male%20infertility
MALE INFERTILITY

Infertility is the inability to conceive despite regular unprotected sexual intercourse for one year.

Male infertility as the sole cause accounts for 20% & 30-40% as a contributory factor to infertility in couples.

Causes include: hypothalamic pituitary disease, primary testicular disease, disorders of sperm transport, genetic disorders, idiopathic infertility, infections, immune system disorders, iatrogenic causes, and chronic illness.

Diagnosis

Endocrine Evaluation

  • Measure luteinizing hormone (LH), follicle-stimulating hormone (FSH) & testosterone levels
    • Serum free testosterone, LH, prolactin - if total testosterone level was low (<300 ng/mL)
  • Indicated for patients w/ abnormal semen analysis especially if w/ <10 millions/mL sperm concentration, impaired sexual function, or w/ high clinical suspicion for endocrine diseases
  • High serum FSH, LH & normal to low testosterone levels may indicate primary hypogonadism (complete testicular failure, hypergonadotrophic hypogonadism)
  • Patients w/ elevated FSH levels may have spermatogenesis abnormalities
  • Low FSH, LH & testosterone levels indicates hypergonadotropic hypogonadism
  • High prolactin & low testosterone levels may be indicative of a prolactin-secreting pituitary tumor

Evaluation

  • To be able to identify correctable causes of male infertility, irreversible causes that can be managed by assisted reproductive techniques, life-threatening conditions underlying infertility, & genetic causes that may affect the offspring in the future
  • Evaluation may be done before 1 year into the marriage & w/ unprotected intercourse if male partner is w/ known history of bilateral cryptorchidism, if female partner is at risk of infertility, especially if >35 years of age, or to confirm the male partner’s fertility potential
Indications for Evaluation
  • Inability to achieve spontaneous pregnancy after >12 months of regular unprotected sexual intercourse
  • If female partner >35 years of age has not conceived after 6 months of regular vaginal intercourse w/o contraceptive interventions
Endocrine/Systemic Disease
  • 80-90% infertile men has primary or secondary hypogonadism, caused by either sperm production impairment/dysfunction, impaired spermatogenesis, or androgen deficiency
Primary Hypogonadism (Testicular Origin)
  • Low testosterone level w/ increased follicle-stimulating hormone (FSH) &  luteinizing hormone (LH) suggest a testicular failure origin for hypogonadism
  • Disorders associated w/ primary hypogonadism include:
  • Congenital disorders: Klinefelter syndrome, Prader-Willi syndrome, familial cerebellar ataxia, Lowe oculocerebellar syndrome
  • Acquired disorders: tumors, infiltrative diseases (eg fungal infections, sarcoidosis, tuberculosis, mumps orchitis), lymphocytic hypophysitis, hepatic cirrhosis, chronic renal failure, radiation, testicular torsion, autoimmune damage, alkylating agents, Ketoconazole, glucocorticoids
Secondary Hypogonadism (Hypothalamic-Pituitary Origin)
  • Low testosterone level w/ decreased FSH & LH is suggestive of a hypothalamic-pituitary origin of disease
  • Disorders associated w/ secondary hypogonadism include Kallmann’s syndrome, DAX-1 & GPR54 mutations, Prader Willi, leptin or leptin receptor mutation, gonadotropin subunit mutation, craniopharyngioma, empty sella syndrome, fractures located at the base of the skull, hyperprolactinemia

