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Fulltext Lifestyle causes of male infertility

Durairajanayagam D

Arab J Urol, 2018 Mar;16(1):10-20.
PMID: 29713532 DOI: 10.1016/j.aju.2017.12.004

Objective: To examine the potential effects of lifestyle factors on male reproductive health. Evidence of a global decline in human sperm quality over recent decades has been accumulating. Environmental, occupational, and modifiable lifestyle factors may contribute to this decline. This review focuses on key lifestyle factors that are associated with male infertility such as smoking cigarettes, alcohol intake, use of illicit drugs, obesity, psychological stress, advanced paternal age, dietary practices, and coffee consumption. Other factors such as testicular heat stress, intense cycling training, lack of sleep and exposure to electromagnetic radiation from mobile phone use are briefly discussed.
Materials and method: A comprehensive literature search was performed to identify and synthesise all relevant information, mainly from within the last decade, on the major lifestyle factors associated with male infertility and semen quality. Database searches were limited to reports published in English only. A manual search of bibliographies of the reports retrieved was conducted to identify additional relevant articles.
Results: In all, 1012 articles were identified from the database search and after reviewing the titles and abstract of the reports, 104 articles met the inclusion criteria. Of these, 30 reports were excluded as the full-text could not be retrieved and the abstract did not have relevant data. The remaining 74 reports were reviewed for data on association between a particular lifestyle factor and male infertility and were included in the present review.
Conclusion: The major lifestyle factors discussed in the present review are amongst the multiple potential risk factors that could impair male fertility. However, their negative impact may well be mostly overcome by behaviour modification and better lifestyle choices. Greater awareness and recognition of the possible impact of these lifestyle factors are important amongst couples seeking conception.
Fulltext Commentary: the value of testing sperm DNA fragmentation in infertile men

Durairajanayagam D

Transl Androl Urol, 2017 Sep;6(Suppl 4):S678-S680.
PMID: 29082198 DOI: 10.21037/tau.2017.03.42
Fulltext Corticosterone-induced oxidative stress alters epididymal sperm fertility in rats

Abd-Aziz, N.A.A., Chatterjee, A., Chatterjee, R., Durairajanayagam, D.

ASM Science Journal, 2014;8(2):117-124.
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Elevated glucocorticoid levels during stressed conditions have been demonstrated to impair reproductive function in rats. In our previous study investigating the dose-related effects of corticosterone (CORT) on the fertilising capacity of epididymal sperm in surgically-manipulated rats, we found that 25 mg/kg/day of CORT given subcutaneously for seven consecutive days significantly decreased the number of implantation sites and increased intrauterine embryonic loss compared to controls. Based on these findings, the current study aims to elucidate the possible mechanisms of action of CORT-induced stress on impaired sperm fertility in rats. Results of the present study showed that compared to controls, 25 mg/kg/day of CORT given subcutaneously for 7 consecutive days significantly increased the level of plasma malondialdehyde (MDA) with corresponding attenuated levels of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities. Plasma adrenocorticotropin (ACTH) and testosterone levels were also found to be decreased in CORTtreated rats. These findings suggest that CORT-induced oxidative stress and exert an inhibitory effect at the hypothalamic-pituitary-gonadal (HPG) axis, as evidenced by increased lipid peroxidation, reduced enzymatic antioxidant activities, and decreased testosterone production. These subsequently result in decreased fertilising capacity of epididymal sperm leading to poor pregnancy outcomes.
Fulltext Misconceptions highlighted among medical students in the annual International Intermedical School Physiology Quiz

Cheng HM, Durairajanayagam D

Adv Physiol Educ, 2012 Sep;36(3):229-32.
PMID: 22952263 DOI: 10.1152/advan.00089.2011
Fulltext Insights into an Award-Winning Summer Internship Program: The First Six Years

Kashou A, Durairajanayagam D, Agarwal A

World J Mens Health, 2016 Apr;34(1):9-19.
PMID: 27169124 DOI: 10.5534/wjmh.2016.34.1.9

