Causes of male infertility

INTRODUCTION — The fertility rate in a couple is influenced by a number of factors, including the age of each partner; severe systemic disease in either partner; the specific disorders described below, and exposure to environmental toxins, drugs, or radiation. (table 1).

The causes of male infertility will be reviewed here. The evaluation and treatment of male infertility and issues related to unexplained infertility are discussed separately. (See "Approach to the male with infertility" and "Treatments for male infertility" and "Unexplained infertility".)

EPIDEMIOLOGY

Definitions and prevalence — Infertility in a couple is often defined as the inability to achieve conception after one year of frequent, unprotected intercourse, but epidemiological studies are inconsistent on the application of this definition [1]. For example, some studies restrict the definition to those who have been evaluated for infertility, while others survey large cohorts for self-reported difficulty in getting pregnant. Furthermore, some studies include miscarriage in the de definition of infertility, while others include all couples who sought infertility care. (See "Overview of infertility", section on 'Description and related terms'.)

The distribution of male and female causes of infertility has not been well defined [1,2]. In a 1982 to 1985 World Health Organization (WHO) multicenter study, 20 percent of cases were attributed to male factors, 38 percent to female factors, 27 percent to both, and 15 percent not clearly attributed to either [3]. While other studies have reported a prevalence of male fertility of approximately 10 to 15 percent [4,5], a WHO systematic review suggested that estimates of prevalence are limited by variability in definitions of male infertility and laboratory approaches to performing semen analyses. [1].

Impact of aging — Aging affects the prevalence of male infertility. Overall, the studies indicate that paternal age >40 years adversely affects couples' fertility, but this effect is small compared with the effect of maternal age >35 years [6,7]. A cross-sectional survey of men in the United States ages 15 to 44 years showed a prevalence of male infertility of 12 percent (95% CI 7-23) [8]. Epidemiologic studies suggest that natural fertility rates are lower and time to conception is longer for men over age 40 years than younger men [6,7,9,10]. Older paternal age might also increase the risk of miscarriage [7,11]. The observed effects of paternal aging on fertility are at least partially due to decreased sperm quality and increased genetic abnormalities in sperm [7,11]. Several, but not all, studies of assisted reproductive technologies (ART) have demonstrated an association between older paternal age and decreased live births with ART [11-13].

Trends in male reproductive function — There is controversy about whether there is a worldwide trend toward a decrease in average quantity and quality of human spermatogenesis and fertility [14-19]. Studies of infertile men in Europe and the United States show marked differences in sperm concentration between different countries and different regions of the same country [20-22]. The role of environmental pollutants or toxins remains unclear [23,24]. There are few data on the sperm parameters of men living in poor, less industrialized countries [1].

CATEGORIES AND CAUSES

●Categories – Male infertility is traditionally categorized based on sperm quantity and quality.

•Sperm quantity – The majority of men with male infertility have lower than normal sperm concentrations (ie, < 15 million/mL) or azoospermia (no sperm cells in the ejaculate), but some infertile men have normal sperm counts [25].

Over 80 percent of infertile men have low sperm concentrations (oligospermia) associated with a decreased sperm motility (asthenozoospermia) and increased abnormal sperm morphology (teratozoospermia).

•Sperm quality – A small percentage of infertile men have normal sperm concentrations but low motility (asthenozoospermia) or abnormal morphology (teratozoospermia).

•Normal semen analysis – A small percentage of infertile men have normal sperm concentrations and normal motility and morphology.

●Causes – The causes of male infertility can be divided into four main areas (table 1). The prevalence of these etiological categories has limitations as it is based upon variable definitions of male infertility and its causes, selection bias, and variations in the evaluation of male infertility.

•Endocrine and systemic disorders with hypogonadotropic hypogonadism – 5-15 percent [1,4,25,26]. (See 'Endocrine and systemic disorders with hypogonadotropic hypogonadism' below.)

•Primary testicular defects in spermatogenesis – 70 to 80 percent; Klinefelter syndrome is the most common identifiable cause of a primary testicular defect, but the majority in this category have idiopathic dysspermatogenesis, an isolated defect in spermatogenesis without an identifiable cause [4,25]. (See 'Primary testicular defects in spermatogenesis' below.)

•Sperm transport disorders – 2 to 5 percent [4,25]. (See 'Sperm transport disorders' below.)