Androgen Deficiency

  • Testicular feminisation & Reifenstein syndrome causes androgen resistance
Idiopathic Hypogonadotropic Hypogonadism
  • Presence of low testosterone/FSH/LH levels even w/o existing anatomical or functional defects in the hypothalamic-pituitary-gonadal axis
Please refer to Hypogonadism in Males - Late-Onset Disease Management Chart for more information
Infections
  • Male urogenital tract infection includes infection in the testis, prostate, epididymal ducts & urethra & other structures where semen passes through
  • Chronic infections causing an increase in leukocytes in the ejaculate may decrease sperm quality, inflammation may cause partial genital tract obstruction
  • Past genital infections (ie gonorrhea, STDs) w/c may cause epididymal & vas obstruction, & history of mumps & orchitis may cause sterility
Please refer to Urinary Tract Infection - Complicated Disease Management Chart for more information
Semen Autoimmunity
  • Present in 4-6% of infertile men
  • Presence of sperm antibodies result in decreased motility & impaired sperm-cervical mucus penetration
Post-Testicular Dysfunction
  • Affects 15-20% of men w/ infertility
Anatomical Obstruction
  • Obstruction in the testicular ducts, epididymis, vas deferens, ejaculatory duct, seminal ducts may cause obstructive azoospermia
  • Investigations for obstruction should be considered for azoospermic or severely oligozoospermic men w/ normal-sized testes & normal endocrine evaluation results
  • Intratesticular obstruction may be caused by an obstruction in the seminiferous tubules or w/in the rete testis
    • Accounts for 15% of men w/ obstructive azoospermia
  • Epididymal obstruction accounts for 30-67% of infertile men w/ obstructive azoospermia
  • Obstruction of the vas deferens is the most common cause of acquired obstruction after vasectomy or hernia repair
    • Congenital bilateral aplasia of vas deferens (CBAVD) is the most common congenital cause of vas deferens obstruction
  • Ejaculatory duct obstruction, caused by either cystic formation or post-infectious fibrosis, accounts for 1-3% of infertility in men w/ obstructive azoospermia
Varicocele
  • Abnormal enlargement or dilatation of the spermatic veins in the pampiniform plexus of the scrotum w/ a diameter increase of >0.3 mm during Valsalva maneuver
  • Accompanied by ipsilateral testicular growth/development failure, pain, male subfertility & hypogonadism
  • Classification:
    • Subclinical - not visible; not evident upon palpation; positive in Doppler ultrasound detection
    • Grade I - not visible; palpable only w/ Valsalva maneuver
    • Grade II - not visible; palpable w/o Valsalva maneuver
    • Grade III - visible through the scrotum; palpable at rest
Cryptorchidism
  • Most common congenital male genital abnormality that may be caused by disruption of endocrine regulation or gene defects
  • Affects 2-5% of newborn male babies, resulting to impaired semen parameters ie low sperm count & quality
  • Severity depends on the duration of suprascrotal location of the testes
  • Low serum inhibin B & increased FSH level indicates high risk for infertility
  • Men w/ history of cryptorchidism are at increased risk for testicular cancer
Sexual Dysfunction
  • Includes erectile dysfunction, anorgasmia, delayed ejaculation, retrograde ejaculation, aesthenic ejaculation, premature ejaculation, & mechanical obstruction (condom, diaphragm)
  • May be caused by problems in ejaculation from spinal cord trauma/disease or autonomic disease
Premature Ejaculation
  • Short, involuntarily controlled, easily stimulated ejaculation that occurs always or nearly always before or w/in 1 minute of vaginal penetration or a clinically significant & bothersome reduction in latency time, often to about 3 minutes or less in patients w/ premature ejaculation
