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Non-Obstructive Azoospermia: Is Your Engine Working?   arrow

For general male infertility background, see Male Infertility: All the Background Details.

Background: If a man with infertility is not obstructed, but has azoospermia (no sperm in ejaculate), there is likely a problem with testicular function and therefore sperm production.  This is called non-obstructive azoospermia (NOA), and can result from a problem in the testicle (primary testicular failure), or in the brain (either hormonal, congenital, or acquired during life).  The brain has the keys or hormones to start the testicular engine.  When these keys fail, this is known as secondary testicular failure.

Nascar EngineCommon causes of NOA are Klinefelter’s syndrome (commonly 47XXY is a male born with an extra X chromosome), radiotherapy, or history of testicular torsion, mumps (infection of the testicle), undescended testicle (cryptorchidism), varicocele-induced damage, or gene (DNA mutations), or medication/environmental toxin effects.  Many of these abnormal genes are under investigation, and many likely still need to be discovered (see Y microdeletion below).  There are also causes in the brain which lead to decreased stimulation of the testis from the hypothalamus or pituitary (pituitary tumors, Kallman syndrome, Praeder-Willi syndrome, and a long list of other brain abnormalities including head trauma).  When the brain is the cause of the decreased testicular function, this is called hypogonadotropic hypogonadism.

Diagnosis: Physical exam will show that testicles are of small size (indicating poor sperm production) and often increased follicle-stimulating hormone (FSH) if there is primary testicular failure or low FSH if there is secondary testicular failure (a problem with the “fuel” supplied by the brain for the testicle).  For men with sperm count lower than 5 million sperm/ml or no sperm in the ejaculate, a chromosomal test (karyotyping, to make sure there are the proper number of X and Y chromosomes) and Y chromosome microdeletion (YCMD) testing should be completed.

Since the testicle is not functioning well in non-obstructive azoospermia by definition, testosterone (which is made primarily by the testis) is often low.  Luteinizing hormone and prolactin also may be checked.  Before any treatment, all correctable abnormalities (abnormal hormonal levels, varicocele, environmental/gonadal toxins) are fixed several months before additional treatment (sperm aspiration, see below).  The diagnosis of NOA is confirmed only by testicular biopsy.

The best studied of gene mutations involved with NOA and male infertility is the Y chromosome (the part of DNA that is specific to men) initially described in 1976.  With its discovery, the first genetic marker of infertility, the azoospermia factor (AZF), was identified.  Y chromosome microdeletions (areas in the DNA that are missing known as AZFa, AZFb, and AZFc) were recognized as markers for male factor infertility and can now be routinely studied for any male patient.  Sperm presence relies upon the specific AZF subregion deleted (functional sperm are not found in men with AZFa or AZFb deletions, while AZFc deletions are associated with sperm 75% of the time).  Many other genes are currently being investigated to determine their roles in NOA.

Treatment: For men without obstruction, the treatment is to first correct hormonal or other abnormalities.  Low testosterone can be raised in men with NOA using a number of medications that result in increased testosterone production and possibly improved sperm production (clomiphene citrate, human chorionic gonadotropin or hCG, anastrazole).  Depending on the genetic testing and the results of raising testosterone, the next step is to consider sperm retrieval from the testicles (may only be a single sperm) using microdissection testicular sperm extraction or micro-TESE (exceptions include AZFa or AZFb deletions which do not have retrievable sperm) to be used with IVF/ICSI. This procedure is performed by a specialized urologist using a microscope to search each testicle for the limited areas of sperm production and the presence of even 1 sperm.  Micro-TESE is successful in approximately 60% of men with NOA, and is done in conjunction with the female partner being prepared for IVF/ICSI.  Anti-oxidant therapy (Vitamin C, E, carnitines, beta-carotene, lycopene) may help with issues of sperm DNA integrity, motility, morphology, which will be discussed in more detail in future posts.

For more information about non-obstructive azoospermia,and factors affecting outcomes, please visit the Center for Male Health and Reproduction site.  You may also contact us with any additional questions and our physician team will respond.


Matthew Wosnitzer, M.D.
August 10, 2014