ResearchPad - male-reproductive-health---from-hormones-to-gametes Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SAT-045 Free Testosterone and Cardiometabolic Parameters in Adult Men - Comparison of Algorithms for Calculation of Serum Free Testosterone]]> Context. Determining the free or bioavailable testosterone level has gained increasing interest over the years and different indirect algorithms have been suggested.

Objective. To compare commonly used algorithms of calculation of serum free testosterone, specifically free androgen index (FAI), free testosterone estimated using the Vermeulen algorithm (cFTV) and the Zakharov algorithm (cFTZ) as well as total testosterone in relation to baseline and long-term cardiometabolic conditions.

Design. A prospective cohort study of men participating in four independent population-based surveys (MONICA I-III and Inter99) from 1982 to 2001 and followed until December 2012 with baseline and follow-up information on cardiometabolic parameters.

Setting and Participants. 5350 randomly selected men from the general population aged 30, 40, 50, 60, or 70 years at baseline participated.

Main Outcome Measures. Baseline cardiometabolic parameters and follow-up information on type 2 diabetes, ischemic heart disease, cardiovascular disease mortality, and all-cause mortality.

Results. Free testosterone levels calculated according to the two algorithms differed systematically but however correlated well (cFTV vs. cFTZ: r=0.9, p<0.01) and the relative standard deviations ranged from 37% to 41%. In general, men having cardiometabolic conditions at baseline had lower absolute levels of FAI, cFTV and cFTZ. However, when age-standardizing the hormone levels, FAI levels were higher in this group of men whereas cFTV and cFTZ remained lower compared to men without these conditions. The associations seen for cFTV and cFTZ were in line with the association seen for total testosterone. Cox proportional hazard models revealed that men in the highest quartiles of cFTV or cFTZ had lower risk of developing type 2 diabetes (cFTV: HR=0.74 (0.49-1.10), cFTZ: HR=0.59 (0.39-0.91)) than men in the lowest quartile. In contrast, men with highest levels of FAI had a 74% increased risk of developing type 2 diabetes compared to men in the lowest quartile (HR=1.74, 95% CI:1.17-2.59). In relation to all-cause mortality, FAI showed the strongest inverse association followed by cFTV, whereas cFTZ and total testosterone did not show any association.

Conclusion. Free testosterone estimated by the Vermeulen and Zakharov algorithms differed systematically. However, the computed values correlated well and showed similar associations to baseline and long-term cardiometabolic parameters; albeit with subtle differences. In contrast, an empiric ratio, FAI showed opposite associations to several of the examined parameters and may reflect limited clinical utility.

<![CDATA[SAT-040 Changes in Metabolic Parameters After Administration of Novel Oral Androgens with Progestational Activity for 28 Days]]> Background: While the metabolic effects of testosterone have been well studied, the effects of co-administration of an androgen and progestin are less established. Two novel compounds being investigated for male hormonal contraception, dimethandrolone undecanoate (DMAU) and 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC), have both androgenic and progestational activity.

Aim: Characterize the effects of DMAU and 11β-MNTDC on metabolic parameters including weight, lipid parameters, insulin resistance, and adiponectin.

Methods: Two randomized, double-blind, placebo-controlled studies in healthy men were previously performed to assess the safety and tolerability of DMAU and 11β-MNTDC taken orally for 28 days. Insulin and adiponectin assays were performed on a subset of banked samples. Changes in weight, LDL-C, HDL-C, fasting glucose, HOMA-IR, and adiponectin were assessed. Two way ANOVA with post hoc Tukey HSD was performed to assess for dosage (0, 200, or 400mg) and drug (DMAU or 11β-MNTDC) effects.

Results: A total of 85 subjects were included in this secondary analysis. There was a statistically significant decrease in HDL-C (mean change -11 and -15 mg/dL) and increase in weight (3 and 2 kg) and LDL-C (18 and 23 mg/dL) in the DMAU and 11β-MNTDC 400mg groups respectively. There was no significant difference between the 200 and 400 mg groups nor differences between the two androgens. There were no statistically significant changes in fasting glucose, adiponectin or HOMA-IR.