•Idiopathic male infertility – 10 to 20 percent [4,25]. Idiopathic male infertility must be distinguished from idiopathic dysspermatogenesis. Idiopathic male infertility describes an infertile man with a normal seminal fluid analysis and no apparent cause for infertility, whereas infertile men with idiopathic dysspermatogenesis have abnormal seminal fluid analyses. (See 'Idiopathic male infertility' below.)

The above prevalences represent an estimate of the approximate proportion of men in each category presenting for infertility treatment at a referral center and likely do not represent the prevalence in the broader community in industrialized countries, nor do these estimations reflect likely regional variations around the world [1,4,25,27].

ENDOCRINE AND SYSTEMIC DISORDERS WITH HYPOGONADOTROPIC HYPOGONADISM — Any hypothalamic or pituitary disease can cause gonadotropin-releasing hormone (GnRH) or gonadotropin deficiency (hypogonadotropic hypogonadism) and, therefore, infertility. These conditions can be subdivided into congenital, acquired, or systemic disorders. It is important to diagnose secondary hypogonadism because gonadotropin treatment often successfully improves spermatogenesis and fertility. All of these disorders are discussed in detail separately. (See "Causes of secondary hypogonadism in males", section on 'Congenital abnormalities' and "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)" and "Induction of fertility in males with secondary hypogonadism", section on 'Gonadotropin therapy'.)

Congenital disorders of gonadotropin secretion (rare)

●Idiopathic hypogonadotropic hypogonadism (IHH) – Isolated GnRH deficiency, also referred to as idiopathic hypogonadotropic hypogonadism (IHH), is a family of genetic disorders that are associated with defects in the production and/or action of hypothalamic GnRH [28]. IHH can occur either with normal olfaction (normosmic IHH) or with anosmia. This latter clinical presentation of IHH with anosmia is referred to as Kallmann syndrome. In addition, many of the men have midline facial defects, color blindness, hearing difficulties, renal agenesis, synkinesias, and/or cryptorchidism. This disorder is reviewed in detail separately. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)

●Gonadotropin subunit mutations causing hypogonadotropic hypogonadism – In studies of a population of Estonian men, a single nucleotide polymorphism in the follicle-stimulating hormone (FSH) beta gene promoter was associated with lower serum FSH concentrations and abnormal sperm parameters [29-31]. (See "Causes of secondary hypogonadism in males".)

●Congenital combined pituitary hormone deficiency – Congenital combined pituitary hormone deficiency syndromes are likely due to genetic defects, but the underlying genetic abnormalities have not been determined in the majority of cases [32]. (See "Causes of hypopituitarism", section on 'Genetic diseases'.)

●Other – Other rare congenital disorders of gonadotropin secretion include multiorgan genetic syndromes such as the Laurence-Moon-Biedl syndrome, Prader-Willi syndrome, and familial cerebellar ataxia [33]. (See "Prader-Willi syndrome: Management".)

Acquired disorders of gonadotropin secretion (common) — Any acquired hypothalamic or pituitary disease can cause hypogonadotropic hypogonadism and therefore infertility by damaging the GnRH neurons in the hypothalamus or the gonadotroph cells of the pituitary, by interrupting the hypothalamic-pituitary portal circulation, or by functional inhibition of GnRH or gonadotropin secretion. These disorders are discussed in detail separately but are listed here (table 2) (see "Causes of secondary hypogonadism in males"):

●Tumors that cause hypogonadotropic hypogonadism include pituitary macroadenomas, craniopharyngiomas, other sellar masses, and surgical or radiation treatment of these lesions. (See "Clinical manifestations and diagnosis of gonadotroph and nonfunctioning pituitary adenomas" and "Causes, presentation, and evaluation of sellar masses".)

●Infiltrative diseases include sarcoidosis, histiocytosis, tuberculosis, fungal infections, iron overload syndromes (eg, transfusion-related hemosiderosis and hemochromatosis). (See "Causes of hypopituitarism" and "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

●Lymphocytic hypophysitis is an autoimmune condition that affects the pituitary and/or the infundibulum [34]. (See "Causes of hypopituitarism", section on 'Lymphocytic hypophysitis'.)

●Head trauma, intracranial radiation, or surgery. (See "Causes of hypopituitarism", section on 'Traumatic brain injury'.)

●Vascular lesions include pituitary infarction and carotid aneurysm. (See "Causes of hypopituitarism", section on 'Pituitary infarction (Sheehan syndrome)'.)

