Azoospermia

Not to be confused with aspermia, which refers to the absence of semen in a male.

Azoospermia
Classification and external resources
Semen analysis revealing no sperm cells and multiple white blood cells

Azoospermia is the medical condition of a man not having any measurable level of sperm in his semen. It is associated with very low levels of fertility or even sterility, but many forms are amenable to medical treatment. In humans, azoospermia affects about 1% of the male population^[1] and may be seen in up to 20% of male infertility situations.^[2]

Classification

Azoospermia can be classified into three major types as listed.^[2] Many conditions listed may also cause various degrees ofoligospermia rather than azoospermia.

Pretesticular azoospermia

Pretesticular azospermia is characterized by inadequate stimulation of otherwise normal testicles and genital tract. Typically, follicle-stimulating hormone (FSH) levels are low (hypogonadotropic) commensurate with inadequate stimulation of the testes to produce sperm. Examples include hypopituitarism (for various causes), hyperprolactinemia, and exogenous FSH suppression by testosterone.Chemotherapy may suppress spermatogenesis.^[3] Pretesticular azoospermia is seen in about 2% of azoospermia^[2]

Testicular azoospermia

In this situation the testes are abnormal, atrophic, or absent, and sperm production severely disturbed to absent. FSH levels tend to be elevated (hypergonadotropic) as the feedback loop is interrupted. The condition is seen in 49-93% of men with azoospermia.^[2] Testicular failure includes absence of failure production as well as low production and maturation arrest during the process of spermatogenesis.

Causes for testicular failure include congenital issues such as in certain genetic conditions (e.g. Klinefelter syndrome), some cases of cryptorchidism or Sertoli cell-only syndromeas well as acquired conditions by infection (orchitis), surgery (trauma, cancer), radiation,^[3] or other causes. Mast cells releasing inflammatory mediators appear to directly suppress sperm motility in a potentially reversible manner, and may be a common pathophysiological mechanism for many causes leading to inflammation.^[4]

Generally, men with unexplained hypergonadotropic azoospermia need to undergo a chromosomal evaluation.

Posttesticular azoospermia

In posttesticular azoospermia sperm are produced but not ejaculated, a condition that affects 7-51% of azoospermic men.^[2] The main cause is a physical obstruction (obstructive azoospermia) of the posttesticular genital tracts. The most common reason is a vasectomy done to induce contraceptive sterility.^[5] Other obstructions can be congenital (example agenesis of the vas deferens as seen in certain cases of cystic fibrosis) or acquired, such as ejaculatory duct obstruction for instance by infection.

Ejaculatory disorders include retrograde ejaculation and anejaculation; in these conditions sperm are produced but not expelled.

Idiopathic azoospermia

Idiopathic azoospermia is where there is no known cause of the condition. It may be a result of multiple risk factors, such as age and weight. For example, a review in 2013 came to the result that oligospermia and azoospermia are significantly associated with being overweight (odds ratio 1.1), obese (odds ratio 1.3) and morbidly obese (odds ratio 2.0), but the cause of this is unknown.^[6] The review found no significant relation between oligospermia and being underweight.^[6]

Diagnosis and evaluation

Azoospermia is usually detected in the course of an infertility investigation. It is established on the basis of two semen analysis evaluations done at separate occasions (when the seminal specimen after centrifugation shows no sperm under the microscope) and requires a further work-up. The following work-up is recommended by the Canadian Urologic Association:^[2]

The investigation includes a history, a physical examination including a thorough evaluation of the scrotum and testes, laboratory tests, and possibly imaging. History includes the general health, sexual health, past fertility, libido, and sexual activity. Past exposure to a number of agents needs to be queried including medical agents like hormone/steroid therapy, antibiotics (sulphasalazine), alpha-blockers, 5 alpha-reductase inhibitors, chemotherapeutic agents, pesticides, recreational drugs (marijuana, excessive alcohol), and heat exposure of the testes. A history of surgical procedures of the genital system needs to be elicited. The family history needs to be assessed to look for genetic abnormalities.

