Condition
Male Infertility
Editors: Kevin R. Loughlin MD; Amir Qaseem MD, PhD, MHA, MRCP (London), FACP; William Aird MD
Background Information
Description
- infertility typically defined as inability to conceive after 1 year of unprotected sexual intercourse,,,
- infertility in couples may be multifactorial and may include
- male factor infertility alone in about 30%
- ovulation disorders in about 25%
- tubal factors in about 20%
- uterine or peritoneal disorders in about 10%
- combined male and female factors in about 40%
- unexplained (no identified male or female causes) in about 25%
Also Called
- subfertility
Definitions
- azoospermia defined as complete absence of sperm cells in ejaculate,
- oligozoospermia (oligospermia),,
- defined as decreased number of sperm cells (absolute number of sperm cells < lower reference limit)
- typically characterized by spermatozoa < 15 million/mL (severe oligozoospermia characterized by spermatozoa < 1 million/mL)
- asthenozoospermia (asthenospermia)
- defined as decreased sperm motility (% number of motile sperm cells < lower reference limit)
- typically characterized by < 32% motile spermatozoa
- teratozoospermia,
- defined as many abnormal forms of sperm (or % number of morphologically normal sperm cells < lower reference limit)
- typically characterized by < 4% normal forms
- oligoasthenoteratozoospermia (OAT) syndrome characterized by combination of sperm abnormalities, typically both of the following,
- absolute number of sperm cells < lower reference limit
- % number of motile sperm cells and % number of morphologically normal sperm cells both < lower reference limit
- mild male factor infertility
- term used extensively in practice but not formally defined
- defined in National Health and Care Excellence (NICE) guideline as ≥ 2 semen analyses with ≥ 1 variable below fifth percentile
Epidemiology
Incidence/Prevalence
- infertility reported in 8%-12% (and up to about 15%) of reproductive-aged couples worldwide, including,,,
- 1 in 8 couples trying to conceive first child
- 1 in 6 couples trying to conceive subsequent child
- reported 0.29% annual increase of age-standardized prevalence of male infertility worldwide between 1990 and 2017
- about 1 in 7 couples in the United Kingdom
- STUDY SUMMARYinfertility in about 9% of male persons aged 15-44 years in the United StatesCROSS-SECTIONAL STUDY: National Health Statistics Reports 2013 Aug 14 PDF
- about 6% of male persons with infertility may have underlying medical pathology
Risk Factors
Obstructive Risk Factors
- congenital bilateral aplasia of vasa deferentia (CBAVD),,
- prostatic cysts (Müllerian cysts)
- epididymal obstruction
- anorchia,
- trauma,
- surgery, including,,
- vasectomy
- orchidopexy
- herniorrhaphy
- orchiectomy
- retroperitoneal and pelvic surgery
- prostatectomy
- other inguinal, scrotal, and perineal surgery
- bariatric surgery
- bladder neck surgery
- transurethral prostate resection
- infection, such as
- sexually transmitted diseases, including,
- gonorrhea
- chlamydia
- tuberculosis
- chronic sinopulmonary infection (Young syndrome),
- urogenital tract infections, including,
- viral orchitis, including mumps orchitis
- urethritis
- prostatitis
- epididymitis
- sexually transmitted diseases, including,
Genetic Risk Factors
- cystic fibrosis,,
- karyotypic chromosomal abnormalities (associated with impaired testicular function)
- may be numerical (trisomy) or structural (inversions or translocations)
- may occur in
- 10%-15% of azoospermic male persons
- about 5% of male persons with severe oligozoospermia (< 5 million/mL),
- < 1% of male persons with normal sperm concentrations
- STUDY SUMMARYchromosomal abnormalities may occur in about 14% of infertile male persons with azoospermia and oligospermiaCOHORT STUDY: Indian J Hum Genet 2012 May;18(2):198
- may include
- sex chromosomal aneuploidy (Klinefelter syndrome; 47,XXY and variants),,,
- most common chromosomal disorder in infertile male persons (accounts for about two-thirds of all chromosomal abnormalities)
- may occur in about 3%-4% of infertile male persons, and about 10%-12% of azoospermic male persons (Sex Dev 2010 Sep;4(4-5):249)
- usually associated with
- hypotrophic or atrophic testicles with firm or fibrotic testicles
- gynecomastia
- elevated follicle-stimulating hormone (FSH) levels
- azoospermia and/or severe oligozoospermia
- STUDY SUMMARYsex chromosome aneuploidies may occur in > 50% of infertile male persons with chromosomal abnormalitiesCOHORT STUDY: J Urol 2010 Apr;183(4):1636
- structural autosomal abnormalities including inversions and balanced translocations, such as,,
- Robertsonian translocations
- reciprocal translocations