Conclusion: There were mild changes in weight, HDL-C, and LDL-C after 28 days of DMAU and 11β-MNTDC without significant changes in markers of insulin resistance or differences between the two compounds. Changes in metabolic parameters should be monitored and considered during further development of compounds for male hormonal contraception.

<![CDATA[SAT-051 Effects of Testosterone Replacement on Glycemic Control and Other Cardiovascular Risk Factors in Hypogonadal Men with Uncontrolled Type 2 Diabetes (Stride Study): Design, Implementation and Baseline Data]]> Up to 40% of men with type II diabetes are testosterone deficient. There is growing evidence that testosterone therapy has a beneficial effect on glycemic control, insulin resistance and may have a cardioprotective effect, contrary to the traditional view that testosterone is detrimental to the heart. Our study aims to evaluate the effect of testosterone therapy on glycaemic control other cardiovascular risk factors, symptomatic benefit and quality of life in a randomised double-blind placebo controlled add-on of testosterone therapy to their normal hypoglycemic medication in hypogonadal men with uncontrolled type 2 diabetes. The study population includes 65 eligible men (140 screened) with poorly controlled diabetes (HbA1c between 53 and 80 mmol/mol) and confirmed hypogonadism by early morning [0800−1200h] total testosterone [TT] ≤12 nmol/L or calculated free testosterone ≤255 pmol/L on two occasions ≥1 week apart, with at least two symptoms of hypogonadism. The trial is divided into 2 phases. Phase 1: patients are randomly assigned to either treatment (depot testosterone undecanoate) arm or the placebo arm for 6 months. Phase 2: open label phase for 6 months with subjects on placebo on placebo initiated on to testosterone therapy while subjects in the treatment group continue to receive treatment for the 12 month duration. No change to anti- glycaemic therapy was made during the first phase of the study. The primary endpoint is HbA1c. Secondary endpoints include body composition (bioelectrical impedence DEXA scan), HOMA-IR, lipid profile, blood pressure (24 hr BP monitor), carotid media intima thickness, monocyte mRNA cytokine expression, Questionnaires include AMS (Aging Male Symptom Score), IIEF-5(International Index of Erectile Dysfunction), SF36-Quality of life, Mini mental score, New questionnaire for hypogonadism in diabetes (to be validated), NERI (New England Research Institute) hypogonadal screener. Baseline data indicate the mean age 59 (42-77) years. Mean Duration of diabetes was 8.6(0-21) years. 18 men were on Insulin. The remaining 47 men were either diet controlled or on oral hypoglycaemic medications. 9 men had pre-existing history of MI and 4 had history of angina. Mean HbA1c at baseline was 65(53-80) mmol/mol. Mean total testosterone level was 8.9(2.1-16.9) nmol/l. Mean weight and BMI at baseline were 107(71-187) kg and 34.5(24-52) respectively. Mean waist circumference was 115.7(46-160) cm The primary aim of this is to determine if testosterone therapy improves glycemic control in men with uncontrolled diabetes. Secondly to assess beneficial effects on specific cardiovascular parameters as well as QOL. This could have a major clinical implication on how we treat patients with hypogonadism and type 2 diabetes.

<![CDATA[SAT-039 The Short-Term Effect of Multiple Kinase Inhibitor (Lenvatinib) on Spermatogenesis in Mice]]> Lenvatinib, a multi-kinase inhibitor, is used in the treatment of solid malignancies. Lenvatinib belongs to a family of tyrosine kinase inhibitors and targets VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor alpha, RET and KIT. However, it is not known whether Lenvatinib like other chemotherapeutic drugs affects spermatogenesis. The objective of this study was to examine whether Lenvatinib induces damage to spermatogenesis in mice. Twenty adult mice (C57BL/6) were randomly divided into 2 groups to receive daily gavage of either water (as control) or Lenvatinib (10 mg/kg) for 6 weeks. All mice were euthanized at the end of the study. We identified that Lenvatinib significantly (p<0.05) decreased testis weight (TW: 91.75±1.49mg) compared to control mice (TW: 111.9±3.07mg). This difference in testis weight however, became non-significant after correcting for body weight. The cauda epididymal sperm count was significantly (p<0.01) decreased in the Lenvatinib treated (0.82±0.04 million/mg cauda) as compared to control (1.26±0.07 million/mg cauda) mice. There were no differences in plasma testosterone concentrations between Lenvatinib treated (29.76±7.67ng/dl) and control (31.72±6.89ng/dl) mice. Lenvatinib did not induce notable morphological changes in testicular histology. We conclude that 6 weeks of Lenvatinib treatment had minimal effect if any on mouse spermatogenesis. The long-term treatment effect of Lenvatinib on spermatogenesis remains to be determined.

