Estrogens in males: what have we learned in the last 10 years?

This review focuses on the role of estrogen in men, mainly in male reproduction. The continuing increase in data obtained, and recent discoveries in this area will enable a better understanding of male physiology; these, in turn, will have important clinical implications.

Role of Estrogens on Human Male Reproductive System

This review focuses on estrogen role on human male physiology. Biological estrogen actions on male reproductive system are summarized with particular regard to the effects of congenital estrogen deprivation in men. The effects of estrogen on spermatogenesis, hormonal secretion and gonadotropin feedback and on sexual behavior are discussed. It is remarked that the role of estrogens in male reproduction is a very recent acquisition in reproductive endocrinology, but it promises new future fields of research to be investigated as well as the possible disclosure of new strategies in clinical practice.

The effect of environmental contaminants on testicular function

Male reproductive health has deteriorated considerably in the last few decades. Nutritional, socioeconomic, lifestyle and environmental factors （among others） have been attributed to compromising male reproductive health. In recent years, a large volume of evidence has accumulated that suggests that the trend of decreasing male fertility （in terms of sperm count, quality and other changes in male reproductive health） might be due to exposure to environmental toxicants. These environmental contaminants can mimic natural oestrogens and target testicular spermatogenesis, steroidogenesis, and the function of both Sertoli and Leydig cells. Most environmental toxicants have been shown to induce reactive oxygen species, thereby causing a state of oxidative stress in various compartments of the testes. However, the molecular mechanism（s） of action of the environmental toxicants on the testis have yet to be elucidated. This review discusses the effects of some of the more commonly used environmental contaminants on testicular function through the induction of oxidative stress and apoptosis.

Endocrine disruptors and estrogenic effects on male reproductive axis

Endocrine disruptors （e.g., polychlorinated biphenyls [PCBs], dichlorodiphenyl-trichloroethane [DDT], dioxin, and some pesticides） are estrogen-like and anti-androgenic chemicals in the environment. They mimic natural hormones, inhibit the action of hormones, or alter the normal regulatory function of the endocrine system and have potential hazardous effects on male reproductive axis causing infertility. Although testicular and prostate cancers, abnormal sexual development, undescended testis, chronic inflammation, Sertoli-cell-only pattern, hypospadias, altered pituitary and thyroid gland functions are also observed, the available data are insufficient to deduce worldwide conclusions. The development of intra-cytoplasmic sperm injection （ICSI） is beyond doubt the most important recent breakthrough in the treatment of male infertility, but it does not necessarily treat the cause and may inadvertently pass on adverse genetic consequences. Many well-controlled clinical studies and basic scientific discoveries in the physiology, biochemistry, and molecular and cellular biology of the male reproductive system have helped in the identification of greater numbers of men with male factor problems. Newer tools for the detection of Y-chromosome deletions have further strengthened the hypothesis that the decline in male reproductive health and fertility may be related to the presence of certain toxic chemicals in the environment. Thus the etiology, diagnosis, and treatment of male factor infertility remain a real challenge. Clinicians should always attempt to identify the etiology of a possible testicular toxicity, assess the degree of risk to the patient being evaluated for infertility, and initiate a plan to control and prevent exposure to others once an association between occupation/toxicant and infertility has been established.

Estrogen,male dominance and esophageal adenocarcinoma:Is there a link?

Esophageal adenocarcinoma is a cancer with poor prognosis, and its incidence has risen sharply over recent decades. Obesity is a major risk factor for developing this cancer and there is a clear male gender bias in the incidence that cannot be fully explained by known risk factors. It is possible that a difference in the expression of estrogen, or its signaling axes, may contribute to this gender bias. We undertook a com- prehensive literature search and analyzed the available data regarding estrogen and estrogen receptor expres- sion, and the possible sex-specific links with esopha- geal adenocarcinoma development. Potentially relevant associations between visceral vs subcutaneous fat deposition and estrogen expression, and the effect of crosstalk between estrogen and leptin signaling were identified. We also found limited studies suggesting a role for estrogen receptor 13 expression in esophageal adenocarcinoma development. The current literature supports speculation on an etiological role for estrogen in the male gender bias in esophageal adenocarcino- ma, but further studies are required.

