Testosterone deficiency：a historical perspective

The biological effects of the testes and testosterone are known since antiquity. Aristotle knew the effects of castration and his hypothesis on fertilization is one of the first scientific encounters in reproductive biology. Over centuries, castration has been performed as punishment and to produce obedient slaves, but also to preserve the soprano voices of prepubertal boys. The Chinese imperial （and other oriental） courts employed castrates as overseers in harems who often obtained high-ranking political positions. The era of testis transplantation and organotherapy was initiated by John Hunter in London who transplanted testes into capons in 1786. The intention of his experiments was to prove the ＇vital principle＇ as the basis for modern transplantation medicine, but Hunter did not consider endocrine aspects. Arnold Adolph Berthold postulated internal secretion from his testicular transplantation experiments in 1849 in Gottingen and is thus considered the father of endocrinology. Following his observations, testicular preparations were used for therapy, popularized by self-experiments by Charles-Edouard Brown-Sequard in Paris （1889）, which can at best have placebo effects. In the 1920s Sergio Voronoff transplanted testes from animals to men, but their effectiveness was disproved. Today testicular transplantation is being refined by stem cell research and germ cell transplantation. Modern androgen therapy started in 1935 when Enrest Lacquer isolated testosterone from bull testes in Amsterdam. In the same year testosterone was chemically synthesized independently by Adolf Butenandt in G6ttingen and Leopold Ruzicka in Basel. Since testosterone was ineffective orally it was either compressed into subcutaneous pellets or was used orally as 17α-methyl testosterone, now obsolete because of liver toxicity. The early phases of testosterone treatment coincide with the first description of the most prominent syndromes of hypogonadism by Klinefelter, by Kallmann, DelCastillo and Pasqualini. In the 1950s longer-acting injectable testosterone enanthate became the preferred therapeutic modality. In the 1950s and 1960s, research concentrated on the chemical modification of androgens in order to emphasize their anabolic effects. Although anabolic steroids have largely disappeared from clinical medicine, they continue to live an illegal life for doping in athletics. In the 1970s the orally effective testosterone undecanoate was added to the spectrum of preparations. Recent transdermal gels and long-acting injectable preparations provide options for physiological testosterone substitution therapy.

Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome： a double blind randomized controlled trial

This study aimed to investigate the effect of intramuscular injection of testosterone undecanoate on overall quality of life （QoL） in men with testosterone deficiency syndrome （TDS）. A randomized controlled trial over a 12-month period was carried out in 2009. One hundred and twenty men aged 40 years and above with a diagnosis of TDS （serum total testosterone 〈12 nmol 1-1 and total Aging Male Symptom （AMS） scores ≥ 27） were invited to participate. Interventions comprised intramuscular injection of either placebo or 1000 mg testosterone undecanoate, given at weeks O, 6, 18, 30 and 42. This paper presents the secondary analysis of QoL changes measured in the scores of Short-Form-12 （SF-12） scale at baseline, weeks 30 and 48 after the first injection. A total of 56/60 and 58/60 men from the active treatment and placebo group, respectively, completed the study. At week 48, before adjusting for baseline differences, the QoL of men in the treatment group improved significantly in five out of the eight domains on SF-12. The physical health composite scores improved 4.0 points from a baseline of 41.9±7.0 in the treatment group compared to 0.8 point from a baseline of 43.7--7.1 in the placebo group （F=3.652, P=0.027）. The mental health composite scores improved 4.4 points from a baseline of 37.1±9.0 in the treatment group compared to 1.0 points from a baseline of 37.6±7.9 in the placebo group （F=4.514, P=-0.018）. After adjusting for baseline differences, significant improvement was observed in mental health composite scores, but not in physical health composite scores. LQng-acting testosterone undecanoate significanUy improved the mental health component of QoL in men with TDS.

Recent topics related to testosterone deficiency syndrome n Japan

Androgens, the levels of which decrease with ageing, play many physiological roles in various organs. Testosterone deficiency syndrome （TDS） has received widespread attention in the last several years. First-line treatment for TDS should be testosterone replacement therapy （TRT）, which is reported to improve several TDS symptoms. Recently, a clinical practice manual for TDS was written and published by a collaborative team from the Japanese Urological Association and the Japanese Society for the Study of the Aging Male to recommend standard procedures for the diagnosis, treatment, prevention and monitoring of adverse reactions to TRT and for post-treatment assessment. In this manual, intramuscular injection of testosterone enanthate or human chorionic gonadotropin and the testosterone gel ＇Glowmin＇ were recommended as TRT. Currently, two topics related to TDS are being focused on in Japan： the relationship between TDS and metabolic syndrome and treatment options for eugonadal patients with TDS symptoms. In this review, the possibility of TRT for metabolic syndrome as well as the relationship between testosterone and adiponectin, which is a key molecule in metabolic syndrome, is discussed. Finally, the possibility of herbal medicines as a treatment option for patients with TDS is addressed, especially for eugonadal patients, because eugonadal men with TDS symptoms account for approximately 30% of the general population. The increase in the levels of several cytokines, such as IL-8, IL-13, interferon.y and tumor necrosis factor-α, after herbal medicine treatment may be the reason for this efficacy.