●Drugs, such as opioids or other central nervous system-activating drugs (including cannabinoids), and many psychotropic drugs, can inhibit GnRH or gonadotropin secretion, resulting in secondary hypogonadism and infertility.

Administration of exogenous testosterone or other androgenic steroids suppress endogenous gonadotropin secretion and thereby reduce spermatogenesis [35]. Androgenic steroid use should be suspected in men with low sperm counts, low serum LH, sex hormone-binding globulin and high-density lipoprotein concentrations, and a muscular phenotype. (See "Use of androgens and other hormones by athletes" and "Causes of secondary hypogonadism in males", section on 'Gonadal steroids'.)

In men, GnRH analogues (agonists and antagonists) are primarily used to treated advanced prostate carcinoma; infertility is an expected effect of this treatment (table 1) [36]. (See "Causes of secondary hypogonadism in males", section on 'Opioids' and "Causes of secondary hypogonadism in males", section on 'GnRH analogs'.)

●Endocrine disorders and their treatment – Hypogonadotropic hypogonadism and infertility can be induced by hyperprolactinemia, estrogen excess, glucocorticoid excess, or androgen excess; overt hypothyroidism or hyperthyroidism might result in decreased spermatogenesis but through mechanisms other than hypogonadotropic hypogonadism [35,37-39].

•Lactotroph adenomas and medications are the most likely cause of hyperprolactinemia in men. (See "Causes of hyperprolactinemia".)

•Estrogen excess may be due to estrogen therapy, secondary exposure (eg, from a female contact who is using topical estrogen), or estrogen production by a testicular tumor. (See "Testicular sex cord stromal tumors", section on 'Endocrine manifestations' and "Testicular sex cord stromal tumors", section on 'Sertoli cell tumors'.)

•Chronic glucocorticoid therapy or other causes of Cushing syndrome in men result in lower serum testosterone concentrations and inappropriately normal serum gonadotropins. (See "Causes and pathophysiology of Cushing syndrome".)

•Androgen overproduction due to tumors of the testis or adrenal glands suppresses gonadotropin secretion. (See "Testicular sex cord stromal tumors", section on 'Leydig cell tumors' and "Clinical presentation and evaluation of adrenocortical tumors", section on 'Clinical presentation'.)

•Ectopic production of human chorionic gonadotropin causes increased androgen and estrogen production and suppression of circulating gonadotropins. (See "Surveillance for stage I testicular germ cell tumors following orchiectomy", section on 'Nonseminomatous GCTs'.)

•Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency – In classic adrenal hyperplasia, chronic glucocorticoid therapy and excessive production of adrenal androgens and estrogens may result in low to low-normal serum testosterone and inappropriately low or low-normal gonadotropin concentrations [40]. In addition, growth of adrenal rest tumors in the testis may cause obstruction of sperm transport out of the testes and may directly cause Leydig cell dysfunction due to mechanical damage and local corticosteroid production by the adrenal rest tumors. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Fertility'.)

•Thyroid dysfunction – While overt (clinically evident) hypothyroidism or hyperthyroidism may be associated with decreased spermatogenesis via several mechanisms, neither disorder has been definitely associated with male infertility [41]. In spite of this, some experts suggest testing for thyroid dysfunction in the evaluation of male infertility.

Clinically significant hyperthyroidism may present with normal or high serum total testosterone concentrations (due to high sex hormone-binding globulin [SHBG] levels), low free testosterone, and elevated FSH and luteinizing hormone (LH) concentrations and decreased sperm motility [41,42]. There is no evidence that mild or subclinical hypothyroidism or hyperthyroidism increases the risk of male infertility [41,42]. (See "Clinical manifestations of hypothyroidism", section on 'Reproductive abnormalities'.)

Systemic disorders

●Any serious systemic illness or chronic nutritional deficiency can cause infertility due to hypogonadotropic hypogonadism that is sometimes combined with primary hypogonadism [43]. (See 'Systemic disorders' below and "Causes of secondary hypogonadism in males", section on 'Chronic, systemic illness'.)