Androgens and estrogens in skeletal sexual dimorphism

Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone （T） to estradiol （E2） by aromatase, or to dihydrotestosterone by 5（x-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of （high resolution） peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refined our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen deficiency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the field of sex steroid actions in male bone homeostasis.

Psychological capital mediates the association between nurses'practice environment and work engagement among Chinese male nurses

Objectives:This study aims to investigate the environmental and individual factors contributing to male nurses'psychological well-being and to explore the psychological mechanisms that may explain the links between nurses'practice environment and work engagement,thereby presenting the implications for nurse managers.Methods:A total of 161 male nurses from three tertiary first-class hospitals in Changsha City in China participated in the study.We collected the data using the Practice Environment Scale of the Nursing Work Index,the Psychological Capital Questionnaire,and the Utrecht Work Engagement Scale.Results:Scores of male nurses'practice environment(2.88±0.31),psychological capital(4.42±0.62),and work engagement(3.17±1.39)were all above the midpoint;however,the subscales"the nursing staffing and resources adequacy"(2.72±0.48),"hope"(4.33±0.72),and"dedication"(2.96±1.61)scored lowest.Nurses'practice environment and psychological capital positively predicted nurses'work engagement;psychological capital fully mediated the influence of nurses'practice environment on work engagement.Conclusions:Creating a supportive nursing practice environment can increase male nurses'work engagement by developing their psychological capital.Nurse managers can then provide reasonable workload and pathways for male nurses to achieve goals,thereby fostering their hope.

Environmental mercury exposure, semen quality and reproductive hormones in Greenlandic Inuit and European men： a cross-sectional study

Several animal studies indicate that mercury is a male reproductive toxicant, but human studies are few and contradictory. We examined semen characteristics and serum levels of reproductive hormones in relation to environmental exposure to mercury. Blood and semen samples were collected from 529 male partners of pregnant women living in Greenland, Poland and Ukraine between May 2002 and February 2004. The median concentration of the total content of mercury in whole blood was 9.2 ng ml-1 in Greenland （0.2- 385.8 ng ml-1）, 1.0 ng m1-1 in Poland （0.2-6.4 ng ml-z） and 1.0 ng ml-I in Ukraine （0.2-4.9 ng ml-1）. We found a significantly positive association between the blood levels of mercury and serum concentration of inhibin B in men from Greenland （p=0.074, 95% confidence interval （CI）=0.021 to 0.126） and in an analysis including men from all three regions （p=0.067, 95% C1=0.024 to O. 110）. The association may be due to beneficial effects of polyunsaturated fatty acids （PUFAs）, which are contained in seafood and fish. No significant association （P〉O.05） was found between blood concentrations of mercury and any of the other measured semen characteristics （semen volume, total sperm count, sperm concentration, morphology and motility） and reproductive hormones （free androgen index {FAI）, follicle-stimulating hormone （FSH）, luteinizing hormone （LH）, testosterone and LH xtestosterone） in any region. In conclusion, the findings do not provide evidence that environmental mercury exposure in Greenlandic and European men with median whole blood concentration up to 10 ng m1^-1 has adverse effects on biomarkers of male reproductive health.

Inhibitory Effect of Estrogens,Phytoestrogens,and Caloric Restriction on Oxidative Stress and Hepato-toxicity in Aged Rats

Objective To investigate the protective effect of 17β-estradiol （E2）, peganum harmala extract （PHE） administration and calorie restriction （CR） treatment （60%） on oxidative stress and hepato-toxicity in aged rats. Methods Eighteen months old animals that were treated at the age of 12 months were divided into 4 groups： normal control group with free access to food, E2 treatment group, PHE treatment group and CR treatment group of the food given to control group. Six male rats at the age of 4 months were used as a reference group. Results Aging significantly decreased superoxide dismutase （SOD）, catalase （CAT） and glutathione peroxidase （GPX）, and increased lactate deshydrogenase （LDH）, gamma-glyiamyl transferase （GGT）, pbosphatase alkalines （PAL）, aspartate and lactate transaminase （AST and ALT） activities in the liver. Aging also induced an increased lipid peroxidation level, histological changes and a decreased E2 level. However, treatment with E2, PHE, and CR increased 17β-estradiol, and decreased hepatic dysfunction parameters and lipid peroxidation as well as histological changes in the liver of aged rats. Conclusion The antioxidant and hepatoprotective activity of PHE and CR is possibly attributed to its ability to increase E2 level, which as an antioxidant, acts as a scavenger of ROS. Further studies on the pharmaceutical functions of E2 in males may contribute to its clinical application.

