MALE INFERTILITY: CAUSES AND CONTRIBUTORS

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MALE INFERTILITY: CAUSES AND CONTRIBUTORS

Poonam Singh*¹, Rakhi Gupta ¹, Devendra Patidar ² and Rama Kant Singh ¹

Division of Toxicology, Central Drug Research Institute ¹, B.S. 10/1 Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh, India

Manipal College of Pharmaceutical Sciences ², Manipal, Karnataka, India

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ABSTRACT: Male infertility is a reproductive health disorder, emerging globally as serious medicaland social problem that results in much trauma, emotional instability and psychological stress of the affected couples. In 50% of the diagnosed cases of infertility males are reported to be the predominant causative factor. Male infertility can assess by the quality and quantity of sperm cells as well as structure. The present review provides an overview on a wide range of factors that are accountable for male infertility. Hormonal imbalances, genetical defects, reproductive anatomical & morphological abnormalities, chemicals & toxins exposure, reactive oxygen species and smoking are the main causative factors. Besides these, pollution, changed lifestyle, lack of proper diet & nutrition, addictions, diseases, medications, illness and psychological problems may also contribute to infertility problems which can temporarily or permanently affect male reproductive system. Some of these factors are lifestyle borne and can possibly be corrected and some are medical which need to be given special attention while some fail to be diagnosed. The knowledge of male infertility is increasing rapidly and will enormously help diagnostic and therapeutic approaches to recuperate human infertility.

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Keywords:

Infertility, Sperm, Testosterone, Ejaculation, Occupational, Obesity, Lifestyle, Smoking, ROS

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INTRODUCTION:Infertility may be defined as a biological inability to achieve conception on one year or after one year of unprotected coital exposure¹. In context of male, a man is said to be infertile if he is unable to impregnate his partner after one year of unprotected intercourse. Male infertility can occur either as an isolated disorder or in combination with other complex disorder or syndrome.

On a world wide scale, 50-80 million people suffer from infertility. The World Health Organization (WHO) estimated approximately 8-10% of couples suffers from this problem ². Several studies have reported that the semen quality and thus male fertility is declining over past decades in several countries all over the world ^{3, 4, 5, 6}. However, different geographical areas vary in sperm count and semen quality ^{7, 8}.

Studies from disparate countries also confirmed these differences. The men from western countries-Denmark, Germany and Norway have poor semen quality with a higher risk of testicular cancer in comparison to eastern countries’ men-Swedish, Finish and Estonian ^{9, 10}. Fertility decline has been also reported in eastern European countries- Bulgaria, the Czech Republic, Hungary, Poland, and Russia ^{11, 12} as well as in Africa ¹³. A decline in fertility, with a reduction in sperm counts is also reported from our country India ¹⁴. A recent report on the status of infertility in India states that almost 50% of infertility is related to reproductive anomalies or disorders in the male ¹⁵. This reduction in fertility from past few decades suggests altered lifestyle, pollution, chemical based foods, lack of nutrition, stress, deskbound work attributes to some extent of infertility. The most commonly attributed factor is increasing industrialization and civilization that exposes hazardous chemicals, pesticides and electro-magnetic waves in the environment that also affect other factors contributing to reproductive disorders. Many cases of idiopathic infertility have a genetic basis such as chromosomal aberration, microdeletion and mutation.

ROS (reactive oxygen species) production and thus apoptosis of spermatozoa frequently occurs in infertility cases as a result of effect of different causative factors, for example, cocaine intake and smoking results into mitochondrial apoptosis and eventually cause sperm DNA damage in a number of ways. All the causative factors results into reduced viability, motility, morphology, and concentration of spermatozoa and different types of derangements in reproductive organs that directly or indirectly cause sexual dysfunction and eventually sterility. Many of these biological factors can be diagnosed and may be solved through medical intervention while some of the cases fail to be traced and termed as unexplained infertility.

Gonadotropins, antioestrogens, carnitines and trace elements may be helpful in improving sperm quality ¹⁶. The disorders of the function of epididymis i.e. during ejaculation and erection of sperm and seminal fluid via the penile urethra can disrupt sexual and reproductive health. Erectile dysfunction (inability to achieve sustained erection) may be an important factor/contributor in male infertility. By elucidating the underlying genetic basis of infertile phenotypes, it may be possible to find the reasons responsible for infertility and determine its effective treatments. There are many papers reported on different factors that are responsible for male infertility ^{17, 18, 19, 20}.

Therefore, several major and minor causative factors and their impact on male fertility have been summarized in this review.

Quality and Quantity of Semen: The morphology of sperm cell is one of the most conservative structures of animal kingdom. The ability of the sperm to fertilize a functional ovum is considered as the ultimate criteria of its function. Male infertility is directly linked to quality and quantity of sperm within the semen. Success of a mating depends upon both quality and quantity of semen delivered to the female and ability of sperm to reach fertilization site or ability of fertilizing sperm to carry out the fertilization process ²¹. Sperm disorders include abnormalities in quality or quantity of sperm produced and sperm ejaculation. More than 90% of cases of male infertility are because of low sperm counts and/or poor semen quality ²².

Sperm abnormalities can be caused by numerous factors, ranging from congenital birth defects and genetic disorders to lifestyle habits and environmental exposures. In many cases, the reasons for sperm abnormalities are unknown. Sperm quality can be assessed by its motility, viability, maturity, morphology and sperm tail membrane integrity. The normal volume of semen per ejaculate is approximately 2.5ml to 5ml having a minimum of 20 million sperms per ml of semen in order to affect a fertilization event and achieve pregnancy ¹⁹.

Though, sperm concentration fluctuates, they can be temporary or permanent, depending upon the causal factor. However, recently, sperm criteria have been reassessed and lower reference points for semen and sperm characteristics have been established by direct, retrospective selection of fertile men, defined as men whose partner conceived within 12 months after stopping use of contraception.

