Pravin K. Rao, MD
BASICS
DESCRIPTION
• Congenital absence of the vas deferens in males can be bilateral (CBAVD) or unilateral (CUAVD)
• Primarily relevant to infertility evaluation
• Absence of the vas deferens interrupts transport of sperm beyond testis/epididymis
• Often accompanied by poor development of epididymides and seminal vesicles (SVs), causing low-volume ejaculate.
• Diagnosis is made by physical exam
• CBAVD present in >98% of cystic fibrosis (CF) patients
• CBAVD
– Always azoospermic (bilateral obstruction)
• CUAVD
– Can be azoospermic due to unidentified contralateral defects or testis failure
– More often (-) CFTR mutations (vs. CBAVD)
– Higher incidence renal anomalies (vs. CBAVD)
EPIDEMIOLOGY
Incidence
• 65–98% of men with CF
• 1.3% of all infertile men
RISK FACTORS
• CF
• Family history of CF or CBAVD
• See associated conditions
Genetics
• Most common: Mutations of cystic fibrosis transmembrane conductance regulator (CFTR)
• CFTR:
– Chromosome 7
– Causes spectrum of conditions ranging from AVD to clinical CF
– Mutations of both chromosomes necessary for clinical CF or CBAVD
– Mutations appear to have incomplete penetrance (1)[B]
– Single chromosome mutations = carrier
– “Severe” vs. “Mild” mutations
• CF patients
– ∼88% have severe mutation of both chromosomes
– ∼11% have severe mutation on 1 CFTR gene and mild on the 2nd (2)[B]
• CBAVD without clinical CF
– ∼88% carry 1 severe mutation and 1 mild mutation
– ∼12% carry mild mutations on both (Claustres 2000)
• Genetics of CUAVD less understood
– Most CUAVD thought to be due to embryologic defect (non-CFTR)
– Some men with CUAVD do have CFTR mutations (3)[B]
– Some may be due to unidentified CFTR mutation or other genetic factor(s)
PATHOPHYSIOLOGY
• CFTR
– Glycosylated transmembrane protein
– Function: Chloride channel
– Sites:
Lungs, liver, pancreas, intestines
Vasa deferentia/GU tract
• CFTR mutation
– Point mutations most common in CF
– Altered chloride transport
– Thick, viscous secretions
Multisystem disease in CF
Obstruction/degeneration of vasa vs. agenesis.
• Vas deferens is a derivative of mesonephric (Wolffian) duct.
– Wolffian abnormalities often seen with AVD
Seminal vesicle (SV) hypoplasia or absence
Causes low-volume ejaculate.
See: Associated Conditions
ASSOCIATED CONDITIONS
• CF
– CBAVD is considered the mildest manifestation of CFTR disease spectrum
– CF is most severe
– Nearly all CF patients have CBAVD
• Genitourinary abnormalities
– Renal agenesis
– Abnormalities of mesonephric structures
Ejaculatory ducts
SVs
• Low testicular volume
– Seen more commonly when CFTR mutations not detected (4)[B]
– May indicate primary testicular cause
GENERAL PREVENTION
CFTR screening of both partners can help assess and manage risk of CF and CBAVD for offspring
DIAGNOSIS
HISTORY
• Medical history
– Presence of associated conditions
• Patients usually asymptomatic except for infertility
• Screen for other causes of infertility/azoospermia
– Developmental/puberty history
Testicular descent
– Sexual function, libido
Hypogonadism, testis failure
• Screen for CF manifestations
– Sinopulmonary symptoms
– GI/digestive problems
PHYSICAL EXAM
• Findings in AVD
– Absent vas deferens (bilateral/unilateral)
– Absent or hypoplastic body/tail of epididymis
– Present caput epididymis, often dilated
• Considerations:
– Evaluate for skip lesions
– Check for other causes of infertility
Varicocele
Atrophic testis
• Normal in CBAVD:
– Testis size (>3.5 cm length, 2–3 cm diameter)
– Digital rectal exam
Prostate usually normal
SVs usually nonpalpable/hypoplastic; may be cystic
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Potential semen analysis findings:
– Low volume (<1.5 cc)
– Azoospermia if bilateral obstruction
– Acidic pH (decreased basic SV fluid)
– Seminal fructose might be negative
– Presence of sperm rules out bilateral obstruction
• Postejaculatory urinalysis
– Evaluates for retrograde ejaculation
– Part of evaluation for low-volume azoospermia
• CFTR genetic mutation screen
– Assesses for mild vs. severe mutations
– Can prove, but not exclude, a congenital form of CF
– Risk is difficult to predict with some rare CFTR mutations
– Negative CFTR screen reduces, but does not eliminate, risk of being a carrier
Thus, suggest screening in female partner
• CFTR screening for partner
