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.

Estrogens and the pathophysiology of the biliary tree

The scientific framework concerning estrogen effects on different tissues has expanded enormously during the last decades, when estrogen receptor （ER） subtypes were identified. Estrogens are not only essential for the female reproductive system, but they also control fundamental functions in other tissues including the cardiovascular system, bone, brain and liver. Recently, estrogens have been shown to target the biliary tree, where they modulate the proliferative and secretory activities of cholangiocytes, the epithelial cells lining bile ducts. By acting on both estrogen receptors （ER-α） and （ER-β） subtypes, and by activating either genomic or non-genomic pathways, estrogens play a key role in the complex loop of growth factors and cytokines, which modulates the proliferative response of cholangiocytes to damage. Specifically, estrogens activate intracellular signalling cascades JERK1/2 （extracellular regulated kinases 1/2, PI3-kinase/AKT （phosphatidylinositol-3＇ kinase/AKT）] typical of growth factors such as insulin like growth factor （IGF1）, nerve growth factor （NGF） and vascular endothelial growth factor （VEGF）, thus potentiating their action. In addition, estrogens stimulate the secretion of different growth factors in proliferating cholangiocytes. This review specifically deals with the recent advances related to the role and mechanisms by which estrogens modulate cholangiocyte functions in normal and pathological conditions.

Protective effects of estrogens and caloric restriction during aging on various rat testis parameters

Aim： To investigate the effects of 17β-estradiol （E2）, Peganum harmala extract （PHE） and caloric restriction （CR） on various testis parameters during aging. Methods： Twelve-month-old male rats were treated for 6 months with either E2 or PHE, or submitted to CR （40%）. Results： Our results show that estrogens and CR are able to protect the male gonad by preventing the decrease of testosterone and E2 levels as well as the decrease of aromatase and estrogen receptor gene expressions. Indeed, E2, PHE and CR treatments induced an increase in the superoxide dismutase activities and decreased the activity of testicular enzymes： gamma-glutamyl transferase, alkaline phosphatase, lactate deshydrogenase as well as the aspartate and lactate transaminases in aged animals. In addition, the testicular catalase and gluthatione peroxidase activities were enhanced in E2, PHE and CR-treated rats compared to untreated animals at 18 months of age. Moreover, the positive effects of estradiol, PHE and CR were further supported by a lower level of lipid peroxidation. Recovery of spermatogenesis was recorded in treated rats. Conclusion： Besides a low caloric diet which is beneficial for spermatogenesis, a protective antioxydant role of estrogens is suggested. Estrogens delay testicular cell damage, which leads to functional senescence and, therefore, estrogens are helpful in protecting the reproductive functions from the adverse effects exerted by reactive oxygen species （ROS） produced in large quanti- ties in the aged testis.

phytoestrogens/insoluble fibers and colonic estrogen receptor β: randomized, double-blind, placebo-controlled study

AIM:To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-β and biological parameters in sporadic colonic adenomas. METHODS:A randomized, double-blind placebo-controlled trial was performed. Patients scheduled to undergo surveillance colonoscopy for previous sporadic colonic adenomas were identified, and 60 eligible patients were randomized to placebo or active dietary intervention (ADI) twice a day, for 60 d before surveillance colonoscopy. ADI was a mixture of 175 mg milk thistle extract, 20 mg secoisolariciresinol and 750 mg oat fiber extract. ER-β and ER-α expression, apoptosis and proliferation (Ki-67 LI) were assessed in colon samples. RESULTS:No adverse event related to ADI was recorded. ADI administration showed a significant increases in ER-β protein (0.822 ± 0.08 vs 0.768 ± 0.10, P = 0.04) and a general trend to an increase in ER-β LI (39.222 ± 2.69vs 37.708 ± 5.31,P = 0.06), ER-β/ER-α LI ratio (6.564 ± 10.04 vs 2.437 ± 1.53, P = 0.06), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (35.592 ± 14.97 vs 31.541 ± 11.54, P = 0.07) and Ki-67 (53.923 ± 20.91 vs 44.833 ± 10.38, P = 0.07) approximating statistical significance. A significant increase of ER-β protein (0.805 ± 0.13 vs 0.773 ± 0.13,P = 0.04), mRNA (2.278 ± 1.19vs 1.105 ± 1.07, P < 0.02) and LI (47.533 ± 15.47 vs 34.875 ± 16.67,P < 0.05) and a decrease of ER-α protein (0.423 ± 0.06vs 0.532 ± 0.11,P < 0.02) as well as a trend to increase of ER-β/ER-α protein in ADI vs placebo group were observed in patients without polyps (1.734 ± 0.20 vs 1.571 ± 0.42, P = 0.07). CONCLUSION:The role of ER-β on the control of apoptosis, and its amenability to dietary intervention, are supported in our study.

