Azoospermia and Male Infertility
Introduction to Azoospermia and Male Infertility
Azoospermia is defined as a complete lack of sperm in the ejaculate when tested. There are 3 possible reasons for azoospermia:
1) Sperm production problems (also called non-obstructive azoospermia, or NOA)
2) Blockage problems (also called obstructive azoospermia, or OA)
3) Ejaculatory or sperm transport problems
Figuring out which of the above reasons is causing the azoospermia involves a detailed evaluation, including blood hormone testing, a physical exam, and a review of the man’s medical history and any medications or supplements he is taking. However, two factors—FSH and testicular volume—are usually fairly accurate at narrowing down which of the above problems is present.
FSH (follicle stimulating hormone)
FSH is the hormone from the brain that tells the testicles to make sperm (see “Hormone Testing and Interpretation" for more information on FSH.
If the FSH is normal (1–7 IU/L), then it is more than 90 percent accurate in predicting that sperm production is normal. A high FSH is generally consistent with abnormal sperm production, because when the brain receives information that the testicles are making less sperm than normal, it secretes more FSH to signal the testicles to make more sperm. However, sometimes a man can have a severe sperm production problem but still have a normal FSH and testicular size. In this scenario, called maturation arrest, the testicles make large numbers of sperm “parts” but are not putting them together into normal functioning sperm (see “Maturation Arrest,” below).
Testicular Size
Normal testicular size is considered to be 20cc or more (see “Fertility-Related Physical Exam” for more details on measuring testicular volume.
Most of the volume of the testicles is made up of the cells that produce sperm. Therefore, if the testicles are not making many sperm, then the spermatogenic cells are usually atrophic (small) or nonexistent. The size of the testicles in men with low sperm production is therefore usually smaller than normal (a condition called atrophy). But as with FSH, men with maturation arrest can have testicles that are busy making sperm parts (though not complete sperm) and therefore may be of normal size.
Diagnosis of Causes of Azoospermia
There are 3 main reasons for azoospermia- these include:
1) Sperm production problems- this is generally called Non-Obstructive Azoospermia, or "NOA"
2) Sperm blockage problems- this is called Obstructive Azoospermia, or "OA"
3) Sperm transport problems, in which there is no blockage but the sperm still cannot reach their destination
Note: Strictly speaking, the term Non-Obstructive Azoospermia (NOA) should include all causes of azoospermia that are not associated with an obstruction. However, in the field of male infertility, the term NOA has become associated with a severe sperm production problem causing azoospermia. So when you hear your medical provider say NOA (or read it in this website), then this means a sperm production problem and not a sperm transport issue.
We will now look at trying to use FSH and testicular volume to try and decide if a man with azoospermia has NOA, OA, or a sperm transport problem. This is split into 3 main sections:
1) Low FSH
2) Normal FSH
3) High FSH
Later in this section, we will delve into more detail regarding the diagnosis and management of NOA, OA, and sperm transport issues.
Low FSH and Azoospermia
When the FSH is low (under 1.0 mIU/mL), then we have to consider that something might be suppressing pituitary function. In this scenario, the brain is not sending the signal (FSH) to the testicles to tell it to make sperm.
Potential reasons for this include:
1) Exogenous androgen use (see “Exogenous Androgens/Anabolic Steroids” for more information)
2) Pituitary insufficiency as a result of illness, surgery, or trauma (see “Medical Conditions and Male Fertility" for more information)
3) Congenital absence of FSH production, such as with Kallman’s syndrome (see "Genetics" for more information).
4) Congenital adrenal hyperplasia (see “Medical Conditions and Male Fertility" for more information)
5) Androgen-secreting tumor (for example, adrenal or testicular tumor)
Usually this is a form of Non-obstructive Azoospermia (NOA), but is typically more amenable to medical (non-surgical) therapies.
Normal FSH and Azoospermia
A normal FSH blood test (1.0–7.0 MIU/ml) typically indicates normal sperm production. However, this test is not 100 percent accurate, as the FSH can be falsely elevated in conditions such as maturation arrest (which will be discussed in more detail later in this section).
Potential reasons for azoospermia in men with a normal FSH include:
1) Blockage problem (obstructive azoospermia)
2) Ejaculatory problem
3) Genital duct sperm transport problem
4) Maturation arrest
High FSH and Azoospermia
When a man has azoospermia and an elevated FSH (especially if it is over 10–15 MIU/ml), then most likely a severe sperm production problem is the cause of the azoospermia. This is typically referred to as non-obstructive azoospermia (NOA). An important point to remember is that this does not necessarily mean that no sperm are being made, but only that none were seen by the lab in that specific semen sample. Sperm production must reach a certain threshold level for sperm to start “spilling over” into the ejaculate. Sometimes men who are azoospermic on one sample have small amounts of sperm in subsequent samples. Studies have shown that men who have had two consecutive semen analyses showing complete azoospermia (and who have no other reversible causes) have about a 20 percent chance of finding small amounts of sperm on a third analysis, a 10 percent chance on a fourth analysis, and then a less than 1 percent chance on subsequent analyses. For azoospermic men in whom I suspect a production problem, I usually check at least three semen specimens, ideally all at least ten weeks apart.
Summary Relationships Between FSH, Testicular Volume and Azoospermia
FSH levels and testicular size often give you an idea of what type of azoospermia you are dealing with, but as with most aspects of medicine, correlations are not 100%
Normal/High FSH and Normal Testicle Size
This is more likely due to a sperm blockage or transport issue, but can also be due to Maturation Arrest (see below).
See "Maturation Arrest" and "Obstructive Azoospermia" sections below for more information.
High FSH and Small Testicle Size
This is usually associated with Non-Obstructive Azoospermia (NOA) due to a severe sperm production problem.
See "Non-Obstructive Azoospermia" section below for management options.
Low FSH and Small Testicle Size
This can be associated with Non-Obstructive Azoospermia (NOA) due to inadequate stimulation of the testicles to make sperm by FSH. The most common cause of this is exogenous androgens/anabolic steroids. Other causes include problems with FSH production (e.g. Kallman's Syndrome or prior pituitary surgery/radiation).
See ""Non-Obstructive Azoospermia" section below for management options.
Normal Testicular Size with either High or Low FSH
Indeterminate- may be a variant of maturation arrest.