- paracentric inversions
- marker chromosomes
- sex chromosomal aneuploidy (Klinefelter syndrome; 47,XXY and variants),,,
- X-linked genetic disorders, such as
- isolated gonadotropin-releasing hormone deficiency in male persons,
- most common X-linked disorder in infertile male persons
- associated with mutation in Kallmann syndrome interval gene 1 (KALIG-1) on Xp22.3
- main mechanism of infertility is failure to initiate spermatogenesis
- mild androgen insensitivity syndrome,
- associated with mutations in androgen receptor (AR) gene (located on long arm of X chromosome)
- may present with infertility as primary or only symptom
- isolated gonadotropin-releasing hormone deficiency in male persons,
- Y-chromosome microdeletions,,,
- occurs in about 8%-12% of male persons with azoospermia and about 3%-7% with severe oligozoospermia (< 1 million/mL) (compared to about 2% of fertile male persons)
- associated with isolated defects in spermatogenesis
- may occur in male persons with other conditions affecting fertility, such as varicocele and/or cryptorchidism
- deletions may occur in
- azoospermia factor region c (AZFc) regions
- in about 65%-70% of cases
- usually affects deleted in azoospermia (DAZ) gene
- AZFb, AZFb+c, or AZFa+b+c regions (in about 25%-30% of cases)
- rarely, AZFa region (in about 5% of cases)
- azoospermia factor region c (AZFc) regions
- many male persons are azoospermic, but those with AZFc deletion can occasionally have sperm in the ejaculate and hence may be candidates for surgical sperm extraction
- gr/gr deletion
- Yq deletion associated with removal of half of gene content of AZFc region
- occurs in about 4% of male persons with oligozoospermia
- frequency of gr/gr deletion and phenotypic expression varies between ethnic groups (depending on Y-chromosome background)
- STUDY SUMMARYpartial azoospermia factor region c deletion (gr/gr deletion) of Y chromosome associated with increased risk of infertility in Italian male personsCASE-CONTROL STUDY: Hum Genet 2008 Nov;124(4):399
- sperm chromosomal aneuploidy,
- may occur in up to 6% of male persons with infertility and normal karyotype
- associated with translocations and severe damage to spermatogenesis
- more common in male persons with karyotypic chromosomal abnormalities, severely abnormal sperm morphology, and nonobstructive azoospermia
- less common genetic disorders associated with infertility include,
- Prader-Willi syndrome (deletion of 15q12 on paternally inherited chromosome)
- Bardet-Biedl syndrome (autosomal recessive 16q21)
- cerebellar ataxia and hypogonadotropic hypogonadism (autosomal recessive)
- Noonan syndrome (autosomal dominant)
- myotonic dystrophy (autosomal dominant 19q13.3)
- autosomal dominant polycystic kidney disease (autosomal dominant 16p13.3 and 4q)
- 5-alpha reductase deficiency (autosomal recessive)
Endocrine/Hormonal Risk Factors
- endocrine disruption
- endocrine disruption due to environmental pollution, reactive oxygen species, or genetic and epigenetic abnormalities may contribute to idiopathic infertility in male persons
- STUDY SUMMARYenvironmental estrogens (polychlorinated biphenyls [PCB] and phthalate esters [PE]) may be associated with poor semen quality in infertile male personsCOHORT STUDY: Fertil Steril 2002 Dec;78(6):1187
- STUDY SUMMARYdimethylarsinic acid (arsenic) exposure associated with decreased sperm concentrationCOHORT STUDY: Environ Health 2012 Jul 9;11:46
- obesity,,
- obesity (body mass index [BMI] ≥ 30) may increase risk of
- erectile dysfunction
- impaired semen parameters
- reduced sperm DNA integrity
- STUDY SUMMARYmale obesity may increase risk of oligozoospermia and azoospermiaSYSTEMATIC REVIEW: Arch Intern Med 2012 Mar 12;172(5):440
- STUDY SUMMARYhigh body mass index associated with decreased testosterone, sex hormone-binding globulin, and estradiol in male personsCOHORT STUDY: Int J Gen Med 2013;6:447
- obesity (body mass index [BMI] ≥ 30) may increase risk of
- pituitary tumor
- hypothyroidism
- systemic disease (may increase risk of testicular deficiency), such as,
Gonadotoxic Risk Factors
- excessive alcohol intake (> 3-4 units/day),,
- cocaine and/or marijuana abuse
- tobacco,,
- STUDY SUMMARYcigarette smoking associated with decreased sperm quality in male personsSYSTEMATIC REVIEW: Eur Urol 2016 Oct;70(4):635
- STUDY SUMMARYsmoking associated with reduced sperm concentration and total sperm countsCOHORT STUDY: Hum Reprod 2007 Jan;22(1):188
- exposure to,
- radiation, including radiation therapy for cancer
- pesticides
- organic solvents
- heavy metals
- electromagnetic energy (including cell phone/laptop exposure)