Full sexual maturity-cycle exposure to environmentally relevant concentrations of 17β-estradiol decreases reproductive capacity of zebrafish

17β-Estradiol(E2)has been widely detected in natural water and treatment with E2 induces potential endocrine disrupting effects in fish.However,effects on fish fecundity and steroid system after treatment with environmentally relevant concentrations of E2 for the full sexual maturation cycle remain unclear.In this study,zebrafish were treatment with 0,10 or100 ng/L E2 from embryo to adult stage,and effects on gonadal development and differentiation,steroid hormone levels,transcription of genes associated with the hypothalamic-pituitary-gonadal-liver(HPG)axis in adults and fertilization rate of offspring were assessed.The results showed that treatment with E2 lead to increased number of feminization in zebrafish.In females,E2 decreased cumulative amount of spawning and inhibited the maturation of oocyte.In males,E2 inhibited the maturation and motility of sperm,as well as decreased the movement speed of sperm.These adverse effects on sperm might be responsible for the reduced fertilization observed in offspring.In addition,treatment with E2 changed the levels of steroid hormones in zebrafish gonad and altered the transcriptional levels of genes associated with HPG axis,which is responsible for the regulation of germ cells maturation and gonadal development in zebrafish.Overall,these results suggested that treatment with environmentally relevant concentrations of E2 for the full sexual maturity cycle resulted in adverse effects on reproduction in zebrafish.

Will male semen quality improve with environmental quality?

Wenzhou has improved its environmental quality because of comprehensive environmental remediation;nevertheless,the semen quality of infertile males remains unclear.This study determined whether better environmental quality improved semen quality in this region.We recorded semen quality data from 22962 infertile males from January 2014 to November 2019 at the Center for Reproductive Health of The First Affiliated Hospital of Wenzhou Medical University(Wenzhou,China).Patients were predominantly 30–35 years old(33.1%)and workers(82.0%),with high school education or lower(77.6%);more than a half of the patients(52.6%)were Wenzhou household registration;and most patients(77.5%)had abnormal semen quality.Patients who were older than 40 years and workers,and those with Wenzhou household registration,had significantly worse semen quality(all P<0.05).From 2014 to 2019,progressive sperm motility,total sperm motility,and semen volume showed increasing linear trends in all patients(P=0.021,0.030,and 0.005,respectively),yet normal sperm morphology showed a linearly decreasing trend(P=0.046).Sensitivity analyses for subgroups yielded similar results.In conclusion,the improvement of environmental quality and better function of the accessory glands are associated with progressive sperm motility,total sperm motility,and semen volume.Normal sperm morphology is influenced by occupational exposures and personal lifestyle and does not improve with environmental quality.

活性污泥中噬菌体的环境雌激素降解功能研究

环境雌激素(EEs)随污水排入自然水体,具有较大的生态环境风险和人体健康风险。采用宏基因组测序技术对普通活性污泥和双酚A(BPA)、邻苯二甲酸二丁酯(DBP)、壬基酚(NP)富集污泥中的噬菌体基因组进行分析发现,普通活性污泥和EEs富集污泥中可以鉴定的噬菌体均以管病毒科(Siphoviridae)、肌病毒科(Myoviridae)和足病毒科(Podoviridae)为主,但是不同污泥的噬菌体相对丰度组成存在显著差异。通过对噬菌体基因组进行功能基因注释发现,BPA富集污泥和NP富集污泥中管病毒科噬菌体分别有编码苯酚单加氧酶和脱氢酶的基因,有助于芳香族有机物矿化去除。噬菌体的细菌宿主分析发现,噬菌体广泛寄生于各类细菌,但主要是BPA富集污泥中有编码羟基化功能的苯酚单加氧酶基因的管病毒科噬菌体具有BPA降解功能,即具有重要的潜在辅助代谢EEs功能。

Bioassay of Estrogenic Activity of Effluent and Influent in a Farm Wastewater Treatment Plant Using an in vitro Recombinant Assay with Yeast Cells