●Significant obesity (with body mass index > 35) may result in hypogonadotropic hypogonadism with low total testosterone, low free testosterone, and low or inappropriately normal gonadotropin concentrations in men [44]. The obesity-associated decrease in serum SHBG contributes to the low serum total testosterone concentrations. Other factors contributing to the hypogonadotropic hypogonadism seen with obesity include metabolic syndrome, diabetes mellitus, and sleep apnea [44-47]. The relationship between obesity, semen parameters, and male infertility is less clear [48-51]. A 2019 systematic review reported that paternal obesity may have a small negative effect on couples' ability to conceive [50]. Although weight loss from bariatric surgery might increase serum testosterone concentrations in men with BMI >35 kg/m² and low to low-normal serum testosterone concentrations, the effects on fertility are unknown [51]. Because of the overall health benefits, we still advise weight loss with lifestyle changes to overweight and obese men seeking treatment for fertility. (See "Overweight and obesity in adults: Health consequences", section on 'Reproductive effects'.)

PRIMARY TESTICULAR DEFECTS IN SPERMATOGENESIS — The most common primary testicular defect is idiopathic dysspermatogenesis, a descriptive term that reflects the general lack of information about its etiology and male infertility. Primary hypogonadism is an important cause of azoospermia and oligozoospermia. Although multiple specific testicular disorders have been identified, the pathogenic basis for testicular dysfunction is often unknown. These disorders, which can be categorized as congenital/developmental or acquired, are reviewed in detail elsewhere but are described briefly here. (See "Causes of primary hypogonadism in males".)

Idiopathic dysspermatogenesis — In the majority of infertile men who have abnormalities in sperm number, morphology, and/or motility, there is no identifiable cause. The percentage of these men who have either a congenital or acquired abnormality in spermatogenesis is unknown.

Genetic causes of dysspermatogenesis — A number of genetic causes have been identified by a number of techniques, including genome-wide association studies (GWAS) [52-56]. Genetic disorders affecting spermatogenesis have been identified in approximately 5 to 10 percent of cases of male infertility [1,57].

Y chromosome and related defects — Infertile men with sperm concentrations <5 million/mL commonly have Y chromosome microdeletions [1,58]. Most of the microdeletions are found in the Yq11 region of the long arm of the Y chromosome. This region is named azoospermic factor (AZF), and it contains three regions: AZFa, AZFb, and AZFc. Deletion of the AZFa and AZFb regions results in severe spermatogenesis defects and azoospermia. Testicular biopsies in these men may show germinal cell maturation arrest or Sertoli cell-only syndrome.

Deletions of AZFc that cause infertility have a variable phenotype ranging from oligozoospermia to azoospermia [59,60]. Y chromosome deletions may also be associated with cryptorchidism, varicocele, and obstruction of the vas deferens [61,62].

A Y chromosome defect in a man is transmissible to his male offspring if assisted reproductive technologies (ART) using his sperm is successful. Thus, genetic testing and counseling should be offered to all men with nonobstructive azoospermia and all men with sperm concentrations with <5 million/mL before ART such as intracytoplasmic sperm injection (ICSI) are considered [1]. A 2019 meta-analysis found that a threshold of ≤1 million/mL would be more cost effective because Y chromosome microdeletions were rare in men with sperm concentrations >1 million/mL [63]. (See "Intracytoplasmic sperm injection", section on 'Pretreatment evaluation and counseling'.)

In Europe, Australia, and many infertility centers in the United States, tests for Y chromosome deletions are offered to the infertile couple. These tests need to be standardized to ensure the quality of the results so that genetic misdiagnosis can be avoided [64]. (See "Approach to the male with infertility", section on 'Genetic tests'.)

Autosomal and X chromosome defects — A number of autosomal and X-linked genes have been identified as regulators of spermatogenesis [52-54]. However, the clinical relevance of these findings is unclear. At this time we do not recommend testing for these pathogenic variants.

Epigenetics in male infertility — Sperm DNA methylation, histone acetylation, and noncoding RNAs may contribute to defective embryogenesis and idiopathic male infertility [65-71]. Both hypo- and hyper-DNA methylation have been reported with imprinted genes in men with infertility [72-75]. Epigenetic changes in DNA methylation, histone acetylation, or non-coding RNAs [76] may explain infertility due to obesity [77] and environmental toxicants [78], and such changes might prove to be useful predictors of male infertility and for health outcomes of offspring [79,80].

Congenital or developmental disorders associated with primary testicular defects — Congenital and developmental disorders that cause primary testicular defects in spermatogenesis (and sometimes concomitant testosterone deficiency) are found in a substantial proportion of infertile men. These include Klinefelter syndrome, cryptorchidism, and other less common disorders.

