Azoospermia, the absence of sperm in the ejaculate, is classified into two types. This article takes you through both, explaining what their causes are, and how they are diagnosed and managed.

A common misconception is that infertility—defined as cases in which a couple is unable to get pregnant after more than 12 months of unprotected sex—is always associated with problems in the female partner. Instead, in up to 50% of cases in which couples are unable to conceive, male factors are found to be important.

One cause of male infertility is azoospermia. This condition refers to a complete absence of spermatozoa (or sperm) in the ejaculate—as opposed to oligospermia, in which sperm count is low. Azoospermia is diagnosed in around 1% of all men, and 10–15% of men experiencing infertility. The condition is classified into obstructive azoospermia and non-obstructive azoospermia, each of which has its own causes and treatments. This article will take you through both conditions, helping you to understand how they are diagnosed and managed. First, we’ll take a brief look at the normal origins and path of sperm in the body.

Sperm production and release: An overview

Production of sperm, or spermatogenesis, begins in the testes (the main reproductive organs in the male). The testes are located in the scrotum, a protective sac of skin located beneath the penis. The process begins with hormonal signals sent from the hypothalamus and pituitary gland, and the release of follicle-stimulating hormone (FSH) and luteinising hormone (LH). The testes contain a system of tightly coiled structures known as the seminiferous tubules, where sperm are produced from stem cells. This process lasts approximately 74 days. In the final step, spermatids—which are sperm cells that contain one set of 23 chromosomes—move into the epididymis, a cordlike structure that sits atop each testicle, where they complete their maturation into sperm and are stored.

When the penis becomes erect and is stimulated, sperm are released from the epididymis into a pair of sperm ducts called the vas deferens. The vas deferens then transport sperm, by means of muscle contractions, past the bladder and toward the prostate gland, where the seminal vesicles are located. These provide seminal fluid, in the form of a whitish fluid, to the ejaculatory ducts. The seminal fluid contains sugars and prostaglandins to help mobilise sperm. The semen then travels past the prostate gland and into the urethra.

At this point, the bladder is sealed off from the urethra in order to prevent the seminal fluid from traveling there. The prostate and bulbourethral gland add additional seminal fluids during this process, which aid in sperm motility (ability to move). In the final step of ejaculation, rhythmic muscular contractions propel semen and the sperm within it out of the urethra. Normally, semen contains between approximately 15 and 200 million sperm per millilitre (mL) of semen, with between 1 and 6 mL being ejaculated.

Obstructive azoospermia

Obstructive azoospermia comprises approximately 40% of cases of azoospermia. In this condition, the male hormonal system typically functions normally, and sperm production occurs as usual in the testes. However, as its name implies, obstructive azoospermia involves an obstruction, or blockage, which prevents sperm from leaving the body during ejaculation. In this condition, semen may still be ejaculated, but without sperm as a component. The obstruction can occur in a number of regions, from the rete testis (a network of tubes that help move sperm from the testicle to the epididymis) to the ejaculatory ducts.

Etiology

There are a number of categories of causes of obstructive azoospermia, including:

  • Congenital abnormalities, including congenital bilateral absence of the vas deferens (CBAVD).
  • Vasectomy. In this surgical procedure, the vas deferens is intentionally blocked, usually as a means of permanent birth control.
  • Infection and/or inflammation of the epididymis, prostate, seminal vesicles or genitourinary tract, which can lead to scarring and blockage.
  • Trauma to the male reproductive tract, which may occur as a result of injury or during surgery (e.g. for hernia repair).
  • Cystic fibrosis. Gene mutations in this disorder cause mucus in the body to become thick and sticky, which can block the vas deferens. In addition, mutations related to cystic fibrosis can cause CBAVD, as described above.

It is possible to have a partial obstruction, which can result in low sperm count (oligospermia) instead of the total absence of sperm seen in azoospermia.

