Cyclophosphamide activates ferroptosis-induced dysfunction of Leydig cells via SMAD2 pathway†.

Cyclophosphamide (CP) is a widely used chemotherapeutic drug and immunosuppressant in the clinic, and the hypoandrogenism caused by CP is receiving more attention. Some studies found that ferroptosis is a new mechanism of cell death closely related to chemotherapeutic drugs and plays a key role in regulating reproductive injuries. The purpose of this study is to explore ferroptosis' role in testicular Leydig cell dysfunction and molecular mechanisms relating to it. In this study, the level of ferroptosis in the mouse model of testicular Leydig cell dysfunction induced by CP was significantly increased and further affected testosterone synthesis. The ferroptosis inhibitors ferrostatin-1 (Fer-1) and iron chelator deferoxamine (DFO) can improve injury induced by CP. The results of immunohistochemistry showed that Fer-1 and DFO could improve the structural disorder of seminiferous tubules and the decrease of the number of Leydig cells in testicular tissue induced by CP. Immunofluorescence and western blot confirmed that Fer-1 and DFO could improve the expression of key enzymes in testosterone synthesis. The activation of SMAD family member 2 (Smad2)/cyclin-dependent kinase inhibitor 1A (Cdkn1a) pathway can improve the ferroptosis of Leydig cells induced by CP and protect the function of Leydig cells. By inhibiting the Smad2/Cdkn1a signal pathway, CP can regulate ferroptosis, resulting in testicular Leydig cell dysfunction. In this study, CP-induced hypoandrogenism is explained theoretically and a potential therapeutic strategy is provided.

Androgen deficiency in hypopituitary women: its consequences and management.

Women with hypopituitarism have various degrees of androgen deficiency, which is marked among those with combined hypogonadotrophic hypogonadism and secondary adrenal insufficiency. The consequences of androgen deficiency and the effects of androgen replacement therapy have not been fully elucidated. While an impact of androgen deficiency on outcomes such as bone mineral density, quality of life, and sexual function is plausible, the available evidence is limited. There is currently no consensus on the definition of androgen deficiency in women and it is still controversial whether androgen substitution should be used in women with hypopituitarism and coexisting androgen deficiency. Some studies suggest beneficial clinical effects of androgen replacement but data on long-term benefits and risk are not available. Transdermal testosterone replacement therapy in hypopituitary women has shown some positive effects on bone metabolism and body composition. Studies of treatment with oral dehydroepiandrosterone have yielded mixed results, with some studies suggesting improvements in quality of life and sexual function. Further research is required to elucidate the impact of androgen deficiency and its replacement treatment on long-term outcomes in women with hypopituitarism. The lack of transdermal androgens for replacement in this patient population and limited outcome data limit its use. A cautious and personalized treatment approach in the clinical management of androgen deficiency in women with hypopituitarism is recommended while awaiting more efficacy and safety data.

[Hypogonadism in men with inflammatory joint diseases: Frequency and clinical characteristics].

AIM: To study the frequency of hypogonadism (HG) in men with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) and to evaluate the impact of HG on the course of RA and and concomitant diseases. MATERIALS AND METHODS: A single-stage continuous study included 170 men with RA, 57 men with AS and 85 men with PsA, who were hospitalized at the Nasonova Research Institute of Rheumatology. Patients were assessed for total testosterone (ТS) levels and subsequently divided into subgroups with normal (>12 nmol/l) and reduced levels. An intergroup comparison was carried out on the main indicators used in clinical rheumatological practice to assess the stage, activity and other medical and demographic characteristics of rheumatic disease, as well as on concomitant conditions. The second stage of the study involved a pairwise intergroup comparison among patients with HG with RA, AS and PsA. RESULTS: The incidence of ТS deficiency among patients with RA was 24.1%, among patients with AS - 17.5%, and with PsA - 31.8%. In patients with RA, HG was associated with a significantly higher mean body mass index, higher fasting blood glucose and uric acid, higher erythrocyte sedimentation rate and anemia. Patients with AS with HG had significantly lower hemoglobin levels and more frequent anemia, as well as higher levels of C-reactive protein and erythrocyte sedimentation rate. In PsA, older age was observed in the androgen deficiency group, as well as higher body mass index and fasting glucose levels; obesity was more common. An intergroup comparison of quantitative and qualitative indicators between patients with androgen deficiency in all three rheumatic diseases (RDs) did not reveal significant differences in the average concentrations of ТS, luteinizing hormone, sex hormone binding globulin, experience of RD, laboratory markers of inflammatory activity, as well as glucose and uric acid. A similar incidence of diabetes mellitus, obesity and anemia was noted for all three nosologies. CONCLUSION: ТS levels and the presence of HG were not associated with the stage and activity of RD, but ТS deficiency was accompanied by higher laboratory indicators of inflammatory activity, lower hemoglobin values, and metabolic disorders. Patients with HG, regardless of nosology, had similar levels of sex hormones and indicators reflecting RD and concomitant conditions.