If sperm due to not return despite the efforts of Sperm Boot Camp, then sometimes a testicular biopsy may be needed to determine if sperm are present. If a biopsy is performed, you should be ready to freeze sperm if it is found (if IVF/ICSI is a possible treatment for the couple). See the "Maturation Arrest" section below for more information on this type of biopsy.
Maturation Arrest- The Great Mimic
Our neat classifications of normal FSH and testicular volume = OA/transport problems vs. high FSH and low testicular volume = NOA is made less predictable by the presence of a pesky type of sperm production problem called Maturation Arrest. To understand what maturation arrest is, we need to explore a little more about the cells that make up the testicle.
Testicular Anatomy and Function
The testicle has two main functions: producing sperm and making testosterone. The Leydig cells are responsible for making testosterone. The spermatogenic cells and their supporting Sertoli cells (located within the seminiferous tubules) produce sperm. When the spermatogenic cells are not making sperm, this is referred to as testicular failure from a spermatogenic standpoint. Biopsy of testicles with spermatogenic failure typically show one of three pathologic findings:
1) Sertoli cells only (SCO). No spermatogenic cells are seen, just the support (Sertoli) cells.
2) Hypospermatogenesis. Spermatogenic cells are present, but in significantly decreased numbers.
3) Maturation arrest. Sperm precursor cells are made, but they do not transform into mature sperm.
Men who have only Sertoli cells (SCO) and those with hypospermatogenesis generally have high FSH levels and smaller testicle volumes (the classic presentation for men with NOA). Maturation arrest, however, can be difficult to diagnose. With maturation arrest, immature sperm parts are often being produced in large numbers, so there is lots of activity going on in the testicle, but no fully formed sperm result from it. Since the testicles are being productive (i.e. making sperm parts), the brain can be tricked into thinking that the testicular production is good, and therefore the FSH level remains normal. Testicular volume is also often normal since the spermatogenic cells are busy making sperm parts. Because these sperm parts are generally not seen in a semen analysis evaluation and FSH and testicular size are both normal, it is often very difficult to distinguish maturation arrest from obstruction as a cause of azoospermia by using just non-invasive testing.
In azoospermic men with a normal FSH and testicular volume, steps should be taken to look for all possible causes of reversible obstructive azoospermia (OA) and sperm transport issues (see the "Obstructive Azoospermia" section below for more details of the recommended evaluation). Also, the man should take the steps described in the Sperm Boot Camp to improve the environment for sperm production as much as possible. If no sperm return to the ejaculate, then the only way to know if there is a blockage/transport vs. maturation arrest sperm production problem is by doing a testicular biopsy. This can be performed in many ways- I personally prefer a testicular sperm aspiration (TESA) approach, but some fertility specialists prefer other techiques (such as TESE)- these are explored in more detail in the "Obstructive Azoospermia" section below. If the couple is interested in the possible IVF/ICSI in the future, it is strongly recommended to have a fertility lab involved and ready to freeze any extracted sperm at the time of the aspiration/extraction, so that if sperm are found, another procedure does not need to be performed just to get usable sperm for IVF/ICSI in the future.
Obstructive Azoospermia and Sperm Transport Problems
Efficient and timely transportation of sperm from the testicles to the urethra is an important part of male fertility, and disruption of this process can result in complete azoospermia. When a man has good testicular sperm production but still has no sperm in his ejaculate, then it stands to reason that he has either a blockage (obstructive azoospermia) or a severe sperm transport problem. Examples of obstructive and transport problems include:
1) Vasectomy
2) Ejaculatory duct obstruction
3) Congenital bilateral absence of the vas deferens
4) Congenital blockages, such as bilateral epididymal obstruction
5) Trauma-related obstruction
6) Obstruction related to prior surgery
7 Non-obstructive transport problems
8 Failure of emission or ejaculation (e.g., neurologic problems)
9 Acontractile seminal vesicles (e.g., polycystic kidney disease, diabetes)
10 Decreased ductal transport of sperm (e.g., from use of alpha blockers or certain antidepressant medications)
Some of these processes are potentially reversible, such as with a vasectomy reversal, resection of ejaculatory duct obstructions, or stopping medications that can inhibit ductal transport of sperm. However, when a reversible cause cannot be readily found or if the treatment fails, then another fertility option is surgical extraction of sperm.
Common Clinical Findings in Azoospermic Men with Normal FSH and Testicular Volume
1) Blockage Problems (Obstructive Azoospermia)
Men with obstructive azoospermia often have a history of trauma, surgery, or infection. On physical exam, the doctor may find no palpable vas deferens on one or both sides (consistent with possible CBAVD; see Chapter 10). A dilated epididymis on each side can be consistent with congenital epididymal obstruction (blockage of epididymal tubules on each side that has been present since birth). A semen analysis that shows a normal semen volume (1.0 cc or more), normal pH (7.2–7.5), and the presence of fructose indicates that the blockage does not involve the ejaculatory ducts.
On the other hand, if the ejaculatory ducts are blocked, the semen analysis is likely to show low ejaculate volume (under 1.0 cc), a low pH (under 7.2), and the absence of fructose. This can be due to ejaculatory duct obstruction (see “Ejaculatory Dysfunction" section link above for more information).
2) Ejaculatory Problems
In men with azoospermia related to ejaculatory problems, typically the semen analysis will show a low semen volume (under 1.0cc) with a normal pH (7.2–7.5) and the presence of fructose. Problems with ejaculation may be seen in men with a history of prior pelvic surgery, men with a neurologic disorder, and men who take medications (such as SSRI antidepressants or alpha blockers) that can disrupt normal ejaculation.
Sometimes men with retrograde ejaculation have a history of milky-colored urine when they void following ejaculation.
3) Genital Duct Sperm Transport Problems
Problems with transport of sperm in the genital duct may be indicated by a semen analysis that shows a normal semen volume (1.0 cc or more), normal pH (7.2–7.5), and the presence of fructose. Sperm transport problems resulting in azoospermia may occur in men who have a history of pelvic surgery, who have a neurologic disorder, who use medication that can disrupt normal ejaculation (such as SSRI antidepressants or alpha blockers), or who have diabetes or polycystic kidney disease.
4) Maturation Arrest
If an azoospermic man’s semen analysis shows normal semen volume (over 1.0 cc), normal pH (7.2–7.5), and the presence of fructose, maturation arrest may be suspected if there is no history of surgery or trauma that could cause sperm blockage.
