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.

Development of methods of male contraception: impact of the World Health Organization Task Force

Objective: To give an historical record of the research of the World Health Organization (WHO) Task Force to develop methods of male contraception; to examine the social, political, medical, pharmaceutical, funding, and other factors that influenced progress; and to suggest reasons why such methods are only now becoming available. Design: Review of basic and clinical research over 30 years. Setting: Task force of a multinational agency and collaborating agencies. Conclusion(s): Through the involvement of many international scientists, the WHO Task Force has uniquely contributed to the exploratory phases of the research in male contraception and by its multicenter contraceptive efficacy studies has accelerated progress towards the ideal hormonal method. Despite an adverse climate involving social and political attitudes, funding constraints, and pharmaceutical industry hesitations, WHO formed coalitions with governments and international agencies to sustain research with results that apply to men in culturally diverse populations and thereby to influence activities across the whole range of global reproductive health and family planning.

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs.Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.

Arthritis and the role of endogenous glucocorticoids

Rheumatoid arthritis and osteoarthritis,the most common forms of arthritis,are chronic,painful,and disabling conditions.Although both diseases differ in etiology,they manifest in progressive joint destruction characterized by pathological changes in the articular cartilage,bone,and synovium.While the potent anti-inflammatory properties of therapeutic(i.e.,exogenous)glucocorticoids have been heavily researched and are widely used in clinical practice,the role of endogenous glucocorticoids in arthritis susceptibility and disease progression remains poorly understood.Current evidence from mouse models suggests that local endogenous glucocorticoid signaling is upregulated by the pro-inflammatory microenvironment in rheumatoid arthritis and by aging-related mechanisms in osteoarthritis.Furthermore,these models indicate that endogenous glucocorticoid signaling in macrophages,mast cells,and chondrocytes has anti-inflammatory effects,while signaling in fibroblast-like synoviocytes,myocytes,osteoblasts,and osteocytes has pro-inflammatory actions in rheumatoid arthritis.Conversely,in osteoarthritis,endogenous glucocorticoid signaling in both osteoblasts and chondrocytes has destructive actions.Together these studies provide insights into the role of endogenous glucocorticoids in the pathogenesis of both inflammatory and degenerative joint disease.

Androgen abuse in sports

Androgens remain the most effective and widely abused ergogenic drugs in sport. Although androgen doping has been prohibited for over 3 decades with a ban enforced by mass spectrometric （MS）-based urine testing for synthetic and exogenous natural androgens, attempts continue to develop increasingly complex schemes to circumvent the ban. A prominent recent approach has been the development of designer androgens. Such never-marketed androgens evade detection because mass spectrometry relies on identifying characteristic chemical signatures requiring prior knowledge of chemical structure. Although once known, designer androgens are readily detected and added to the Prohibited List. However, until their structures are elucidated, designer androgens can circumvent the ban on androgen doping. To combat this, in vitro androgen bioassays offer powerful new possibilities for the generic detection of unidentified bioactive androgens, regardless of their chemical structure. Another approach to circumvent the ban on androgen doping has been the development of indirect androgen doping, the use of exogenous drugs to produce a sustained increase in endogenous testosterone （T） production. Apart from estrogen blockers, however, such neuroendocrine active drugs mostly provide only transient increases in blood T. Finally the ban on androgen doping must allow provision for rare athletes with incidental, proven androgen deficiency who require T replacement therapy. The Therapeutic Use Exemption mechanism makes provision for such necessary medical treatment, subject to rigorous criteria for demonstrating a genuine ongoing need for T and monitoring of T dosage. Effective deterrence of sports doping requires novel, increasingly sophisticated detection options calibrated to defeat these challenges, without which fairness in sport is tarnished and the social and health idealization of sporting champions devalued.