– Helps guide genetic counseling regarding CF risk for offspring
Imaging
• Renal ultrasound
– For all men with vasal agenesis
– Evaluates for renal anomalies/agenesis
– Optional if CFTR mutation detected
Renal anomalies rare
• Transrectal ultrasound (TRUS)
– Part of evaluation for low-volume azoospermia
– Not necessary with CBAVD
– Evaluates for ejaculatory duct obstruction
– Normal findings:
Vasal diameter: 0.3–0.5 cm
SV width: 0.3–1.5 cm
SV length: 1.4–4.6 cm
Ejaculatory duct diameter: <0.1 cm
– Optional: Aspiration of dilated SVs
Ejaculatory Disturbances
• Vasography (see below)
Diagnostic Procedures/Surgery
• Vasography
– Fluoroscopic injection of contrast material
– Assesses patency of vas/vasa
– Only done at time of planned microsurgical reconstruction of ejaculatory duct(s), due to risk of damage/obstruction at vassal entry point
– Of limited utility in CBAVD since reconstruction usually not an option
Pathologic Findings
N/A
DIFFERENTIAL DIAGNOSIS
• Spermatogenic failure causing azoospermia
– Congenital/genetic causes
Y chromosome microdeletions
Sex chromosome abnormalities (XXY male)
Undescended testes
– Gonadotoxin exposure
Chemotherapy
Radiation
Environmental
– Varicocele
• Obstruction causing azoospermia
– Inflammatory or infectious causes
Sexually transmitted infections
Tuberculosis
– Vasal obstruction/vasectomy
– Epididymal obstruction
– Ejaculatory duct obstruction
• Poor development of accessory sex organs causing low-volume ejaculate
– Hypogonadotropic hypogonadism
– Pituitary tumor
– Disorders of sexual differentiation
• Respiratory infections and male infertility can also be due to primary ciliary dyskinesis
– This condition is characterized by immotile sperm and situs inversus
TREATMENT
GENERAL MEASURES
• Infertility treatment requires assisted reproductive techniques (ART)
• Sperm retrieval techniques
– See Surgery, below
• Donor semen
– Intrauterine insemination
– IVF/ICSI
• Consider referral for genetic counseling regarding CF risk for offspring
MEDICATION
First Line
• Medications used only to treat other conditions found on evaluation (eg, hypogonadism)
– Clomiphene citrate
– Avoid exogenous testosterone if patient is planning to use his own sperm for ART
Suppresses endogenous gonadotropins and testosterone/sperm production
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Sperm retrieval for ART
– Testicular sperm extraction (TESE)
– Testicular sperm aspiration (TESA)
– Microsurgical epididymal sperm aspiration (MESA)
– Sperm can be used for IVF or ICSI
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Besides association with CF/CFTR disease spectrum, no other known detriment to health
• Fertilization and pregnancy rates with ART in obstructive azoospermia are most closely tied to female factors.
COMPLICATIONS
CF or CBAVD in offspring
FOLLOW-UP
Patient Monitoring
N/A
Patient Resources
N/A
REFERENCES
1. Shin D, Gilbert F, Goldstein M, et al. Congenital absence of the vas deferens: Incomplete penetrance of cystic fibrosis gene mutations. J Urol. 1997;158(5):1794–1798.
2. Claustres M, Guittard C, Bozon D, et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143–156.
3. Kolettis PN, Sandlow JI. Clinical and genetic features of patients with congenital unilateral absence of the vas deferens. Urology. 2002;60(6):1073–1076.
4. Robert F, Bey-Omar F, Rollet J, et al. Relation between the anatomical genital phenotype and cystic fibrosis transmembrane conductance regulator gene mutations in the absence of the vas deferens. Fertil Steril. 2002;77(5):889–896.
ADDITIONAL READING
Ratjen F, Doring G. Cystic Fibrosis. Lancet. 2003;361(9358):681–689.
See Also (Topic, Algorithm, Media)
• Assisted Reproductive Techniques (ART)
• Cystic Fibrosis, Urologic Considerations
• Ejaculatory Disturbances (Delayed, Decreased, or Absent)
• Infertility, Urologic Considerations
• Retrograde Ejaculation
• Vasography
CODES
ICD9
• 606.0 Azoospermia
• 606.9 Male infertility, unspecified
• 752.89 Other specified anomalies of genital organs
ICD10
• N46.01 Organic azoospermia
• N46.8 Other male infertility
• Q55.4 Other congenital malformations of vas deferens, epididymis, seminal vesicles and prostate
CLINICAL/SURGICAL PEARLS
Low-volume ejaculate in CBAVD and CUAVD is usually due to poor development of accessory sex organs (SVs).