Steps that can be taken to help figure out the cause of azoospermia in men with a normal FSH
Step 1) Review the medical history for potential causes of sperm blockage
a) Previous scrotal/inguinal surgery. This includes inguinal hernia repair, hydrocele repair, or undescended testicle repair. In adults, the risk of injury to the vas deferens during the repair of an inguinal hernia is 0.8–2 percent, while the risk of damage to the testicular blood supply is 1–5 percent. For children, the risk of injury to the vas during inguinal hernia repair is higher, at 10–27 percent, with the risk of damage to the testicular blood supply at 2–5 percent. In children, the risk of injury to the epididymis during a hydrocelectomy is 5.5 percent, while risk of epididymal injury during spermatocelectomy is 17 percent.
b) Scrotal trauma. Every man has had some incidents of scrotal trauma, and severe trauma can result in damage to the testicle and genital duct system. Most scrotal trauma (kicks to the area, bike accidents, etc.) do not cause significant damage. In general, if you did not have to go to the emergency room for the trauma, then it likely was not significant enough to damage the scrotal contents.
c) Previous abdominal/pelvic surgery or trauma. The vas deferens runs through the pelvis and deep abdominal area in its route from the testicles to the urethra. Abdominal or pelvic surgery or significant trauma can potentially disrupt the vas deferens in this area.
d) Gonadal duct infections. Most infections that affect the gonadal duct, such as chlamydia and gonorrhea, do not cause obstruction, but some infections can be associated with intense inflammation in the ducts, which can lead to scarring and blockage. Some reports have found that the HPV virus (which causes genital warts) can be associated with ductal scarring, but the vast majority of men with HPV do not have subsequent blockage issues.
Step 2) Do a physical exam
a) Vas deferens. Can a normal vas deferens be palpated on each side?
b) Epididymis. Is the epididymis engorged, enlarged, or absent?
c) Testicles. Is the testicular size normal?
Step 3) Review all medications and supplements being taken
Some medications, especially SSRI antidepressants, can cause decreased ductal transport of sperm. Alpha blockers (used to treat prostate enlargement and hypertension) can also cause decreased ductal transport as sperm as well as retrograde ejaculation.
Step 4) Review the sexual history
a) Erections and orgasm. Does the patient have any problems with getting or keeping an erection, or with reaching orgasm?
b) Ejaculation. Does semen come out of the penis when he ejaculates?
c) Semen. Any recent changes in the volume or quality of the semen?
Step 5) Review the medical history
a) Neurologic problems. Conditions such as multiple sclerosis, spinal cord injury, and so on can decrease ductal transport of sperm as well as affect ejaculation.
b) Diabetes. Diabetes-related neurologic changes can affect ejaculation and ductal transport of sperm. Diabetes can also lead to calcification of the seminal vesicles, which can decrease their ability to contract during ejaculation.
c) Polycystic kidney disease. This can result in cystic changes in the seminal vesicles that prevent effective contraction with ejaculation.
Step 6) Check ejaculate volume
The normal amount of semen fluid passed during ejaculation is 1.0 cc or more. A low ejaculate volume (under 1.0 cc) can be due to incomplete collection of the specimen), blockage, or retrograde ejaculation. Low testosterone levels can also cause decreases in ejaculate volume as well. (see “Reversible Analysis Factors” for more detailed information).
Step 7) Evaluate semen fructose and pH
The seminal vesicles make most of the ejaculate volume. Seminal vesicle fluid is alkaline in pH and contains fructose. By contrast, the prostatic fluid has an acidic pH and does not contain fructose. Since the seminal vesicles produce the majority of the fluid, the overall pH of normal semen is alkaline (pH between 7.2 and 7.5). The ejaculatory ducts join the vas deferens to the ducts draining the seminal vesicles, whereupon the semen enters the prostatic urethra at the verumontanum along with the prostatic fluid. If the ejaculatory ducts are completely blocked, then the fluid from the testicles and seminal vesicles is blocked, and only the prostatic fluid comes out with ejaculation. If the semen is acidic and has no fructose, then fluid from the seminal vesicles and testicles is not making it into the ejaculate.(see “Reversible Semen Analysis Factors” link above for more information).
Step 8) Do a post-ejaculatory urinalysis (PEU)
If there is a suspicion of ejaculatory problems (such as low ejaculate volume), then a PEU should be performed to look for the presence of retrograde ejaculation. See “Ejaculatory Dysfunction” section for more information.
Management of Obstructive Azoospermia and Sperm Transport Problems
Management of azoospermia in men with a normal FSH and testicular volume depends on what has determined to be the most likely cause: obstruction, ejaculation/sperm transport problems, or maturation arrest.
1) Obstruction
Obstructions resulting in azoospermia are generally managed in one of two ways:
A) Surgical reconstruction
B) Sperm extraction combined with IVF/ICSI
These topics are covered in more detail below.
2) Ejaculatory Issues
When the azoospermia is a result of issues with ejaculation, see “Ejaculatory Dysfunction" section for more information.
3) Sperm Transport Problems
If sperm transport problems are suspected, the first solution is to try to identify any reversible causes, such as the use of SSRI antidepressants or the use of alpha blockers, especially tamsulosin and silodosin. (Any medication changes should be done only under the close supervision of a medical professional.) If this is not effective, then sperm extraction combined with IVF/ICSI is an option. Sometimes problems of emission (flow of sperm through the ejaculatory ducts and into the urethra) can be disrupted by neurologic issues such as diabetes. Please see the "Ejaculatory Dysfunction" section (link above) for more information on the management of emission issues.
4) Maturation Arrest
Ejaculatory and ductal sperm transport problems are usually fairly straightforward to identify. Men with ejaculatory problems usually have either a low ejaculate volume or a clearly evident problem with reaching orgasm. Genital duct transport issues are usually accompanied by a history of neurologic problems or the use of medications such as alpha blockers or anti-depressants, with the sperm returning after the medications are discontinued. Some causes of obstruction are also fairly easy to diagnose, such as men who do not have a palpable vas on each side, or who had a complicated bilateral hernia repair as a child.