Absence of the vas deferens may be detectable on physical examination and can be confirmed by a transrectal ultrasound (TRUS). If confirmed genetic testing for cystic fibrosis is in order. Retrograde ejaculation is diagnosed by examining a postejaculatory urine for presence of sperm after making it alkaline and centifuging it.^[7]

Low levels of LH and FSH with low or normal testosterone levels are indicative of pretesticular problems, while high levels of gonadotropins indicate testicular problems. However, often this distinction is not clear and the differentiation between obstructive versus non-obstructive azoospermia may require a testicular biopsy.

Serum inhibin-B weakly indicates presence of sperm cells in the testes, raising chances for successfully achieving pregnancy through testicular sperm extraction (TESE), although the association is not very substantial, having a sensitivity of 0.65 (95% confidence interval [CI]: 0.56–0.74) and a specificity of 0.83 (CI: 0.64–0.93) for prediction the presence of sperm in the testes in non-obstructive azoospermia.^[8]

Seminal plasma proteins TEX101 and ECM1 were recently proposed for the differential diagnosis of azoospermia forms and subtypes, and for prediction of TESE outcome.^[9]

It is recommended that men primary hypopituitarism may be linked to a genetic cause, a genetic evaluation is indicated in men with azoospermia due to primary hypopituitarism.^[1]Azoospermic men with testicular failure are advised to undergo karyotype and Y-micro-deletion testing.^[10][11]

Genetic causes of azoospermia

Genetic factors can cause pretesticular, testicular, and posttesticular azoospermia (or oligospermia) and include the following situations:^[11] The frequency of chromosomal abnormalities is inversely proportional to the semen count, thus males with azoospermia are at risk to have a 10-15% (other sources citing 15-20% incidence^[7]) abnormalities on karyotyping versus about <1 % in the fertile male population.^[1]

Pretesticular azoospermia may be caused by congential hypopituitarism, Kallmann syndrome, Prader-Willi syndrome and other genetic conditions that lead to GnRH orgonadotropin deficiency. Testicular azoospermia is seen in Klinefelter syndrome(XXY) and the XX male syndrome. In addition, 13% of men with azoospermia have a defective spermatogenesis that is linked to defects of the Y chromosome.^[11] Such defects tend to be de novo micro-deletions and affect usually the long arm of the chromosome. A section of the long arm of the Y chromosome has been termed Azoospermia Factor (AZF) at Yq11 and subdivided into AZFa, AZFb, AZFc and possibly more subsections. Defects in this area can lead to oligospermia or azoospermia, however, a tight genotype-phenotype correlation has not been achieved.^[11] Spermatogenesis is defective with gene defects for theandrogen receptor.

Posttesticular azoospermia can be seen with certain point mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene commonly associated with congenital vas deferens abnormalities.

Genetic counselling is indicated for men with genetic causes of azoospermia. In terms of reproduction, it needs to be considered if the genetic defect could be transmitted to the offspring.

What causes azoospermia?

Azoospermia may occur if the flow of sperm is blocked and cannot leave the body (obstructive cause). Azoospermia may also be caused by a problem with sperm production (nonobstructive cause).

• Obstructive azoospermia:
  
  
  • Genetic conditions , such as congenital bilateral absence of the vas deferens, may affect sperm transport.
    
  • Infections of the male reproductive system, such as in the testicles or prostate, may affect male fertility.
    
  • Trauma may cause azoospermia. Previous injury or surgery to the spine, pelvis, lower abdomen, or male sex organs may cause damage to the male reproductive system. This may include surgery on an inguinal (groin) hernia. Trauma may affect sperm production or cause an obstruction in the flow or transport of sperm.
    
  • A varicocele is a condition that causes the veins (blood vessels) in the scrotum to become enlarged and dilated (widened).
• Nonobstructive azoospermia:
  
  
  • Medicines , such as steroids, antibiotics, and medicines used to treat inflammation or cancer may affect male fertility.
    
  • Smoking, drinking alcohol, and using illegal drugs may also cause problems with sperm production.
    
  • Genetic conditions may affect sperm production or development of reproductive organs. These include Klinefelter syndrome and Kallmann syndrome.
    
  • Abnormal hormone levels may be caused by disorders of the testicles. This may affect the production of sperm.
    