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.

Removal characteristics of steroid estrogens in trickling filters

The discharge of steroid estroens from sewage treatment works (STW) is to be regulated by Environmental Quality Standard in the UK,thus requiring the understanding of removal characteristics of steroid estroens in trickling filters to benefit UK water industry with trickling filters used in 75% STWs. Two pilot-scale trickling filters were operated in parallel to treat synthetic sewage spiked with oestrone (E1),oestradiol (E2) and 17α-ethinyl oestradiol (EE2) at environmentally related concentrations. Control experiments show that biodegradation is the dominant removal mechanism although adsorption onto biofilm solids prior to biodegradation would be part of the overall mechanisms of estrogen removal. Approximately 44.7%-58.9% is removed by the pilot trickling filter normally operated,whilst the 1:1 recirculation increases 29.0%-32.2% estrogen removals by improved wetting rate and hydraulic retention time supported by tracer experiment with lithium chloride. Extra feed solids with 32.0% higher suspended solids levels inhibited estrogen removals by 10.8%-34.4% rather than helping bridge adsorption to the biofilm,and the change of particle characteristics with higher adsorption potency would benefit the removal.

Xenoestrogens challenge 17β-estradiol protective effects in colon cancer

Several epidemiological,cellular,and molecular studies demonstrate the role of environmental chemicals with endocrine disrupting activities,typical of Westernized societies,in the pathogenesis of numerous diseases including cancer.Nonetheless this information,the design and execution of studies on endocrine disruptors are not yet cognizant that the specific actions of individual hormones often change with development and ageing,they may be different in males and females and may be mediated by different receptors isoforms expressed in different tissues or at different life stages.These statements are particularly true when assessing the hazard of endocrine disruptors against 17β-estradiol(E2)actions in that this hormone is crucial determinant of sexrelated differences in anatomical,physiological,and behavioral traits which characterize male and female physiology.Moreover,E2 is also involved in carcinogenesis.The oncogenic effects of E2 have been investigated extensively in breast and ovarian cancers where hormone-receptor modulators are now an integral part of targeted treatment.Little is known about the E2preventive signalling in colorectal cancer,although this disease is more common in men than women,the difference being more striking amongst pre-menopausal women and age-matched men.This review aims to dissect the role and action mechanisms of E2 in colorectal cancer evaluating the ability of estrogen disruptors(i.e.,xenoestrogens)in impair these E2 actions.Data discussed here lead to define the possible role of xenoestrogens in the impairment and/or activation of E2signals important for colorectal cancer prevention.

Estrogens and the regulation of glucose metabolism

The main estrogens:estradiol,estrone,and their acyl-esters have been studied essentially related to their classical estrogenic and pharmacologic functions.However,their main effect in the body is probably the sustained control of core energy metabolism.Estrogen nuclear and membrane receptors show an extraordinary flexibility in the modulation of metabolic responses,and largely explain gender and age differences in energy metabolism:part of these mechanisms is already sufficiently known to justify both.With regard to energy,the estrogen molecular species act essentially through four key functions:(1)Facilitation of insulin secretion and control of glucose availability;(2)Modulation of energy partition,favoring the use of lipid as the main energy substrate when more available than carbohydrates;(3)Functional protection through antioxidant mechanisms;and(4)Central effects(largely through neural modulation)on whole body energy management.Analyzing the different actions of estrone,estradiol and their acyl esters,a tentative classification based on structure/effects has been postulated.Either separately or as a group,estrogens provide a comprehensive explanation that not all their quite diverse actions are related solely to specific molecules.As a group,they constitute a powerful synergic action complex.In consequence,estrogens may be considered wardens of energy homeostasis.