Non-obstructive azoospermia

Etiology

Around 60% of cases of azoospermia are found to be non-obstructive azoospermia (NOA). In this condition, sperm production is impaired. There are generally two forms of NOA, in which either:

  • Problems with sperm production occur in the testicles, referred to as primary testicular failure; or
  • Problems with sperm production begin with impaired messaging from the hypothalamus and/or pituitary gland, resulting in low levels of gonadotropins (FSH and LH). This is known as secondary testicular failure, or hypogonadotropic hypogonadism.

In addition to hormonal problems, causes of non-obstructive azoospermia include:

  • Undescended testes
  • Varicocele, or enlargement of the veins in the scrotum.
  • Chromosome or gene abnormalities, including Klinefelter syndrome
  • Sertoli cell-only syndrome, in which only cells that nurture immature sperm (Sertoli cells) are found within the seminiferous tubules of the testes.
  • Anejaculation. This occurs when a men has an orgasm but no semen is released, usually due to nerve damage of some kind.
  • Retrograde ejaculation. In this condition, semen enters the urethra, but instead of being ejaculated through the penis, it flows backward into the bladder.

Diagnosis and differentiation

In general, azoospermia is diagnosed by semen analysis. This involves examining ejaculate under a microscope to look for sperm. At least two semen samples are usually examined, in order to confirm the diagnosis. A sample might also be placed into a centrifuge, and the sediment from the ejaculate examined. If in this process a few sperm are found, instead of none, this is known as cryptozoospermia or severe oligospermia.

In addition, certain qualities of semen can suggest certain problems. For example, a low semen volume, a clear and watery consistency and low semen pH suggests ejaculatory duct obstruction. This condition can result from trauma, surgery, infection, or congenital cysts.

In order to differentiate between non-obstructive (NOA) and obstructive azoospermia (OA), the following are carried out:

  • A medical history. Factors such as past surgery, infection, injury, or cancer treatment are relevant, as well as whether an individual has fathered children in the past.
  • Physical examination, especially of the testes. OA is characterised by normal testicular volume, while in NOA, the testes often present as small and soft, and the epididymis as flat. If a varicocele (varicose vein on the testicle) is seen, this may be a factor related to NOA. Ultrasound imaging of the testicles may also be done. Development of secondary sexual characteristics, such as pubic hair, is also taken into account.
  • Blood tests. In particular, the level of follicle-stimulating hormone (FSH) will be examined, as this tends to be normal in OA and elevated in NOA. However, this is not diagnostic, as in secondary testicular failure
  • Genetic testing. When NOA is diagnosed, genetic testing is recommended to identify whether the cause could be one of a number of disorders including Klinefelter syndrome, which may affect around 10% of men with azoospermia, or Kallmann syndrome.

Management

Obstructive azoospermia

For some men with obstructive azoospermia, especially those who have undergone vasectomy, reconstructive microsurgeries known as vasovasostomy and vasoepididymostomy are an option that can allow sperm to be found in semen again. These procedures may allow pregnancy to occur without intervention.

In other men, the blockage cannot be reversed, or a less invasive procedure is desired. In this case, sperm retrieval procedures, reviewed below, can often be used instead. These techniques fall into two main categories, and each has advantages and limitations. Doctors tend to choose a technique by taking into account the suspected cause of a man’s condition, and his goals (along with his partner). All of the following are carried out with either local anesthesia or intravenous sedation.

Percutaneous sperm retrieval techniques

These techniques are less invasive, 'through the skin' procedures.

  • Testicular sperm aspiration (TESA). This involves a needle, connected to a syringe, being inserted into the testicle through the scrotal skin. Negative (vacuum) pressure is then used while moving the needle around to disrupt and extract sperm from the seminiferous tubules.
  • Percutaneous epididymal sperm aspiration (PESA). In this procedure, a needle is passed through the scrotal skin and into the epididymis, and negative pressure is used to extract fluid which may contain sperm.