[The role of antioxidants in the therapy of metabolic syndrome in men].

INTRODUCTION: Metabolic syndrome (MetS) is a combination of hormonal, metabolic and clinical disorders. Currently, MetS in men is considered as one of the main risk factors for the development of cardiovascular diseases, insulin resistance, and pathology of the reproductive system. AIM: To study the effect of a complex of folic acid, L-carnitine, vitamin E, zinc and selenium, which are part of the biologically active food supplement "Speroton", on the parameters of carbohydrate and lipid metabolism in men with MetS, especially in the early stages of its development, as well as on erectile function and quality of life of patients. MATERIALS AND METHODS: A total of 64 patients aged 30 to 51 years with MetS of varying severity were included in the study. The main group consisted of 34 patients aged 32 to 51 years (mean age 46.2+/-2.1 years), while in the control group, there were 30 patients aged 30 to 49 years (mean age 45.4+/-3.4 years). The standard therapy in the main group was supplemented by taking the dietary supplement "Speroton" for 3 months. In the control group, patients received only standard therapy for MetS. The results were evaluated after 3 and 6 months from the start of treatment. All patients underwent laboratory evaluation of sex hormones, carbohydrate metabolism and lipid profile. In addition, the concentration of zinc in the spermatozoa was measured, as well as the level of total antioxidant capacity of the sperm. The uroflowmetry, ultrasound of the bladder with the measurement of the postvoid residual, and transrectal ultrasound of the prostate were also performed. RESULTS: An addition of the antioxidant complex "Speroton" to the combination treatment of MetS in the main group allowed to decrease the parameters of oxidative stress by almost two times. By the 6th month of follow-up, the level of insulin improved, which was accompanied by a decrease in the level of HbA1c by 16.3%, suggesting the stabilization of carbohydrate metabolism. A decrease in body mass index by almost 14% (p<0.05) in the main group was found, as well as normalization of the lipid profile. According to the analysis of the erectile function in patients of the main group after 6 months from the beginning of therapy, there was a decrease in the total score to a moderate erectile dysfunction (12.5+/-2.1 points). There was a decrease in storage symptoms and, in part, voiding symptoms in patients in the main group, who received antioxidant therapy. In addition, a positive correlation between the concentration of zinc and the level of total antioxidant capacity in the ejaculate was seen. CONCLUSIONS: Our results suggest the high therapeutic efficiency of dietary supplement "Speroton" as an antioxidant complex for the treatment of patients with MetS of varying severity. The addition of antioxidants "Speroton" to the standard therapy of MetS contributes to the improvement of the sensitivity of insulin receptors, the normalization of carbohydrate and lipid metabolism, endothelial function and blood pressure, which is accompanied by a significant decrease in LUTS severity, as well as an improvement in the erectile function of patients.

Comparison of neuroprotective effects of dihydrotestosterone, 17ß-estradiol, and Pueraria mirifica herb extract on cognitive impairment in androgen deficient male rats.