- STUDY SUMMARYcell phone use might be associated with decreased semen qualityCOHORT STUDY: Fertil Steril 2008 Jan;89(1):124
- STUDY SUMMARYcarrying cell phone close to testes (hip pocket or belt) associated with decreased sperm concentration and percentage of mobile spermCOHORT STUDY: Biol Lett 2005 Sep 22;1(3):253
- STUDY SUMMARYmarijuana smoking associated with lower follicle-stimulating hormone (FSH) levels, but not sperm concentration in male persons with subfertilityCOHORT STUDY: Hum Reprod 2019 Apr 1;34(4):715
- high scrotal temperatures due to
- saunas and hot tubs
- tight underwear
- bicycling > 30 minutes at a time
- laptop computer use (Hum Reprod 2005 Feb;20(2):452full-text), commentary can be found in J Urol 2005 Aug;174(2):661
- medications, such as,
- alpha- and beta-blockers
- anabolic steroids (including testosterone replacement therapy)
- thiazide diuretics
- spironolactone
- gentamicin
- erythromycin
- nitrofurantoin
- cimetidine
- sulfasalazine
- nitrofurantoin
- allopurinol
- colchicine
- finasteride
- chemotherapy
- calcium-channel blockers
Occupational Risk Factors
- occupations that may increase risk of male factor infertility include
- baker
- steel work
- welding
- painting
- printer and dye manufacturing
- sedentary jobs (may increase scrotal temperature)
- nuclear power plant work
- STUDY SUMMARYGulf War veterans may have increased risk for infertility and increased time to conception compared to nondeployed servicepeopleCOHORT STUDY: BMJ 2004 Jul 24;329(7459):196
Other Risk Factors
- increasing age
- male persons > 35 years old may have reduced fertility compared to younger male persons due to increased sperm DNA fragmentation rates and reduced germ cell apoptosis, semen volume, sperm morphology, and sperm motility
- STUDY SUMMARYpaternal age > 40 years associated with reduced chance of conception in female persons ≥ 35 years oldCOHORT STUDY: Fertil Steril 2006 May;85(5):1420COHORT STUDY: Am J Obstet Gynecol 2003 Oct;189(4):901
- diet
- STUDY SUMMARYhigh intake of full-fat dairy associated with reduced normal sperm morphology and mobility in young male personsCOHORT STUDY: Hum Reprod 2013 Aug;28(8):2265
- STUDY SUMMARYhigh intake of processed meat and sweets each associated with increased risk of asthenozoospermiaCASE-CONTROL STUDY: Hum Reprod 2012 Nov;27(11):3328
- STUDY SUMMARYhigh dietary soy intake associated with reduced sperm concentrationCASE-CONTROL STUDY: Hum Reprod 2008 Nov;23(11):2584
- risk factors for ejaculatory disorders
- alcohol consumption
- neurogenic risk factors
- spinal cord injury
- cauda equina syndrome
- multiple sclerosis
- autonomic neuropathy (diabetes mellitus)
- retroperitoneal lymphadenectomy
- sympathectomy or aortoiliac surgery
- colorectal and anal surgery
- Parkinson disease
- urethral risk factors
- ectopic ureterocele
- urethral stricture
- urethral valves or verumontanum hyperplasia
- congenital dopamine beta-hydroxylase deficiency
- pharmacological risk factors
- antihypertensives
- alpha-1-adrenoceptor antagonists (relaxation of bladder neck results in retrograde ejaculation)
- antipsychotics and antidepressants
- antiandrogens
- ganglion blockers
- bladder neck incompetence due to
- congenital defects/dysfunction of hemitrigone
- bladder exstrophy
- bladder neck resection
- prostatectomy
- use of lubricants during intercourse may decrease sperm motility, including
- all commercially available lubricants (may also contribute to sperm DNA damage)
- saliva
- vegetable oil
Associated Conditions
- testicular germ cell tumor reported in about 1% of subfertile male persons
- STUDY SUMMARYcancer may be associated with azoospermia in infertile male personsCOHORT STUDY: Fertil Steril 2013 Sep;100(3):681
- STUDY SUMMARYinfertility may be associated with increased risk of testicular cancerCOHORT STUDY: BMJ 2000 Sep 30;321(7264):789
- STUDY SUMMARYinfertility may be associated with increased risk of prostate cancerCOHORT STUDY: Cancer 2010 May 1;116(9):2140
Etiology and Pathogenesis
Causes
- infertility in couples may be multifactorial and may include
- male factor infertility alone in about 30%
- ovulation disorders in about 25%
- tubal factors in about 20%
- uterine or peritoneal disorders in about 10%
- combined male and female factors in about 40%
- unexplained (no identified male or female causes) in about 25%
- male infertility may be due to congenital, acquired, or idiopathic etiologies
- about 30%-50% of cases of male factor infertility may be idiopathic
- male factor infertility may result from any factor affecting sperm production and quality, including,,,
- varicocele (associated but causal relation not determined)
- in about 40% of male persons unable to initiate pregnancy