Loss of the vitamin D receptor in human breast and prostate cancers strongly induces cell apoptosis through downregulation of Wnt/β-catenin signaling

Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D, 1,25-dihydroxy-vitamin D [1,25（OH）2D] are mediated through binding to the vitamin D receptor （VDR）. Here, we report on the unexpected finding that stable knockdown of VDR expression in the human breast and prostate cancer cell lines, MDA-MB-231 and PC3, strongly induces cell apoptosis and inhibits cell proliferation in vitro. Implantation of these VDR knockdown cells into the mammary fat pad （MDA-MB-231）, subcutaneously （PC3） or intra-tibially （both cell lines） in immune-incompetent nude mice resulted in reduced tumor growth associated with increased apoptosis and reduced cell proliferation compared with controls. These growth-retarding effects of VDR knockdown occur in the presence and absence of vitamin D and are independent of whether cells were grown in bone or soft tissues. Transcriptome analysis of VDR knockdown and non-target control cell lines demonstrated that loss of the VDR was associated with significant attenuation in the Wnt/0-catenin signaling pathway. In particular, cytoplasmic and nuclear β-catenin protein levels were reduced with a corresponding downregulation of downstream genes such as Axin2, Cyclin D1, interleukin-6 （IL-6）, and IL-8. Stabilization of 0-catenin using the GSK-3β inhibitor BIO partly reversed the growth-retarding effects of VDR knockdown. Our results indicate that the unliganded VDR possesses hitherto unknown functions to promote breast and prostate cancer growth, which appear to be operational not only within but also outside the bone environment. These novel functions contrast with the known anti-proliferative nuclear actions of the liganded VDR and may represent targets for new diagnostic and therapeutic approaches in breast and prostate cancer.

Endogenous Glucocorticoids and Bone

While the adverse effects of glucocorticoids on bone are well described, positive effects of glucocorticoids on the differentiation of osteoblasts are also observed. These paradoxical effects of glucocorticoids are dose dependent. At both physiologicaland supraphysiological levels of glucocorticoids, osteoblasts and osteocytes are the major glucocorticoid target cells. However, the response of the osteoblasts to each of these is quite distinct. At physiology levels, glucocorticoids direct mesenchymal progenitor cells to differentiate towards osteoblasts and thus increase bone formation in a positive way. In contrast with ageing, the excess production of glucocorticoids, at both systemic and intracellular levels, appear to impact on osteoblast and osteocytes in a negative way in a similar fashion to that seen with therapeutic glucocorticoids. This review will focus on therole of glucocorticoids in normal bone physiology, with particular emphasis on the mechanism by which endogenous glucocorticoids impact on bone and its constituent cells.

Rationale and Design of the Randomized Controlled Trial of Intensive Versus Usual ECG Screening for Atrial Fibrillation in Elderly Chinese by an Automated ECG System in Community Health Centers in Shanghai(AF-CATCH)

Objective:The randomized controlled trial(ClinicalTrials.gov identifier NCT02990741)will investigate whether more frequent electrocardiographic(ECG)recordings and analyses with an automated ECG system would improve detection of atrial fibrillation compared with a single annual ECG screen in elderly Chinese in community health centers.Design:Men and women(≥65 years)will be randomized into intensive(n=3500)and usual(n=3500)screening groups,and within the intensive screening group into intensive screening(n=2625)and more intensive screening(n=875)subgroups.ECG recordings will be performed with an automated ECG analysis system(AliveCor heart monitor)at 1 year in the usual screening group,at 3,6,9,and 12 months in the intensive screening subgroup,and at 1,2,3,and 4 weeks and 3,6,9,and 12 months in the more intensive screening subgroup.The primary outcome is the detection rate of atrial fibrillation between the usual screening group and the intensive screening group.Sample size estimation was based on a projected detection rate of atrial fibrillation of 2.0% by a single ECG recording at 12 months,an improvement of 50% with more frequent ECG recordings,α=0.05,power of 80%,and a one-sided test.Conclusions:The trial will provide evidence on the clinical effectiveness of more frequent ECG recordings by a handheld automated analysis system in the detection of atrial fibrillation.