  • Either present from the first sexual experience or following a new bothersome change in ejaculatory latency
  • Causes negative personal consequences (eg distress, bother, frustration, avoidance of sexual intimacy & interpersonal difficulty)
Delayed ejaculation or Anejaculation
  • Persistent or recurrent delay in, or absence of, orgasm after a normal sexual excitement phase during sexual activity
  • Disturbance causes marked distress or interpersonal difficulty & can be a lifelong or an acquired problem
  • Hypogonadism, low testosterone levels, hypothyroidism & hyperprolactinemia are all associated w/ delayed ejaculation
Malignancy
  • Testicular germ cell tumor may manifest as low sperm quality prior to diagnosis, w/c may be due to spermatogenic failure& Leydig cell dysfunction
    • Hypogonadism & sexual dysfunction may occur after treatment
  • Cryptorchidism, hypospadias, & dysgenic testis increases the risk for testicular cancer
Testicular Microlithiasis
  • Intratesticular hyperechogenic lesions w/o shadowing measuring <3 mm in diameter
  • Commonly seen in men w/ testicular germ cell tumor, cryptorchidism, testicular dysgenesis, testicular torsion & atrophy, Klinefelter’s syndrome, hypogonadism, epididymal cysts, etc
Genetic Disorders
Cystic Fibrosis Gene Mutations
  • Most common cause of congenital bilateral absence of the vasa diferentia (CBAVD)
  • Patient usually presents w/ low semen volume & nonpalpable vasa
  • Caused by a defect in the CFTR gene
  • Patients w/ this condition should also be evaluated for seminal vesicle hypoplasia or agenesis
  • Additional imaging studies of the renal system is suggested for patients w/ unilateral vasal agenesis & congenital bilateral absence of the vasa diferentia but w/o CFTR gene abnormalities
  • Gene sequencing should also be considered if the female partner is a CFTR gene defect carrier & male partner is positive for CFTR gene mutations
Chromosomal Abnormalities
  • Affects 10-15% azoospermic men, 5% men w/ severe oligozoospermia, & 1% men w/ normal sperm volumes
  • Klinefelter’s syndrome accounts for 2/3 of infertile men w/ chromosomal abnormalities & therefore the most common cause of primary hypogonadism
  • Most common autosomal chromosome abnormalities include Robertsonian translocations, reciprocal translocations, paracenteric inversions, & marker chromosomes
Y-Chromosome Microdeletions
  • Affects 5-7% of infertile men w/ severe impaired spermatogenesis, 16% azoospermic or severely oligozoospermic men
    • Increases as testicular deficiency increases
  • The specific deletion on the long arm of the Y chromosome determines the effect on spermatogenesis
    • AZFc deletions, the most common type, causes azoospermia or severe oligozoospermia
    • AZF deletions transmission to male offspring is guaranteed
    • Y-chromosome gr/gr deletion removes 1/2 of the genes in the AZFc region, significantly increasing the risk for oligozoospermia by 2.5-8 fold
  • Inherited disorders w/ known disorders in fertility include Prader-Willi syndrome, Bardet-Biedl syndrome, Noonan’s syndrome, myotonic dystrophy, 5-a reductase deficiency, etc
Genetic Defects
  • Includes x-linked genetic disorders, Kallman syndrome, mild androgen insensitivity syndrome, & other X-linked disorders
  • Kallman syndrome patients present w/ hypogonadotropic hypogonadism
  • Clinical presentation of patients w/ androgen insensitivity syndrome depends on its severity
    • Mild: asymptomatic; diagnosed only upon work-up for male infertility
    • Complete: female external genitalia w/ absent pubic hair (Morris syndrome)
    • Partial (Reifenstein syndrome): female phenotype w/ ambiguous genitalia, or male phenotype w/ micropenis, perineal hypospadias, & cryptorchidism