Sometimes, however, the cause of the azoospermia is less clear. An example would be an azoospermic man who has not conceived children in the past and who has a normal FSH, normal testicular size, a normal palpable vas deferens on each side, normal semen volume and pH, fructose in the semen, and no reason in his history for possible blockage or sperm transport problems. Is this a congenital blockage deep in the pelvis involving the vas deferens on both sides, or is this actually maturation arrest with severe sperm production problems (see “Maturation Arrest” earlier in section for more detail). Sometimes the only way to find out is with a testicular biopsy, in which a small number of testicular tubules are removed and evaluated for the presence of sperm. If no sperm are found, then the condition should be managed as non-obstructive azoospermia (see “Management of Non-Obstructive Azoospermia,” later in this chapter). If sperm are found, then this is consistent with a blockage at an unknown location. Any retrieved sperm should be frozen at the time of the biopsy so that they can be used for IVF/ICSI in the future. Surgical exploration can be considered to try to locate a potentially reconstructable area of obstruction, although if the area of obstruction is deep within the pelvis, then it is not typically considered to be reconstructable.
Indirect anti-sperm antibody testing can sometimes be helpful in distinguishing azoospermia caused by blockage from azoospermia caused by maturation arrest (see the "Antisperm Antibodies" section of this website for more detailed informaiton). About 70 percent of men with acquired obstructive azoospermia will be positive for anti-sperm antibodies on indirect ASA testing of the blood, whereas men with nonobstructive azoospermia typically should not be positive for anti-sperm antibodies. Note, however, that men with a congenital blockage (one that has existed since birth) typically do not have elevated levels of anti-sperm antibodies. This information may help to guide treatment options, though a definitive diagnosis cannot be made without testicular biopsy, as described above.
Surgical Reconstruction of Obstructive Azoospermia
Surgical reconstruction options for obstructive azoospermia (OA) depend on the cause and location of the obstruction.
Blockage Involving the Epididymis
Epididymal blockage can be a result of trauma, previous surgery, or congenital abnormalities. Surgical reconstruction (vasoepididymostomy) can sometimes be performed if the vas deferens and ejaculatory ducts are otherwise normal and unobstructed.
See the "Fertility Following Vasectomy" section for more information on the vasoepididymostomy procedure.
Blockage Involving the Vas Deferens Within the Scrotum
Vasal blockage, too, can result from trauma, previous surgery, or congenital abnormalities. Surgical reconstruction can be performed if the rest of the vas deferens and ejaculatory ducts are normal. By far the most common reason of obstructive azoospermia is elective vasectomy for contraception. The "Fertility Following Vasectomy" link above reviews microsurgical vasectomy reversal techniques, including vasovasostomy and vasoepididymostomy.
Blockage Involving the Inguinal Ring
Inguinal hernia repairs are typically the cause of vasal blockage in this location. Vasal damage at the inguinal ring is very difficult to repair microsurgically due to the location of the obstruction as well as the intensive scar tissue related to the use of mesh in most hernia repairs. Some reports have described attempted repairs with a combined laparoscopic (transabdominal) and scrotal approach, but success rates are relatively low. Sperm extraction combined with IVF/ICSI provides the highest chance of success as well as the least risk of complications in this situation.
Blockage of the Vas Deferens Deep in the Pelvic Region
Blockages deep within the pelvis or retroperitoneum usually are the result of either a previous surgery in the area or a congenital abnormality (such as congenital bilateral absence of the vas deferens, or CBAVD). These are generally not candidates for surgical reconstruction. Sperm extraction combined with IVF/ICSI usually represents the best approach for these men if they want to have a biologically related child.
See the "Genetics" section for more information on CBAVD.
Blockage Involving the Ejaculatory Ducts
See “Ejaculatory Dysfunction section for more information on the treatment of ejaculatory duct obstruction (EDO).
Sperm Extraction Procedures for Obstructive Azoospermia and Sperm Transport Problems
Sperm can be extracted from either the testicle or the epididymis. Techniques involve needle extraction or making a small incision in the scrotum to access the testicle or epididymis.
An important point to remember is that extracted sperm must always be used in conjunction with IVF/ICSI. A common question is whether extracted sperm can be used with intrauterine insemination, and the answer is no. The extracted sperm are not of a density or maturity to work with IUI, and must be used with IVF/ICSI. The "Female Fertility Treatments" section of this website has more detailed information on IVF/ICSI.
Sperm Extraction Methods
Multiple different methods can be used to extract sperm in men with obstruction or sperm transport problems. These include:
1) Testicular sperm aspiration (TESA) uses a small needle to extract sperm from the testicles.
2) Percutaneous epididymal sperm aspiration (PESA) uses a small needle to extract sperm from the epididymis.
3) Testicular sperm extraction (TESE) involves making an incision in the scrotum and removing sperm directly from the testicles
4) Microepididymal sperm aspiration (MESA) uses a larger incision in the scrotum. The epididymis is then opened under microscopic guidance, after which sperm is extracted.
These extraction procedures can be performed under either local anesthesia alone, local anesthesia with IV sedation, or full general anesthesia.
Fresh Versus Frozen
Sperm can be extracted either fresh at the time of the IVF egg retrieval or at some other time beforehand and then frozen. Once the sperm are frozen, then the woman can start her IVF cycle, with plans for the sperm to be thawed at the time of egg retrieval and injected into each egg. Studies have clearly shown that for men with blockage or transport issues, extracted fresh sperm and frozen sperm have essentially equivalent success rates with IVF. Most people therefore use frozen sperm, as trying to time a fresh sperm extraction with an egg retrieval can be difficult. During an IVF cycle the exact date that the woman’s eggs are going to be ready for retrieval is not known until a few days beforehand. This makes trying to time a simultaneous extraction for the male a challenge, since sperm extraction requires the coordination of a procedure room and any necessary staff, as well as making sure that the lab has time set aside to properly process the extracted tissue. By extracting and freezing the sperm before starting the IVF cycle, the date and time of the procedure can be planned so that there are no problems with the availability of the surgeon, procedure room, anesthesia, and lab. In addition, by extracting the sperm beforehand, the man and the woman are not simultaneously undergoing procedures, so they can help each other out during the recovery process. The presence of sperm can also be confirmed prior to starting an expensive IVF cycle. There is no rush to use frozen sperm; once it is frozen it can be used successfully years later if needed, without a significant loss in its fertility potential.
Testicular Sperm Versus Epididymal Sperm
Studies have shown that for men with sperm blockage or transport problems, IVF success rates are equivalent for sperm extracted from the testicle and sperm extracted from the epididymis. Some labs prefer to use epididymal sperm, since these tend to have more immediate motility and therefore it can be easier to identify live sperm. However, other labs feel that testicular sperm tend to survive the freeze-and-thaw process better than epididymal sperm. The other advantage of testicular sperm is that newly made sperm are being extracted, whereas the sperm from the blocked epididymal region can contain higher numbers of stagnant sperm that have been sitting around trapped in the epididymis for a long time waiting to be reabsorbed by the body. Studies in men with blockages have shown higher rates of elevated sperm DNA fragmentation in epididymal sperm in comparison to testicular sperm.