The reference values for human semen from fertile men were determined approximately 1.5ml normal volume of semen having 39 million sperms per ejaculate and 15 million per ml of semen with 58% vitality, 32% progressive motility and 40% total motility and 4% morphologically normal forms ²².

Normally oligozoospermia and 13 % of azoospermia with defective spermatogenesis are linked to defects of the Y chromosome – Y chromosome microdeletion in AZF region ²⁴. Any morphological change in sperm is also likely to have adverse effect on its functional efficiency. Empirical evidences indicate that double headed sperms, sperms having defective tail or dysfunctional acrosome or other morphological defects are incapable to take part in fertilization process. Morphological abnormality of sperm (tetratozoospermia) and insufficient sperm motility (asthenozoospermia) are some of the aspects of infertility. The combination of them can also occur, out of which oligoasthenoteratozoospermia (OAT) is most frequent ²⁵. Approximately 30% of OAT infertile men are diagnosed as idiopathic ²⁶.

Idiopathic oligoasthenoteratozoospermia (iOAT) is defined as defective spermatogenesis of unknown etiology and is regarded as undetectable by the common laboratory methods²⁷. Mast cells releasing inflammatory mediators are reported to directly suppress sperm motility in a potentially reversible manner, and may be a common pathophysiological mechanism for several factors responsible for infertility²⁸. Any of the factors described below or combination of them can result into abnormal changes into quality and quantity of semen and sperm within it. The reason behind unpredictable exact cause is that the terms used to describe semen-analysis abnormalities have overlapping definitions and are often misinterpreted which needs better science technologies; the better course is to discard these indistinct and difficult labels and simply report semen analyses quantitatively ²⁹.

Hormonal Disruption and Hormonal Imbalance: In vertebrates, hormones play a major and central role in the growth, development, metabolism and reproduction. Hormones reinforce homeostasis by controlling and coordinating various body activities. Testicular dysgenesis syndrome (TDS) is a congenital derangement of seminiferous tubular structure and function, inextricably linked to improper concentration of sex hormones at different stages of life cycle leading to male infertility. Hormonal factors work in a mutually interacting circuit wherein they have self-limiting effects on their own rates of manufacture and secretion.

In fact, most of the hormones operate by means of a negative feedback mechanism. The hypothalamus and pituitary gland controls the dual task of testis: production of immature spermatozoa (spermatogenesis) and production of testosterone (steroidogenesis) which in turn controls hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary gonadotropin secretion by negative feedback regulation. Testosterone deficiency leads to a clinical condition called as hypogonadism. The abnormalities such as reduced sperm production and fertilizing capability occur in male reproductive system due to irregular action of androgen during development ³⁰.

Recent researchers have indicated that copious quantities of circulating estrogens may suppress the spermatogenesis and adversely affect the male fertility power. Germ cell tumors produce β–human chorionic gonadotropin (β-HCG) and α-fetoprotein (AFP). The increased level of β-HCG of intratesticular estradiol production decreases or impairs spermatogenesis in the contralateral testis ³¹ while increased level of AFP decreases total sperm countoligozoospermia ³² Moreover, it has been found that the patients suffering from germ cell tumors had an increased level of serum follicle stimulating hormone (FSH), a rare cause of treatable male infertility.

A recent research has suggested that administration of clomiphene citrate; hCG and hMG to non-obstructive azoospermic patients can results in an increased level of FSH, and total testosterone level and thus the rate of sperm in the ejaculate ³³. Plasma SHBG (sex hormone-binding globulin) levels tended to be lower in idiopathic infertile men (OAT) compared to normal fertile men; affecting sperm count, motility and morphology. However, much attention is required to elucidate the role of SHBG gene polymorphism in male infertility. Recent population-based studies suggest endocrine dysregulation in obese men as they exhibit reduced inhibin B levels and elevated estrogen levels which reduce androgen and SHBG levels, explaining the increased risk of abnormal semen parameters and infertility ¹⁸.

No therapeutic measures for obesityassociated male infertility have been studied yet. Thus, greater clinical awareness is needed for understanding its mechanism and treatment.

Receptor Dysfunction and defect in biosignalling pathways also contribute to male infertility problem. In several cases, development and organization of male gonadal organs are affected by faulty receptors mediating the biosignalling pathway of sex steroids. The development of male sex organs requires an optimal interplay between various hormonal factors particularly testosterone. Male sex hormone i.e. testosterone works in a paracrine manner and its effect in the target cell is mediated by cytosolic receptor. A defective receptor is not able to mediate the function of testosterone and these results into the development of the clinical condition known as testicular feminization or androgen insensitivity which may be considered as a factor of male infertility. According to a research paper, insufficient androgen and FSH signaling are unable to respond to an endogenous hormonal milieu that stimulates the initiation of spermatogenesis and may be responsible for the azoospermia of the infantile primate testes ³⁴.

Anatomical Abnormalities: Various disorders in different male reproductive organs might cause testicular or post-testicular abolition of fertility. In industrialized countries, one of the major anatomical abnormalities related with male infertility is a condition known as cryptorchidism, affecting 2-4% of male infants, more frequent in premature infants ³⁵. In this condition, testicles fail to descend into scrotal sacs before birth. Abdominal testicles are unable to support the process of spermatogenesis because it requires temperature (2ºC) below the normal human body temperature for sperms cells to mature into viable, functional and fertilizable sperms.

However, the exact cause of cryptorchidism remains elusive. Various factors, mainly hormonal, genetic and environmental factors may contribute to the development and increased incidence of cryptorchidism. This increases the risk factor for impaired fertility (33% to 66%) and testicular cancer, 5-10 times greater than normal³⁶. Mutations in insulin-like factor 3 gene, its receptor gene and androgen receptor gene explain a minor reason of cryptorchidism ³⁷ presented a report in support of intrauterine environment and maternal inheritance contributing to the phenomenon of cryptorchidism.