Klinefelter syndrome — One of the most common causes of primary hypogonadism with impaired spermatogenesis and testosterone deficiency is Klinefelter syndrome, which may occur in up to 1 out of 500 to 700 phenotypic males and in up to 10 to 15 percent of infertile men with azoospermia. It is characterized by sex chromosome aneuploidy, with an extra X (XXY) chromosome being the most frequent. These patients often have very small testes and almost always have azoospermia. However, mild phenotypes of Klinefelter syndrome are likely more common than previously recognized, and these men may present with low sperm concentrations. This is one of the reasons that many experts recommend karyotyping of all men with sperm concentrations <5 million/mL before ART are considered [1]. (See "Causes of primary hypogonadism in males", section on 'Klinefelter syndrome' and "Clinical features, diagnosis, and management of Klinefelter syndrome".)

Cryptorchidism — Men with a history of undescended testes have lower sperm counts, sperm of poorer quality, and lower fertility rates than men with normally descended testes. Impaired spermatogenesis in the undescended testis is probably related to underlying genetic, hormonal, and developmental abnormalities, some of which are partially preventable or reversible through early surgical intervention (eg, before age 5). Sperm counts in adulthood are directly related to prepubertal germ cell counts and type of cell at the time of orchiopexy. (See "Undescended testes (cryptorchidism) in children: Management", section on 'Subfertility'.)

Inactivating mutation in the FSH receptor gene — A rare cause of male infertility is an inactivating mutation in the follicle-stimulating hormone (FSH) receptor gene [81,82]. One report described five men who were homozygous for an inactivating mutation of the FSH receptor [81]. These men had variably low sperm counts and serum inhibin B concentrations and high serum FSH concentrations.

Myotonic dystrophy — Myotonic dystrophy is an autosomal disorder with delayed onset (age 30 to 40 years) of impaired motor function, cataracts, premature frontal balding, mild developmental delay, and infertility due to impaired spermatogenesis. Some men with myotonic dystrophy also have low serum testosterone concentrations. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Endocrine abnormalities'.)

Androgen receptor or biosynthesis disorders — Normal sexual differentiation and spermatogenesis require testosterone and a normal androgen receptor. Polymorphisms of the androgen receptor gene are associated with male infertility [83,84]. Men with partial androgen insensitivity due to androgen receptor or postreceptor abnormalities and those with 5-alpha-reductase deficiency are nearly always infertile. Men with partial androgen insensitivity have varying degrees of ambiguous external genitalia, hypogonadism, and infertility [84]. Mild androgen insensitivity can cause infertility without evidence of androgen deficiency [84]. (See "Pathogenesis and clinical features of disorders of androgen action", section on 'Partial androgen insensitivity (PAIS)' and "Steroid 5-alpha-reductase 2 deficiency".)

The number of trinucleotide (CAG) repeats in exon 1 of the androgen receptor are inversely correlated with the transcriptional activity of the androgen target gene [83]. In a study of normal, fertile men, those with short CAG repeats had the highest sperm output [85]. Reports of CAG repeat lengths in men with idiopathic infertility have been inconsistent. In some [86-88], but not all [89], reports, a modest association of longer CAG repeat length with male infertility and/or abnormal semen quality has been observed. In a meta-analysis of 33 studies of men with idiopathic infertility and fertile controls, those with infertility had significantly longer CAG repeat lengths than controls [90]. Although androgen receptor CAG repeat length may be a valuable tool for epidemiological studies and pharmacogenomic evaluation of efficacy in treatment trials, it is not useful for clinical assessment of individual patients.

Estrogen biosynthesis or receptor disorders — Estrogen and the estrogen alpha receptor appear to be important for normal spermatogenesis. Case reports of men with decreased estrogen production to aromatase deficiency or absence of estrogen receptor alpha have variable degrees of spermatogenesis [91]. Certain polymorphisms of the estrogen receptor are associated with significantly decreased spermatogenesis in men.

Acquired disorders of the testes — Virtually all acquired testicular disorders can cause infertility, often without accompanying Leydig-cell dysfunction. Some acquired disorders are reviewed briefly here; they are discussed in detail elsewhere. (See "Causes of primary hypogonadism in males".)