Since its inception in 2008, the American Center for Reproductive Medicine's summer internship program in reproductive research and writing has trained 114 students from 23 states within the United States and 10 countries worldwide. Its fundamental goal is to inspire pre-medical and medical students to embrace a career as a physician-scientist. During this intensive course, established scientists and clinicians train interns in the essential principles and fundamental concepts of bench research and scientific writing. Over the first six years (2008~2013), interns have collectively published 98 research articles and performed 12 bench research projects on current and emerging topics in reproductive medicine. Interns have also developed and honed valuable soft skills including time management, communication and presentation skills, as well as life values, which all enhance personal and professional satisfaction. Program graduates are able to recognize the value of medical research and its potential to impact patient care and gain insight into their own career pathway. Between 2011 and 2014, the internship program was thrice awarded a Scholarship in Teaching Award by Case Western Reserve School of Medicine for its innovative teaching approach and positive impact on medical education and student careers. This report highlights the demographics, logistics, implementation, feedback, and results of the first six years of the American Center for Reproductive Medicine's summer internship program at Cleveland Clinic (Cleveland, OH, USA). This may be helpful to other research and academic institutions considering implementing a similar program. In addition, it creates awareness among potential physician-scientists of what the world of research has to offer in both scientific writing and bench research. Finally, it may stimulate further discussion regarding narrowing the gap between physicians and scientists and refinement of the current program.
Fulltext Leptin and its actions on reproduction in males

Malik IA, Durairajanayagam D, Singh HJ

Asian J Androl, 2018 12 13;21(3):296-299.
PMID: 30539926 DOI: 10.4103/aja.aja_98_18

Leptin, an adipocyte-derived hormone, serves numerous physiological functions in the body, particularly during puberty and reproduction. The exact mechanism by which leptin activates the gonadotropin-releasing hormone (GnRH) neurons to trigger puberty and reproduction remains unclear. Given the widespread distribution of leptin receptors in the body, both central and peripheral mechanisms involving the hypothalamic-pituitary-gonadal axis have been hypothesized. Leptin is necessary for normal reproductive function, but when present in excess, it can have detrimental effects on the male reproductive system. Human and animal studies point to leptin as a link between infertility and obesity, a suggestion that is corroborated by findings of low sperm count, increased sperm abnormalities, oxidative stress, and increased leptin levels in obese men. In addition, daily leptin administration to normal-weight rats has been shown to result in similar abnormalities in sperm parameters. The major pathways causing these abnormalities remain unidentified; however, these adverse effects have been attributed to leptin-induced increased oxidative stress because they are prevented by concurrently administering melatonin. Studies on leptin and its impact on sperm function are highly relevant in understanding and managing male infertility, particularly in overweight and obese men.
Afterword: An update on clinical utility and diagnostic value of various andrological techniques

Durairajanayagam D, Agarwal A, Baskaran S, Vij S

Andrologia, 2021 Mar;53(2):e13819.
PMID: 33620116 DOI: 10.1111/and.13819
Causes and consequences of sperm mitochondrial dysfunction

Durairajanayagam D, Singh D, Agarwal A, Henkel R

Andrologia, 2021 Feb;53(1):e13666.
PMID: 32510691 DOI: 10.1111/and.13666

Mitochondria have multiple functions, including synthesis of adenine triphosphate, production of reactive oxygen species, calcium signalling, thermogenesis and apoptosis. Mitochondria have a significant contribution in regulating the various physiological aspects of reproductive function, from spermatogenesis up to fertilisation. Mitochondrial functionality and intact mitochondrial membrane potential are a pre-requisite for sperm motility, hyperactivation, capacitation, acrosin activity, acrosome reaction and DNA integrity. Optimal mitochondrial activity is therefore crucial for human sperm function and semen quality. However, the precise role of mitochondria in spermatozoa remains to be fully explored. Defects in sperm mitochondrial function severely impair the maintenance of energy production required for sperm motility and may be an underlying cause of asthenozoospermia. Sperm mtDNA is susceptible to oxidative damage and mutations that could compromise sperm function leading to infertility. Males with abnormal semen parameters have increased mtDNA copy number and reduced mtDNA integrity. This review discusses the role of mitochondria in sperm function, along with the causes and impact of its dysfunction on male fertility. Greater understanding of sperm mitochondrial function and its correlation with sperm quality could provide further insights into their contribution in the assessment of the infertile male.
An update on clinical utility and diagnostic value of various andrological techniques