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.

Effects of menopausal hormone therapy-based on the role of estrogens,progestogens,and their metabolites in proliferation of breast cancer cells

Menopausal hormone therapy(MHT)has been widely used for the clinical treatment of symptoms associated with menopause in women.However,the exact nature of the relationship between MHT and the increased risk of breast cancer has not been fully elucidated.The results of the Women’s Health Initiative’s randomized controlled clinical studies showed that estrogen monotherapy was associated with a lower incidence of breast cancer as compared to estrogen-progesterone combined therapy,with an elevated risk of breast cancer.The evidence currently available from randomized trials and observational studies is based on data from different populations,drug formulations,and routes of administration.Even though the risks of MHT and breast cancer have received a great deal of attention,information regarding the unpredictable toxicological risks of estrogen and progestogen metabolism needs to be further analyzed.Furthermore,the diversity and complexity of the metabolic pathways of estrogen and different progestogens as well as the association of the different estrogen and progestogen metabolites with the increased risk of breast cancer need to be adequately studied.Therefore,this review aimed to describe the biological effects of estrogen,progesterone,and their metabolites on the proliferation of breast cancer cells,based on relevant basic research and clinical trials,to improve our understanding of the biological functions of estrogen and progestogen as well as the safety of MHT.

Biodegradation of natural and synthetic estrogens in moving bed bioreactor

Estrogen hormones as a group of endocrine disruptive compounds （EDC） can interfere with endocrine system in humans and animals. The goal of this study was to investigate the elimination rate of Estrone （El）, 17β-estradiol （E2） and 17α-ethinyl estradiol （EE2） in Moving Bed Bioreactor （MBBR）. These analytes extracted by Dispersive Liquid-Liquid Microextraction （DLLME） technique, followed by derivatization, and detected by GC/MS. Estrogen removal efficiency in MBBR improved at high solid retention times （SRTs）, which notion is owing to development ofnitrification. Estrogenspecificremovalratewasbetween 0,22-1.45μg.（gVSS） 1.d -1 for natural and synthetic hormones. The adsorption rate was 0.9%-3.2% 0-1.3%, and 0.7%-5.7% for E1, E2, and EE2, respectively. In addition, the biodegradation rates were more than 95% for these compounds. These results illustrated that in MBBR, the hiodegradation and the adsorption to biomass are considered as two significant routes for elimination of estrogenic compounds. As a whole, the deterioration rate of estrogens enhanced by MBBR compared to other biological wastewater treatment processes such as conventional activated sludge.

Simultaneous Determination of Four Estrogens in Compost Based on Ultrasonic Solvent Extraction, Solid-Phase Extraction Clean-Up and Analysis by UHPLC-MS/MS

A rapid, cost effective and reliable analytical method was developed and validated for the simultaneous determination of four estrogens (17 β-estradiol, 17 α-ethinylestradiol, estrone, and estriol) in compost samples from the biodegradation of biological infectious hazardous wastes. Ultrasonic solvent extraction, using methanol as extraction solvent, coupled with SPE clean-up, using cartridges HLB 60 mg - 6 ml Supelco® and acetonitrile for reconstitution of eluents, was used for the simultaneous extraction of the four estrogens. Mean recoveries in the range of 98% - 107% were obtained. All compounds were separated in a single gradient run by UHPLC KinetexTM 2.6 μm XB-C18 100 ÅLC (50 × 4.6 mm) column. Analytes were detected via multiple reaction monitoring (MRM) using an AB SCIEX API-5000TM triple quadrupole (Applied Biosystems/MDS SCIEX) with electrospray ionization in negative mode. Isocratic mobile phase of Water:ACN (50:50) resulted to be the optimum. Limits of detection and quantification were on the order of 0.66 ng·g-1 and 2 ng·g-1 for all the estrogens. These limits were lower than most of the values reported in the literature for similar matrices. Suitable level of linearity, good repeatability and reproducibility with coefficients of variation is lower than 11.7%, 6.8% and 8.3%, respectively.

