTION AND OBJECTIVES:Low testosterone (low T) affects around 38.7% of men over the age of 45 and prescriptions to younger men is on the rise. Exogenous long-acting testosterone replacement t...

Reintroducing testosterone in the db/db mouse partially restores normal glucose metabolism and insulin resistance in a leptin-independent manner

BackgroundTestosterone signals through the androgen receptor (AR) and AR knockout mice develop obesity, suggesting a functional association between AR and leptin signaling. Furthermore, physiological blood concentrations of testosterone have been found to inhibit the development of arteriosclerosis, obesity and diabetes. However, these findings have not been verified by testosterone replacement in animal models and whether or not testosterone acts directly by activating AR to enhance leptin signaling, or indirectly by its conversion into estrogen remains unclear. Therefore, we investigated the effect of exogenously supplemented testosterone on glucose and lipid metabolism.MethodsFour-week-old male leptin receptor-knockout db/db mice were used as controls for a model of obesity retaining low testosterone. Mice were divided into sham-operated, castrated, or castrated and testosterone-supplemented groups and fed a high-fat diet (HFD) for 2 weeks from 5 weeks of age. Testosterone concentrations, blood glucose, plasma insulin levels, and intraperitoneal glucose tolerance and insulin tolerance were measured. At 7 weeks, triglyceride and glycogen content were measured in the liver and muscle. Lipid accumulation in the liver and soleus muscle was determined by immunohistochemistry with Oil Red O. Statistical analyses were performed using the Student’s t-test or ANOVA where applicable.ResultsLower testosterone levels in db/db mice compared with wild type (WT) db/+ mice were associated with glucose intolerance and fatty liver. Furthermore, castrated male db/db mice at 4 weeks of age progressively developed glucose intolerance accompanying a 15% increase in liver fat. Male mice fed a HFD had lower levels of testosterone compared with those fed a normal diet. We found that exogenous testosterone replacement injected subcutaneously into castrated male db/db mice alleviated the exacerbation of fatty liver and glucose intolerance, suggesting a leptin-independent mechanism. This mechanism is most likely mediated through gonadal axis suppression in this mouse model.ConclusionsIn summary, testosterone may use a novel pathway to complement leptin signaling to regulate glucose and lipid metabolism, and thus offers a new therapeutic target to treat metabolic disorders.

"Cherchez La Femme": Modulation of Estrogen Receptor Function With Selective Modulators: Clinical Implications in the Field of Urology.

Selective estrogen receptor modulators (SERMs) have been used off-label in men for more than 50 years. SERMs exert their action on the estrogen receptor agonistically or antagonistically. A fundamental knowledge of the complex molecular action and physiology of SERMs is important in understanding their use and future directions of study in men. To review the basic science and mechanism of the action of estrogens, the estrogen receptor, and SERMs, and the existing clinical publications on the use of SERMs in men for infertility and hypogonadism with their strengths and weaknesses and to identify the need for future studies. After a review of publications on the basic science of estrogen receptors, a chronologic review of published evidence-based studies on the use of SERMs in men for infertility and hypogonadism was undertaken. Clinical publications were assessed for type of study, inclusion criteria, outcome measurements, and results. Strengths and weaknesses of the publications were assessed and discussed. Few prospective rigorously controlled trials have been undertaken on the use of SERMs in men. Most existing trials are largely retrospective anecdotal studies with inconsistent inclusion and end-point measurements. The SERMs are complex and at times can produce paradoxical results. Their action likely depends on the genetics of the individual, his tissue-specific composition of estrogen receptors, the molecular structure and pharmacodynamics of the SERMs, and their metabolism. Rigorously controlled trials of the use of SERMs in men are needed to better identify their clinical benefit and long-term safety in infertile and hypogonadal men. Recent placebo-controlled pharmaceutical industry SERM trials have demonstrated short-term safety and efficacy in men with secondary hypogonadism and eventually might provide an alternative to exogenous testosterone replacement therapy in men with secondary hypogonadism. Helo S, Wynia B, McCullough A. "Cherchez La Femme": Modulation of Estrogen Receptor Function With Selective Modulators: Clinical Implications in the Field of Urology. Sex Med Rev 2017;5:365-386.