Which Approach is Best?
There is no absolutely correct approach, and different male fertility specialists will have their individual preferences and opinions. I will just discuss why I prefer performing a TESA (testicular sperm aspiration) procedure under IV sedation with sperm cryopreservation for men with blockage/sperm transport problems. Again, this does not mean that other specialists are wrong with choosing a different approach!
One reason I prefer extracting sperm from the testicle (instead of the epididymis) is that the nerve supply to the testicle is clustered around the epididymis, making the epididymal area generally the most sensitive part of the scrotal contents for most men. Therefore, retrieving sperm from the testicle avoids the sensitive epididymis and can potentially decrease discomfort. I also prefer to extract testicular sperm, since the labs that I work with feel that they survive the freeze-and-thaw process better than epididymal sperm. There is good evidence as well that the fresher testicular sperm may be healthier than the potentially stagnant epididymal sperm. Even though IVF success rates have been shown to be comparable between epididymal and testicular sperm, higher rates of sperm DNA fragmentation are found in epididymal sperm in men with blockages, so I prefer to retrieve freshly made testicular sperm for use with IVF.
I like the needle extraction (TESA) technique, since it minimizes trauma to the testicle. Recovery times are faster if an incision is not needed, which is possible at least 90 percent of the time. In less than 10 percent of TESA cases, the testicular tubules are of a thicker consistency and so are very difficult to draw up into the needle; consequently a small incision may be needed to retrieve sperm from the testicle.
Most men are nervous about having a procedure on their scrotum, and that nervousness can translate into a tight scrotum, which can make the procedure more difficult and more uncomfortable. By using IV sedation provided by trained anesthesia personnel, the patient remains safe, relaxed, and comfortable throughout the procedure.
Using the TESA technique in men with normal sperm production, I am almost always able to get enough sperm for multiple IVF cycles, so if more than one IVF cycle is needed, the man does not have to go through the extraction procedure again. My goal is generally to extract enough for three vials of frozen sperm, with the labs I generally work with defining one vial as sufficient for one fresh IVF cycle. In my experience, PESA usually extracts less sperm, and therefore fewer vials can be frozen for future IVF cycles. The MESA procedure typically extracts lots of sperm, so multiple backup frozen vials can be obtained. However, the MESA procedure also tends to be very invasive, requiring a large scrotal incision, and it is more expensive. In my experience, TESA is well tolerated, minimally invasive, and significantly less expensive. It requires less anesthesia, has a shorter recovery time, does not damage the epididymis (see below), and yields enough sperm for multiple IVF cycles.
Men who have had a previous vasectomy often choose to do a sperm extraction and IVF/ICSI instead of a vasectomy reversal. Most of these men have good results and high chances of pregnancy with this procedure as long as the female partner is a good candidate for IVF. However, a few times a year I get a couple who has had a successful sperm extraction but then did not have a good experience with IVF (for example, the woman did not respond well to the IVF medications or had significant complications, such as hyperstimulation). These couples often come back asking if a reversal is still a possible option. If TESA has been performed, then there is minimal extra scar tissue in the scrotum and the epididymis is still intact, so vasectomy reversal rates should not be negatively impacted by the prior extraction procedure. However, if an epididymal sperm extraction was performed initially, then this significantly increases the risk that obstructing scar tissue may be present within the epididymis (especially if MESA was used). This epididymal damage can increase the chances that a vas-to-epididymis reversal connection will be needed (which is less optimal in terms of success rates) or that a microsurgical reconstruction might not even be able to be performed (see the "Fertility Following Vasectomy" section for more information on vasectomy reversals).
Non-Obstructive Azoospermia
As mentioned at the start of this section, Non-Obstructive Azoospermia (or NOA) technically means any cause of azoospermia that is not related to an obstruction. Technically, this could also mean a sperm transport problem, but its use in the field of male infertility has become synonymous with a severe sperm production problem (so in this website "NOA" does not refer to sperm transport problems).
Causes of Non-Obstructive Azoospermia (NOA)
There can be a variety of causes for NOA:
1) Testicular damage
Severe trauma to the testicles can sometimes damage them to the point where sperm production stops. With time, some production may return, but in some cases the damage has been so severe that sperm production never returns.
2) Infection
Bacterial and viral testicular infections can disrupt normal sperm production. Production typically returns with time in most men, but in some circumstances (such as orchitis resulting from mumps) the damage can be permanent. Also, systemic body infections (that is, infections of the body that do not directly involve the testicles themselves—for example, flu with a high fever) can place enough stress on the body to temporarily cause sperm production to decrease or stop altogether. Sperm production in these men typically recovers with time, but it can take three to six months, or even longer in some circumstances.
3) Environment for sperm production
Of course, a poor environment for sperm production might also be the cause of NOA. One of the primary goals of male infertility management is to try to optimize the environment for sperm production as much as possible. There are a variety of negative environmental factors that can decrease sperm production in some men, including the use of hot tubs or saunas, taking very hot showers, using a laptop computer directly on the lap, and so on. By themselves, these environmental factors typically do not result in complete azoospermia, but they can play a role in combination with other factors. The effects of negative environmental factors are generally reversible with time, typically within three to six months.
4) Hormonal problems
Abnormal testosterone and estradiol levels can result in significant decreases in sperm production in some circumstances. Also, if the pituitary gland is not functioning properly and sending the right signal (FSH) to the testicles to make sperm, then azoospermia can result. See “Hormone Testing and Interpretation" for more information.
Another common hormonal problem causing non-obstructive azoospermia is the use of exogenous androgens/anabolic steroids. This is an increasingly common problem and usually reversible. See "Exogenous Androgens/Anabolic Steroids" for more detailed information on this.
6) Varicoceles
Dilated veins in the scrotum can be associated with a progressive decrease in sperm production over time. This can lead to complete azoospermia in some men. See “Varicoceles” section for more information.
7) Chemotherapy or radiation therapy
Cancer treatments are designed to kill cells that are rapidly dividing. Since cancer cells divide rapidly, chemotherapy and radiation therapy are often an effective treatment. Unfortunately, the cells that make sperm are also rapidly dividing, and therefore are often damaged or killed during the course of cancer treatments. See “Health Problems and Male Fertility" for more information.
