The Effect Of Testosterone Synthesis And Conversion On Serum Testosterone Levels In Obese Men

[Background]Overweight and obesity have reached epidemic proportions globally.Obesity in men is associated with male infertility.It has a great risk of suffering from testosterone levels decreased and spermatogenesis impaired.Testosterone is the major sex hormone in males,and it is synthesis by a series of testosterone synthetic enzymes in the Leydig cells,such as steroidogenic acute regulatory protein(StAR),cytochrome P450 cholesterol-side-chain cleavage enzyme(P450scc)and 3?-hydroxysteroid dehydrogenase(3?-HSD),which is stimulated by luteinizing hormone(LH).Testosterone also can converts to estradiol via aromatase enzyme,aromatase converts androgens into estrogens irreversibly,the increase in estradiol levels feedback negatively suppresses the hypothalamic-pituitary-testicular(HPT)axis,further reducing the secretion of testosterone,whereas the adipose tissue is an important site of estrogens biosynthesis in men,the expression of aromatase is proportional to body fat mass.In previous studies always ignored the role of testosterone conversion in obese men,to further explore the influence factors on serum testosterone levels,so as to provide a new targeted therapy for male obesity-associated hypogonadism,we carried on the related research.[Objective]The objective of this study was to examine testosterone synthesis and conversion and to systematically analyze the factors that influence decreased testosterone levels in male obesity,in order to provide theoretical basis for clinical diagnosis and treatment.[Methods]302 human male subjects(aged 25-45 years old)in Jinan community were included.According to BMI,subjects were divided into normal weight:18.5-23.9 kg/m2;overweight:24-27.9 kg/m2;and obesity:?28 kg/m2.Anthropometric measurements and serum parameters were collected.The triglyceride(TG),total cholesterol(TC),high-density lipoprotein cholesterol(HDL),low-density lipoprotein cholesterol(LDL)and fasting plasma glucose(FPG)levels were measured using the BECKMAN Chemistry Analyzer.Serum testosterone,estradiol,sex hormone-binding globulin(SHBG),LH and follicle stimulating hormone(FSH)levels were measured in serum by using Cobas assay and serum aromatase levels was measured using ELISA.Male C57BL/6 mice were divided into 2 groups:normal diet group(ND)and high-fat diet induced obesity group(HFD).Serum sex hormones,serum aromatase and adipose tissue aromatase were measured using ELISA.Testosterone synthetic enzymes were measured in testis by reverse transcription polymerase chain reaction(RT-PCR).[Result]The serum testosterone levels in the overweight(4.84�1.42,ng/ml)and obesity(4.23�1.39,ng/ml)were significantly decreased compared to the normal weight(6.28�2.01,ng/ml;p=0.00).Testosterone to estradiol(T/E2)ratio can serve as a surrogate marker of aromatase.In our study,a significant reduction of T/E2 ratio in the overweight(0.175�0.777)and obesity(0.147�0.68)compared to the normal weight(0.231 �0.117;p=0.00).BMI was significant correlated positively and linearly with fasting insulin(FINS),HOMA-IR and free testosterone index(FTI),negatively and linearly with serum testosterone,T/E2ratio,LH and SHBG levels.Serum LH levels were associated with testosterone levels after multivariate regression analysis.No differences were observed in serum aromatase among the groups,and testosterone was not correlated with aromatase.In mice,steroidogenic acute regulatory protein(StAR)was decreased in the HFD group compared to the ND group,whereas the aromatase levels in subcutaneous adipose tissue were higher in the ND group than in the HFD group.[Conclusion]Obesity in young men can lead to insulin resistance,serum testosterone and SHBG levels decreased.Males serum LH levels can promote the synthesis and release of testosterone.This study suggested that decreased testicular synthesis function was more important than conversion of testosterone for explaining the reduction in testosterone levels in male obesity.Obesity has increased dramatically worldwide,which is associated with male infertility.Androgen deficiency,impaired spermatogenesis and erectile dysfunction are characteristics of male infertility.The balance of androgens and estrogens is essential for maintaining normal reproductive function in males.Aromatase,the rate-limiting enzyme in the conversion of androgens into estrogens,is present in various tissues.The expression of aromatase is proportional to body fat mass and causes more fat accumulation,thus forming a vicious cycle.Excessive aromatase activity in adipose tissue leads to increased conversion of androgens into estrogens,eventually results in a reduction of testosterone levels and is the underlying reason for obesity-related infertility.In the male reproductive system,all testicular somatic cells and germ cells express aromatase,except for peritubular myoid cells.The results of studies regarding the effect of aromatase in testicular somatic cells and germ cells have been contradictory.The effect of estrogens in testicular somatic cells is inhibitory,leading to reduced testosterone levels and sperm production;however,it has been observed that aromatase participates in the acquisition of sperm motility.The overall effect of estrogen modulation is an inhibition of spermatogenesis.Aromatase inhibitors are an effective therapy for obesity-associated hypogonadism because they restore normal sex hormone levels and improve semen parameters.This article systematically introduces the basic knowledge of aromatase and provides information of the current advances relating to aromatase in male reproductive function.Increasing our knowledge on the role of aromatase in male obesity could help in proposing new approaches to treat infertile men.