The Effects of Testosterone Deficiency and Its Replacement on Inflammatory Markers in Rats: A Pilot Study.

BackgroundTestosterone deficiency is linked to low-grade inflammation in humans, but this condition is not replicated in an animal study. The current study aims at determining the effects of testosterone deficiency and its replacement on the circulating inflammatory cytokine level in orchidectomized male rats.MethodsThree-month-old Sprague-Dawley male rats (n = 18) were randomized equally into 3 groups. Bilateral orchidectomy was performed on 2 groups. The sham group was subjected to similar surgical stress, but their testes were retained. One of the orchidectomized groups received intramuscular injection of 7 mg/kg testosterone enanthate suspended in peanut oil weekly and the other 2 groups received equivolume of peanut oil injection. After 8 weeks, the rats were sacrificed and their blood was collected for the analysis of the levels of inflammatory cytokines and testosterone.ResultsTestosterone level was significantly lower in the untreated orchidectomized group compared to the sham group. Testosterone replacement significantly increased the level of testosterone in the orchidectomized rats compared to the sham and untreated orchidectomized rats. Interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β), and tumor necrosis factor alpha (TNFα) showed an increasing trend in orchidectomized rats, albeit not statistically significant. Interleukin-6 (IL-6) level increased significantly in the orchidectomized group compared to the sham group. Testosterone replacement at the supraphysiological dose did not alter the level of inflammatory cytokines significantly in orchidectomized rats.ConclusionsTestosterone deficiency can elicit a state of low-grade inflammation, shown by an increase in interleukin-6 level, but exogenous supraphysiological testosterone replacement does not suppress the inflammation.

MP76-01 CLOMIPHENE CITRATE RESULTS IN A SIGNIFICANTLY LOWER INCIDENCE OF POLYCYTHEMIA COMPARED TO EXOGENOUS TESTOSTERONE REPLACEMENT IN HYPOGONADAL MEN.

You have accessJournal of UrologySexual Function/Dysfunction: Medical, Hormonal & Non-surgical Therapy I1 Apr 2016MP76-01 CLOMIPHENE CITRATE RESULTS IN A SIGNIFICANTLY LOWER INCIDENCE OF POLYCYTHEMIA COMPARED TO EXOGENOUS TESTOSTERONE REPLACEMENT IN HYPOGONADAL MEN. Karen Wheeler, Raj Kumar, Shaan Setia, Raymond Costabile, Parviz Kavoussi, and Ryan Smith Karen WheelerKaren Wheeler More articles by this author , Raj KumarRaj Kumar More articles by this author , Shaan SetiaShaan Setia More articles by this author , Raymond CostabileRaymond Costabile More articles by this author , Parviz KavoussiParviz Kavoussi More articles by this author , and Ryan SmithRyan Smith More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1852AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES It is established that exogenous testosterone replacement therapy (TRT) may be detrimental to a man's fertility. Clomiphene citrate (CC) is commonly used, off-label, to treat hypogonadal men in a fertility preserving manner. Polycythemia is a concerning side effect of direct TRT, however, there is no data regarding CC and polycythemia risk. METHODS The incidence of polycythemia was retrospectively assessed in men diagnosed with hypogonadism and treated with CC versus TRT at different institutions between 3/2011 - 4/2015. Polycythemia was defined as a hematocrit > 52%. RESULTS A total of 188 CC- and 175 TRT-treated men were included. CC treated men were younger (38 vs 51.5 years of age). TRT treated men had longer treatment durations than CC treated men, 19.6 months vs 9.2 months respectively. The incidence of polycythemia in men receiving CC was 1.7% versus 11.2% in men on TRT (p=0.0003). This significance remained after correction for age, site, smoking history, and pre-treatment hematocrit via logarithmic regression. The mean changes in Hct were 3.0% and 0.6%, and the mean changes in serum testosterone (T) were 333.1 ng/dL and 367.6 ng/dL in TRT-treated and CC-treated men, respectively. CONCLUSIONS The incidence of polycythemia in men treated with CC is markedly lower than that of TRT treated men. The improvement in absolute serum T levels was similar to TRT treated men. There is not a significant risk of polycythemia in men treated with CC for hypogonadism. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1007 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Karen Wheeler More articles by this author Raj Kumar More articles by this author Shaan Setia More articles by this author Raymond Costabile More articles by this author Parviz Kavoussi More articles by this author Ryan Smith More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

On the mark? Is alkaline phosphatase a surrogate for bone density in men with hypogonadism?