<![CDATA[SAT-041 Testosterone Reduces Atherosclerosis and Plaque Specific Inflammatory Markers in the ApoE-/- Mouse Model]]> Low serum testosterone in men is an established cardiovascular risk factor and epidemiological evidence demonstrates an association between low testosterone and with coronary events. Clinical evidence suggests that testosterone therapy (Tth) can improve key cardiovascular risk factors in men and surrogate measures of atherosclerosis, the chronic inflammatory process underlying cardiovascular disease. Atherosclerotic plaque-specific testosterone actions are not fully understood. The present study investigates the influence of testosterone on mediators of vascular inflammation and plaque burden in an in vivo model of atherosclerosis. ApoE-/- mice were either sham operated, castrated or castrated and received fortnightly intramuscular injections of physiological doses of testosterone (mixed testosterone esters, Sustanon 100) to create 3 experimental groups; normal testosterone, testosterone deficient and testosterone replaced respectively. All groups were fed a high-fat ‘Western’ diet for 16 weeks. Lipid deposition in the aortic root was assessed by Oil Red O as an indication of atherosclerotic burden. Plaque composition was assessed immunohistochemically for indicators of stability including collagen content via Masson’s trichrome, and α-smooth muscle actin (αSMA) as well as markers of inflammation including vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), endothelial-leukocyte adhesion molecule 1 (E-Selectin), and a pan monocyte/macrophage marker (MOMA2). Testosterone deficient castrated mice had significantly increased lipid accumulation in the aortic root compared to testosterone replete sham-operated littermates (48% intima-media area vs 40%, p<0.05). Tth in castrated mice reversed this effect (39%, p<0.05). Plaque stability was not altered between groups. MOMA2 staining indicated increased infiltration and localisation of monocytes/macrophages in the plaques of castrated mice compared to sham-operated (positive staining (% of plaque) 77% vs 59%, P=0.062) and Tth treatment reduced this (77% vs 63%, P=0.1). Vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) expression were reduced in castrated mice receiving Tth compared to castrated mice receiving saline (33% vs 46%, p<0.05; and 39% vs 58%, P=0.084 respectively). No significant difference in expression of E-Selectin and αSMA were observed between groups. These findings demonstrate that low testosterone increases aortic root lipid deposition and inflammatory composition in a mouse model of atherosclerosis. Increasing testosterone levels through Tth reduces plaque specific inflammatory markers and atherosclerotic burden. This indicates an anti-inflammatory mechanism by which testosterone can protect against the development and progression of atherosclerosis to reduce cardiovascular risk in men.