Although, the long-term therapy is still in its infancy, the surgical treatment by orchiopexy is recommended between 6 and 12 months as to preserve the spermatogonia ³⁵. Early surgical therapy may reduce the risk of subfertility and/or malignancy. The patients who undergo orchiopexy after the age of 12 years or no orchiopexy have 2 to 6 folds of risk of testicular cancer as compared to those who undergo between 10 to 12 years of age³⁸. Although, hypospadias is not closely associated with cryptorchidism due to major difference in pathogenesis; placental abnormality may cause both cryptorchidism and hypospadias as it occurred in many other congenital malformations ³⁹.

Chromosomal abnormalities in patients with cryptorchidism and hypospadias have been reported ⁴⁰. Varicocele, another abnormality is a collection of abnormally dilated, swelled spermatic veins that drain the testicle. It can occur on both side, but most frequent on the left side. A clinical varicocele is found in about 15% of all adult males⁴¹. Varicocele can lower sperm quality and quantity, and even testicles may shrink. In addition, epididymitis, anomalies of seminal vesicle and tubular damage/dysfunction due to infection may contribute to male infertility. Congenital anomalies may be either infrequent, with a localized defect in the proximal part of the vas deferens, or an inclusive abnormal development ⁴².

Hendry et al. investigated 370 azoospermic males with normal serum FSH levels and observed 5% unilateral absence of the vas deferens and 18% bilateral absence.Inherited deformities of the penis can deflect the ejaculate and prevent it from emerging at the tip of the penis ⁴³. Epispadias is a type of congenital defect with shorter, wider size and abnormal curvature which can make successful sexual intercourse difficult. It can be surgically corrected and pregnancies may be produced ⁴⁴. Epididymitis is caused due to inflammation of the epididymis which can progress to acute and chronic forms. Anomalies of the seminal vesicles can be categorized into abnormalities of number (agenesis, fusion), canalization (cysts) and maturation (hypoplasia) ⁴⁵.

Chemical / Occupational Exposure: In modern world, economy is based on the notions of conspicuous consumerism, mass-scale methods of production, ever expanding industrial processes and rising trends of chemical farming that has exposed man to umpteen numbers of chemicals which were not even in thought for decades ago. There are many chemicals that can temporarily or permanently affect the fertility of men either by altering spermatogenesis, sperm parameters or hormonal imbalance. The infertility problem in patients seeking infertility treatment may frequently be due to the chemical occupational exposures ⁴⁶. Among such chemicals are lead ⁴⁷, diaminostilbene ⁴⁸, benzo(a)pyrene (BaP) ⁴⁹, dibromochloropropane ⁵⁰, carbon disulphide ⁵¹ ,alkyl mercury ⁵², ethylene glycol ether ⁵³,methylene chloride ⁵⁴, manganese ⁵⁵, carbaryl ⁵⁶ and vinyl chloride ⁵⁷.

Prenatal diethylstilbestrol (DES) exposure may slightly increase the risk of infertility, but does not affect the number of fathered pregnancies or live births ⁵⁸. Sulfasalazine might cause male infertility by inducing oxidative stress ⁵⁹. Among heavy metals, lead was first to be reported to have antifertility effect. Moderate exposure to lead and cadmium can decrease semen quality ⁶⁰. Exposure to copper can result into oligoteratozoospermia and asthenozoospermia⁶¹. In human studies ⁶² observed reduced sperm quality in welders exposed to chromium. The nematocide dibromodichloropropane (DBCP) have negative effect on spermatogenesis ⁶³. Ethane 1,2-dimetane sulphonate (EDS) cause toxicity to Leydig cells as a result of lack of plasma testosterone level ⁶⁴. Boric acid is also a reproductive toxicant which reduces the testosterone level ⁶⁵. Chromium compounds mainly cause testicular tissue damage by increasing oxidative stress ⁶⁶. Aluminium causes reduced weight of reproductive organs and impair fertility ⁶⁷. Ammonium metavanadate is reported to have toxic effect on reproduction and fertility ⁶⁸.

Certain pesticides are able to disturb the sex steroid hormone system and act as antiandrogens. Exposure to pesticides may cause foetal loss, alteration in gestational age at delivery, formation of terata (birth defects), infant/child morbidity and mortality, male/female sexual dysfunction, sperm abnormalities, amenorrhea, dysmenorrhea and illness during pregnancy and parturition and endocrine effects. Male infertility could be associated with exposure of mothers of subfertile men to environmental organochlorine, dichloro-diphenyldichloroethylene (p,p′-DDE), restricted to intra-uterine and thus undetected in subfertile men ⁶⁹. A research paper explored that higher concentration of chlorinated pesticides viz. α-, β-, γ-, δ-HCH, DDT, pp′DDE and pp′DDD affect semen quality parameters, causing infertility ⁷⁰. Pesticides affect the particular stages of reproduction, mainly the prenatal stage and results in damage to the reproductive organs and ultimately impair fertility ⁷¹. Prenatal exposure of phthalates in the womb of human adversely affects male reproductive system and impairs testicular functions ⁷².

Many pesticides particularly persistent organic pollutants (POP) i.e. nonmetabolic and non-biodegradable are serious reproductive toxicants, which upon entering into food chain get biologically magnified and cause serious problems into human system including reproductive toxicity and infertility. 1,2-dibromo-3-chloropropane (DBCP) causes dose dependent reduced fertility by affecting post-testicular sperm through the mechanism of decrease in the metabolism of glucose to CO2 by epididymal ejaculated sperm ⁷³.