This study investigated the neuroprotective effects of dihydrotestosterone (DHT), 17ß-estradiol (E2), and Pueraria mirifica herb extract (PME; an alternative source of natural estrogens) on the (i) learning and memory in androgen-deficient male rats, and on the hippocampus expression levels of (ii) mRNA of genes associated with synaptic transmission and structure, neurofibrillary tangles, and amyloid plaques, and (iii) total and phosphorylated tau proteins. The four-month-old male rats were sham-operated or orchidectomized (ODX). The ODX rats were divided into four groups, and orally treated for 2 months with either 1 mL/d of distilled water or 100 mg/kg/d of PME; or subcutaneously injected with 1 mg/kg/d of DHT or 80 µg/kg/d of E2. The impairment of spatial learning behavior and memory capacity in the ODX rats was prevented by DHT, E2, and PME. Recovery of the orchidectomy-induced deterioration of the synaptic plasticity in the hippocampus of rats was ranked as E2 ≥ PME > DHT. Both DHT and PME mitigated the increased Tau3 and Tau4 mRNA levels, and Tau-5 and P-Tau Ser396 protein levels more than E2 (DHT ≥ PME > E2). Only DHT tended to decrease App mRNA expression level. In conclusion, DHT showed a stronger efficacy for mitigation of the impaired spatial learning behavior and memory capacity in androgen-deficient male rats compared to E2 and PME, and their mechanisms of action are slightly different.

[Adverse effects of opioids, antidepressants and anticonvulsants on sex hormones : Often unnoticed but clinically relevant]. / Unerwünschte Wirkungen von Opioiden, Antidepressiva und Antikonvulsiva auf Sexualhormone : Häufig unbeachtet, aber klinisch relevant.

Androgen insufficiency under treatment with opioids, antidepressants and anticonvulsants in chronic pain diseases is a side effect with a high prevalence. It can lead to clinical metabolic alterations, adynamia, stress intolerance, anemia or osteoporosis and has a significant impact on the quality of life. Opioids, antidepressants and anticonvulsants affect the hypothalamic-pituitary-gonadal axis of sex hormones. A urologist, andrologist or endocrinologist should be involved in the treatment at an early stage. The recommendation of a differential therapeutic selection of certain substances is only indicative and does not meet evidential criteria. The indications for androgen substitution must be individualized and in consideration of the risk-benefit profile. Awareness of this side effect of an otherwise lege artis medicinal pain therapy must be sharpened and compulsory included in the differential diagnostic considerations.

Measurement of salivary testosterone in adolescents and young men with Duchenne muscular dystrophy.

BACKGROUND: Many young adults with Duchenne Muscular Dystrophy (DMD) receive long-term glucocorticoids (GC). GC can cause hypogonadotrophic hypogonadism and adolescents may therefore be candidates for pubertal induction. It is unclear whether men with DMD on or off GC have age-appropriate endogenous testosterone production. METHODS: We undertook a quality improvement project to assess the feasibility of measuring salivary testosterone (SalT) levels in men with DMD at home. A Sal-T sampling kit was sent by post to all patients with DMD, aged 17 and older, registered at the John Walton Muscular Centre in Newcastle (n = 75). Submitted Sal-T samples were collected and submitted for analysis. RESULTS: Twenty-eight out of seventy-five patients returned samples (age range: 17-34 years). 6/28 samples were unsuitable for analysis. Overall Sal-T levels (n = 22) were significantly lower than in the healthy population (178 ± 107 v 287 ± 109 pmol/l, p = 0.0001). Sal-T was lower in those on GC compared to those off GC (144 ± 81 versus 218 ± 125 pmol/l, p = 0.05). Three patients were unable to collect a sample due to ventilator dependence. CONCLUSION: Sal T can provide information about androgen status in DMD patients at home, overcoming barriers such as mobility difficulties and challenging venepuncture. However we only obtained samples in a minority of patients suggesting that Sal-T measurement may not be appropriate or acceptable to everyone. There needs to be a more detailed exploration of the barriers to sample submission.