<![CDATA[SAT-046 Insulin-Like Growth Factor and Fibroblast Growth Factor 21 in Men with Klinefelter Syndrome]]> Background: Men with 47, XXY Klinefelter syndrome (KS) commonly present with obesity, metabolic disorders, and insulin insensitivity. The insulin-like growth factor (IGF) system has pleiotropic effects including regulation of glucose metabolism. Fibroblast growth factor 21 (FGF21) is associated with weight loss and favourable metabolic changes, but patients with obesity or type 2 diabetes might be resistant to this effect despite presenting with increased levels. Aim: To describe levels of components in the IGF system and FGF21 among men with KS, either treated or not treated with testosterone supplementation therapy (TT), in comparison with control males. Methods: A total of 66 men with KS were included, 33 without current TT and 33 with current TT. A control group of 70 healthy age-matched males were included. Serum levels of insulin-like growth factor 1 (IGF-1), insulin-like growth factor-binding protein 3 (IGFBP3), pregnancy-associated plasma protein A (PAPP-A), FGF21, and fibroblast activation protein (FAP) were compared between the three groups applying the Kruskal-Wallis test. Results: Levels of (IGF-1 µg/L) were not different between the groups (median (25-75 %), untreated KS 162 (140-201.5), treated KS 165 (128.5-215), controls 176.5 (150.8-214.5), p=0.5). Similarly, FGF21 levels (ng/L) were comparable between the groups (median (25-75 %), untreated KS 84.7 (53.3-217.6), treated KS 97.2 (56.4-224.8), controls 100.3 (66.0-191.0), p=0.9). Levels of IGFBP3, PAPP-A and FAP were also found to be comparable between the groups (p≥0.2). Conclusion: This was the first study investigating FGF21 in men with KS. Our results indicate that regulation of the IGF-1 system and levels of FGF21 are not altered in men with KS compared with age-matched controls, and that TT in men with KS does not affect these systems.

<![CDATA[SAT-036 Redefining Eunuchoid Body Proportions in Adults]]> Different population groups have different normal adult body proportions.A retrospective study was done on 100 males with age range of 20 to 58 years.Thirty (30%)males had arm span greater than height and upper segment and lower segment ratio(US/LS) below 0.9 which was a proposed criterion for eunuchoid body proportion by Winters.1Moreover,sixty-three(63%) males had arm span greater than 5 cm which was greater than the 2 cm criterion of Santen.2 Only three(3%) males had arm span 1 SD above mean(172.55 ± 12.01 cm) and US/LS 1 SD below mean(0.91 ± 0.04 cm). Hence,eunuchoid body proportions in adults should be defined in terms of SD from mean for the particular sex and race.The body proportion could be due to delayed puberty in Indians compared to the Western population.


1.Winters SJ:Clinical Disorders of the Testis.In Leslie J Degroot eds.Endocrinology.3rded. W. B. Saunders Company 1995;2377-2403.

2.Santen RJ:The Testis.In P.Felig eds.Endocrinology and Metabolism.2nd ed.McGraw Hill,1981,821-905.