Human sperm chromatin condensation can be altered by exposure to organophosphorus (OP) with greater susceptibility to DNA denaturation and may adversely affect reproductive system via mechanism of protein phosphorylation ⁷⁴. Although, the basic mechanism of antiandrogenic pesticides to irregulate the sex steroid hormone system is not clear, it may act as 5α-reductase inhibitor which can interfere with endocrine system ⁷⁵.

Genetic / Congenital Factors: A gene is a molecular hereditary unit of living organisms that occupies a specific location on a chromosome as a sequence of DNA and holds the information to build and maintain an organism cell and pass genetic traits to offsprings. Sperm DNA integrity is crucial for the accurate flow of genetic information in the offsprings. Each and every gene has been characterized for specific roles, the accurate transmission of epigenetic information influence fertility in males and in their offsprings. Genetic pre-disposition is certainly an important aspect in the development and progression of most of the diseases and accounts 10-15% for severe male infertility including chromosomal aberrations and single gene mutations ⁷⁶.

Variability in the differential gene expression and its modification constitute an important component of epigenetic which has critical role in sperm development and function, fertilization and post fertilization events. Defective spermatogenesis lead to male infertility either due to pituitary disorders, testicular cancer, germ cell aplasia, varicocele, environmental factors or defective sperm transport due to congenital abnormalities or immunological and neurogenic factors. Interference with germ cell generation and maturation or production of non-functional spermatozoa increases the frequency of genetic disorders associated with male fertility ⁷⁷.

The gene CREM and ACT have regulatory functions in human spermatogenesis and help to understand its molecular mechanisms ⁷⁸. The factors such as paternal age and environmental toxicants responsible for poor semen quality, initiate DNA strand breakage in the spermatozoa, causing mutation in the embryo ⁷⁹ reported that XPA (–4) G/A polymorphism in XPA promoter of nucleotide-excision repair (NER) pathway lowers the transcriptional activity and increases sperm DNA damage and thus may contribute to male infertility.

The polymorphic gene CYP1A1 (CYP1A1*2A CC genotype) encodes CYP1A1 enzyme that catalyzes the bioactivation of polycyclic aromatic hydrocarbons (PAHs) which are able to form DNA adducts. The DNA adducts in sperm cells can cause severe DNA damage and interfere with meiotic division during spermatogenesis, which can be related with infertility in men⁸⁰. It has been recently reported by⁸¹ that the genetic polymorphisms of glutathione S-transferase (GST M1 and GST T1) and CYP1A1*2C of xenobiotic-metabolizing enzymes may possibly play an important role in male factor infertility.

Safarinejad et al ⁸² has investigated the association of the (TAAAA)n repeat and Asp237Asn polymorphisms in SHBG gene with idiopathic male infertility and relation to serum SHBG concentration. It has been demonstrated that Asp237Asn polymorphism and long SHBG (TAAAA)n alleles (i.e. >8 repeats) in SHBG gene may affect SHBG levels and thus increases the risk of infertility. Studies has also been carried out to investigate whether the polymorphism in aryl hydrocarbon receptor (AHR), aryl hydrocarbon receptor repressor (AHRR) and aryl hydrocarbon receptor nuclear translocator (ARNT) genes of aryl hydrocarbon receptor pathway are associated with male factor infertility in Estonian men. Allele and genotype frequencies were compared between infertile men and controls and separately in the normozoospermia, oligozoospermia and azoospermia groups. It was found that AHRR (Pro185Ala) polymorphism contribute to male infertility development ⁸³.

Some genetic problems with chromosomes occur in about 2 to 20% of infertile men and can affect their fertility in two ways-

(i)     Male sex partner having chromosomal abnormalities can disrupt cell division and sperm production, and

(ii)   The development of testicles may be affected by chromosomal disorders mainly of sex chromosome, of which Klinefelter’s syndrome is the most common with an additional X chromosome (47 XXY).

In chromosomally derived infertility, spermatogenic breakdown results due to Y chromosome microdeletion (with a frequency of 9.1%) and structural chromosomal abnormalities, which are linked with histological changes in testis ⁸⁴. However, in the case of genetic infertility, the molecular mechanisms of spermatogenic damage (for example Yq microdeletions) are still not known. The interstitial Y-chromosomal microdeletions of SRY gene (associated with gonadal differentiation) and DAZ, SPGY and related genes on the Y chromosome (associated with spermatogenesis) encompassing the AZFa, b or c region cause genetic abnormalities and eventually male infertility ⁸⁵.

Mutations in the genes responsible for fertility lead to defects in development of the germ cell lineage that causes infertility. This type of infertility can be repaired via increased frequency of mutations in DNA of infertile males with meiotic arrest⁸⁶. As already discussed in hormonal section that excessive exposure to estrogen negatively impacts spermatogenesis, the polymorphisms of the estrogen receptor (ER) genes have been implicated in male infertility. ER-α (ESR-1) PvuII TT, ER-α XbaI AA, ER-β (ESR-2) RsaI AG, and ER-β Alul AG genotypes are associated with increased infertility risk, significantly lowers the level of SHBG, luteinizing hormone (LH) and values for sperm density, sperm motility, and percentage of sperm with normal morphology⁸⁷. However, further researches are needed to establish better association between the biological mechanism of ESR-α, and ER-β and incidence of male infertility.

Alcoholism, Smoking and Club Drug Usage: Empirical evidences and few studies have suggested that regular consumption of alcohol negatively impacts the fertility power in men. Alcohol not only reduces the sperm counts and concentration but may also induce morphological deformities in sperm (e.g. double headed sperm) which makes sperm incapable of fertilization. There are evidences to indicate that miscarriage is also associated with alcohol. A research paper reported that heavy chronic alcohol intoxication have a slow progressive negative impact-moderate teratozoospermia followed by oligoastheno-teratospermia, then a severe cryptozoospermia and ultimately azoospermia. At this stage the maturation of germinal cells at the pachytene stage was arrested and no mature sperm cells were found. However, within 3 months, alcohol withdrawal allowed fast and drastic improvement of the semen parameters to normal ⁸⁸.