Varicocele — Varicocele is a dilatation of the pampiniform plexus of the spermatic veins in the scrotum. Left-sided varicoceles are 10 times more common than right-sided ones because of difference of the anatomy of the venous drainage of the two sides that results in lower blood flow in the left spermatic vein. Based on very weak evidence, varicoceles that are palpable on examination might be associated with abnormal spermatogenesis and decreased fertility [63]. Varicoceles that are detected only by imaging are not likely to affect spermatogenesis or fertility. (See "Nonacute scrotal conditions in adults", section on 'Varicocele' and "Treatments for male infertility", section on 'Surgical repair of varicocele'.)

Infection — Viral orchitis, especially mumps, is a well-recognized cause of infertility. Among those with mumps, clinical orchitis is rare in prepubertal males but occurs in 15 to 25 percent of adult men. Some, but perhaps not all, of these men become infertile, due either to germinal cell damage, ischemia, or the immune response to the infection [92,93]. In mumps and other viral causes of orchitis (echovirus and arbovirus), germ cell failure is much more common than androgen deficiency. (See "Mumps", section on 'Orchitis or oophoritis'.)

Other infectious causes of orchitis, impaired spermatogenesis and male infertility include tuberculosis and leprosy; the former may also cause epididymal obstruction [94]. Sexually transmitted diseases (STDs) such as gonorrhea and chlamydia can also cause orchitis.

Drugs and radiation

●Drugs – Many drugs are associated with impaired spermatogenesis and/or Leydig cell dysfunction [95]. Among them, the most important are the alkylating drugs (cyclophosphamide and chlorambucil). Antiandrogens (flutamide, cyproterone, bicalutamide, spironolactone), ketoconazole, and cimetidine may cause dysspermatogenesis by inhibiting testicular androgen production or action [47]. Sulfasalazine has been associated with reversible azoospermia or oligospermia in men, along with reduced sperm motility and an increased proportion of abnormal forms. These topics are reviewed in detail separately. (See "Effects of cytotoxic agents on gonadal function in adult men" and "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in males with rheumatic diseases", section on 'Sulfasalazine'.).

Marijuana use may decrease sperm concentrations and sperm quality, including motility, but it does not appear to affect serum testosterone, LH, or FSH [96]. The impact on male fertility remains unclear as most data come from animal models.

●Radiation – Ionizing radiation impairs spermatogenesis. Doses as low as 0.015 Gy (15 rads) may transiently suppress spermatogenesis, while doses above 6 Gy (600 rads) usually cause irreversible azoospermia and infertility [97].

A transient decline in spermatogenesis may occur for up for up to 18 months after a single dosage of ≤150 mCi, but persistent spermatogenic dysfunction is only seen with higher doses. Treatment of thyroid cancer with radioiodine has a dose-dependent effect on spermatogenesis is commonly associated with direct testicular toxicity and transient abnormal spermatogenesis and seminal fluid analyses [98,99]. [98,99]. Lower dosages of radioiodine used to treat Graves' disease are not associated with significant alterations in seminal fluid analyses [100]. The impact of radioiodine on testicular function is reviewed in detail separately. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Gonadal function and fertility' and "Radioiodine in the treatment of hyperthyroidism", section on 'Gonadal function'.)

Environmental factors, smoking, and hyperthermia

●Environmental toxins – Environmental toxins are potential causes of male infertility [65,66,72,101,102]. The pesticide dibromochloropropane is a well-known cause, as are lead, cadmium, and mercury [103]. The possibility that chemicals with estrogenic or antiandrogenic activity ("endocrine disruptors"), including insecticides, fungicides, and phthalates may lower sperm counts has attracted much attention lately, although direct proof of an effect in men is lacking [102,104]. (See "Endocrine-disrupting chemicals", section on 'Men'.)

Review of data of men exposed to pesticides indicates that changes in semen quality might be multifactorial, including DNA damage to germ cells and abnormal sperm morphology. Occupational and environmental exposure has been associated with lower-quality semen analyses; limited data suggest that consumption of fruits and vegetables with high pesticide residues might also be associated with lower semen quality [105].

Because of the rapid increase in cell phone use around the world, studies have been done to investigate whether cell phone usage has any detrimental effects on sperm parameters. This issue is controversial, and definitive data are not yet available [106-108].

●Tobacco smoking

•Personal exposure – There is some evidence that tobacco smoking is associated with decreased sperm quantity and quality and possibly fertility [1]. The data are inconsistent, but meta-analyses have shown that tobacco smoking is associated with decreases in all semen parameters [84,109].