Baskaran S, Agarwal A, Durairajanayagam D, Vij S

Andrologia, 2021 Mar;53(2):e13783.
PMID: 33620115 DOI: 10.1111/and.13783
Fulltext Role of L-carnitine in female infertility

Agarwal A, Sengupta P, Durairajanayagam D

Reprod Biol Endocrinol, 2018 Jan 26;16(1):5.
PMID: 29373970 DOI: 10.1186/s12958-018-0323-4

BACKGROUND: L-carnitine (LC), and its acetylated form, acetyl L-carnitine (ALC), have immense functional capabilities to regulate the oxidative and metabolic status of the female reproductive system. The vulnerability of this system to free radicals demand for advanced strategies to combat them. For this purpose, the 'quasi vitamins' LC and ALC can be used either individually, or in combination with each other or with other antioxidants.
MAIN BODY: This review (a) summarizes the effects of carnitines on female fertility along with the findings from various in vivo and in vitro studies involving human, animal and assisted reproductive technology, and (b) proposes their mechanism of actions in improving female fertility through their integrated actions on reducing cellular stress, maintaining hormonal balance and enhancing energy production. They reportedly aid β-oxidation in oocytes, maintain its cell membrane stability by acetylation of phospholipids and amphiphilic actions, prevent free radical-induced DNA damage and also stabilize acetyl Co-A/Co-A ratio for adequate acetyl storage as energy supply to maintain the robustness of reproductive cells.
CONCLUSION: While both LC and ALC have their applications in improving female fertility, ALC is preferred for its better antioxidant properties and LC for amelioration of energy supply to the cells. These beneficial effects show great promise in its application as a treatment option for women facing infertility disorders.
Fulltext Leptin induces the expression of tumorigenic genes in the gastric mucosa of male Sprague-Dawley rats

Isyraqiah F, K Kutty M, Durairajanayagam D, Salim N, Singh H

Exp Biol Med (Maywood), 2018 Oct;243(14):1118-1124.
PMID: 30449153 DOI: 10.1177/1535370218813909
Leptin enhances N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced tumour growth in gastric mucosa of male Sprague-Dawley rats

Isyraqiah F, Kutty MK, Durairajanayagam D, Singh HJ

Mol Biol Rep, 2019 Dec;46(6):5967-5975.
PMID: 31444698 DOI: 10.1007/s11033-019-05030-z

Individuals who are obese are at a greater risk of developing gastric cancer. They are however also hyperleptinaemic. Chronic leptin treatment has been shown to upregulate numerous cancer-causing genes in the stomach of male Sprague-Dawley rats. It is however unclear if leptin enhances the effect of gastric carcinogens in vivo. This study was therefore done to investigate the effect of leptin on gastric carcinogenesis in rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Twenty-four, 6-week old male Sprague-Dawley rats were divided equally into three groups: G1 served as age-matched controls; G2 was treated with MNNG in drinking water ad libitum (200 mg L-1); G3 was given leptin and MNNG. Rats were euthanized after 40 weeks of treatment and their stomachs were removed for histopathology, microarray, and RT-qPCR analysis. Fisher's exact test and one-way ANOVA were used to analyse the data. Fifty percent of the MNNG-treated rats developed gastric hyperplasia (p
Proteomics, oxidative stress and male infertility

Agarwal A, Durairajanayagam D, Halabi J, Peng J, Vazquez-Levin M

Reprod Biomed Online, 2014 Jul;29(1):32-58.
PMID: 24813754 DOI: 10.1016/j.rbmo.2014.02.013