Fourteen Days Post-Ovariectomy Estrogens Decline Is Associated with Anxiogenic Effects on Wistar Rats

On study of the effects of estrogen deficiency on anxiety disorder by using ovariectomised animals, one discrepancy was the difference in behavioral testing delay following ovariectomy and the paradigms used. Thus, the aim of this study was to evaluate the anxiogenic effects of fourteen-day estrogen decline subsequent to ovariectomy on Wistar rats using EPM （elevated plus-maze） and open field tests. As results, fourteen days of estrogens decline has induced an increase of anxiety-related behaviour by a reduction of the percentage of the number of entries into the open arm （p 〈 0.01） and an increase of the percentage of the number of entries into the closed arm （/9 〈 0.01） during the elevated plus-maze test. This anxiety-like behaviour was confirmed on the open field test by a reduction of time spent in the centre of the arena （p 〈 0.05） as well as a reduction of crossing （p 〈 0.05） and an increase of the weight of faecal boli （p 〈 0.05） and grooming （p 〈 0.01）. Meanwhile, the administration of diazepam or estradiol valerate （1 mg/kg BW each） has corrected the anxious-like behaviour in both tests paradigms. These results suggest that fourteen days of estrogens decline was associated with an anxiety-related behaviour. This experimental model can constitute an excellent tool for the study of anxiolytic substances in menopause-related anxiety.

Does local vaginal estrogen after tension-free transobturator vaginal tape reduce overactive bladder symptoms in postmenopausal women? A prospective randomized, controlled study

Objective:We aimed to evaluate the efficacy of topical estrogen after transvaginal tension-free vaginal tape-obturator(TVT-O)in the treatment of de novo overactive bladder symptoms that appear after surgery.Methods:This is a prospective randomized controlled study performed in the Urology and Gynecology Departments,Kasr Al Ainy Hospital,Cairo University,Cairo,Egypt.Two hundred and ten postmenopausal females presenting during the period between January 2017 and November 2020 with stress urinary incontinence were included in the study.Patients were divided into two groups,105 patients in Group A(treatment group)and 105 patients in Group B(control group).Patients in Group A underwent transvaginal TVT-O followed by local vaginal estrogen treatment for 6 months,while patients in Group B underwent transvaginal TVT-O only.The study included any postmenopausal female with urodynamic stress urinary incontinence.All patients had to fulfill a 3-day bladder diary,overactive bladder symptoms score,urine analysis,urodynamic study,and post-voiding residual urine measurement by abdominal ultrasound preoperatively and at 3-month and 6-month follow-ups.Results:At 6-month follow-up,daytime frequency was reduced to 8%in Group A(increased to 21%in Group B)with a statistically significant difference between both groups(p=0.009).At 6-month follow-up,nocturia was 8%in Group A(11%in Group B)with no statistically significant difference between both groups(p=0.469).There was a statistically significant difference between both groups as regards to urinary urgency at 6-month follow-up(p=0.024).There was a statistically significant difference in postoperative wound healing events as regards to cure,hyperemia,gapping,and wound infection 1 week after intervention between both groups(p=0.008).No local or systemic side-effects were reported from local estrogen use.Conclusion:Local vaginal estrogen treatment given to postmenopausal patients after midurethral sling procedures can reduce the symptoms of daytime frequency and urinary urgency.Long-term follow-up is needed.

Combined collision-induced dissociation and photo-selected reaction monitoring mass spectrometry modes for simultaneous analysis of coagulation factors and estrogens

Oral estrogens are directly associated with changes in plasma levels of coagulation proteins. Thus, the detection of any variation in protein concentrations due to estrogen contraceptives, by a simultaneous analysis of both coagulation proteins and estrogens, would be a very informative tool. In the present study, the merit of photo-selected reaction monitoring （SRM）, a new analytical tool, was evaluated towards estrogens detection in plasma. Then, SRM and photo-SRM detection modes were combined for the simultaneous analysis of estrogen molecules together with heparin co-factor and factor XIIa, two proteins involved in the coagulation cascade. This study shows that photo-SRM could open new multiplexed analytical routes.