<![CDATA[SAT-033 U-Shaped Association of Plasma Testosterone, and No Association of Plasma Estradiol, with Incidence of Any Fracture and Hip Fracture in Older Men]]> 0.050). SHBG was not associated with incidence of any fracture, but was associated with hip fracture (Q4 vs Q1: HR=1.76, CI=1.05-2.96, p=0.033). In conclusion, we found a non-linear or U-shaped association of T with fracture risk, with no association of E2. Mid-range plasma T was associated with lower incidence of any fracture and hip fracture, and higher SHBG with increased risk of hip fracture. Circulating androgen rather than estrogen may be a biomarker for hormone effects on bone driving fracture risk. A randomised controlled trial of T therapy powered for the outcome of fracture may be warranted and should recruit men with baseline T in the lowest quartile of values. Reference: (1) Hyde Z, et al. J Clin Endocrinol Metab 2010; 95: 3165-3172. ]]> <![CDATA[SAT-LB9 Anti-Cancer Properties of RISUG Against Prostrate Cancer Cell Line PC-3 -Invitro Study]]> <![CDATA[SAT-038 Ambulatory Blood Pressure Increases in Hypogonadal Men Who Develop Increases in Hematocrit on Oral Testosterone Undecanoate]]> 52%), the largest increases in ambulatory systolic BP (8.3 mmHg) were observed, whereas the changes in ambulatory systolic BP in the lower 3 quartiles were substantially smaller (1.6, 3.2, and 2.7 mmHg in quartiles 1, 2 and 3 of hematocrit change, respectively). In conclusion, these data demonstrate increases in ambulatory BP occurred following 4 months of oral testosterone undecanoate, particularly in those men whose hematocrit rose by > 6% or whose resultant hematocrit was 52% or higher. Hence, hematocrit maybe a useful clinical parameter that could effectively predict the risk of developing increases in BP on oral testosterone undecanoate. ]]> <![CDATA[SAT-052 A Novel Oral Testosterone Therapy (TLANDO) Safely Restores Testosterone to Eugonadal Levels with Fixed Dose Treatment]]> <![CDATA[SAT-032 Follistatin-Like 3 (FSTL3) and Early Postnatal Testicular Development]]> <![CDATA[SAT-035 In Vitro Effect of Different Follicle-Stimulating Hormone Preparations on Sertoli Cells]]> <![CDATA[SAT-049 Testosterone Therapy Reduces Inflammatory Activation of Human Monocytes in Hypogonadal Type-2 Diabetic Men as a Potential Mechanism to Improve Atherosclerosis]]> <![CDATA[SAT-034 The Effect of Natesto on Spermatogenesis, Reproductive Hormones, and Hypogonadal Symptoms. A Phase IV Study]]> 5 million in a phase IV clinical trial. Eligible men received Natesto for 6 months. Serum T, luteinizing hormone (LH), follicle stimulating hormone (FSH), 17-hydroxyprogesterone (17-OHP), 2 SA, and testis volume were collected at baseline and after 3 and 6 months of therapy. Symptoms were evaluated using the international index of erectile function 6 (IIEF-6) and the short form 36 (SF-36) questionnaires. The primary endpoints were change in T, LH, FSH, sperm concentration, sperm motility, and TMSC. Secondary end points were change in symptoms, testis volume, and adverse events (AEs). Data are presented as means (SD), t-test was used to compare changes after 3 and 6 months, p<0.05 was considered significant.RESULTS: In total, 102 men were screened, and 60 men (age 19-55 years) enrolled. Of the 60 men, 44 completed 3 months, 33 completed 6 months, and 17 dropped out. Mean serum T increased from hypogonadal at baseline to 3 and 6 months (p=0.005), LH and FSH decreased (p=0.03) but remained within the normal range (2-5 IU/mL). Most importantly, semen parameters remained unchanged after 3 and 6 months of T therapy. Only 3 (7.5%) men had severe oligospermia and one (2.5%) became azoospermic but recovered at 6 months after discontinuation. Testis volume and intratesticular T (serum 17-OHP) were maintained at 3 and 6 months. There was improvement across all sub-domains of the IIEF as well as improvement in questions related to energy in the SF-36. A total of 10 men dropped out due to nasal irritation.CONCLUSIONS: This phase IV clinical trial demonstrated that Natesto increased serum T, improved hypogonadal symptoms, maintained gonadotropins, testis volume, intratesticular testosterone and semen parameters. Natesto, and other short acting forms of testosterone therapy may help hypogonadal men maintain fertility. ]]> <![CDATA[SAT-037 Effect of Weight on Serum Testosterone with Subcutaneous Testosterone Enanthate in Men with Testosterone Deficiency]]> 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. References: (1) Dobs et al., J Sex Med 2014;11:857–864; (2) Kaminetsky et al., J Urol. 2019;201:587–94. ]]> <![CDATA[SAT-031 Linking Gonadotropin-Regulated Testicular RNA Helicase (GRTH/DDX25) to Histone Ubiquitination Network and Acetylation During Spermiogenesis]]> <![CDATA[SAT-047 Adoption of an Age Adjusted Testosterone Reference Range Reduces Referrals to Endocrine Clinic and New Prescriptions of Testosterone]]> <![CDATA[SAT-LB5 Prevalence of Hypogonadism in Young Obese Males]]> 0.05) ]]> <![CDATA[SAT-043 Utility of Ultrasensitive Inhibin B Measurement for the Management of Men with Non-Obstructive Azoospermia]]> 3.67 pg/mL (determined by ROC analysis) was associated with increased odds ratio (OR= 4.82; 95% CI: 1.647-12.93) for positive TESE. Inhibin A, Activin B and Activin A serum concentrations did not differ significantly between the two groups.Conclusion: FSH measurement which is routinely performed in men with azoospermia was not predictive of successful TESE whereas, Inhibin B was found to be a valuable marker in predicting TESE success in this population using ultrasensitive Inhibin B assay. ]]>