精子生成和性生活的客观非侵人性标记物

Objective studies of men＇s reproductive function are hindered by their reliance on： （i） self-reporting to quantify sexual activity and （ii） masturbation to quantify sperm output rendering both types of estimate vulnerable to unverifiable subjective factors. We therefore examined whether detection of spermatozoa and measurement of prostate-specific antigen （PSA） in urine could provide objective semiquantitative estimates of sperm output and recent ejaculation, respectively, using widely available laboratory techniques. Of 11 healthy volunteers who provided urine samples before and at intervals for 5 days after ejaculation, sperm was present in 2111 men before, and in all 11111 samples immediately after ejaculation, but by the second and subsequent void, spermatozoa were present in -10%. PSA was detectable at high levels in all urine samples, peaking at the first post-ejaculatory sample but returning to baseline levels by the second post-ejaculatory void. We conclude that urinary spermatozoa and PSA are objective biomarkers for sperm production and sexual activity, but only for a short-time window until the first post-ejaculatory urine void. Hence, for a single urine specimen, the presence of spermatozoa and PSA are valid biomarkers, reflecting sperm production and recent ejaculation only until the next micturition, so their measurement should be restricted to the first morning urine void.

Osteoblastic glucocorticoid signaling exacerbates high-fat-diet-induced bone loss and obesity

Chronic high-fat diet(HFD)consumption not only promotes obesity and insulin resistance,but also causes bone loss through mechanisms that are not well understood.Here,we fed wild-type CD-1 mice either chow or a HFD(43%of energy from fat)for 18 weeks;HFD-fed mice exhibited decreased trabecular volume(-28%)and cortical thickness(-14%)compared to chow-fed mice.In HFD-fed mice,bone loss was due to reduced bone formation and mineral apposition,without obvious effects on bone resorption.HFD feeding also increased skeletal expression of sclerostin and caused deterioration of the osteocyte lacunocanalicular network(LCN).In mice fed HFD,skeletal glucocorticoid signaling was activated relative to chow-fed mice,independent of serum corticosterone concentrations.We therefore examined whether skeletal glucocorticoid signaling was necessary for HFD-induced bone loss,using transgenic mice lacking glucocorticoid signaling in osteoblasts and osteocytes(HSD2^(OB/OCY)-tg mice).In HSD2^(OB/OCY)-tg mice,bone formation and mineral apposition rates were not suppressed by HFD,and bone loss was significantly attenuated.Interestingly,in HSD2^(OB/OCY)-tg mice fed HFD,both Wnt signaling(less sclerostin induction,increased P<atenin expression)and glucose uptake were significantly increased,relative to diet-and genotype-matched controls.The osteocyte LCN remained intact in HFD-fed HSD2^(OB/OCY)-tg mice.When fed a HFD,HSD2^(OB/OCY)-tg mice also increased their energy expenditure and were protected against obesity,insulin resistance,and dyslipidemia.Therefore,glucocorticoid signaling in osteoblasts and osteocytes contributes to the suppression of bone formation in HFD-fed mice.Skeletal glucocorticoid signaling is also an important determinant of glucose uptake in bone,which influences the whole-body metabolic response to HFD.

《亚洲男性学杂志》“21世纪精液分析特刊”前言

精液分析成为不育研究的重要部分经历了一个极其漫长的历史变迁过程，并声名狼藉，曾经被排除在常规的病理学检查之外，直到近些年才引起学术界的重视。精液分析起源于19世纪，那时对精子的认识仅仅局限于检测性交后宫颈黏液中是否存在精子，曾认为是“有失体面的，不自重的^[1]。”

《亚洲男性学杂志》“21世纪精液分析特刊”后序

对这期特刊中各位作者讨论的主题予以总结和评论。

Early infant male circumcision:Systematic review,risk-benefit analysis,and progress in policy