Objective Environmental estrogens at an elevated concentration are known to produce adverse effects on human and animal life. However, the majority of researches have been focused on industrial discharges, while the impact of livestock wastes as a source of endocrine disrupters in aquatic environments has been rarely elucidated. In order to investigate the contribution of environmental estrogens from livestock, the estrogenic activity in water samples from a farm wastewater treatment plant was analyzed by a recombinant yeast screening method. Methods The extracts prepared from 15 selected water samples from the farm wastewater treatment plant, among which 6 samples were from pre-treatment section （influents） and 9 from post-treatment section （effluents）, were analyzed for estrogenic activity by cellar bioassay. Yeast cells transfected with the expression plasmid of human estrogen receptor and the Lac Z reporter plasmid encoding β-galactossidase, were used to measure the estrogen-like compounds in the farm wastewater treatment plant. Results The wastewater samples from influents showed a higher estrogenic potency than the effluent samples showing a low induction of β-galactossidase relative to solvent control condition. By comparison with a standard curve for 17β-estradiol （E2）, estrogenic potency in water samples from the influents was calculated as E2-equivalent and ranged from 0.1 to 150 pM E2-equivalent. The estrogenic potency in water samples from the effluents was significantly lower than that in the influents, and 7 water samples had less detectable limit in the total of 9 samples. Conclusion Yeast bioassay of estrogenic activity in most of the samples from the farm wastewater after disposal by traditional sewage treatment showed negative results.

Decline of semen quality among 10 932 males consulting for couple infertility over a 20-year period in Marseille, France

Semen from 10 932 male partners of infertile couples was analysed and sperm parameter trends were evaluated at the Reproduction Biology Laboratory of the University Hospital of Marseille （France） between 1988 and 2007. After 3-6 days of abstinence, semen samples were collected. Measurements of seminal fluid volume, pH, sperm concentration, total sperm count, motility and detailed morphology of spermatozoa were performed. Sperm parameters were analysed on the entire population and in men with normal total numeration （ 〉~ 40 million per ejaculate）. The whole population demonstrated declining trends in sperm concentration （1.5% per year）, total sperm count （1.6% per year）, total motility （0.4% per year）, rapid motility （5.5% per year） and normal morphology （2.2% per year）. In the group of selected samples with total normal sperm count, the same trends of sperm quality deterioration with time were observed. Our results clearly indicate that the auality of semen decreased in this population over the study period.

Treatment of hypogonadotropic male hypogonadism: Case-based scenarios

The aim of this study is to review four case-based scenarios regarding the treatment of symptomatic hypogonadism in men. The article is designed as a review of published literature. We conducted a PubMed literature search for the time period of 1989-2014, concentrating on 26 studies investigating the effcacy of various therapeutic options on semen analysis, pregnancy outcomes, time to recovery of spermatogenesis, as well as serum and intratesticular testosterone levels. Our results demonstrated thatexogenous testosterone suppresses intratesticular testosterone production, which is an absolute prerequisite for normal spermatogenesis. Cessation of exogenous testosterone should be recommended for men desiring to maintain their fertility. Therapies that protect the testis involve human chorionic gonadotropin （hCG） therapy or selective estrogen receptor modulators （SERMs）, but may also include low dose hCG with exogenous testosterone. Off-label use of SERMs, such as clomiphene citrate, are effective for maintaining testosterone production long-term and offer the convenience of representing a safe, oral therapy. At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data. We concluded that exogenous testosterone supplementation decreases sperm production. It was determined that clomiphene citrate is a safe and effective therapy for men who desire to maintain fertility. Although less frequently used in the general population, hCG therapy with or without testosterone supplementation represents an alternative treatment.