History

Medical History
  • Obtain the patient’s complete review of systems, family reproductive history, & social history (include use of anabolic steroids, recreational drugs, smoking, & alcohol history)
Reproductive History
  • Includes coital frequency & timing, duration of infertility, previous fertility, childhood/developmental medical history, systemic disease history, previous surgery, past & present medications, history of allergies, sexual history including STDs, gonadotoxin exposure

Physical Examination

  • Should include an examination of the following:
    • Penis - palpate, & include inspection of the urethral meatus
    • Testis - measurement & palpation
    • Vas deferens & epididymis - palpate for presence of nodules or masses, inspect for enlargement
  • Note for the presence of varicoceles, gynecomastia, & secondary sexual characteristics
  • A digital rectal exam may be performed as necessary

Laboratory Tests

Sperm Analysis
  • Primary test for male infertility
  • Used to evaluate the severity of infertility
  • Initially, two sperm analysis taken 1 month apart is recommended
  • Repeat sperm analysis 3 months after initial test if 1st analysis is abnormal (earlier if abnormality is due to azoospermia or severe oligozoospermia)
Sperm Analysis: Lower Limits of Accepted Reference Values

    Parameter

    Reference values

    Ejaculate volume

    1.5 mL

    pH

    7.2-7.5

    Sperm concentration

    15 x 106 spermatozoa/mL

    Total sperm number

    39 x 106 spermatozoa/ejaculate

    Percentage motility

    40%

    Forward progression

    32%

    Normal morphology

    4% normal

    Vitality

    58% live spermatozoa

    Sperm agglutination

    Absent

    Viscosity

    2 cm thread after liquefaction

Adapted from: Cooper TG, Noonan E, von Eckardstein S, et al. WHO reference values for human semen characteristics. 2010.
Specialized Semen/Sperm Tests
  • Quantification of leukocytes in semen
    • Increased leukocyte count (>106 wbc/mL) may indicate presence of genital infection leading to poor semen function & motility
  • Antisperm antibodies (ASA) tests
  • Eg immunobead test (IBT), mixed antiglobulin reaction
    • ASA appears as a result of a breach in the blood-testis barrier, sperm antigen exposure, or post-vasectomy especially in patients w/ history of trauma, torsion, biopsy, orchitis, & testicular carcinoma
    • Should not be routinely offered, as more studies are needed to confirm its benefit in the evaluation of male infertility
    • May be indicated for patients w/ isolated asthenospermia or sperm agglutination on sperm analysis
    • Presence of surface antibodies may result in spermatozoal failure in cervical mucus penetration
  • Semen culture
    • May be considered for samples w/ presence of inflammatory cells
  • Fluorescent In Situ Hybridization (for sperm DNA aneuploidy testing)
  • Sperm viability tests
    • Used to determine the viability of nonmotile sperm by examining the sperm’s cell membranes
  • Sperm DNA fragmentation tests
    • Helps identify sperm DNA damage & integrity that may affect a couple’s reproductive performance or an embryo’s development
  • Other testing: sperm penetration assays, sperm creatine kinase measurement, sperm-cervical mucus interaction
Post-ejaculatory Urinalysis
  • An ejaculate volume of <1 mL signifies the need for post-ejaculatory urinalysis
  • Done to rule out retrograde ejaculation, except for those w/ hypogonadism, congenital bilateral absence of the vasa diferentia (CBAVD)
Testicular Biopsy
  • Helps identify patients w/ obstructive azoospermia suspected of having acquired seminal duct obstruction & to exclude those w/ spermatogenic failure
  • May be considered w/ the intention of obtaining sperm for cryopreservation (for assisted reproductive techniques)
  • Obtaining >1 biopsy sample is recommended
  • 50% of men w/ non-obstructive azoospermia is positive for spermatozoa upon extraction

Imaging

Ultrasonography
  • Used for the detection of scrotal or penile pathologies
Scrotal ultrasound
  • Mandatory test in male infertility, especially those w/ suspected testicular mass
  • Helps detect scrotal pathologies not commonly seen during physical examination (eg varicoceles, tumors, spermatoceles, vas deferens aplasia, testicular microlithiasis, obstruction)
  • Provides better examination of patients w/ testes located in the upper scrotum, small scrotal sac, & other anatomic defects
Transrectal ultrasound (TRUS)
  • Used to diagnose ejaculatory duct obstruction in patients w/ azoospermia, palpable vasa, low ejaculate volume, & normal testicular size
Penile ultrasound
  • Helps detect penile pathologies ie hypospadia, phimosis
Vasography
  • Radiographic examination used to identify the presence of sperm in the vasal fluid & obstruction w/in the seminal vesicles, epididymis, vas deferens, or ejaculatory duct
  • Indications:
    • Absolute indications - azoospermia plus complete spermatogenesis & numerous mature spermatids on biopsy plus at least 1 palpable vas
    • Relative indications - severe oligospermia but normal on testicular biopsy, increased sperm-bound antibodies, low semen volume, sperm motility grades 0-2
Other Imaging Modalities
  • Magnetic resonance imaging (MRI) & computed tomography (CT) scan may be considered in patients w/ hypogonadism suspected to be caused by a tumor

Screening

Genetic Screening
  • Recommended for patients w/ non-obstructive azoospermia & severe oligospermia (<5 million sperm/mL) (eg karyotype abnormalities, Y-chromosome microdeletions, cystic fibrosis transmembrane conductance regulating [CFTR] gene)
  • Karyotype analysis is recommended for men w/ azoospermia or oligospermia of <10 million/mL
  • Indications for Y-chromosome testing include azoospermia & severe oligozoospermia
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