  • Radiation used to treat cancer may affect sperm production.
    
  • Retrograde ejaculation is a condition that causes semen to travel into the bladder instead of outside the body. It is usually caused by a problem with the neck of the bladder and may be due to spinal cord injuries, medicines, or diabetes.
    
  • Other causes include pesticides, heavy metals, heat, and undescended testes (testicles that did move from the abdomen into the scrotum). Any of these can affect sperm production.

What are the signs and symptoms of azoospermia?

• Inability to get your partner pregnant
  
• Increased body fat, body hair, and breast tissue
  
• Clear, watery, or whitish discharge from the penis
  
• Presence of a mass or swelling on the scrotum that feels like a bag of worms (varicocele)
  
• Stress or emotional pressure from not being able to conceive a child
  
• Testicles that are small, soft, or cannot be felt
  
• Veins that are enlarged, twisted, and may be seen in the scrotum (varicocele)

How is azoospermia diagnosed?

Your caregiver will ask questions about your health and the medicines you take. He will also ask how long you have been trying to have a baby. He may ask about the timing and frequency of your sexual activities, and any problems with sexual urges and functions. Your caregiver will also ask about your lifestyle, such as alcohol intake and smoking. You may need any of the following:

• A physical exam may be done. Your caregiver will look for signs of any imbalance in your hormones, such as increased body fat, body hair, and breast tissue. The size and shape of your testicles will also be examined. Your caregiver may also do a digital rectal exam (DRE) to check your prostate and other parts of your reproductive system.
  
• A biopsy is a procedure used to take a sample of your testicle. Your caregiver may take the sample with a needle or through a small incision in the scrotum. The sample is sent to a lab for tests. This will help determine the ability of the testicles to produce normal sperm.
  
• Blood tests may be done to get information about your overall health.
  
• Genetic testing may be done to look for abnormal genes. Abnormal genes may cause problems with sperm production, sperm transport, or formation of the male reproductive organs.
  
• An MRI takes pictures of your pituitary gland to look for other causes of your infertility. You may be given dye to help the pictures show up better. Tell the caregiver if you have ever had an allergic reaction to contrast dye. Do not enter the MRI room with anything metal. Metal can cause serious injury. Tell the caregiver if you have any metal in or on your body.
  
• A spermatic venography is a test that will examine and show the position of the veins in the scrotum. It may be used to check for a varicocele.
  
• A scrotal or transrectal ultrasound uses sound waves to find lumps and other changes in your testicles and scrotum. These tests may be used to check for a varicocele or any missing parts of the reproductive system.
  
• A semen analysis is a test to check a man's fertility. It is done by taking a semen sample.
  
• A post-ejaculatory urinalysis is a test that is done on your urine after you have ejaculated. This test looks for sperm in the urine. Sperm in urine can be a sign of an obstruction or problems with ejaculation.

How is azoospermia treated?

The treatment will depend on the cause of your azoospermia. You may need any of the following:

• Medicines may be given to treat an infection of the reproductive system. Hormones may be used to treat a hormonal imbalance.
  
• Percutaneous embolization is a procedure that may be used to treat a varicocele. An obstruction (blockage) is made in the enlarged veins. This stops the flow of blood within the vein.
  
• A sperm extraction is a procedure to remove sperm from the testicles or epididymis if there is an obstruction. The sperm that is taken out may be saved or used to fertilize a woman's egg.
  
• Surgery may need to be done to remove a varicocele or repair a blocked vas deferens.

Epididymal Obstruction

On This Page

• Background
• Diagnosis
• Treatment

BACKGROUND
Believe it or not, there is a twenty-foot-long, thin-walled, tightly coiled duct within the scrotum that collects sperm from the seminiferous tubules, where sperm are manufactured, called the epididymis. It's a crescent-shaped duct that runs longitudinally along the back of the testis and as its walls become thicker and straighter it becomes the vas deferens. While sperm are passing through the epididymis, they mature and gain movement. In some men, the epididymis becomes blocked, preventing sperm from entering the vas deferens and getting into the ejaculate. A blockage can occur on either one side or on both sides. This blockage may be natural or may be caused by a hernia or hydrocele repair.