Oxidative stress has been established as one of the main causes of male infertility and has been implicated in many diseases associated with infertile men. It results from high concentrations of free radicals and suppressed antioxidant potential, which may alter protein expression in seminal plasma and/or spermatozoa. In recent years, proteomic analyses have been performed to characterize the protein profiles of seminal ejaculate from men with different clinical conditions, such as high oxidative stress. The aim of the present review is to summarize current findings on proteomic studies performed in men with high oxidative stress compared with those with physiological concentrations of free radicals, to better understand the aetiology of oxidative stress-induced male infertility. Each of these studies has suggested candidate biomarkers of oxidative stress, among them are DJ-1, PIP, lactotransferrin and peroxiredoxin. Changes in protein concentrations in seminal plasma samples with oxidative stress conditions were related to stress responses and to regulatory pathways, while alterations in sperm proteins were mostly associated to metabolic responses (carbohydrate metabolism) and stress responses. Future studies should include assessment of post-translational modifications in the spermatozoa as well as in seminal plasma proteomes of men diagnosed with idiopathic infertility. Oxidative stress, which occurs due to a state of imbalance between free radicals and antioxidants, has been implicated in most cases of male infertility. Cells that are in a state of oxidative stress are more likely to have altered protein expression. The aim of this review is to better understand the causes of oxidative stress-induced male infertility. To achieve this, we assessed proteomic studies performed on the seminal plasma and spermatozoa of men with high levels of oxidative stress due to various clinical conditions and compared them with men who had physiological concentrations of free radicals. A variety of sperm and seminal plasma proteins were found to be expressed either in abundance (over-expressed) or in a lesser amount (underexpressed), while other proteins were found to be unique either to men with oxidative stress or to men with a balanced ratio of antioxidants/free radicals. Each study included in this review suggested several proteins that could possibly act as biomarkers of oxidative stress-induced male infertility, such as protein DJ-1, PIP, lactotransferrin and peroxiredoxin. Pathway analysis performed in these studies revealed that the changes in seminal plasma proteins in men with oxidative stress could be attributed to stress responses and regulatory pathways, while changes in sperm proteins were linked to stress responses and metabolic responses. Subsequent studies could look into post-translational modifications in the protein profile of men with idiopathic infertility. We hope that the information in this review will contribute to a better understanding of the main causes of idiopathic male infertility.
Afterword to an update on male infertility: Factors, mechanisms, and interventions

Durairajanayagam D, Agarwal A, Baskaran S, Ko E, Ramasamy R

Andrologia, 2021 Feb;53(1):e13752.
PMID: 33484502 DOI: 10.1111/and.13752
An update on male infertility: Factors, mechanisms, and interventions

Ko E, Ramasamy R, Durairajanayagam D, Baskaran S, Agarwal A

Andrologia, 2021 02;53(1):e13741.
PMID: 33135797 DOI: 10.1111/and.13741
Tocotrienol-rich fraction supplementation prevents foetal loss in females mated with corticosterone-treated male Sprague-Dawley rats

Abd Aziz NAA, Chatterjee A, Chatterjee R, Durairajanayagam D

Andrologia, 2019 Apr;51(3):e13199.
PMID: 30461035 DOI: 10.1111/and.13199

This study examined whether tocotrienol supplementation to corticosterone-treated male rats could prevent foetal loss in females upon their mating. Epididymides of adult male Sprague-Dawley (SD) rats with proven fertility were surgically separated at the testis-caput junction. Twenty-four hours post-surgery, these animals received for 7 days either: tocopherol-stripped corn oil (Control), corticosterone 25 mg/kg s.c. (CORT), CORT 25 mg/kg s.c. and tocotrienol-rich fraction (TRF) 100 mg/kg orally (CORT + TRF) or TRF 100 mg/kg orally (TRF). On day 8, males were cohabited with proestrus females. A spermatozoa-positive vaginal smear indicated pregnancy. Males were euthanised for analysis of testosterone and antioxidant activities. Reproductive organs were weighed. On day 8 of pregnancy, females were laparotomised to count the number of implantation sites. Pregnancy was continued until term. Number of pups delivered and their weights were determined. Data were analysed using ANOVA. Malondialdehyde levels were significantly lower in CORT + TRF group compared with CORT group. Enzymatic antioxidant activities, testosterone level and reproductive organ weights were significantly higher in CORT + TRF group compared with CORT group. Number of implantation sites and live pups delivered, and their birth weights from females mated with CORT + TRF males were significantly higher compared to CORT group. Therefore, TRF prevents foetal loss in females mated with CORT + TRF-treated males.
Could leptin be responsible for the reproductive dysfunction in obese men?

