No Sperm / Azoospermia

The first step in the evaluation is the physical exam. Since most of the bulk of the testes is comprised of sperm producing elements (the seminiferous epithelium), if the size of the testicle is severely diminished, this is usually because of issues with the sperm producing part of the testicle. Many men with small testes and problems with sperm production still have normal testosterone levels, though many will not.  This is because the testosterone is made by a different type of cells in the testes, called Leydig cells.

Absence of the Vas Deferens Can Be the Cause of No Sperm Delivery

Some men are missing from birth both of the tubes that carry the sperm, the vas deferens. This condition is called Congenital (at birth) Bilateral (both sides) Absence of the Vas Deferens or CBAVD. Most of these men will carry two mutations for cystic fibrosis, a major and a minor one. This combination does not give them the disease but does not allow the vas deferens to develop. This does not in any way cause a problem with sperm production. Thus, unless there is another different problem also occurring, sperm can be retrieved surgically from the testicle or the duct draining the sperm from the testicle, called the epididymis.

It is important that these men have genetic testing for cystic fibrosis mutations. If this mutation is found, his partner must be tested, and if she is positive for the mutation, then all embryos created should be checked prior to being transferred into the uterus to make sure they don’t carry both copies of the gene, and would thus have the disease itself.

Obstruction of the Epididymis or Vas Deferens

Also, during examination of the ductal structures, the epididymis (which is the first part of the sperm carrying duct) may feel as though it is enlarged and/or firm. Generally, it is flat, and the middle cannot be felt. If the epididymis is enlarged and hard there may be a blockage.

Likewise, the vas deferens, the tubes carrying the sperm may have become blocked from infection or surgery (including a vasectomy.) This can sometimes be felt during the exam.

Varicoceles

The scrotum is examined for the presence of dilated veins, varicoceles. Their presence can be confirmed by a scrotal ultrasound, which is done non-invasively by applying a probe to the scrotal skin.

Follicle stimulating hormone (FSH) is the hormone, made by the pituitary, which is responsible for stimulating the testes to make sperm. When the sperm-producing capacity of the testes is diminished, the pituitary makes more FSH in an attempt to make the testes do their job. Therefore, if a man’s FSH is significantly elevated, there is a strong indication that his testicles are not optimally producing sperm. If a man has a very low FSH, then he is lacking the ability to make FSH, which is needed by the testis to promote sperm production. This may actually be good news in terms of treating the azoospermia, as many men have sperm in the ejaculate after treatment with FSH.

Testosterone, estradiol, prolactin, luteinizing hormone (LH), and thyroid stimulating hormone (TSH) are also measured to assess a man’s hormonal status. These may reveal problems that can significantly impact sperm production.

This is an area of active research.

At this point, it is recommended that all azoospermic men receive basic genetic testing, called a karyotype.  This measures the number of chromosomes and looks at the large blocks of genetic material to make sure they are correctly aligned in the proper chromosome. Extra chromosomal material, or chromosomal material improperly aligned, can have a significant effect on sperm production.

There are tests for specific genetic abnormalities on the male (Y) chromosome in the areas that code for sperm production that can cause low levels of sperm or complete and irreversible azoospermia. These mutations are called Y microdeletions. If a son were to inherit one of the mutations that caused a significant decrease in sperm production, he would be expected to have the same problem.

Screening for the mutations that can cause cystic fibrosis is sometimes suggested. If present, it can cause problems with the sperm ducts.

It is possible that ejaculation is occurring “backwards”; instead of the ejaculate being pushed forward and ejaculated out of the tip of the penis, the sperm is being pushed into the bladder. This is not medically dangerous. The ejaculate is washed out the next time the man urinates.

To test for this, we have the patient empty his bladder and then ejaculate into a cup. He is then asked to urinate again into a different specimen container, which tested for sperm. This is called the post ejaculatory urinalysis. If there are significantly more sperm in his urine than his ejaculated specimen he has ejaculated backwards. Sometimes, this can be corrected by oral medication. If not, the urine can be prepared so that it does not damage the sperm as much, and the sperm is then harvested from the post-ejaculatory urine.

In order to rule out a blockage of the ejaculatory duct, an ultrasound of the ejaculatory duct and seminal vesicles is often performed. In this test, the ultrasound probe is placed in the rectum since the ducts lie near the rectal wall. Also, the ejaculatory duct traverses the prostate (a gland that can be felt through a man’s rectal wall.) If the seminal vesicles are dilated, this indicates that they may be full of semen because they cannot empty properly. Cysts blocking the ejaculatory ducts by exerting pressure on their walls, or calcifications in the ejaculatory ducts themselves, may also be noted. A cyst, in some cases, may be unroofed by operating through the urethra to open it. This decompressing the ejaculatory duct. If the blockage occurs within the ejaculatory duct, the blockage may be removed in a similar operation.

The three major causes for lack of sperm production (Non-Obstructive Azoospermia, or NOA) are hormonal problems, testicular failure, and varicocele.

Hormonal Causes of No Sperm

The testicles need pituitary hormones to be stimulated to make sperm, specifically FSH and LH. If these are absent or severely decreased, the testes will not maximally produce sperm and possibly not produce any sperm at all.

