Estradiol increases cortical and trabecular bone accrual and bone strength in an adolescent male-to-female mouse model of gender-affirming hormone therapy

The effects of gender-affirming hormone therapy on the skeletal integrity and fracture risk in transitioning adolescent trans girls are unknown.To address this knowledge gap,we developed a mouse model to simulate male-to-female transition in human adolescents in whom puberty is first arrested by using gonadotrophin-releasing hormone analogs with subsequent estradiol treatment.Puberty was suppressed by orchidectomy in male mice at 5 weeks of age.At 3 weeks post-surgery,male-to-female mice were treated with a high dose of estradiol(~0.85 mg)by intraperitoneal silastic implantation for 12 weeks.Controls included intact and orchidectomized males at 3 weeks post-surgery,vehicle-treated intact males,intact females and orchidectomized males at 12 weeks post-treatment.Compared to male controls,orchidectomized males exhibited decreased peak bone mass accrual and a decreased maximal force the bone could withstand prior to fracture.Estradiol treatment in orchidectomized male-to-female mice compared to mice in all control groups was associated with an increased cortical thickness in the mid-diaphysis,while the periosteal circumference increased to a level that was intermediate between intact male and female controls,resulting in increased maximal force and stiffness.In trabecular bone,estradiol treatment increased newly formed trabeculae arising from the growth plate as well as mineralizing surface/bone surface and bone formation rate,consistent with the anabolic action of estradiol on osteoblast proliferation.These data support the concept that skeletal integrity can be preserved and that long-term fractures may be prevented in trans girls treated with GnRHa and a sufficiently high dose of GAHT.Further study is needed to identify an optimal dose of estradiol that protects the bone without adverse side effects.

Testosterone therapy reduces hepatic steatosis in men with type 2 diabetes and low serum testosterone concentrations

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is highly prevalent in people with diabetes with no available treatment.AIM To explore the effect of testosterone treatment on liver.Testosterone therapy improves insulin resistance and reduces total body fat,but its impact on the liver remains poorly studied.METHODS This secondary analysis of a 40 wk,randomised,double-blinded,placebocontrolled trial of intramuscular testosterone undecanoate in men with type 2 diabetes and lowered serum testosterone concentrations evaluated the change in hepatic steatosis as measured by liver fat fraction on magnetic resonance imaging(MRI).RESULTS Of 88 patients enrolled in the index study,39 had liver MRIs of whom 20 received testosterone therapy and 19 received placebo.All patients had>5%hepatic steatosis at baseline and 38 of 39 patients met diagnostic criteria for NAFLD.Median liver fat at baseline was 15.0%(IQR 11.5%-21.1%)in the testosterone and 18.4%(15.0%-28.9%)in the placebo group.Median ALT was 34units/L(26-38)in the testosterone and 32units/L(25-52)in the placebo group.At week 40,patients receiving testosterone had a median reduction in absolute liver fat of 3.5%(IQR 2.9%-6.4%)compared with an increase of 1.2%in the placebo arm(between-group difference 4.7%P<0.001).After controlling for baseline liver fat,testosterone therapy was associated with a relative reduction in liver fat of 38.3%(95%confidence interval 25.4%-49.0%,P<0.001).CONCLUSION Testosterone therapy was associated with a reduction in hepatic steatosis in men with diabetes and low serum testosterone.Future randomised studies of testosterone therapy in men with NAFLD focusing on liver-related endpoints are therefore justified.

Diagnosis and treatment of hypogonadism in older men： proceed with caution

Male hypogonadism, defined as clinical features of androgen deficiency combined with confirmed unequivocally low testosterone levels [1], is a straightforward diagnosis in younger men with tmderlying testicular and pituitary pathology. The diagnosis ofhypogonadism in older men is challenging, because of the non-specificity of symptoms and the age-related decline in testosterone levels which is accelerated by chronic disease and obesity.

Male androgen deficiency： a multisystem syndrome

Androgens have important effects on .multiple organ systems, which play critical roles in the regulation of a myriad of male sexual, somatic, and behavioral functions critical to lifelong health. Androgen deficiency is a multisystem syndrome, presenting with typical clinical features in association with a confirmed low serum testosterone level. The clinical presentation of androgen deficiency is modified by age and other patient-specific characteristics such as comorbidities, genetic, environmental, and sociocultural factors.

ndrogen-deprivation therapy in men with metastatic rostate cancer： less may not necessarily be more