7) Genetic causes
Some men are born with genetic changes that do not allow their testicles to make sperm. These are typically new mutations that have arisen (because if their fathers had the same mutations, they would not have had children, since currently used techniques for assisted reproduction were not available to them). Current genetic testing options for suspected NOA look at the man’s karyotype (all of his chromosomes) for any extra or missing chromosomes, as well as imbalances called translocations, or at the Y chromosome (which only men have), looking for microdeletions, or the absence of certain genes that we know help encode for normal sperm production. Genetic testing can be done by swabbing the cheek but are more commonly done with a simple blood test.
Two important caveats about genetics testing. One is that gene therapy is not currently available to treat any genetic abnormalities that may be found. I hope that within the next ten to twenty years scientific research will be able to develop effective gene and stem cell therapy, but as of now these treatments are not possible. The second is that if the results of genetic testing come back as normal, this does not mean that the man does not have a genetic problem; it only means that he does not have a problem that we can test for right now. Scientific research keeps discovering new genes that are involved in sperm production, so in the future we will be able to test for additional genetic abnormalities. See the "Genetics" section for complete details on genetic abnormalities and testing.
Management of Non-Obstructive Azoospermia
The first step in managing non-obstructive azoospermia (NOA) is to identify and treat any reversible causes that could be contributing to the sperm production problem. These include all of the general interventions that are reviewed in the Sperm Boot Camp.
Sometimes with these interventions sperm counts can be restored to good levels, such as in men who have been taking exogenous androgens. Pregnancy with natural intercourse or low-tech treatments from the female side (clomiphene, insemination, etc.) are often successful for these couples. If small amounts of sperm return to the ejaculate, then the semen will need to be evaluated to make sure enough sperm are present to proceed with IVF/ICSI (see “Virtual Azoospermia” section for more information).
However, for men in whom all reversible factors have been treated but who still remain azoospermic, genetic testing is indicated, along with genetic counseling if appropriate. In this situation, fertility options include adoption, the use of donor sperm with IUI, donor embryos, and sperm extraction combined with IVF/ICSI (see below).
Sperm Extraction for NOA
Some men with non-obstructive azoospermia have small “islands” of sperm production that exist within the testicles but simply do not produce enough sperm to spill over into the ejaculate. In these cases, it may be possible to extract small amounts of sperm from the testicles for use with IVF/ICSI. To find usable sperm in men with NOA, different techniques of testicular sperm extraction need to be used instead of those employed for men with obstructive azoospermia.
Many couples in whom the male partner is found to have non-obstructive azoospermia choose either adoption, the use of donor embryos, or donor sperm combined with intrauterine insemination. Men with NOA who wish to explore their chances of having a child who is biologically related to them need to consider a few issues. If there is no obvious reason for the NOA (such as previous chemotherapy or radiation therapy, exogenous testosterone use, etc.), then most likely there is a genetic basis for the sperm production problem. Some of these genetic problems can be uncovered by currently available tests. However, if genetic testing comes back normal, this does not mean that a genetic abnormality is not present, but only that the man does not have a genetic problem that science can currently test for. Either way, it should be assumed that genetic sperm production problems will most likely be passed on to any male offspring, who would then be expected to have similar sperm production problems. By the time these offspring are old enough to have children themselves, new gene or stem cell therapies may be available. However, this might not be the case, and couples must be comfortable with passing on this potential genetic legacy to future generations. Genetic counseling is sometimes helpful for couples facing these tough decisions.
Genetic testing may also provide prognostic information on the chances of finding sperm by testicular sperm extraction. If Y chromosome microdeletions involving the AZFa and/or AZFb regions are found, then any attempts at testicular sperm extraction will generally not be successful. However, if an AZFc deletion or another type of genetic problem (including Klinefelter’s disease) is discovered, then the man may be a candidate for testicular sperm extraction. See the "Genetics" section of this website for more information.
Prior to any attempted sperm extraction procedure in NOA men, the environment for sperm production should be fully optimized in order to improve the odds of a successful sperm extraction (per the recommendations in the Sperm Boot Camp). There is also a chance that with some intervention, small numbers of sperm might return to the ejaculate, allowing them to be used for IVF/ICSI without having to perform an extraction procedure.
Potential interventions include:
1) Treating low testosterone levels (at a minimum testosterone levels should be 300ng/dL, and ideally higher)
2) Treatment of clinically significant varicoceles
3) Lifestyle changes (e.g., avoiding hot tubs and saunas, stopping smoking, etc.)
4) Modification of medications that might be detrimental to sperm production
Once the environment for sperm production has been optimized, several choices need to be made, including the type of surgical sperm extraction procedure that will be performed and whether the sperm are going to be extracted at the same time as the woman’s egg retrieval or if the sperm extraction is going to be performed first, with the woman proceeding with IVF only if sperm are found at the time of the extraction.
Types of Extraction Procedures for NOA
Standard Testicular Sperm Aspiration (TESA)
The TESA procedure involves a needle aspiration of testicular tubules and is 90–95 percent successful in retrieving sperm in men with obstructive azoospermia, such as in post-vasectomy patients. However, the standard TESA procedure does not achieve a good sampling of multiple different areas of the testicle, which is necessary for finding the small islands of sperm production in men with NOA. Success rates of finding sperm in NOA men with use of a standard TESA procedure on one side are typically around 10–20 percent at most.
Upper/Middle/Lower Pole Biopsy
Testicular sperm extraction (TESE) is the procedure used when sperm are extracted through an incision in the scrotum (as opposed to TESA, which involves a needle aspiration and no incision). Performing a TESE or TESA of the upper pole, middle pole, and lower pole of each testicle allows better sampling than the standard single site TESA procedure. Some studies have reported success rates of up to 45 percent with these TESE procedures, but I have found them typically to yield lower success rates (20-25 percent) in finding sperm. This procedure can be performed under local anesthesia, IV sedation, or general anesthesia.