Importantly, men who take androgens (steroids) for body building, either by mouth or injection, shut down the production of hormones needed for sperm production, and thus often shut down sperm production completely or decrease it significantly.  Fortunately, this can almost always be reversed.

A prolactin producing tumor, a prolactinoma (which fortunately is almost never metastatic and usually treated with medication) can significantly decrease sperm production.

Thyroid problems can also have a negative effect on sperm production.

Treatment Options

The most common hormonal treatment for men with a testosterone level of less than 400 is selective estrogen receptor modulator (SERM) or Clomiphene Citrate. This pushes the pituitary gland to make more FSH and LH, which in turn pushes the testes to (try to) make more sperm and testosterone. The man may also notice that he feels better, since a higher testosterone level may help energy level, libido, muscle mass, erections etc.

It is crucial that a man not go on testosterone replacement therapy, as this will shut down the production of sperm in the testes. 

The only way to get the high concentration of testosterone in the testes needed to make sperm, is for the testosterone to be made in the testes itself.

Some men are not making enough FSH and LH because of a problem with their pituitary gland. In this case, these hormones need to be administered.

Men with prolactin or thyroid problems also need to be treated as described above.

Testicular Failure Causing Azoospermia

In general, this means that the sperm-producing part of the testicle (the seminiferous epithelium) isn’t making adequate numbers of mature sperm. This failure may occur at any stage in sperm production for several reasons. Either the testicle may completely lack the cells that divide to become sperm (this is termed “sertoli cell-only syndrome”) or there may be an inability of the sperm to complete their development (this is termed a “maturation arrest.”) This situation may be caused by diagnosable genetic abnormalities. The screening for this must happen prior to any other diagnostic or therapeutic procedures. However, often we cannot find a reason for testicular failure.

Varicoceles Can Reduce Sperm Production

One of the best options is to correct a patient’s varicocele, which is a dilated complex of veins in the scrotum (varicocelectomy). These can suppress sperm and also testosterone production. 44% of men with azoospermia are found to have sperm after a varicocelectomy is performed! More than one in eight will actually go on to achieve a pregnancy naturally.

A man with a varicocele and azoospermia should not be considered azoospermic until after a varicocelectomy is performed.

Treatment Option: Varicocelectomy

There are several ways to fix a varicocele. Fortunately, studies show, with an unusual degree of unanimity, that there is one best way. This is the microscopic sub-inguinal varicocelectomy with ultrasound guidance. This can only be performed by a urologist specializing in fertility and microsurgery. Learn more about this procedure performed by Dr. Michael Werner at Maze.

Generally, a sperm delivery issue (Obstructive Azoospermia, or OA), is caused by a problem in the ducts that carry the sperm, or problems with ejaculation.

Treatment Options for Blockage/Absence of the Vas Deferens or Epididymis

As described above, a man may be missing the tubes that carry the sperm, Congenital Absence of the Vas Deferens. He may have obstructions either at the level of the delicate tubular structure draining the testes (the epididymis) or higher up in the more muscular vas deferens. He may have become mechanically blocked during hernia or hydrocele repairs.  Of course, a previous vasectomy would be known cause of ductal obstruction.)

Vasal Reconstruction

In certain cases, the flow of sperm through the reproductive tract can be re-established. The most common case is after a man has a vasectomy (though sometimes it can be done after a man has a blockage from an epididymal infection.)  If this is successful, it may be possible for his partner to conceive naturally through intercourse, and not need IVF/ICSI.  Success rates vary by length of time since the vasectomy, and the findings during the surgery.

Sperm Retrieval

If there is evidence that the sperm are being made (based on testicular size, the rest of the scrotal exam, and hormonal profile) but can’t get out, a specialist can go in and get (retrieve) the sperm. However, the numbers retrieved are low and the sperm themselves move slowly, so this must be combined with in vitro fertilization, and injection of an individual sperm into each egg. The two main options for sperm retrieval are:

Micro Epididymal Sperm Aspiration (MESA)

This procedure is done by the specialist in the operating room, under light anesthesia. An incision is made in the scrotum, and the epididymis isolated. Using an operating microscopic, the urologist makes a small incision in the tubule of the epididymis and then has his lab specialist look at the fluid under a regular microscope to see if there are moving sperm. This may be done in multiple locations of the scrotum and possibly on both sides until adequate sperm are retrieved.

The sperm are frozen in multiple vials, which means that it is very rare that a second procedure would be needed for subsequent IVF/ICSI procedures if performed.

Also, it can be done in advance of the partner’s egg retrieval, which makes scheduling much easier.  Frozen sperm, if moving when thawed, produces the same results as freshly-retrieved sperm.

Needle (Percutaneous) Testicular Biopsy

The day before his partner’s eggs are to be retrieved, the man comes to his urologist’s office for this very simple procedure. The nerves leading to the testis are injected with a local anesthetic, as is the skin. A small skin incision is then made.

A biopsy core is taken of the testis, placed in specialized fluid, and then a drop is examined for sperm. The testis is then compressed for five minutes to stop bleeding.