•In utero exposure – In utero exposure to smoking may have a detrimental effect on sperm production (approximately 20 percent decrease) in adulthood. [110].

The fertility implication of this difference is not known. In another study, there were no significant differences in mean sperm concentrations in men whose mothers either smoked or did not smoke during pregnancy [111]. However, men whose mothers had smoked ≥10 cigarettes per day while pregnant were at higher risk of having oligozoospermia (defined as sperm concentration <20 x 10⁶/mL in this study). Smoking has been shown to change microRNA content in spermatozoa. These microRNAs are associated with cell death and apoptosis [112].

●Hyperthermia – Hyperthermia has long been thought to impair spermatogenesis, but data to support this conclusion are limited [1]. Prolonged high testicular temperature may explain the infertility associated with spinal cord injuries, varicocele, and chronic sauna or hot tub exposure [113]. Studies in men have shown that small increases in testicular temperature accelerate germ cell loss through apoptosis [114]. Similarly, febrile illness, prolonged sitting during work or truck driving, welding, baking, tight fitting underwear, and laptop use with increased heat to the testes have been proposed to adversely affect male fertility. The data to support these associations are inconsistent [115,116].

Antisperm antibodies — Some infertile men have antisperm antibodies in serum or semen, and both could impair spermatogenesis. Whether antibodies occur spontaneously or only after some testicular injury is not known. A systematic review in 2013 concluded that there was little evidence that antisperm antibodies contributed to infertility [117]. (See "Causes of primary hypogonadism in males", section on 'Autoimmune damage'.)

Systemic disorders — Some systemic disorders, such as chronic kidney disease or malnutrition of any cause, may cause primary hypogonadism in addition to secondary hypogonadism [118-121]. The infertility in men with sickle cell anemia is presumably due to intratesticular ischemia.

Abnormalities in sperm motility and morphology as well as a biochemical picture of androgen resistance (high serum testosterone and high luteinizing hormone [LH] concentrations) have been reported in men with celiac disease [122-124]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Menstrual and reproductive issues'.)

SPERM TRANSPORT DISORDERS — The epididymis is an important site for sperm maturation and an essential part of the sperm transport system. The vas deferens then transports sperm from the epididymis to the urethra, where they are diluted by secretions from the seminal vesicles and prostate. Abnormalities at any of these sites, particularly the epididymis and vas deferens, can cause infertility. Finally, for successful natural conception, sperm must be ejaculated into the female partner's vagina. Disorders of sperm transport include the following:

●Abnormalities of the epididymis – Absence, dysfunction, or obstruction of the epididymis leads to infertility even though testicular sperm production is normal. Intrauterine exposure to estrogens may cause epididymal dysfunction [91]. Little is known about functional abnormalities of the epididymis, but drugs used in some countries (eg, triptolide) and chemical toxins (chlorhydrin) affect the function of metabolism of spermatozoa within the epididymis [125].

●Abnormalities of the vas deferens – Male infertility can result from acquired or congenital abnormalities of the vas deferens. Bilateral obstruction, ligation, or altered peristalsis of the vas deferens results in infertility. Obstruction may result from infection (gonorrhea, chlamydia, tuberculosis), while ligation of the vas deferens (vasectomy) is an intentional, medically induced cause of infertility. It may be reversible by surgical re-anastomosis, but some men have an immune response to sperm granulomas that form on the proximal side of the ligation and remain infertile [126].

One to 2 percent of infertile men have bilateral congenital absence of the vasa deferentia. Most have mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene [127]. Many infertile men with mutations of CFTR present with infertility and absence of the vasa differentia without other manifestations of cystic fibrosis (eg, respiratory and pancreatic disease). (See "Treatments for male infertility", section on 'Congenital bilateral absence of the vasa deferentia' and "Approach to the male with infertility", section on 'Genetic tests'.)

Primary ciliary dyskinesia is a genetically heterogeneous disease that affects cilia function and structure. The clinical presentations include recurrent sinopulmonary infections, bronchiectasis, situs inversus, and male infertility (with asthenozoospermia or oligozoospermia [128]). Genetic mutations of dynein proteins or thioredoxin-nucleoside diphosphate kinase have been implicated to cause primary ciliary dyskinesia [129,130]. A similar genetic defect that may lead to abnormal transport of sperm is Young syndrome, in which inspissated secretions within the vas and epididymis interfere with transport of sperm, leading to obstructive azoospermia [131,132].