Microscopic Testicular Sperm Extraction (mTESE)
In the mTESE procedure, the testicle is carefully opened widely and the tubules are thoroughly examined using an operating microscope. Small areas of dilated tubules can sometimes be seen, and these often contain viable sperm. Success rates have been reported to be as high as 50–65 percent in some studies, although most studies report a 40–55 percent success rate in men without AZFa or AZFb microdeletions on the Y chromosome. Microscopic testicular sperm extraction is generally performed on an outpatient basis under general anesthesia. Due to the more invasive nature of the mTESE procedure, some degree of testicular damage can occur. Studies have shown that about 5–10 percent of men undergoing mTESE need to have testosterone replacement started after the procedure, though these men often have testosterone production production problems to begin with.
Fine-Needle Mapping of the Testicle
Mapping the testicle using fine-needle aspiration (FNA) is another approach that can be used in men with non-obstructive azoospermia. FNA mapping of the testicles is performed under local anesthesia or IV sedation and involves taking ten to fifteen small biopsies from each testicle using a very thin needle. The very small size of the needles used retrieves just enough tissue for analysis but is small enough that it does not significantly damage the testicle. The extracted tissue is then placed on separate glass slides and evaluated by a pathologist for the presence of sperm. The location of each extracted piece of tissue is labeled and tracked so that if sperm are found on that slide, the surgeon knows exactly which area of the testicle that sperm came from. Excellent sampling of all parts of the testicles can generally be safely accomplished.
The main drawback of the FNA mapping procedure is that it is diagnostic only. All of the tissue extracted by the very small needles is placed on glass slides and stained for analysis, so any sperm that are found are not usable for IVF/ICSI. If sperm are identified, then a second procedure is needed to go back to the place where they were found and retrieve more for use in IVF/ICSI. This process typically involves a focused mTESE that looks only at the areas of the testicle where sperm were seen by the FNA sampling. Success rates of FNA mapping combined with mTESE are comparable to mTESE used alone. Advantages of this procedure include that if no sperm are seen on any of the FNA samples, then the man is spared the more invasive mTESE procedure and the woman does not needlessly start an expensive IVF cycle. Studies have shown that if a man with NOA has no sperm found on an FNA mapping procedure, that the chance of finding sperm on a subsequent mTESE is less than 3–5 percent. The disadvantage of the FNA mapping is that in order to successfully retrieve usable sperm, two surgeries are necessary instead of one. Also, there is a small chance (about 15%) that when small numbers of sperm are found at the time of the mapping, the subsequent mTESE procedure will not be successful in retrieving usable sperm.
CONSIDERATIONS WHEN CHOOSING THE TYPE OF SPERM EXTRACTION PROCEDURE
Repeated Sperm Extractions
It is generally recommended that if a man is going to have a repeat sperm extraction on the same testicle, six months should pass between the extraction attempts. This allows the testicle time to heal and can potentially increase the chance of finding sperm. However, with the mapping procedure, the needles used for FNA are so small that minimal testicular damage occurs and subsequent mTESE does not need to be delayed.
Fresh vs. Frozen Sperm for IVF/ICSI with Non-Obstructive Azoospermia
In general, the odds of finding sperm in men with non-obstructive azoospermia using the latest mTESE techniques is around 45 percent. This sperm can either be frozen for use with a later IVF cycle, or used “fresh” if the woman’s eggs have already been retrieved. Since sperm are not going to be found in at least half of men with NOA, many couples find it appealing to do a sperm extraction and freezing first, so that if sperm are not present then they do not have to proceed with the expense and invasiveness of an IVF cycle. However, the topic of using fresh versus frozen sperm for IVF in men with NOA is an area of debate.
Significant controversy exists as to whether IVF/ICSI success rates are improved when freshly extracted sperm is used from men with NOA, as opposed to frozen sperm. Leading experts in the field regularly debate the subject, so far with no definitive answer. Some studies have shown improved rates of success with fresh sperm, while others show equivalent rates of success using fresh or frozen sperm. My overall opinion is that it is not clear that fresh sperm from men with NOA have any better IVF outcomes compared with frozen sperm in cases where enough viable sperm are available to use. However, when the frozen sperm approach is used, there is a chance that the extracted sperm will not survive the freeze/thaw process. A recent study out of the University of Illinois, Chicago found that when small numbers of sperm were found at mTESE and frozen, about 8% of the time there were not viable sperm available to use when these sperm were later thawed.
Egg Vitrification (Freezing)
Until recently, unfertilized eggs did not freeze well (as opposed to embryos, which are routinely frozen and used later with good outcomes). However, new freezing techniques now allow successful egg freezing. Some encouraging preliminary studies have suggested that pregnancy rates using vitrified eggs for IVF were similar to those using fresh eggs. However, the field of egg vitrification is quite new, and some IVF lab directors question whether these early positive studies are applicable to the IVF population as a whole. I have heard estimates of up to a 20 percent decrease in expected pregnancy rates with the use of vitrified eggs, although these numbers will need to be evaluated further with future well-designed research trials. What is clear is that egg freezing technology has made great strides and opens up another potential option for couples with NOA.
Donor Sperm Backup
Any time there is a question of whether enough sperm are going to be present at the time of egg retrieval, it’s a good idea to consider having donor sperm backup. Any eggs that are not fertilized by the patient’s sperm can then be injected with the donor sperm. This strategy allows for a backup plan in situations where otherwise there may be limited options left for conception. See Appendix F for more details on donor sperm.
DISCUSSION OF SURGICAL SPERM EXTRACTION OPTIONS FOR NON-OBSTRUCTIVE AZOOSPERMIA
There are several approaches that can be used to extract sperm for use with IVF/ICSI in men with non-obstructive azoospermia (NOA). It is important to remember that in most men with NOA, there is about a 45% chance that there are small islands of sperm production that potentially be found. To extract those sperm, couples can either go straight to the mTESE procedure (in which there is the potential to directly extract usable sperm) or they can proceed first with the diagnostic only FNA testicular mapping procedure. As described above, if sperm are going to be retrieved, a mTESE is going to need to be performed, so some couples decide to go straight to this procedure first. However, the FNA mapping is a much smaller procedure with a quicker recovery. Some couples feel that since there is a <50% chance that there are usable sperm present in the testicles, that they would like to first do the smaller less-invasive diagnostic FNA procedure. If sperm are not found on the FNA, then the more invasive mTESE procedure success rate drops to <3-5%, and if sperm are found on the FNA mapping then a subsequent mTESE procedure would be expected to have at least an 85% success rate in finding usable sperm. The obvious disadvantage of the FNA approach is that if sperm are present, two scrotal procedures (FNA then mTESE) are then required to extract usable sperm instead of just one (just mTESE).