Sperm concentration, percentage motility, morphology, and percentage viability are significantly affected due to tobacco chewing in Indian men that lead to infertility ⁸⁹. Cigarette smoking and passive inhalation of smoke may adversely impact male fertility. Smoking on a regular basis has been shown to reduce sperm count in males.

Most of the reports showed negative impact of cigarette smoking on male reproductive system; such as lower semen volume, reduced sperm count, production, motility, viability, morphology, fertilizing capacity of spermatozoa through increased seminal oxidative stress, DNA damage and lower implantation rates of embryos, correlated with cigarette smoking/day and smoking duration ⁹⁰. In addition to above, there are increased seminal leucocytes, oval sperm percentage, defective head-piece spermatozoa and spermatozoa with cytoplasmic droplets in smokers ^{91, 92}.

Moreover, it decreases the antioxidant activity of superoxide dismutase and increases leucocytospermia which adversely affect sperm motility⁹³ but the negative impact of smoking on intracellular antioxidant enzymes does not increase oxidative DNA damage ⁹⁴. Nicotine, the main constituent of smoke has a significant impact on sperm morphology and sperm count ⁹⁵. Consumption of more than 20 cigarettes/day shows elevated seminal cadmium (Cd) level in smokers ⁹⁶.

Smoking has negative correlation between cadmium in blood and sperm density ⁹⁷. Also, lead in seminal plasma affects fertility of men ⁹⁸. Besides above, smoking also induces erectile dysfunction associated with vascular (arterial and venous) impotence, elevated serum estradiol levels and lowered sperm density, greater numbers of leucocytes in the seminal fluid and lower sperm penetration with greater associations in patients with pre-existing impaired function ⁹⁹. On analyzing the degree of DNA fragmentation in spermatozoa using the TUNEL-assay with flow cytometry detection, it was found to be higher in smokers concluding that smoking may have negative impact on sperm nuclear quality ¹⁰⁰.

Including the research papers indicating nonsignificant association of semen parameters with smokers and non-smokers, it is concluded that men with marginal semen quality experience reduced fertility which regarded smoking as an infertility risk factor ¹⁰¹. Even male cigarette smoking can significantly decreased live birth rates¹⁰². However, further studies are required to establish this beyond reasonable doubts.

Another serious negative factor is use of club drugs, pharmacologically heterogeneous group of psychoactive drugs that tend to be abuse by teenagers and young adults at bars, nightclubs, concerts and parties. These drugs vary by country and region. Ecasty (MDMA), gamma-hydroxybutyrate (GHB), ketamine, methamphetamine, rohypnol, marijuana, caffeine, heroin, morphine, poppers, and cocaine are some examples of such drugs that are increasing in popularity as a part of western lifestyle ¹⁰³ and these addictions are responsible for deleterious effects on entire sperm structure ¹⁰⁴.

A study explore the people who use marijuana weekly or who exposed to marijuana since adolescents, and examined them to had twice the testicular deficiencies, erectile dysfunction, infertility anomalies and cancer risk when compared to men who smoked a couple of times and those who never smoked marijuana ¹⁰⁵. Its continuous use reduces sperm quality and testosterone level and increase impotence ¹⁰⁶. Delta-9-tetrahydrocannabinol, the primary psychoactive cannabinoid in marijuana, can impair sperm functions and adversely affect male fertility ¹⁰⁷. The addiction of heroin and methadone result into asthenospermia (100%), teratospermia & hypospermia (24%) and oligozoospermia (17%) ¹⁰⁸.

A study analyzed the semen of 40 years old man who had been addicted to heroin, morphine, hashish, and other narcotics for 12 years and 2 years after self-denial from drugs and revealed oligozoospermia, asthenozoospermia, and morphologically abnormal spermatozoa ¹⁰⁹. Chronic intake of cocaine has a deleterious effect on spermatogenesis and fertility ¹¹⁰. Cocaine cause reproductive system injury and may involve Fasmediated apoptosis ¹¹¹. Cocaine induced testicular injury which could be related to apoptosis ¹¹² and may involve Fas-mediated mediated pathway ¹¹¹ or mitochondria-associated pathway¹¹³. Cocaine exposure appears to involve the release of cytochrome c from mitochondria and its subsequent activation of caspase 9 and caspase 3 in testes and play a key role in cocaine-induced testicular germ cell loss/apoptosis ^{113, 114}.

Lifestyle, Nutrition & Diet Factors: In recent years, a number of lifestyle factors have been suggested which may be adversely affecting the male fertility. Unhealthy and imbalanced lifestyle can aid the risk of impotency in males. Desk bound work, tight clothing, composition of diet and keeping mobile phones close to scrotum may have adverse effects on male fertility. The decreased human semen quality over recent decades may be related to a change in living habits, illustrated by a more deskbound work with high energy intake and increased incidence of obesity ¹¹⁵. However it is still unclear how these factors are actually exerting their effects. Further studies are required to establish a concrete link between lifestyle factors and incidence of male infertility.

Vitamin E supplement increases the semen quality and quantity parameters by protecting testicular cell membrane and mitochondria from antioxidant activities ¹¹⁶. The oral administration of antioxidants (vitamins C and E, zinc, selenium, folate, carnitine and carotenoids) in infertile men could improve sperm quality and pregnancy rates ¹¹⁷ but no particular antioxidant is able to improve fertilization rate in infertile men, whereas a combination of them provide a better effect ¹¹⁸. The high intake of dietary antioxidants-vitamin C, vitamin E, β-carotene, folic acid, zinc, papaya, lactoferrin and lipophilic foods improve the semen parameters ^{119, 120, 121}.