Co-Treatment of Purified Annatto Oil (Bixa orellana L.) and Its Granules (Chronic®) Improves the Blood Lipid Profile and Bone Protective Effects of Testosterone in the Orchiectomy-Induced Osteoporosis in Wistar Rats.

This study aimed to evaluate and compare the effects of co-treatment with purified annatto oil (PAO) or its granules (GRA, Chronic®) with that of testosterone on the orchiectomy-induced osteoporosis in Wistar rats. After surgery, rats were treated from day 7 until day 45 with testosterone only (TES, 7 mg/kg, IM) or TES + PAO or GRA (200 mg/kg, p.o.). The following parameters were evaluated: food/water intake, weight, HDL, LDL, glucose, triglycerides (TG), total cholesterol (TC), alkaline phosphatase levels, blood phosphorus and calcium contents, femur weight, structure (through scanning electron microscopy), and calcium content (through atomic absorption spectrophotometry). Our results show that orchiectomy could significantly change the blood lipid profile and decrease bone integrity parameters. Testosterone reposition alone could improve some endpoints, including LDL, TC, bone weight, and bone calcium concentration. However, other parameters were not significantly improved. Co-treatment with PAO or GRA improved the blood lipid profile and bone integrity more significantly and improved some endpoints not affected by testosterone reposition alone (such as TG levels and trabeculae sizes). The results suggest that co-treatment with annatto products improved the blood lipid profile and the anti-osteoporosis effects of testosterone. Overall, GRA had better results than PAO.

Effectiveness of testosterone therapy in hypogonadal patients and its controversial adverse impact on the cardiovascular system.

Testosterone is the major male hormone produced by testicles which are directly associated with man's appearance and secondary sexual developments. Androgen deficiency starts when the male hormonal level falls from its normal range though, in youngsters, the deficiency occurs due to disruption of the normal functioning of pituitary, hypothalamus glands, and testes. Thus, testosterone replacement therapy was already known for the treatment of androgen deficiency with lesser risks of producing cardiovascular problems. Since from previous years, the treatment threshold in the form of testosterone replacement therapy has effectively increased to that extent that it was prescribed for those conditions which it was considered as inappropriate. However, there are some research studies and clinical trials available that proposed the higher risk of inducing cardiovascular disease with the use of testosterone replacement therapy. Thus under the light of these results, the FDA has published the report of the increased risk of cardiovascular disease with the increased use of testosterone replacement therapy. Nevertheless, there is not a single trial available or designed that could evaluate the risk of cardiovascular events with the use of testosterone replacement therapy. As a result, the use of testosterone still questioned the cardiovascular safety of this replacement therapy. Thus, this literature outlines the distribution pattern of disease by investigating the data and link between serum testosterone level and the cardiovascular disease, also the prescription data of testosterone replacement therapy patients and their tendency of inducing cardiovascular disease, meta-analysis and the trials regarding testosterone replacement therapy and its connection with the risks of causing cardiovascular disease and lastly, the possible effects of testosterone replacement therapy on the cardiovascular system. This study aims to evaluate the available evidence regarding the use of testosterone replacement therapy when choosing it as a treatment plan for their patients.

Independent Association of Erectile Dysfunction and Low Testosterone Levels With Life Dissatisfaction in Men With Chronic Spinal Cord Injury.