Exosomes derived from BMSCs ameliorate cyclophosphamide-induced testosterone deficiency by enhancing the autophagy of Leydig cells via the AMPK-mTOR signaling pathway

Cyclophosphamide-induced testosterone deficiency (CPTD) during the treatment of cancers and autoimmune disorders severelyinfluences the quality of life of patients. Currently, several guidelines recommend patients suffering from CPTD receive testosteronereplacement therapy (TRT). However, TRT has many disadvantages underscoring the requirement for alternative, nontoxictreatment strategies. We previously reported bone marrow mesenchymal stem cells-derived exosomes (BMSCs-exos) could alleviatecyclophosphamide (CP)-induced spermatogenesis dysfunction, highlighting their role in the treatment of male reproductive disorders.Therefore, we further investigated whether BMSCs-exos affect autophagy and testosterone synthesis in Leydig cells (LCs). Here,we examined the effects and probed the molecular mechanisms of BMSCs-exos on CPTD in vivo and in vitro by detecting theexpression levels of genes and proteins related to autophagy and testosterone synthesis. Furthermore, the testosterone concentrationin serum and cell-conditioned medium, and the photophosphorylation protein levels of adenosine monophosphate-activatedprotein kinase (AMPK) and mammalian target of rapamycin (mTOR) were measured. Our results suggest that BMSCs-exos couldbe absorbed by LCs through the blood–testis barrier in mice, promoting autophagy in LCs and improving the CP-induced low serumtestosterone levels. BMSCs-exos inhibited cell death in CP-exposed LCs, regulated the AMPK-mTOR signaling pathway to promoteautophagy in LCs, and then improved the low testosterone synthesis ability of CP-induced LCs. Moreover, the autophagy inhibitor,3-methyladenine (3-MA), significantly reversed the therapeutic effects of BMSCs-exos. These findings suggest that BMSCs-exospromote LC autophagy by regulating the AMPK-mTOR signaling pathway, thereby ameliorating CPTD. This study provides novelevidence for the clinical improvement of CPTD using BMSCs-exos.

Both comorbidity burden and low testosterone can explain symptoms and signs of testosterone deficiency in men consulting for sexual dysfunction

Low testosterone(T)is frequent in men with chronic illnesses.The clinical features of T deficiency(TD)overlap with those of chronic diseases.The aim of this study is to evaluate the relative contribution of chronic disease score(CDS)and low T to the presenee of TD symptoms.A consecutive series of 3862 men(aged 52.1±13.1 years)consulting for sexual dysfunction were studied.Several clinical and biochemical parameters were collected,in eluding the structured interview,ANDROTEST,for the assessme nt of TD symptoms.Penile color Doppler ultrasound(PCDU)was also performed.Based on the medications taken,the CDS was calculated.For a subset of 1687 men,information on mortality was collected(follow-up of 4.3±2.6 years).Higher CDS was associated with lower free and total T(TT)as well as with higher ANDROTEST score.When introducing CDS and TT in multivariable models adjusted for age,severe erectile dysfunctio n and impaired morning erectio ns were associated with both CDS(odds ratio and 95%confide nee interaval,OR[95%Cl]=1.25[1.13;1.37]and 1.38[1.29;1.48],respectively)and low TT(OR[95%Cl]=1.11[1.00;1.23]and 1.13[1.06;1.21],respectively).Similar results were obtained for PCDU parameters.Hypoactive sexual desire was associated with low TT(OR[95%Cl]=1.21[1.13;1.30]),whereas it was inversely related with CDS(OR[95%Cl]=0.91[0.84;0.97]).When considering mortality for major cardiovascular events,TT<8 nmol I1,but not CDS,was a significant predictor(hazard ratio[95%Cl]=5.57[1.51;20.63]).Chronic illnesses are associated with an overt TD.Both chronic diseases and low T can be invoIved in determining symptoms present in subjects complaining for sexual dysfunction.This should be considered in the diagnostic workup for TD.

Metabolic syndrome,levels of androgens,and changes of erectile dysfunction and quality of life impairment 1 year after radical prostatectomy

Robust data evaluating the association of preoperative parameters of the patients with quality of life after radical prostatectomy are lacking.We investigated whether clinical and biological preoperative characteristics of the patients were associated with impaired patient-reported quality of life(QoL)and sexual outcomes 1 year after radical prostatectomy.We evaluated patient-reported outcomes among the 1343 men participating in the AndroCan trial(NCT02235142).QoL and erectile dysfunction(ED)were assessed before and 1 year after radical prostatectomy using validated self-assessment questionnaires(Aging Male's Symptoms[AMS]and the 5-item abridged version of the International Index of Erectile Function[IIEF5]).At baseline,1194 patients(88.9%)accepted to participate.A total of 750(55.8%)patients answered the 1-year postoperative questionnaires.Out of them,only 378(50.4%of responders)provided answers that could be used for calculations.One year after prostatectomy,ED had worsened by 8.0(95%confidence interval[CI]:7.3–8.7;P<0.0001)out of a maximum of 20.The global AMS score has worsened by 2.8(95%CI:1.7–3.8;P<0.0001).ED scores 1 year postsurgery were positively correlated with preoperative age and percentage of fat mass,and negatively correlated with total cholesterol,dehydroepiandrosterone(DHEA),and androstenediol(D5);AMS were poorly correlated with preoperative parameters.QoL and sexual symptoms significantly worsened after radical prostatectomy.Baseline bioavailable testosterone levels were significantly correlated with smaller changes on AMS somatic subscores postprostatectomy.These findings may be used to inform patients with newly diagnosed prostate cancer.