Low intake or deficiency of these nutrients cause poor semen quality and increases the risk of male infertility ¹²². Long term use of isoflavone phytoestrogens containing soybean have adverse effect on the development and function of the male reproductive system resulting into decrease in sperm count and fertility ¹²³. Carnitine, a water-soluble antioxidant derived from the human diet provides the primary fuel for sperm motility and protect sperm DNA from ROS-induced damage and apoptosis ¹²⁴. Patients with defective sperm motility have a reduced Lacetylcarnitine/ L-carnitine ratio ¹²⁵. However, its oral supplementation improves the motility of spermatozoa ¹²⁶.

Human studies have shown direct relationship between obesity and infertility ¹²⁷ demonstrated that diet induced obesity in male mice cause a significant reduction in fertility. Obesity resulted in reduced number of plugs and pregnancies of control females paired with obese versus lean males. Neither the reversibility of infertility associated with obesity with weight loss nor effective therapeutic interventions have been known till time.

However, contradictory results have been reported on obesity associated male infertility. A decreased sperm count and volume of ejaculation had been reported in men with increasing body mass index (BMI) and no correlation with sperm concentration, motility and morphology ¹²⁸ while contrast papers had reported a negative correlation between BMI and sperm count and concentration ¹²⁹.

Hofny and Hammoud reported positive correlation between BMI and abnormal sperm morphology¹³⁰ and sperm count¹³¹.According to a recent paper obesity may induce oxidative stress and decrease testosterone levels which may alter testicular functions and thus concluding that obesity can be an important factor in the etiology of the male infertility ¹³². High blood pressure is another condition that affects impotency and is a result of poor lifestyle choices. This may be because of increased pressure which may damage small vessels in the penis or that hormonal levels are affected. Added weight, lack of exercise, unhealthy or high-sodium diet and alcohol; all contribute to high blood pressure.

Wdowiak et al (2007) ¹³³ studied the effect of GSM equipment on the semen and found an increased proportion of abnormal sperm cell morphology positively related with the time period of exposure to the waves emitted by the GSM phones and decrease in sperm cells progressing motility in the semen with the frequency of using mobile phones. People using mobile phones to a greater degree may be exposed to stress, which by affecting the level of cortisol, prolactin and testosterone may contribute to the decrease in concentration of the semen¹³⁴. The radio-frequency electromagnetic waves (EMW) from these devices decreases sperm count, motility, viability and morphology leading to poor sperm quality ¹³⁵ depending upon the daily exposure time period to it ¹³⁶.

Ageing: The effect of age on male fertility is not clear. However, evidence is growing that the genetic quality of sperm, its concentration and motility typically decreases with age. According to a research paper, increasing male age cause decline in semen volume, sperm motility, and sperm morphology but not sperm concentration ¹³⁷. Recently, a paper evaluating the impact of age on the expression of apoptotic biomarkers in human spermatozoa provided the evidence that increasing male age is associated with reduced sperm concentration ¹³⁸. The decrease in fertility with age is associated with a decline in testicular weight, sperm production and the testosterone levels ¹³⁹. A research presented the evidence of age-related increase in the number of sperm with chromosomal breaks and fragments (ie. structural chromosomal aberrations in sperm) which have significant effects on the viability and genetic health of human pregnancies and offspring ¹⁴⁰. Vagnini L. et al ¹⁴¹ investigated the influence of age on sperm DNA damage. They demonstrated a significant increase in sperm DNA fragmentation index (DFI) with age. With TUNEL assay they showed an increase in sperm DNA damage with age.

Oxidative Stress and Reactive Oxygen Species: Reactive oxygen species (ROS) are highly reactive oxidizing agents belonging to the class of free radicals. ROS generated within semen are believed to play both sperm pathological and physiological role in male fertility ¹⁴² facilitating capacitation, hyperactivation, acrosome reaction, motility, fertilization, sperm-oocyte fusion ¹⁴³. However, ROS-induced sperm damage is considered as the primary basis for impaired fertility ¹⁴⁴. Its high concentration causes altered sperm pathology through intracellular ATP depletion leading to insufficient axonemal phosphorylation, lipid peroxidation, decreased motility, and viability and increased morphology defects with deleterious effects on sperm capacitation and acrosome reaction ¹⁴⁵ and have been implicated in prostate cancer ¹⁴⁶. The increased levels of malondialdehyde, nitric oxide and decreased levels of zinc and superoxide also play a role in disruption of spermatozoa membrane integrity and reduction of sperm DNA integrity ¹⁴⁷.

Oxidative stress has been considered a major contributory factor for ROS-induced male infertility ¹⁴⁸. It takes place due to imbalance between ROS and total antioxidant capacity (TAC) within the body and leads to sperm damage, deformity and eventually male infertility ¹⁴⁹. Oxidative stress induced lipid peroxidation also damage sperm membrane affecting its fluidity and motility ¹⁵⁰ as spermatozoa are rich in polyunsaturated fatty acids, which are susceptible to ROS.

Leuckocytes (mainly macrophages and neutrophils) and immature spermatozoa are the main source of excessive ROS production, leading to sperm dysfunction ^{151, 152, 153}. When pathogens invade the human body, it produces polymorphonuclear leukocytes and macrophages which generate ROS and lead to sperm damage ¹⁵⁴. Prostatitis, and accessory gland infection increases oxidative stress and results into excessive damage to spermatozoa ¹⁵⁵.

ROS may promote apoptosis, the mechanism to remove old, senescent and destructive cells from the body ¹⁵⁶ ,which can cause numerous forms of sperm DNA damage, e.g. chromatin cross-linking, chromosome deletion, DNA strand breaks and  base oxidation, mutations, and other lethal genetic effects ¹⁵⁷, leading to decreased sperm concentration ¹⁵⁸ and other physiological and pathological changes. As the regulated caspase cascade plays a critical role in sperm differentiation, testicular maturation; ROS and higher levels of cytochrome c, caspases 9 and 3 generated in apoptotic pathway causes increased sperm damage ¹⁵⁹ and thus can be associated with multiple andrological pathologies – impaired spermatogenesis, membrane integrity, decreased sperm motility, increased levels of sperm DNA fragmentation- single and double DNA strand breaks, testicular torsion, varicocele and immunological infertility^{160,161,162,163}. Thus, seminal oxidative stress, ROS, apoptosis and sperm DNA damage are interconnected, and eventually results into infertility problems.