BACKGROUND: The loss of global functional independence, along with bladder, bowel, and sexual dysfunctions, may contribute to psychological distress and life dissatisfaction after spinal cord injury (SCI). AIM: To explore the relationship of erectile function and androgenic status with life satisfaction, independently from confounders recognizable in spinal cord-injured men. METHODS: 100 consecutive men (49 ± 17 years) admitted to a rehabilitation program because of chronic SCI (≥1 year) underwent clinical/biochemical evaluations, including the assessment of life and sexual satisfaction using the Life-Satisfaction Questionnaire-9 (LiSat-9), erectile function using the International Index of Erectile Function-5 (IIEF-5), global and bowel-bladder functional independence using the Spinal Cord Independence Measure (SCIM) and measurement of total testosterone (TT) levels. The free testosterone level was calculated using the Vermeulen formula. OUTCOMES: The outcomes include the relationship between sexual health and life satisfaction in men with SCI. RESULTS: A LiSat-9 score <4, suggestive for life dissatisfaction, was exhibited by 49% of men. When compared with the life-satisfied group, a significantly higher percentage of them had sexual dissatisfaction and erectile dysfunction (ED); they also exhibited significantly lower levels of TT and calculated free testosterone (cFT) and a more severe impairment of bowel-bladder function. The life satisfaction degree correlated with sexual satisfaction degree, IIEF-5 score, TT, cFT, and bowel-bladder function degree. At the logistic regression model, including sexual LiSat-9 subscore and bowel-bladder SCIM subscore, only the former exhibited a significant negative association with life dissatisfaction. In a further logistic regression model, including the putative key determinants of sexual satisfaction, erectile function, and cFT levels, a higher odd of life dissatisfaction was independently associated both with a lower IIEF-5 score (OR: 0.93; 95% CI: 0.88, 0.98) and lower cFT levels (OR: 0.98; 95% CI: 0.98, 0.99). CLINICAL IMPLICATIONS: In men with chronic SCI, assessment of erectile function and testosterone levels can help to predict life satisfaction. STRENGTHS & LIMITATIONS: This is the first demonstration of the independent association of androgen deficiency and ED with life satisfaction in men with SCI. Prospective studies are warranted to clarify the cause-effect relationships. CONCLUSIONS: In men with SCI, ED and low testosterone levels exhibit a significant independent association with life dissatisfaction; longitudinal intervention studies could explore possible effects of their treatment in improving sexual and life satisfaction in this population. D'Andrea S, Minaldi E, Castellini C, et al. Independent Association of Erectile Dysfunction and Low Testosterone Levels With Life Dissatisfaction in Men With Chronic Spinal Cord Injury. J Sex Med 2020;17:911-918.

Role of irisin in androgen-deficient muscle wasting and osteopenia in mice.

Androgen deficiency plays a crucial role in the pathogenesis of male osteoporosis and sarcopenia. Myokines have recently been identified as humoral factors that are involved in the interactions between muscle and bone; however, the influence of androgen deficiency on these interactions remains unclear. Therefore, we herein investigated the roles of humoral factors linking muscle to bone using orchidectomized mice with sarcopenia and osteopenia. Orchidectomy (ORX) significantly reduced muscle mass, grip strength, and trabecular bone mineral density (BMD) in mice. Among the myokines examined, ORX only significantly reduced fibronectin type III domain-containing 5 (Fndc5) mRNA levels in both the soleus and gastrocnemius muscles of mice. In simple regression analyses, Fndc5 mRNA levels in the soleus muscle positively correlated with trabecular BMD, but not cortical BMD. The administration of irisin, a product of Fndc5, significantly protected against the decrease induced in trabecular BMD, but not muscle mass, by androgen deficiency in mice. In conclusion, the present results demonstrated that androgen deficiency decreases the expression of irisin in the skeletal muscle of mice. Irisin may be involved in muscle/bone relationships negatively affected by androgen deficiency.

Reductions in testosterone are not indicative of exercise performance decrement in male endurance athletes.

Our findings indicate that the participants of an 18 week intensive endurance exercise training program experienced significant (p < 0.001) reductions in resting testosterone (-25 to -45% decrease from pre-training), with some reaching the clinical criteria for androgen deficiency during the training regimen. Nonetheless, none of the participants displayed any running performance decrement, in fact, the opposite occurred (+18.6% improvement; p < 0.05). These preliminary findings suggest acute decreases in testosterone in and of itself may not be entirely indicative of a compromised exercise performance potential although elements of reproductive and bone health may still be compromised.

Pharmacoepidemiology of testosterone: Impact of reimbursement policy on curbing off-label prescribing.