In couples proceeding with mTESE (with our without prior FNA mapping), a choice needs to be made whether to do the mTESE either “frozen” or “fresh”. A frozen mTESE is when the sperm are extracted and then frozen for later use with an IVF/ICSI cycle. A fresh mTESE is when the woman’s eggs have already been extracted and therefore any sperm that are surgically removed from the testicles do not need to be frozen. A fresh mTESE can be done in two ways from the female side. One way is to time the mTESE with the woman’s egg retrieval for IVF. The second way is to have the woman’s eggs extracted and cryopreserved beforehand, and then thawed if sperm are found at the time of the mTESE.
There are significant logistical hurdles that need to be faced when trying to do a fresh mTESE that is timed to the woman’s egg retrieval. When a woman is undergoing an IVF cycle, she is being constantly monitored to determine the exact time when her eggs will be ready for retrieval. The IVF lab will generally aim for a three-day window in which the eggs will most likely be ready for retrieval, but the exact day will not be known until a few days prior. These retrieved eggs must then be injected with sperm within a fairly narrow time frame, around six hours, so any sperm retrieval procedure must be closely coordinated with the time of the egg retrieval if fresh sperm are going to be used. Most sperm extraction procedures for NOA are quite long (around 2+ hours), and trying to find operating room time for such lengthy procedures with only a few days’ notice is often difficult, if not impossible, in many places. Surgery centers are usually booked weeks to months ahead of time and cannot hold open blocks of time that span several days. Hospitals have more flexibility, but non-emergency surgical cases that are added on at the last minute are often pushed late into the evening when the IVF labs (which are needed to evaluate and process the sperm) are no longer open. Hospital facility fees are also often extremely high for these procedures, which are usually not covered by insurance. The other factor to consider is the extremely important role of the fertility lab in being able to successfully find sperm in NOA men. Specialized laboratory personnel must devote a large amount of time to thoroughly processing and searching through the extracted tissue to find whatever sperm may be there, if any. The uncertain nature of trying to coordinate the extraction with the time of the egg retrieval often leaves the lab unable to devote as much time as they would like for properly processing the extracted tissue.
The majority of mTESE procedures in the United States are performed frozen (i.e. the mTESE is performed first, and then the sperm are frozen and used at a later IVF/ICSI cycle. With this approach, the logistical challenges of trying to time the mTESE with egg retrieval are avoided. Also, the couple is not committed to proceeding with cost and invasive procedures associated with IVF until the fertility lab has confirmed that usable sperm are present. The downside of this approach is that about 8% of the time, when sperm are found at mTESE, these sperm do not survive the freeze/thaw process.
PROS AND CONS OF VARIOUS APPROACHES
As detailed above, there are several options for men with NOA who want to attempt testicular sperm extraction, all of which have positives and negatives associated with them.
FNA Mapping of the Testicles
Positives:
1) If no sperm are found on any of the FNA specimens, then the chances of a subsequent mTESE being successful is <3-5%. A larger testicular procedure (mTESE) can therefore be avoided in these cases, as well as the expense and invasiveness of IVF/ICSI for the woman.
2) If sperm are found on the FNA, then the chances of a mTESE finding usable sperm for IVF/ICSI increases to about 85% or more (depending on the number of FNA cores that were positive for sperm).
Negatives:
1) The FNA is diagnostic only, so if sperm are found at the FNA procedure, a 2nd scrotal procedure (mTESE) is needed to extract usable sperm.
“Frozen” mTESE (Extracted sperm are frozen for later use)
Positives:
1) The sperm extraction can be performed on an elective basis, allowing the IVF lab to plan for adequate staffing. This permits them to fully process and evaluate the extracted tissue in an ideal setting
2) If sperm are not found (there is up to a 55–60 percent chance of this), then an unnecessary, expensive IVF procedure can be avoided.
Negatives:
1) About 8-10% of men with small amounts of sperm successfully extracted and frozen will not have viable sperm upon thawing of the specimens. This risk can be mitigated by having donor sperm backup available.
“Fresh” mTESE and “Fresh” Eggs (Fresh sperm extraction timed with fresh egg retrieval)
Positives:
1) Any sperm that are found do not need to be frozen.
2) Retrieved eggs do not need to be frozen.
Negatives:
1) Coordination of the extraction procedure with the exact day of egg retrieval can be very difficult.
2) Uncertainty as to egg retrieval date can mean that the IVF lab will not have enough staff available to optimally process the tissue obtained with sperm extraction.
3) There is up to a 55–60 percent chance that sperm may not be found, and therefore an expensive IVF cycle will have been performed needlessly. This risk can be mitigated by having donor sperm backup.
“Fresh” mTESE and “Frozen” Eggs (Egg retrieval freezing followed by fresh mTESE)
Positives:
1) Any sperm that are found do not need to be frozen.
2) The sperm extraction can be performed on an elective basis, with the IVF lab being able to plan for adequate staffing to fully process and evaluate the extracted tissue.
Negatives:
1) The need to freeze the eggs, which may decrease pregnancy rates by up to 20 percent (though this is controversial).
2) Up to a 55–60 percent chance that sperm will not be found, and therefore an expensive IVF cycle will have been performed needlessly. This risk can be mitigated by having donor sperm backup.
RECOMMENDATIONS
I cannot give a definitive recommendation regarding the best choice of an extraction procedure for all couples with NOA. Some couples choose to do the less invasive FNA mapping procedure first, since if sperm are found on FNA then they know that there is good (85%) chance that there are potential usable islands of sperm production within the testicles prior to proceeding with the more invasive mTESE procedure. Other couples choose to go straight to the mTESE procedure as they do not like the prospect of requiring 2 scrotal procedures (FNA + mTESE) to retrieve usable sperm instead of just one (mTESE alone). There are pros and cons to each of these approaches as described above, so couples need to make the decision for what is the best approach for them.
As for “fresh” vs. “frozen” mTESE, as mentioned above, most mTESE procedures in the United States are performed “frozen”. The logistical difficulties of timing a mTESE with a fresh IVF egg retrieval as well as the commitment to proceeding with an IVF cycle prior to knowing if usable sperm are present both contribute to making fresh mTESE less commonly performed.
This goal of this website section is not to give you the definitive answer on the best surgical approach for NOA sperm retrieval, but rather to provide you with the necessary information to have a meaningful and informative conversation with your male fertility doctor to choose the approach that is right for you.