Pollution and Radiation: The different types of pollution such as air, water, land, sound and radioactive affects the human beings in many ways by causing adverse effects to their body organs and thus leading to serious diseases. Air pollution is associated with reduced sperm motility, two to three months after exposure ¹⁶⁴. According to a finding diesel exhaust particles (DEP) suppress expression of sex steroid hormone receptors (ER-α) in TM3 mouse Leydig cells by approximately 50% ¹⁶⁵.

Continuous exposure to traffic pollutants impairs sperm quality and reduced fertility in young and middle-aged men. A study for the first time found a new group of anti-androgen chemicals affecting wildlife including humans which when enter into the water system may cause reproductive problems - reduced breeding capability and feminizing effects in male fish. A research team investigated that untreated (influent) and treated (effluent) textile dye wastewaters cause decrease in body weight (7–25%) and reproductive organ weight (testis, epididymis, prostate gland and seminal vesicle, 2–48%), total protein (14–70%), cholesterol (14–91%) and total lipid (10–30%) content of reproductive organs and spermatozoa, and for fructose levels in seminal vesicle (18–44%). Histopathological examination revealed altered spermatogenesis along with higher sperm abnormalities, reduced sperm counts (10–59%) and altered motility (14–56%) ¹⁶⁶. Similar research on pulp and paper-mill effluents showed reduction in the relative weight of the testis, decline in total sperm count, motility, testosterone level and a drop in the activity of epididymal α-glucosidase¹⁶⁷. This factor may be related with increasing male infertility caused by TDS but no stronger evidence has been reported yet.

In recent years, researches have shown that ozone produced as a secondary pollutant in the troposphere compartment of the atmosphere reduces sperm quality, sperm density in semen and adversely affects male fertility through oxidative damage pathway as it is a powerful oxidant; indicating ozone may be a reproductive toxicant¹⁶⁸. A large number of researches have been done on the adverse effects of radiation on male and female reproductive systems.

The 10-GHz microwave radiation has negative impact on the reproductive system which causes infertility ¹⁶⁹. Radiofrequency electromagnetic waves (RF-EMW) emitted from cell phones may lead to oxidative stress in human semen which negatively affect spermatozoa and impair male fertility ¹⁷⁰. Radiation may have effects on male and female reproductive organs, hypothalamus–pituitary–gonadal axis and on genetic aspects ¹⁷¹.

Diseases: There are several general medical disorders or conditions that may reduce male fertility. Mumps, tuberculosis and sexually transmitted diseases can affect sperm production by causing inflammation and obstruction in the male genital tract. The infectious agents such as bacteria, fungi, viruses and parasites may interfere human physiological functions including reproduction in both the sexes. About 15% cases of male infertility are due to the infection of male genitourinary tract ¹⁷².

It can affect different sites of the male reproductive tract, such as testis, epididymis and male accessory sex glands and spermatozoa at different levels of their development, maturation and transport. The infectious process may deteriorate spermatogenesis, impair sperm function and obstruct seminal tract.

Chlamydia trachomatis and Nisseria gonorrhoeae are the most common microorganisms while Escherichia coli being less frequent affecting male fertility ¹⁷². Chlamydia infection impairs sperm parameters, proportion of DNA fragmentation, and acrosome reaction capacity which may adversely affect male fertility ¹⁷³. Prolonged fever could affect sperm production. In cases of pneumonia, influenza or even severe cold results in high fever inhibits production of sperm and its quality. These changes usually recover over few weeks. Febrile illness episode to a fertile man cause temporary decrease in total sperm count, percentage motility and viability, and increased DNA fragmentation DNA stainability, representing marked effects on semen parameters and sperm DNA integrity ¹⁷⁴.

Diabetes is another medical pathology which can cause problems with erection and ejaculation. Surplus sugar in blood can directly affect the quality of sperms and gradually lead to male infertility. In the cases of chronic diabetes, functions of autonomous nervous system get damaged which results in problems associated with erection and ejaculation. It has a direct effect on fertility causing DNA damage in sperm. Moreover, the occurrence of primary and secondary infertility was significantly higher in diabetic men as compared to non-diabetic men providing strong evidence of diabetes induced male infertility ¹⁷⁵.

Neurological disorders such as multiple sclerosis, stroke and spinal cord injury and disease can cause problems with erection and ejaculation. Cancers affecting the genital tract and endocrine system may directly decrease male fertility. Chemotherapies and radiation used for treating cancer may severely affect sperm production or even stop it. Many forms of stress can affect fertility and reproduction and cause changes in the body at hormonal level.

Mild-to-severe emotional stress and psycho-pharmacologic agents may reduce testosterone levels and possibly interrupts with spermatogenesis in men. Infertility measurement and treatment can lead to pain and negatively affect sperm samples ¹⁷⁶. Difficulty with erection either directly or indirectly is a major problem associated with hypertension. Stress reduces a man's libido. Under much stress condition they often lack of sexual desire.

This happens due to increase blood pressure and irregular blood circulation throughout the body, decreasing the amount of blood going to the penis. In some men, depression may be linked to heart disease and erectile dysfunction. ROS-induced oxidative stress within semen, damage sperm membrane which further reduce sperm motility and ability to fuse with oocyte. Moreover, it also destroys sperm DNA integrity, compromising the paternal genomic contribution to the embryo¹⁷⁷.