OBJECTIVES: To estimate the impact on testosterone prescribing over 3 years following the 2015 tightening of Pharmaceutical Benefits Scheme (PBS) criteria. DESIGN: Analysis of testosterone prescribing data from PBS and private (non-PBS) sources between 2012 and 2018 covering 2015 change in PBS prescribing criteria. MAIN OUTCOME MEASURES: New and total PBS testosterone prescriptions estimating usage by quarter analyzed by product type, patient age-group, indication and prescriber type. Total national testosterone prescriptions (private plus PBS) was verified from an independent data supplier (IQVIA). RESULTS: PBS usage peaked in 2014 declining by 30% in 2017-8 with PBS prescribing covering a fall from 97.6% by usage in 2014 to 74% in 2017-18 of all testosterone prescribing. The tighter 2015 PBS restrictions sustained the selective reduction in GP initiation of prescriptions for middle-aged men without pathological hypogonadism whereas specialist initiations and prescription for adult hypogonadism or pediatric/prepubertal indications were largely unaffected. CONCLUSIONS: The tightening of PBS criteria from 1 April 2015 to curb off-label prescribing remained effective and selective over 3 years yet total national testosterone prescribing continued with little change, reflecting a shift to private prescriptions. The continuation of off-label testosterone prescribing for unproven indications suggests that long-term androgen dependence is created in men without pathological hypogonadism who commence testosterone. This highlights the need to avoid prescribing testosterone to men without pathological hypogonadism in the absence of sound evidence of efficacy and safety, the latter including the little unrecognized risks of long-term androgen dependency when trying to quit.

A double blind, placebo-controlled randomized comparative study on the efficacy of phytosterol-enriched and conventional saw palmetto oil in mitigating benign prostate hyperplasia and androgen deficiency.

BACKGROUND: The present clinical trial was conducted to evaluate the efficacy and tolerability of a standardized saw palmetto oil containing 3% ß-sitosterol in the treatment of benign prostate hyperplasia (BPH) and androgen deficiency. METHODS: Subjects aged 40-65 years with symptomatic BPH were randomized to 12-week double-blind treatment with 500 mg doses of ß-sitosterol enriched saw palmetto oil, conventional saw palmetto oil and placebo orally in the form of capsules (n = 33 in each group). BPH severity was determined using the International Prostate Symptom Score (IPSS), uroflowmetry, serum measurement of prostate specific antigen (PSA), testosterone and 5α-reductase. During the trial, the androgen deficiency was evaluated using Aging Male Symptoms (AMS) scale, the Androgen Deficiency in the Aging Male (ADAM) questionnaire, serum levels of free testosterone. RESULTS: Subjects treated with ß-sitosterol enriched saw palmetto oil showed significant decrease in IPSS, AMS and ADAM scores along with reduced postvoiding residual volume (p < 0.001), PSA (p < 0.01) and 5α-reductase from baseline to end of 12-week treatment as compared to placebo. There was also a significant increment in the maximum and average urine flow rate (p < 0.001), and serum free testosterone level of subjects treated with enriched saw palmetto oil as compared to placebo. CONCLUSION: This study demonstrates the efficacy of ß-sitosterol enriched saw palmetto oil superior to conventional oil thus extending the scope of effective BPH and androgen deficiency treatment with improved quality of life through the intake of functional ingredients. TRIAL REGISTRATION: CTRI/2018/12/016724 dated 19/12/2018 prospectively registered. URL: http://ctri.nic.in/Clinicaltrials/advsearch.php.

[Benefits of androgen replacement therapy and audio-visual correction inclusion in the prevention of premature aging.]