●Ejaculatory duct disorders – Patients with ejaculatory duct obstruction present with a low ejaculate volume and seminal fructose with no sperm count and/or very low sperm motility. Ejaculatory duct obstruction is uncommon but can be treated surgically with minimally invasive techniques. Spinal cord disease or trauma, sympathectomy, or autonomic disease (eg, diabetes mellitus) can cause decreased or retrograde ejaculation and lead to decreased fertility. Some men with severe retrograde ejaculation (eg, due to neuropathy or medications) may also be infertile.

●Seminal vesicles and prostate – It is not known if abnormal function of the seminal vesicles and prostate contributes to infertility, but chronic infection of the accessary glands might contribute to infertility.

●Sexual dysfunction – Erectile dysfunction, premature ejaculation, and infrequency of vaginal intercourse (less than twice per week [133]) also may be contributing factors to male infertility.

IDIOPATHIC MALE INFERTILITY — Idiopathic male infertility refers to men with repeatedly normal semen analyses who cannot achieve pregnancy with an apparently normal female partner, despite careful assessment of all possible causal mechanisms. (See "Unexplained infertility".)

ASSOCIATION WITH TESTICULAR CANCER — Based upon available data, we do not suggest routine screening for testicular cancer in men with infertility. However, we do suggest careful palpation of the testes for masses whenever the male genital examination is performed. There is evidence of an increased incidence of testicular cancer in men presenting with infertility (even in the absence of a history of cryptorchidism) [134,135]. In one observational study of 3847 men with oligozoospermia (using previously published rather than current World Health Organization [WHO] criteria for normal semen parameters [136], defined as sperm concentration less than 20 million/mL with concomitant defects in total motility [less than 50 percent]), 10 cases of testicular cancer were seen (8 of 10 with no history of cryptorchidism) [135]. When compared with a control population, this represented approximately an 18-fold greater incidence of testicular cancer (standardized incidence ratio 18.3, 95% CI 18.0-18.8).

In a study from United States fertility centers, 34 cases of germ cell tumors were found in 22,562 male partners of the couples seeking infertility treatment, giving a hazard ratio (HR) of 2.8 (95% CI 1.5-2.8) compared with men without male infertility [137]. However, both studies are limited by the small number of cases. (See "Epidemiology and risk factors for testicular cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Male infertility or hypogonadism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Male infertility (The Basics)")

●Beyond the Basics topics (see "Patient education: Treatment of male infertility (Beyond the Basics)")

SUMMARY

●Causes of male infertility – The causes of male infertility can be divided into four main categories (table 1).

•Endocrine and systemic disorders causing hypogonadotropic hypogonadism (5 to 15 percent) Many endocrinopathies and any severe systemic disorders may cause hypogonadotropism, decreased spermatogenesis and infertility. These conditions can be subdivided into congenital, acquired, or systemic disorders. (See 'Endocrine and systemic disorders with hypogonadotropic hypogonadism' above.)

•Primary testicular defects in spermatogenesis (70 to 80 percent) – Primary hypogonadism with or without a defect in sex steroidogenesis is an important cause of azoospermia and oligozoospermia. Although multiple specific testicular disorders include genetic abnormalities such as Klinefelter syndrome, specific drugs (alkylating agents), and irradiation have been identified, the pathogenic basis for testicular dysfunction is often unknown. The most common cause of male infertility is an idiopathic testicular defect in spermatogenesis. (See 'Primary testicular defects in spermatogenesis' above.)

•Sperm transport disorders (2 to 5 percent) – The epididymis is an important site for sperm maturation and an essential part of the sperm transport system. The vas deferens then transports sperm from the epididymis to the urethra, where they are diluted by secretions from the seminal vesicles and prostate. Abnormalities at any of these sites, particularly the epididymis and vas deferens, can cause infertility. Erectile dysfunction, premature ejaculation, and infrequency of vaginal intercourse (less than twice per week) also may be contributing factors to male infertility. (See 'Sperm transport disorders' above.)

•Idiopathic male infertility (10 to 20 percent) – Idiopathic male infertility is characterized by a normal seminal fluid analysis (unlike idiopathic dysspermatogenesis that is characterized by an abnormal seminal fluid analysis. (See 'Idiopathic male infertility' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Ronald Swerdloff, MD, and Christina Wang, MD, who contributed to earlier versions of this topic review.