- American Society for Reproductive Medicine (ASRM) report on varicocele and infertility can be found in Fertil Steril 2014 Dec;102(6):1556
- genital tract obstruction
- obstructive azoospermia in about 15%-20% of male persons with azoospermia
- types of obstruction include
- epididymal obstruction
- most common cause of obstructive azoospermia
- occurs in about 30%-67% of azoospermic male persons
- about 82% of cases associated with ≥ 1 mutation in cystic fibrosis gene
- vas deferens obstruction
- most common cause of acquired obstruction after vasectomy
- unilateral agenesis or partial defect associated with ≥ 1 of
- contralateral seminal duct anomalies (in about 80% of cases)
- renal agenesis (in about 26% of cases)
- intratesticular obstruction
- in about 15% of male persons with obstructive azoospermia
- may be acquired (postinflammatory/traumatic) or congenital (less common)
- acquired forms usually associated with obstruction of epididymis and vas deferens
- congenital forms usually associated with disjunction between rete testis and efferent ductules
- ejaculatory duct obstruction
- occurs in about 1%-3% of cases of obstructive azoospermia
- may be cystic or postinflammatory
- cystic obstructions usually congenital and medially located in prostate between ejaculatory ducts
- postinflammatory obstruction usually secondary to urethroprostatitis
- epididymal obstruction
- testicular deficiency/failure, including
- primary (hypergonadotropic) hypogonadism due to testicular dysfunction
- secondary (hypogonadotropic) hypogonadism due to insufficient gonadotropin-releasing hormone (GnRH) and/or gonadotropin (follicle-stimulating hormone and/or luteinizing hormone) secretion
- androgen insensitivity (end-organ resistance)
- DNA damage due to,
- oxidative stress (in 30%-80% of infertile male persons)
- reactive oxygen species
- protamine sulfate deficiency
- abortive apoptosis
- alterations in topoisomerase II activity
- hyperprolactinemia
- defined as serum prolactin concentration ≥ 20 ng/mL in male persons
- may be associated with pituitary tumor, hypothyroidism, hepatic disease, psychotropic drugs, or antihypertensive drugs
- endocrine/hormonal dysfunction (in about 3% of infertile male persons)
- urogenital tract infection
- cryptorchidism
- gonadotoxin exposure
- genetic conditions
- immunological conditions
- varicocele (associated but causal relation not determined)
- less common causes of male factor infertility include
- sexual dysfunction and/or ejaculatory disorders, such as,
- anejaculation
- anorgasmia
- delayed ejaculation
- retrograde ejaculation
- asthenic ejaculation
- premature ejaculation
- painful ejaculation
- sexual dysfunction and/or ejaculatory disorders, such as,
Pathogenesis
- pathogenesis varies by underlying disorder affecting sperm production and quality
- obesity (body mass index ≥ 30) may cause infertility due to high estrogen production from fat stores (aromatization) and/or accumulation of environmental toxins in fatty tissue,
- varicocele may cause infertility by progressive increase in sperm DNA damage (may begin in adolescence)
- bilateral cryptorchidism may be associated with oligozoospermia and azoospermia
- urogenital tract infections may impair excretory function of sex glands, increase leukocyte counts in sperm, and alter conventional semen parameters, contributing to infertility
- treatment for testicular malignancy may increase risk of hypogonadism and sexual dysfunction and decrease semen quality, resulting in infertility
- testicular microcalcification may induce infertility through calcification within testicular parenchyma due to
- dysgenesis of testes (degenerate cells sloughed inside obstructed seminiferous tubule)
- failure of Sertoli cells to phagocytose debris
- oxidative stress may result from excess production of free radicals (reactive oxygen species [ROS] or reactive nitrogen species [RNS])
- oxidative stress in sperm membrane may decrease sperm motility and morphology
- DNA damage due to oxidative stress may result in improper embryo development, embryo fragmentation, and gamete apoptosis
- STUDY SUMMARYsperm DNA damage associated with reduced pregnancy rates but not reduced fertilization ratesCOHORT STUDY: Fertil Steril 2004 Apr;81(4):965
- anejaculation associated with failure of semen emission from seminal vesicles, prostate, and ejaculatory ducts into urethra
- antisperm antibodies (ASA)
- may decrease sperm motility and block penetration of cervical mucus to prevent fertilization
- may occur when breach in blood-testis barrier exposes immune system to large amounts of sperm antigens, as after testicular trauma or after vasectomy
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