Drugs: Studies have shown that many drugs used to treat various diseases are detrimental to reproductive health as they can induce infertility. Some types of prescribed medicines that can lead to male infertility are high blood pressure monitoring drugs, antibiotics, CNS depressant and drugs used for treatment of gastric problems that interfere with sperm production and ejaculation. A group of drugs-calcium channel blockers (CCB) are typically prescribed for patients of hypertension as they increase the amount of blood and oxygen supply to heart helping to minimize its work. However, they interfere with the fertilization process by preventing the sperm from being able to penetrate an egg and are commonly associated with male infertility. Long term administration of such drugs suppress spermatogenesis as many sperm functions such as motility¹⁷⁸, hyperactivity¹⁷⁹, acrosome reaction¹⁸⁰ and capacitation¹⁸¹ are regulated by cytoplasmic calcium. Previous papers had also reported that the effect of CCBs get reverse on the withdrawn on the drug¹⁸².

Antibiotics: Antibiotics are often prescribed to deal with a variety of bacterial infections and problems. Some antibiotics show short term and others have long term effects. Major classes of antibiotics have significant negative impact on spermatogenesis or spermatozoal functions. Some of the antibiotics that are known or suspected to interfere with male fertility ¹⁸³ (Table no. 1).

Antibiotic	Use	Effects
Nitrofurantoin	Urinary tract infections	Reduced sperm count
Neomycin	Bacterial infections	Reduced sperm production and motility
Macrolides	Legionnaires disease	Reduced sperm motility
Sulfasalazine	Rheumatoid arthritis, Ulcerative colitis	Reduced sperm count, motility and abnormal Morphology
Ketoconazole	Fungal infections	Reduced sperm count

Chemotherapy: The chemotherapeutic measures such as drugs and radiation often used for the treatment of cancer result in decrease in sperm count and motility and severely reduce sperm production (oligozoospermia) and even lead to azoospermia. These effects can be temporary or permanent.

Plants: There are several commonly used plants that are reported with antifertility properties. Different plants affect male reproduction by different ways: impair testicular functions, suppress spermatogenesis, hinder Leydig cells function and steroidogenesis and reduce hormone production¹⁸⁴. The leaf powder of Azadirachta indica (neem) causes reversible histological and biochemical changes in testes¹⁸⁵ and the aqueous extract of old and tender neem leaves is a potent spermicide¹⁸⁶. According to another study neem causes marked structural and functional alteration in testes, epididymis and seminal vesicle and reverse after cessation of its use ¹⁸⁷. It causes significant decreases in epididymal sperm counts, serum testosterone levels and increases in sperm head abnormality and subsequently the quality and quantity of spermatozoa ¹⁸⁸. Chloroform extract of Carica papaya seeds induces long-term reversible azoospermia¹⁸⁹. Its aqueous extract has a significant dose dependent suppressive affect on cauda epididymal sperm motility with reduction in sperm count and viability which completely restore on its withdrawn¹⁹⁰. Momordica charantia seed have antispermatogenic, antisteroidogenic and androgenic properties¹⁹¹. It causes dose dependent significant decline in sperm number, motility, testicular testosterone concentrations and testicular volume leading to suppress sperm production¹⁹² and reversible histological alterations in the prostate and testes ¹⁹³.

Indian Status: Census of 1981 estimated infertility around 4-6% in India ¹⁹⁴. Nearly 50% of infertility is related to reproductive abnormalities or disorders in male ¹⁹⁵. However, in 25% of cases from India, their causal factors are failed to be detected are categorized under unexplained infertility ¹⁹⁶. Danadevi et al (2003) ¹⁹⁷ found significant decrease sperm motility, morphology and semen abnormalities of 57 south Indian welders occupationally exposed to welding fumes of nickel and chromium. A similar research paper reported significant higher numbers of morphologically abnormal sperms in 61 industrial workers occupationally exposed to chromium, 53% of which showed less than 30% normal form of sperm ¹⁹⁸. According to a survey from 1993 to 2005, sperm density, morphology and sperm motility are deteriorating in the southern part of India ¹⁹⁹. Mukhopadhyay et al (2009) ²⁰⁰ reported a significant decline in the sperm motility and volume between two decades (1980s and 2000s) and the age related changes in semen parameters of 3729 male of Kolkata city.

CONCLUSION: A wide range of factors and causes contribute to the development and progression of male infertility. Overall, fertility issues are usually caused with the state of one’s general health. Men who live a healthy lifestyle are more likely to produce healthy sperm. The present review has revealed many factors that are responsible for male infertility. Some cases are due to anatomical abnormalities such as cryptorchidism, hormone imbalance and genetic defects but for many factors humans themselves are responsible, such as harmful environmental exposures, irregular lifestyle, improper diet and addiction to alcohol and smoke. Several recent studies have focused on the impact of free radicals and role of antioxidants on male fertility. Although many treatment options are available, many times treatments do not work. Thus there is a need to limit the exposure of human beings to noxious chemical agents, pesticides, fertilizers, drugs, radiations and stressful lifestyles etc. which play a major role in leading to infertility. In addition to above factors, several plants are also reported to have harmful effects on reproductive system. Thus, future research should be directed towards studying the toxic effects of all the factors including plants and drugs and the detailed mechanism of their action should also be elucidated. Governments all over the world ought to come up with the progressive legislation which can phase out the manufacture, use and disposal of hazardous chemicals. In this context REACH (Registration Evaluation and Authorization of chemicals), a legislation floated by EU is a welcome gesture. Finally a sound and informed public opinion must be created so as tackle the issue of male infertility.

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How to cite this article:

Singh P., Gupta R. , Patidar D.  and Singh R.K.: Male Infertility: Causes And Contributors: A Review. Int J Pharm Sci Res 2014; 5(6): 2095-12.doi: 10.13040/IJPSR.0975-8232.5(6).2095-12

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