The current issue of the BJUI contains a paper by Dubaja et al. 1 that may be of interest to physicians who have patients with hypogonadism. The authors speak to an unappreciated aspect of low testosterone; namely, the loss of bone in men and the possible recovery with treatment. Their retrospective study looked at 140 men with hypogonadism treated with exogenous testosterone replacement or clomiphene citrate testosterone enhancement. These men were also assessed for bone mineral density (BMD) markers at 6, 12 and 24 months after initial treatment. Importantly, dual-energy X-ray absorptiometry (DEXA) was performed a second time after 2 treatment years for a subset of these men. DEXA showed that there was a gain in BMD and a loss of serum alkaline phosphatase (AP) for all the men over time. The loss of AP was rapid but stabilized at 6 months. Testosterone and free testosterone increased as expected but there were no changes in vitamin D, calcium, parathyroid hormone or sex hormone-binding globulin. There was a correlation between AP and testosterone. The authors recognized poor bone density at baseline in those men with testosterone levels <250 ng/dl. Bone mineral density is the best way to predict osteoporosis and fragility fractures 2. Women loose BMD after menopause and that is accompanied by many changes, including gains in AP 3. The decline in serum oestrogens is a factor for women, and oestrogen replacement therapy historically has been used to prevent that loss. Not all men undergo a similar loss, i.e. andropause is not recognized in the same way as menopause. Even though osteoporosis is less common in men, the associated comorbidity may be more significant. There is an age-related decline in testosterone and an acute loss for some men such that they approach their physicians with symptoms. The underlying cause of bone loss in men and women may be the same: serum oestrogen loss. Men who lose testosterone are also losing oestrogen because testosterone is the precursor via aromatase. Repros Therapeutics is developing a way to treat men with secondary hypogonadism. An ongoing 1-year DEXA study recruited eligible men. Key inclusion factors were age < 60 years and body mass index > 25 kg/m2. Remarkably 24% of men failed the screening test because of osteopenia, despite the fact that few of them were old or underweight. The present paper by Dubaja et al. suggests that a readily available serum test may be able to monitor men on testosterone therapies for gain in BMD. Given the relatively low incidence of osteoporosis, screening every man by DEXA is not cost-efficient. The 1 year or more needed to find BMD loss by DEXA also wastes time and resources. Quantitative CT is more costly and is accompanied by high radiation exposure. The use of AP, as suggested in the present study, may represent a reasonable alternative. The paper is not without its weaknesses. There was no indication of whether these men had primary or secondary hypogonadism. Transdermal testosterone should raise testosterone and oestrogen in both groups of men whereas clomiphene citrate works through changes in LH and FSH and requires an intact hypothalamic-pituitary-gonadal axis (useful in men with secondary hypogonadism only). Indeed, the two kinds of treatment will have the opposite effect on LH and FSH 4. The authors recognized the importance of Leydig cells in producing testosterone, yet the effects of a transdermal testosterone would be to shut down testosterone production. We commend their suggestion that other factors that contribute to both bone and Leydig cell function, insulin-like 3 5 and osteocalcin 6 should be studied in relation to AP. The loss of subjects throughout the 2 years was troubling, but it is known that men on transdermal treatments discontinue with disturbing frequency despite satisfaction 7. If those who stayed in the present study were those with the best outcomes in terms of testosterone and BMD, potential bias may exist. If men can be encouraged to continue therapy through positive effects on BMD being detected as early as 6 months, AP monitoring may improve patient compliance. Only DEXA can give that assurance now. The authors noted the need for a larger prospective trial. Nevertheless, their paper provides a rationale for monitoring men on testosterone therapies that can be implemented with minimal cost or the need for new diagnostics. Authors are employees and/or stockholders in Repros Therapeutics.