There are changes in the metabolism, reproductive and nervous systems with ageing, which have a systemic and interrelated nature. The purpose of this work was to demonstrate the effectiveness of audiovisual correction and therapy with testosterone drugs in addition to the standard therapy in patients with polymorbid pathology. 89 men aged 35-55 years old with diabetes mellitus, polymorbid cardiovascular disease, obesity, anxiety and depressive disorders were examined. They were divided into 3 groups depending on the treatment: the 1st - standard therapy and escitalopram / tofisopam; the 2nd - standard therapy + audiovisual correction; the 3rd - standard therapy + audiovisual correction + testosterone undecanoate. Laboratory examination was carried out in all patients before the start of treatment and 9 months after the treatment. The severity of androgen deficiency was determined using IIEF-5 questionnaire and the AMS male aging scale. In was shown a decrease in testosterone levels, signs of erectile dysfunction and symptoms of moderate to severe androgen deficiency, increased proatherogenic and decreased antiatherogenic lipoproteins, increased glucose, glycated hemoglobin, insulin, HOMA index in our study. In group of audiovisual correction we saw a more significant improvement in the lipid profile after treatment. Audiovisual correction and androgen therapy contributed to the improvement of erectile function indices and a decrease in the severity of the symptoms of ageing in men.

Clinical practice update on testosterone therapy for male hypogonadism: Contrasting perspectives to optimize care.

US Endocrine Society (ES) published a clinical practice guideline on testosterone therapy in men with hypogonadism, and Endocrine Society of Australia (ESA) a position statement on management of male hypogonadism. Both emphasize the importance of diagnosing men who are androgen deficient due to organic (classical or pathological) hypogonadism arising from disorders of the hypothalamus, pituitary or testes, who assuredly benefit from testosterone therapy. Both recognize that men with an intact gonadal axis may have low testosterone concentrations, for instance older men or men with obesity or other medical comorbidities. ES guidelines classify such symptomatic men as having organic (advanced age) or functional (obesity, medical comorbidities) hypogonadism, giving an option for testosterone therapy as a shared decision between clinicians and individual patients. ESA did not recommend testosterone therapy in these men. ES offers a reference range for total testosterone established in young men, while ESA cites age-standardized reference ranges. ES recommends using free testosterone as well as total testosterone to identify men with hypogonadism in conditions where sex hormone-binding globulin (SHBG) is altered, or when total testosterone is borderline. ESA recommends confirmatory biochemical testing with total testosterone, recognizing that this may be lower than expected if SHBG concentrations are low. Both emphasize the importance of identifying pre-existing prostate and cardiovascular disease prior to initiating testosterone therapy, with ES providing specific recommendations for PSA measurement, deferring testosterone therapy after major cardiovascular events and indications for pituitary imaging. These contrasting approaches highlight gaps in the evidence base where individualized patient management is required.

Can the positive association of osteocalcin with testosterone be unmasked when the preeminent hypothalamic-pituitary regulation of testosterone production is impaired? The model of spinal cord injury.

PURPOSE: Osteocalcin (OCN), released from the bone matrix during the resorption phase, in its undercarboxylated form, stimulates testosterone (T) biosynthesis in mouse and a loss-of-function mutation of its receptor was associated with hypergonadotropic hypogonadism in humans. Nevertheless, when population-based studies have explored the OCN-T association, conflicting results have been reported. Hypothesizing that the evidence of a positive association between OCN and T could have been hindered by the preeminent role of a well-functioning hypothalamus-pituitary axis in promoting T biosynthesis, we explored this association in men with chronic spinal cord injury (SCI), exhibiting high prevalence of non-hypergonadotropic androgen deficiency. METHODS: Fifty-five consecutive men with chronic SCI underwent clinical/biochemical evaluations, including measurements of total T (TT), OCN and 25(OH)D levels. Free T (FT) levels were calculated by the Vermeulen formula. Comorbidity was scored by Charlson comorbidity index (CCI). RESULTS: A biochemical androgen deficiency (TT < 300 ng/dL) was observed in 15 patients (27.3%). TT was positively correlated with OCN, 25(OH)D and leisure time physical activity and negatively correlated with age, BMI and CCI. OCN was also positively correlated with calculated FT and negatively correlated with BMI and HOMA-IR. At the multiple linear regression analyses, a positive association of OCN with TT and calculated FT persisted after adjustment for confounders. CONCLUSIONS: The positive association here found between OCN and T levels in men with chronic SCI reinforces the notion that a bone-testis axis is also functioning in humans and suggests that it can be unmasked when the preeminent hypothalamic-pituitary regulation of T production is impaired.