Voltammetric Determination of Estrogens Based on the Enhancement Effect of Surfactant at Carbon Paste Electrode

Highly sensitive voltammetric method for the determination of estrogens, based on the enhancement effect of cetyltrimethylammonium bromide (CTAB) has been described. In the presence of CTAB, the oxidation peak currents of estrogens (estradiol, estrone, estriol, estradiol valerate and diethylstilbestrol) as the carbon paste electrode (CPE) increased significantly after open-circuit accumulation. The peak current was proportional to the concentration of estradiol over the range from 5×10?9 to 2.5×10?6 mol·L?1. The detection limit was 8×10?10 mol·L?1 at 6 min of accumulation. The total amounts of estrogens in the blood serums were determined and the average recovery was 104.92%. Under the conditions used, the electrode process of estradiol was examined the mechanism for peak current enhancement was also discussed.

Biodegradation of Natural Estrogens by Biofilms from Biological Activated Carbon: Effect of Temperature

In order to obtain information on the biodegradation potential of biofilms involved in the removal of natural estrogens by biological activated carbon (BAC) columns, batch degradation of estrone (E1) and 17β-estradiol (E2) at temperature of 5℃, 20℃ and 35℃ by biofilms from four BAC columns (packed with activated carbon of particle size ranging from 0.5 - 0.59 mm and 1.0 - 1.19 mm into two bed depths) was studied. The results indicated that E2 was degraded faster by than E1 at all three temperatures and with the increasing of temperature, the amount of E1 converted from E2 increased. By fitting observed concentration data with a first-order rate expression, the bio-mass based degradation rate constants (kVSS) for E1 and E2 under all experimental conditions were estimated and linear relationship between lnkVSS and 1/T (T = absolute temperature) was demonstrated, resulting that with the increasing of the experimental temperature, degradation rate of biofilms for both E1 and E2 increased, and the increasing rate for E2 was higher than that for E1.

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.

Radiation removal of synthetic estrogens in aqueous solution:influence of reduction or oxidation system and toxicity test

Estrogens as a kind of steroidal sex hormone are widely used in humans, especially quinestrol(QS),dienestrol(DS) and norethindrone(NET, 19-nor-17-alphaethinltestoster-one), which cannot be completely degraded after application. Steroidal estrogens at low concentration pulling into environment can disturb the normal biological function of wide life and thus lead to great threat to humans. So it is important to explore its degradation mechanism and its behavior in the environment. In this study, we investigated the oxidation or reduction system under gamma irradiation for reducing estrogenic activity in the aqueous solutions as well as degradation kinetics, its by-products and yield of transformation by different analytical methods such as GC–MS and HPLC. Gamma irradiation could effectively degrade estrogens in aqueous solution. The degradation reaction of estrogens could be depicted by first-order reaction kinetics. The total organic carbon of solution decreased with an increasing absorbed dose with the order: quinestrol [ norethindrone [ dienestrol. The toxicity of the three estrogens was declined after irradiation. Mono- and quadric-hydroxylated intermediates as well as organic acids were formed after gamma irradiation.

Intricate roles of estrogen and estrogen receptors in digestive system cancers:a systematic review

Gender disparities are evident across different types of digestive system cancers,which are typically characterized by a lower incidence and mortality rate in females compared to males.This finding suggests a potential protective role of female steroid hormones,particularly estrogen,in the development of these cancers.Estrogen is a well-known sex hormone that not only regulates the reproductive system but also exerts diverse effects on non-reproductive organs mediated through interactions with estrogen receptors(ERs),including the classic(ERαand ERβ)and non-traditional ERs[G protein-coupled estrogen receptor(GPER)].Recent advances have contributed to our comprehension of the mechanisms underlying ERs in digestive system cancers.In this comprehensive review we summarize the current understanding of the intricate roles played by estrogen and ERs in the major types of digestive system cancers,including hepatocellular,pancreatic,esophageal,gastric,and colorectal carcinoma.Furthermore,we discuss the potential molecular mechanisms underlying ERα,ERβ,and GPER effects,and propose perspectives on innovative therapies and preventive measures targeting the pathways regulated by estrogen and ERs.The roles of estrogen and ERs in digestive system cancers are complicated and depend on the cell type and tissue involved.Additionally,deciphering the intricate roles of estrogen,ERs,and the associated signaling pathways may guide the discovery of novel and tailored therapeutic and preventive strategies for digestive system cancers,eventually improving the care and clinical outcomes for the substantial number of individuals worldwide affected by these malignancies.