Azoospermia is a condition in which there is no sperm in the ejaculate. Azoospermia is present in 1% of men in the general population and in 15% of men with infertility. Azoospermia is not the same as aspermia, which is the complete absence of seminal fluid upon ejaculation. A patient has azoospermia if microscopic examination of two separate concentrated semen samples reveals no sperm.

Azoospermia may be caused by a variety of different diseases or conditions. The potential causes of azoospermia may be divided into three categories: pretesticular, testicular, and post-testicular. In pretesticular azoospermia, the testicles and genital tract are normal but are not appropriately stimulated by the hormonal system to produce sperm. In testicular azoospermia, the testicles themselves are abnormal and unable to produce sperm. Together, pretesticular and testicular azoospermia are called nonobstructive azoospermia.  In post-testicular azoospermia, also called obstructive azoospermia, sperm is produced by normal testicles but is not ejaculated due to an obstruction of the genital tract. Obstructive azoospermia is intentionally induced by physicians performing a vasectomy.

Definition: In pretesticular azoospermia, abnormalities in the hypothalamus and/or pituitary gland, both located in the brain, cause a hormonal imbalance that prevents otherwise normal testicles from being stimulated to make sperm.

Diagnosis: Smaller than normal testicles in the presence of low serum follicle-stimulating hormone (FSH) and testosterone levels is consistent with this diagnosis, also called hypogonadotropic hypogonadism or secondary testicular failure. Microscopic examination of two separate centrifuged semen samples will reveal no sperm.

Causes: Pretesticular azoospermia is associated with poor nutrition, the use of certain medications (e.g., particular chemotherapies, narcotics), pituitary tumors, trauma, and low testosterone (hypogonadism). It may also be caused by other disorders of the pituitary gland, including hypopituitarism and hyperprolactinemia.  Another important cause of pretesticular azoospermia is the use of testosterone replacement therapy and/or the abuse of anabolic steroids. Anabolic steroids suppress natural testosterone synthesis, inhibiting sperm production.

Treatment: The specific therapy to correct pretesticular azoospermia depends on the underlying cause of the disorder. Pretesticular azoospermia is often amenable to treatment by physician-supervised hormone replacement therapy.

Definition: Testicular azoospermia implies that there is a disorder of sperm production in the testicles themselves. The disorder may be congenital (i.e., the problem is present from birth) or acquired. Sperm production may be entirely absent or may involve arrest during an early or late stage of sperm maturation.

Diagnosis: Abnormal, atrophic, or rarely, even somewhat normal testicles in the presence of an elevated serum FSH and a normal or low testosterone level is consistent with this diagnosis, also called primary testicular failure. Microscopic examination of two separate centrifuged semen samples will reveal no sperm. In rare instances, a testicular biopsy may be carried out to better characterize the exact histology of the disease.

Congenital Causes: Congenital causes of testicular azoospermia include conditions such as undescended testicles (cryptorchidism), Klinefelter’s syndrome, and Sertoli-cell-only syndrome (germ cell aplasia). A variety of genetic abnormalities may also impair sperm production. The two most common categories of genetic errors causing testicular azoospermia are (1) chromosomal abnormalities resulting in impaired testicular function and (2) deletions in the Y chromosome leading to isolated impairment of sperm maturation and growth.

Acquired Causes: Testicular azoospermia may be acquired due to infection (e.g., mumps orchitis, malaria), exposure to pesticides and chemicals, testicular trauma, cancer and cancer treatment, or radiation therapy. Azoospermia may also be associated with a varicocele (an abnormal enlargement of the veins that drain the testicle), which may cause testicular hyperthermia (overheating). Other factors associated with testicular azoospermia include increasing age, low testosterone, and the frequent use of hot tubs or baths.

Treatment: The specific therapy to treat testicular azoospermia depends on the underlying cause of the disorder. In some congenital cases of testicular azoospermia in which late maturation arrest results in abnormal sperm production, testicular sperm extraction (TESE) may be performed if isolated areas of mature sperm are found with an operating microscope. These sperm can be used with intracytoplasmic sperm injection (ICSI) and in vitro fertilization (IVF) to achieve fertility.

The use of TESE/ICSI may allow up to 55% of couples previously considered hopelessly infertile to achieve pregnancy. For example, some men with small deletions within the “c” region of the AZF gene on the Y chromosome may have retrievable sperm for ICSI. However, the use of assisted reproductive technology in this setting is not without drawbacks. The same condition causing the couple’s own infertility may be transmitted to any male children produced by bypassing the natural barriers to reproduction. The couple must, therefore, be counseled on the risk of passing down compromised fertility to all male offspring.

Unfortunately, some cases of congenital testicular azoospermia are simply not amenable to treatment. For example, successful testicular sperm extraction has not been reported in infertile men with large deletions in the “a” and “b” regions of the AZF gene on the Y chromosome. These couples may wish to explore the use of donor sperm or adoption to achieve

The specific treatment for acquired testicular azoospermia also depends on the etiology of the condition. For example, azoospermia associated with a varicocele may in some instances be corrected by a surgical procedure known as varicocelectomy (varicocele repair). Testicular azoospermia due to a toxic exposure, such as chemotherapeutic drugs or other gonadotoxins, may resolve with time after discontinuation of the offending agents. TESE/ICSI may also be used to treat some cases of acquired testicular azoospermia. In instances in which irreversible testicular damage precludes the extraction of sperm, couples may explore the use of donor sperm or adoption.