Steroidogenic abnormalities in translocator protein knockout mice and significance in the aging male.

The translocator protein (TSPO) has been proposed to act as a key component in a complex important for mitochondrial cholesterol importation, which is the rate-limiting step in steroid hormone synthesis. However, TSPO function in steroidogenesis has recently been challenged by the development of TSPO knockout (TSPO-KO) mice, as they exhibit normal baseline gonadal testosterone and adrenal corticosteroid production. Here, we demonstrate that despite normal androgen levels in young male TSPO-KO mice, TSPO deficiency alters steroidogenic flux and results in reduced total steroidogenic output. Specific reductions in the levels of progesterone and corticosterone as well as age-dependent androgen deficiency were observed in both young and aged male TSPO-KO mice. Collectively, these findings indicate that while TSPO is not critical for achieving baseline testicular and adrenal steroidogenesis, either indirect effects of TSPO on steroidogenic processes, or compensatory mechanisms and functional redundancy, lead to subtle steroidogenic abnormalities which become exacerbated with aging.

[Hormonal feature of the androgen status in different-aged males.]

The examined males (n=374) aged from 20 to 69 years were divided into five age groups: the 1st - 20-29 years; the 2nd - 30-39 years; the 3rd - 40-49 years; the 4th - 50-59 years; the 5th - 60-69 years. There was 16,1±7 nmol/l total testosterone level in serum of all aged group. Hormonal signs of androgen deficiency, increased elderly aged groups, were revealed in males of the 2nd group as compared with males of the 1st group. The frequency of androgen deficiency (total testosterone level less than 12,1 nmol/l) in the 1st group was 26,9%; in groups 2, 3 and 4 this index was similar, composed 30,6-33,9%. However, the frequency of androgen deficiency increased and amounted to 44% in the 5th group. The frequency of hypogonadism hormonal signs (total testosterone level less than 8 nmol/l) did not significantly differ in groups 1-4 (6,2-9,3%), and only in group 5 it increased and amounted to 28%. The age-related androgenic deficiency in males was associated with decrease in androgenic function both the gonads, and the adrenal glands, increased level of sex steroid-binding globulin, increased metabolism of testosterone in estradiol and was accompanied by compensatory increase of luteinizing hormone synthesis in the pituitary gland.

Prolactin in hypertensive men with androgen deficiency: an éminence grise?

OBJECTIVE: Introduction: Considering significant gap of convincing knowledge in the field of cardiovascular effects of prolactin and its role as a stress hormone in men precise investigations of these peculiarities has become necessary. The aim of this study was to find out the relationship of prolactin concentration with parameters of arterial stiffness in hypertensive men with low testosterone. PATIENTS AND METHODS: Materials and methods: In total 83 men were examined including 27 apparently healthy individuals as the control group. Physical examination, ABPM, non-invasive evaluation of arterial stiffness and central hemodynamics parameters, answering AMS questionnaire, evaluation of total testosterone and prolactin levels using ELISA were performed. RESULTS: Results: Initially 56 hypertensive patients were divided into 2 groups with regard to their total testosterone level: group 1 included 31 hypogonadal men, group 2 - 25 male patients who had their testosterone concentrations within the normal range. Prolactin levels appeared to be significantly higher in hypertensive men with lower testosterone, they had more unfavorable parameters of arterial stiffness and the difference between 1 and 2 group in terms of central aoSBP and aoPWV became statistically significant. Prolactin concentration was not related with RWTT and index Aix% 75, a significant correlation was observed between prolactin and aoPWV. A strong correlation was found between prolactin concentration and psychological symptoms in AMS. CONCLUSION: Conclusion: Our study suggests the positive association of prolactin concentration with psychological domain of andropause symptoms and worse parameters of arterial stiffness among hypertensive men with androgen deficiency.