AB03. Intermittent androgen suppression: current status

Hormone therapy has been a major treatment for advanced prostate cancer. This therapy aims at inhibiting growth of prostate tumor cells by deprivation of male hormones which stimulate prostate cells to grow. However, in spite of its temporally high effectiveness for tumor regression, most patients suffer from a relapse within a few years after initiation of treatment. The main cause of relapse is that cancer cells become resistant to hormone suppression. The toxicities of androgen deprivation have been well described, with a number of potential adverse effects on quality of life, including sexual dysfunction, hot flashes, fatigue, anemia, decreased bone density and muscle mass, altered blood lipid profile, depression, cognitive dysfunction, and worsening of the metabolic syndrome with effects on glucose metabolism and cardiovascular morbidity. The introduction of PSA testing into clinical practice in the early 1990’s provided an objective evaluation of the efficacy of definitive treatment and biochemical failure became an accepted end point. This ability to determine early treatment failure created a clinical dilemma for the practitioner. The justification for lifelong androgen deprivation is more apparent in the face of obvious clinical disease than in an asymptomatic individual with a slowly rising PSA, either with or without primary therapy aimed at the prostate.A possible clinical strategy to prevent or delay hormone-refractoriness of prostate tumor is intermittent hormone therapy. This treatment is also effective in reduction of side effects during off-treatment periods and thereby quality of life of patients can be improved. Bruchovsky and Goldenberg used the androgen-dependent Shionogi carcinoma to demonstrate that castration followed by re-exposure to androgens prior to tumor progression caused surviving stem cells to remain androgen-dependent, and thus amenable to further treatment by repeated androgen withdrawal. Successive castration and re-exposure to androgens in the mouse model produced multiple apoptotic regressions, resulting in a 3-fold delay in development of androgen independence. Cycles of androgen deprivation followed by re-exposure to testosterone form the basis of intermittent androgen deprivation (IAD).Multiple phase 2 clinical studies and 3 definitive phase-III trials of IAS have been published and will be reviewed. All phase 2 studies, including a meta-analysis strongly suggested that IAS is not inferior to continuous therapy and offers the potentials of QOL improvement and financial savings. The optimal protocol of IAS therapy, that is, how to determine the appropriate lower and upper thresholds of the serum PSA level for switching on- and off-treatment periods is quite varied but the most common approach is to treat for 6 to 8 months and resume at a predetermined PSA level. In clinical practice, a tailor-made patient-specific regimen is usually adopted because the best protocol of hormone therapy must depend upon individual patients.The multicentre randomized, prospective studies (NCIC PR8, SWOG 9346 and SEUG 9901) have been somewhat controversial. The large PR7 trial of IAS for men suffering PSA relapse after radiation strongly suggests non-inferiority. However, the PR8 study of men with metastatic cancer was not definitive in its conclusions and actually reported as “not non-inferior”. Many, but not all intermittent patients showed significant improvements in global QOL.A recently published metaanalysis of 5,508 patients in 9 RCT’s confirmed a cost savings of 48% with a pooled hazard ration for overall survival of 1.02 in favour of IAS (95% CI, 0.94 to 1.11). The HR for cancer specific survival was 1.08 for IAS vs. CAS (95% CI, 0.85 to 1.38). The authors pointed out some limitations of their metaanalysis but concluded that there was no notable compromise in health outcomes in eligible men treated with IAS as all showed either superiority or equivalence. They do caution the use of IAS in men with asymptomatic non-metastatic disease which reflects the question of appropriate timing of therapy along this disease’s continuum. Future work in this field includes the question of exogenous testosterone replacement for men in whom endogenous levels do not recover, the role of mathematical modeling in predicting an individual’s likely response to cycled therapy, choline PET scanning and the layering on of novel agents with low toxicity during the off-treatment interval.