In a pivotal phase 3 randomized con trolled trial, Hussain et al. tested thehypothesis that, with respect to survival, intermittent androgen deprivation therapy （ADT） is noninferior to continuous in men with newly diagnosed metastatic prostate cancer. While the trial findings were statis tically inconclusive, the study suggests, but does not prove, that intermittent may do more harm than good, although findings are not definitive. While outcomes of ongoing trials are awaited, the trial by Hussain et al., in conjunction with an ear lier trial in men with nonmetastatic pro state cancer by Crook et al., does provide important new guidance regarding the choice of ADT in men with androgensensitive prostate cancer. ADT is one of the most effective palliat ive therapies for patients with metastatic prostate cancer, but not without drawbacks. While not as toxic as chemotherapy, ADT carries a significant risk of morbidity, including sexual dysfunction, fatigue, ane mia, accelerated bone loss and fractures, sarcopenia, increased risk of diabetes, and possibly, of cardiovascular events.1＇2 In addition, despite an initial response rate of more than 90%, most patients develop res istance to ADT, resulting in a median sur vival of 2.53 years. Predinical data suggest that continuous use of ADT may accelerate the emergence of resistance to this therapy, and that reexposure of prostate cancer stem cells to androgens can reinduce dif ferentiation and increase their apoptotic potential.3 These ADTassociated shortcom ings, in addition to treatment expense, havespurred the development of strategies to min imize the exposure to ADT, including the use of intermittent ADT. While several smaller randomized controlled clinical trials have compared the use of intermittent with con tinuous ADT, no definitive information is available for patients with metastatic prostate cancer. To fill this evidence gap, a large mul tinational randomized controlled trial led by Hussain et al.4 was designed in 1993, and out comes have been published recently in the New England Journal of Medicine. In a coprimary end point, the authors tested the hypotheses that （i） intermittent ADT is not inferior to continuous ADT with respect to survival in men with metastatic, hormone sensitive prostate cancer; and （ii） compared to continuous therapy, intermittent ADT improves quality of life. The primary finding from the study was inconclusive, that is, intermittent ADT was not proven to be as good as continuous ADT, and there was instead a trend to inferiority. While intermit tent ADT was associated with better erectile function and mental health, this benefit did not persist beyond 3 months. Due to the inconclusive finding of this noninferiority trial its findings may be difficult to interpret and apply to clinical practice. Therefore, we explore this trial in more detail. The study by Hussain et al.4 enrolled 3040 men from the Unite States, Canada and UK who had newly diagnosed prostate cancer with lymph node, visceral or bone metastases and a prostatespecific antigen （PSA） 〉 5 ng ml 1. Men received a 7month induction course with a luteinizing hormone releasing hormone agonist and antiandrogen （goser elin and bicalutamide, or equivalent） to select androgendependent disease, defined by a PSA G〈 4 ng ml 1 at induction end. One thou sand five hundred and thirtyfive men fulfilled this criterion and were then rando mized but not blinded to intermittent orcontinuous ADT, stratified by performance status, prior hormone therapy and extent of disease. Men assigned to continuous therapy continued, whereas men assigned to intermit tent therapy discontinued ADT at completion of the 7-month induction course. The

Testicular volume and clinical correlates of hypothalamic–pituitary–testicular function:A cross-sectional study in obese men

The aim of this study was to determine whether testicular volume is correlated with clinical and biochemical markers of hypothalamic–pituitary–testicular(HPT)axis function.This was a cross-sectional substudy of a larger randomized controlled trial including obese men,body mass index(BMI)≥30 kg m−2,with a total testosterone level<12 nmol l−1.Testicular volume was measured by orchidometer,testosterone by liquid chromatography/tandem mass spectrometry,and body composition by dual-energy X-ray absorptiometry.Men completed the Aging Males'Symptoms(AMS)score,International Index of Erectile Function-5(IIEF-5),physical function,and handgrip dynamometer testing.Eighty-nine men participated with a median(interquartile range[IQR])age of 53.1(47.6,59.2)years,BMI of 37.0(34.6,40.5)kg m−2,and a total testosterone of 7.0(6.1,7.9)nmol l−1.Median testicular volume was 18(IQR:10,20)ml.Testicular volume was negatively correlated with BMI(τ=−0.1952,P=0.010)and total fat mass(τ=−0.2115,P=0.005)independent of age and testosterone.When BMI,testosterone,sex hormone-binding globulin(SHBG),and luteinizing hormone(LH)were present in a multivariable model,only BMI(-0.38 ml change in testicular volume per 1 kg m-2BMI;95%CI:−0.74,−0.02;P=0.04)and LH(-0.92 ml change in testicular volume per 1 IU l-1 LH;95%CI:−1.75,−0.095;P=0.03)remained independent significant predictors of testicular volume.Testicular volume was positively correlated with IIEF-5(τ=0.2092,P=0.021),but not related to handgrip strength,physical function tests,or AMS.In obese men,testicular volume is inversely and independently associated with measures of adiposity,but not with most clinical or biochemical markers of HPT axis action.From a clinical perspective,this suggests that obesity might compromise the reliability of reduced testicular volume as a sign of androgen deficiency in men.

Testosterone treatment in older men： glass half empty or half full？

In a series of randomized controlled trials published in JAMA and JAMA Intern Med,US researchers have examined the effect of testosterone treatment in older men with testosterone levels 〈275 ng dl^-1 on coronary artery plaque volume, cognitive function, anemia,and volumetric bone density.

Plasma miRNA expression profile in the diagnosis o＇ late-onset hypogonadism

Researchers reporting in the Nature journal Scientific Reports haveused next generation sequencing and quantitative reverse transcriptase PCR （RT-PCR） technology to profile plasma microRNA （miRNA） expression in cohorts of men with and without late-onset hypogonadism （LOH）. The study proposes a panel of three miRNAs as novel biomarkers to aid in the diagnosis of LOH.