The next day, individual sperm are taken by the embryologist at the wife’s doctor’s lab and injected in her eggs.

The advantage of this procedure is that it is less invasive than a MESA, does not require an anesthesiologist or hospital, and is cheaper.

The disadvantage is that often there are only enough sperm for the one IVF cycle, and it may need to be repeated in the future.

Treatment Options for Ejaculatory Duct Obstruction

Sperm are stored in sacs called the seminal vesicles, and then are deposited in the urethra, which is the tube through which men urinate and ejaculate. The sperm must pass through the ejaculatory ducts to get from the seminal vesicles to the urethra. If these are blocked on both sides, no sperm will come through, even if some fluid does.

Trans-Urethral Resection of the Ejaculatory Duct (TURED)

A cyst, in some cases, may be unroofed by operating through the urethra to open it, thus decompressing the ejaculatory duct. If the blockage occurs within the ejaculatory duct, the blocked part may be removed in a similar operation.

In some cases, this results in normal amounts of sperm being ejaculated, and a pregnancy can occur through natural intercourse, or intrauterine inseminations.

Treatment Options for Ejaculatory Dysfunction

Finally, there may be problems with ejaculation. Before a man ejaculates, the sperm must first be deposited in the urethra. This process is called emission. There may be neurological damage from surgery, diabetes, or spinal cord injury that prevents this from happening. Also, for the sperm to be pushed out the tip of the penis, the entry to the bladder must be closed, which happens naturally and unconsciously during normal ejaculation.  If it does not close, the sperm will be pushed into the bladder (rather than out the tip of the penis) and then subsequently washed out when the patient urinates.

Medications for Ejaculatory Dysfunction

There are many suggested medications and regimens to get men to deposit the sperm in their urethras with orgasm (emission) and to convert them from ejaculating backwards into the bladder, to forward, out the tip of the penis.

We most commonly use pseudophedrine 30mg immediate release tablets. (These are the ones that are kept behind the pharmacy counter, but don’t need a prescription. They are tracked as they are a needed component for crystal meth.) Regimens vary.

Other medications used include imipramine, midodrine, ephedrine, phenylephrine, and chlorpheniramine.

After an orgasm, the man should milk his urethra into a specimen cup to see if any fluid comes out. This sometimes has enough sperm to be frozen (cryopreserved) and avoid the necessity for sperm retrieval procedures, as described above.

Unfortunately, this is often unsuccessful, and sperm retrieval is necessary.

Extended Sperm Search & Microfreeze may be able to find sperm that even a careful conventional semen analysis with a post ejaculatory urinalysis can’t find. This may be because the numbers are so low, that they are not seen in a random drop of sperm used for a conventional semen analysis. Even if the specimen is spun down with a centrifuge, and the pellet at the bottom evaluated, unless every drop is looked at thoroughly, individual sperm may be missed.

An ESSM is performed by processing the specimen and dividing the entire sample into 5 microliter droplets and carefully scanning the drops under a high-powered microscope. Any live sperm located can be moved with a micromanipulator into a micro-drop on a specialized freezing receptacle so that it can be successfully frozen. This will ensure that the sperm will be found and viable when thawed and needed for injection into his partner’s eggs.

In those cases where appropriate interventions have been performed (i.e. hormone treatment and/or varicocelectomy) and where the ESSM did not locate sperm in the ejaculate, there may be the possibility of harvesting sperm directly from the testes. In 43-68% of azoospermic men there may be small number of sperm, which have been produced in the testis, but exist in such small quantities that they do not reach the semen, even when an extended search has been done.

In these cases, an in-office procedure called Sperm Mapping can determine if there are sperm producing areas in the testes, and where they are. This is relatively painless in office procedure, using only a local anesthetic, and involves taking multiple needle biopsies of the testes using a grid, so that all areas of the testes are sampled

The advantages of the sperm mapping procedure is that it is less invasive, less painful, and there is less damage to the testicles than a micro-TESE (Testicular Sperm Extraction). Also, if no sperm are found in any of the needle biopsies, micro-TESE is avoided, and the female partner need not necessarily go through an IVF cycle.  (For example, donor sperm with intrauterine inseminations or adoption may be pursued.)

If sperm are found, then the couple can proceed with in-vitro fertilization and an open sperm retrieval procedure, called micro-TESE.

In most centers, the next step after a diagnosis is made of complete azoospermia is micro-TESE. (We hope that in the future, all men will have an ESSM procedure prior to this step.) This procedure is performed as an outpatient in a surgical setting, with anesthesia, and involves opening the scrotum and testis, and then taking numerous samples (biopsies) of the testis. These are immediately evaluated by an onsite specialized lab technician to see if sperm are found, and if so, the sperm are then injected directly into his partner’s eggs (ICSI), whether already frozen or being retrieved that day.

If extra sperm are found, these can be frozen and used in subsequent IVF cycles, and we recommend the tissue be evaluated and frozen in the same way as done in an ESSM, as this makes it more likely that a few sperm can be isolated and subsequently thawed successfully and found.