AIM To determine whether recent evidence-based United States polices on male circumcision(MC) apply to comparable Anglophone countries,Australia and New Zealand.METHODS Articles in 2005 through 2015 were retrieved from PubM ed using the keyword "circumcision" together with 36 relevant subtopics.A further PubM ed search was performed for articles published in 2016.Searches of the EMBASE and Cochrane databases did not yield additional citable articles.Articles were assessed for quality and those rated 2+ and above according to the Scottish Intercollegiate Grading System were studied further.The most relevant andrepresentative of the topic were included.Bibliographies were examined to retrieve further key references.Randomized controlled trials,recent high quality systematic reviews or meta-analyses(level 1++ or 1+ evidence) were prioritized for inclusion.A risk-benefit analysis of articles rated for quality was performed.For efficiency and reliability,recent randomized controlled trials,metaanalyses,high quality systematic reviews and large welldesigned studies were used if available.Internet searches were conducted for other relevant information,including policies and Australian data on claims under Medicare for MC.RESULTS Evidence-based policy statements by the American Academy of Pediatrics(AAP) and the Centers for Disease Control and Prevention(CDC) support infant and later age male circumcision(MC) as a desirable public health measure.Our systematic review of relevant literature over the past decade yielded 140 journal articles that met our inclusion criteria.Together,these showed that early infant MC confers immediate and lifelong benefits by protecting against urinary tract infections having potential adverse long-term renal effects,phimosis that causes difficult and painful erections and "ballooning" during urination,inflammatory skin conditions,inferior penile hygiene,candidiasis,various sexually transmissible infections in both sexes,genital ulcers,and penile,prostate and cervical cancer.Our risk-benefit analysis showed that benefits exceeded procedural risks,which are predominantly minor,by up to 200 to 1.We estimated that more than 1 in 2 uncircumcised males will experience an adverse foreskin-related medical condition over their lifetime.Wide-ranging evidence from surveys,physiological measurements,and the anatomical location of penile sensory receptors responsible for sexual sensation strongly and consistently suggested that MC has no detrimental effect on sexual function,sensitivity or pleasure.United States studies showed that early infant MC is cost saving.The evidence supporting early infant MC has further strengthened since the positive AAP and CDC reviews.CONCLUSION Affirmative MC policies are needed in Australia and New Zealand.Routine provision of accurate,unbiased education,and access in public hospitals,will maximize health and financial benefits.

体育运动中通过阻断雌激素间接使用雄性激素兴奋剂

雄激素具有增加肌肉和力量的作用,是体育运动中使用最广泛的兴奋剂,各种天然的或合成的雄激素均在禁用之列.但由此却导致许多人寻找各种增加内源性雄激素的方法来达到间接使用雄激素的目的,如增加体内黄体生成素(LH)以刺激LH依赖的睾丸间质细胞合成和分泌睾酮,应用雌激素受体阻断剂或芳香化酶抑制剂以阻断雌激素等.……

An old emperor finds new clothing： rejuvenation in our time

Those who don＇t understand their history are condemned to repeat it （Santayana） History repeats itself, first as tragedy and then as farce （Marx）

Falling sperm counts and global oestrogenic pollution：postscript

This Special Issue provides reflections after 20 years, summarized in 12 papers, on the controversial issue of alleged decline in human sperm output due to global oestrogen pollution by industrial chemicals.

Hormones and sport： physiology, pharmacology ＆ forensic science

Sport is probably the most ubiquitous voluntary human social activity. Defined as the playing of competitive games according to rules, sport forms a microcosm of human society that combines playfulness （＂homo ludens＂）, healthfulness,

DNA damage, NF-κB and accelerated aging

The aging process is the major risk factor for disease and disability yet the cel- lular mechanisms for aging are uncertain.

Vlendelian randomization： loosening the Gordian knot of testosterone and male ageing

It is unknown whether the reduced blood testosterone among unselected older men （＂andropause＂） compared to healthy younger men is due to ageing per se or as a non-specific adaptive reaction to chronic diseases accumulating during ageing.

The skeleton gets a （reproductive） life

To most well-informed scientists who do not work on bone, the idea that bones determine anything other than your posture and location for the miseries of arthritis would come as quite a surprise. It would be like imagining that the walls of our home played something more than a passive role in the complexities of the lives conducted within. Yet something precisely as radical as that is what Karsenty and his colleagues boldly imagined,1 and then provocatively established in a series of studies over the past decade.20steocalcin （OCN） is a vitamin K- dependent peptide hormone secreted by the bone-formine osteoblasts.