Almabhouh F, Abdul Aziz NAA, Durairajanayagam D, Singh HJ

Reprod Biol, 2020 Mar;20(1):106-110.
PMID: 31987773 DOI: 10.1016/j.repbio.2020.01.003

Low sperm concentration, increased fraction of morphologically abnormal sperm, and raised levels of markers of oxidative stress are often reported in the seminal plasma of infertile obese males. The precise reason for changes remains unknown. This short review summarises evidence from human and animal studies linking leptin to the reproductive dysfunction reported in obese males and presents a possible mechanism for this based on the available data in the literature. Serum leptin concentrations correlate positively with body fat mass but its precise link to semen abnormalities reported in obese males has yet to be conclusively established. Decreased sperm concentration, increased fraction of morphologically abnormal sperm and increased markers of oxidative stress have been reported following six weeks of daily leptin treatment to normal weight rats. In addition, decreased expression of endogenous antioxidant enzymes and increased expression of respiratory chain enzymes noted in the testes of leptin treated rats increases the propensity to oxidative stress. Besides that, leptin's interference with histone to protamine transition in the DNA of sperm increases the susceptibility of sperm to free radical attack and may explain the often reported higher DNA fragmentation index in sperm of obese males. Concurrent supplementation of melatonin, a natural anti-oxidant, to these rats prevents the effects of leptin. The role of leptin in obesity-related reproductive dysfunction has to be considered seriously and these effects of leptin might involve increased oxidative stress.
Fulltext Editorial: Omics for infertility and contraception: two sides of same coin

Jena SR, Mohanty G, Kesari KK, Durairajanayagam D, Samanta L

Front Cell Dev Biol, 2023;11:1293677.
PMID: 37822867 DOI: 10.3389/fcell.2023.1293677
Differential proteomic profiling of spermatozoal proteins of infertile men with unilateral or bilateral varicocele

Agarwal A, Sharma R, Durairajanayagam D, Cui Z, Ayaz A, Gupta S, et al.

Urology, 2015 Mar;85(3):580-8.
PMID: 25733269 DOI: 10.1016/j.urology.2014.11.030

To compare the sperm protein profile between infertile men with unilateral varicocele and infertile men with bilateral varicocele.
Role of Withania somnifera (Ashwagandha) in the management of male infertility

Sengupta P, Agarwal A, Pogrebetskaya M, Roychoudhury S, Durairajanayagam D, Henkel R

Reprod Biomed Online, 2018 Mar;36(3):311-326.
PMID: 29277366 DOI: 10.1016/j.rbmo.2017.11.007

To manage male infertility caused by hormonal imbalance, infections and other predicaments, multifarious treatment strategies are emerging worldwide. Contemporary treatments, such as assisted reproductive techniques, are costly with low success rates of only 10-30%; however, herbal remedies are gaining more attention as an alternative or supplementary therapeutic modality for male infertility. The beneficial effects induced by oral intake of the roots of a small evergreen shrub, Withania sominifera (Ashwagandha) on semen quality of infertile men have previously been studied. Oral intake of Ashwagandha roots has been found to inhibit lipid peroxidation, improve sperm count and motility, and regulate reproductive hormone levels. The molecular mechanisms of these effects, however, are yet to be unveiled. In this review, we will discuss the role of herbal medicines in male infertility; provide a detailed analysis of various human and animal studies involving Withania somnifera; describe a proposed direct oxidative mechanism involving mitigation of oxidative stress as well as an indirect mechanism consisting of a gamma-aminobutyric acid-like-mimetic pathway ameliorating hormonal balance through crosstalk among different endocrine glands to improve male fertility; and how Withania somnifera supplementation mitigates risk factor-induced male infertility as well as ameliorates male fertility.

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