Microsurgical techniques

The following procedures are carried out with the help of an operating microscope:

  • Microsurgical epididymal sperm aspiration (MESA). In this case, sperm are retrieved from the epididymis. A small incision is made in the epididymis, and fluid from its tubules then pools in the bed of the epididymis. This fluid is removed (also known as aspirated) and later processed for sperm in a laboratory.
  • Testicular sperm extraction (TESE). In the conventional form of this technique, a small incision is made through the scrotal skin and the covering of the testicle, and a sample of testicular tissue (which contains the seminiferous tubules) is extracted.

After having had one of these procedures, men may have to use ice to decrease swelling, as well as refrain from ejaculation and strenuous exercise for seven to ten days.

The success rate for sperm retrieval is in the range of 90–100% for obstructive azoospermia. Retrieved sperm can be used in an assisted reproductive technology, such as in vitro fertilisation (IVF) or intra-cytoplasmic sperm injection (ICSI). Alternatively, they can be frozen, using standard cryopreservation techniques, for later use.

Non-obstructive azoospermia

There are several treatment options for men with NOA who wish to get pregnant with their partner. In men with low levels of gonadotropins, treatment with synthetic forms of human chorionic gonadotropin (hCG) or FSH can be effective in restoring production of sperm and enabling men to contribute to pregnancy without further intervention.

In men with normal levels of gonadotropins, the main option is to attempt to retrieve sperm from the testes. This is because even when there is no sperm in the ejaculate, there can be some being produced in the testes. This involves use of some of the options described in the previous section, especially TESE.

An additional procedure known as micro-TESE is available to these patients, and has the highest rate of success among them. This involves not just extracting the testicular tissue, as in TESE, but dissecting it during the surgery to search for enlarged areas of the seminiferous tubules, where sperm production is more likely to have occurred.

These procedures are able to retrieve sperm in many, but not all, individuals with NOA. A meta-analysis found that across studies, TESE (including both TESE and micro-TESE) had an average sperm retrieval rate of 47% per procedure. Men found to have chromosomal abnormalities are also candidates for these procedures. One meta-analysis found that men with Klinefelter syndrome who underwent surgical sperm retrieval had pregnancy and live birth rates of close to 50% with their female partners.

Commonly asked questions

I’ve been diagnosed with azoospermia following a semen analysis. What do I do next?

Apart from making sure that you have had at least two semen samples analyzed—as results can vary—your next step is to work with a doctor who specialises in urology or reproductive medicine. They will help you determine what the cause of your azoospermia may be, and what treatment options are available to you.

Will I have to have a testicular biopsy?

In the past, determining whether someone had obstructive or non-obstructive azoospermia was commonly done through a testicular biopsy (a surgical procedure where a piece of tissue is removed from the testicles). Today, however, doctors tend to use lab tests, together with history-taking and physical examination, to understand the cause of azoospermia and the treatment options.

Does azoospermia mean I have problems with testosterone?

Not necessarily. Testosterone is necessary for spermatogenesis, but the two are also produced independently—testosterone by the Leydig cells in the testes, and sperm by testicular stem cells. In some cases, the Leydig cells still have their normal function, while sperm production is impaired. With obstructive azoospermia, both testosterone and sperm are typically normally produced.

Will I still be able to get my partner pregnant?

Depending on the type of azoospermia you have, different treatment options that can either restore fertility or otherwise help you to contribute to a pregnancy may be appropriate. A doctor can outline the options available to you.

Takeaway

Azoospermia refers to the absence of sperm in ejaculate, and is a common cause of male infertility. It has two forms, obstructive azoospermia (in which sperm produced by the testes are blocked from exiting the body) and non-obstructive azoospermia, in which sperm are not produced as usual. Depending on the type of azoospermia, a number of treatments are available; these include hormone treatments and sperm retrieval techniques.

At Cada, we specialise in male and female fertility. Do you want to discuss this topic, or another having to do with fertility, with us? Get in touch so that we can help you on your journey. Reserve your spot for a free consultation now.