Expression of estrogen receptor (ER) -α and -βtranscripts in the neonatal and adult rat cerebral cortex, cerebellum, and olfactory bulb

In the present study expression of estrogen receptor subtype -alpha (ERalpha) and -beta (ERbeta) in the cerebral cortex, cerebellum, and olfactory bulb was investigated and compared between neonatal (1 to approximately 3-days-old) and adult (250 to approximately 350 g) rats, using reverse transcription-polymerase chain reaction (RT-PCR). No ERalpha transcripts were detectable in the adult cerebellum and olfactory bulb, whereas very weak expression of ERalpha was present in the adult cerebral cortex. No significant difference in ERbeta transcripts was detectable between the neonatal and adult rats. While transcripts for both ER subtypes were co-expressed in these brain areas of neonatal rats, although ERalpha expression was significantly weaker than ERbeta. Even in the cerebral cortex known to contain both ER subtypes in adult rats, ERalpha transcripts in neonatal rats were much higher than in adult. These observations provide evidence for the existence of different expression patterns of ERalpha/ERbeta transcripts in these three brain areas between the neonatal and adult rats, suggesting that each ER subtype may play a distinct role in the regulation of differentiation, development, and functions of the brain by estrogen.

Effects of rainfall, temperature and illumination on outcrossing rate of male sterile line in soybean

To improve seed yield of male sterile line,the relationship between outcrossing rate and climate factors was explored.Data of blooming period,outcrossing rate of male sterile line and climate during 2006–2016 growing seasons were investigated and analyzed.The shortest blooming period was 18.8 d with mean temperature of 24℃–25℃and 18.5 d with about 125 h natural illumination.More rainfall caused a longer blooming period,and a high outcrossing rate was found with about 100 mm rainfall and the mean temperature of 24℃–25℃.Increased natural illumination time by tapetum lucidum mulching improved outcrossing rate by 42.48%compared tocontrol.Overall,the selective combination of climate and environmental factors could be effective for increasing outcrossing rate and hybrid seed yield in the male sterile line of soybean.

Development of Newer Approaches to Male Contraception: Prospects of Availability for Mass Application in the Near Future

Progress in development of a simple, effective reversible male contraceptive has been difficult due to the indispensable role of testosterone in spermatogenesis and maintenance of secondary sexual characters. Efforts are in progress to develop methods, which do not interfere with testosterone production. These include blockade of FSH action by immunization against FSH or FSHR, and interfere with sperm maturation by interfering with estrogen action or by immunization against epididymal or sperm specific proteins. An evaluation of these various approaches for practical application is also presented.

环境因素与男性生殖损害研究进展与展望

男性生殖损害是我国和国际面临的重大卫生健康挑战。环境因素是当前导致男性生殖损害的重要原因之一。识别这些环境因素,阐明其损伤机制并研发针对性的防治策略,对于维护男性生殖健康,提升国家人口安全具有重要意义。本文概述近期环境因素导致男性生殖损伤相关研究进展:在有害因素识别方面,电磁辐射、新兴环境污染物、新冠病毒等物理、化学和生物因素的男性生殖损害效应正逐步被认识;在生殖损害的发生机制方面,铁死亡、昼夜节律与生物钟、表观遗传与染色质特征以及肠道菌群介导的环境因素致男性生殖损害机制成为新的研究热点。未来本领域将紧跟环境变化新形势,借助基础理论研究新进展及多学科交叉融合,深入探索复杂暴露等关键问题,人群与实验室研究相结合推动研究成果向卫生防控实践转化。

Tetramethrin Identified in Fat Adjacent to Mammary Carcinoma in a Male Dog—Case Report

Canine mammary tumors (CMT) are very common in female dogs, representing approximately 50% of all tumors in this species, but are highly uncommon in male dogs and are primarily related to hyperestrogenism. There is considerable scientific interest in the possible role of environmental contaminants in the etiology of mammary tumors, specifically in relation to synthetic chemical substances released into the environment to which living beings are either directly or indirectly exposed. In this study, the presence of pyrethroid insecticide was observed in adipose tissue adjacent to canine mammary tumors. High Precision Liquid Chromatography—HPLC was adapted to detect and identify environmental contaminants in adipose tissue adjacent to malignant mammary tumor in one male dog, Akita, 12 years old. After surgery, the mass was carefully examined for malignant neoplastic lesions. Five grams of adipose tissue adjacent to the tumor was collected to detect environmental contaminants. The pyrethroid was identified as tetramethrin, at 0.20 μg/g. This is the first report in which the environmental contaminant level was detectable in adipose tissue of this male dog with a malignant mammary tumor, by HPLC. Results suggest the possible involvement of pyrethroid in the canine mammary tumor carcinogenesis since this animal did not present any other tumor that could cause hyperestrogenism.