If a man has an epididymal obstruction on one side, he may suffer a lowered sperm count. If a man has epididymal obstructions on both sides, this will lead to azoospermia (a zero sperm count).

DIAGNOSIS
Your doctor can actually feel an epididymal obstruction when he performs a physical exam. During examination of the ductal structures, the epididymis may feel as though it is dilated and hardened. Generally, it is flat in the middle and cannot be felt. What this means is that if you have a dilated and hardened epididymis it may indicate a blockage.

If an epididymal obstruction is suspected in a man with no sperm in the ejaculate, you might have to undergo other tests to try and correct the problem. (Please refer to the section on azoospermia.)

TREATMENT
If, after all the testing, your doctor tells you that he suspects an epididymal obstruction, the next step would be a testicular biopsy. A piece of the testis is taken either through an incision in the scrotum and testicle or with a needle. If good sperm production is found, then it is clear that production of sperm is not the issue, but the delivery of it into the ejaculate is. If other blockages are ruled out, a bypass of the blockage can be performed. This is called a vasoepididymostomy (because the vas deferens is reconnected to the epididymis.) As we've discussed in other sections, it's important that a skilled specialist, experienced with this type of surgery, perform this operation.

If the obstruction cannot be repaired, there are still options available. Sperm may be retrieved from the scrotum. This can be done in a number of ways. It can be done with a needle into the testis, or an incision in the testis. Most commonly a Microscopic Epididymal Sperm Aspiration (MESA) is done to get sperm from the epididymis. There are two advantages to this procedure over retrieval of sperm from the testis. The first is that the sperm are more mature, and thus usually have better movement (motility). The second is that there are significantly more sperm in the epididymis than the testis. This is because the ducts within the testis have collected the sperm already and delivered them into the epididymis. Often, the sperm retrieved through MESA can be frozen and used in multiple IVF cycles.

Sperm retrieved from the testis or epididymis may be used to attempt conception for couples using in-vitro fertilization (IVF) combined with intracytoplasmic sperm insertion (ICSI). IVF means that the eggs are retrieved from the woman. ICSI means that the sperm are injected directly in an egg.

A positive note here is that an epididymal obstruction does not mean you have untreatable infertility. There are a number of options available to patients suffering from the blockage. A male infertility specialist will be able to review treatment options with the patient and provide the greatest likelihood of success.

Vas deferens

By Dr Sherazi clinic staff

Structure

There are two ducts, connecting the left and right epididymis to the ejaculatory ducts in order to move sperm. Each tube is about 30 centimeters (0.98 ft) long (in humans), 3 to 5 mm in diameter and is muscular (surrounded by smooth muscle). Its epithelium is lined by stereocilia.
They are part of the spermatic cords. ^[1]

Blood supply

The vas deferens is supplied by an accompanying artery (artery of vas deferens). This artery normally arises from the superior (sometimes inferior) vesical artery, a branch of the internal iliac artery.

Function

During ejaculation, the smooth muscle in the walls of the vas deferens contracts reflexively, thus propelling the sperm forward. This is also known as peristalsis. The sperm is transferred from the vas deferens into the urethra, collecting secretions from the male accessory sex glands such as the seminal vesicles, prostate gland and the bulbourethral glands, which form the bulk of semen.

Clinical significance

Contraception

The procedure of deferentectomy, also known as a vasectomy, is a method of contraception in which the vasa deferentia are permanently cut, though in some cases it can be reversed. A modern variation, which is also known as a vasectomy even though it does not include cutting the vas, involves injecting an obstructive material into the ductus to block the flow of sperm.
Investigational attempts for male contraception have focused on the vas with the use of the intra vas device and reversible inhibition of sperm under guidance.

Disease

The vas deferens may be obstructed, or may be completely absent in a condition called as Congenital Absence of Vas Deferens ( CABD ), (the latter a potential feature of cystic fibrosis), causing male infertility. Acquired obstructions can occur due to infections. It can be overcome by testicular sperm extraction (TESE), Micro Epididymis Sperm Extraction ( MESA ), collecting sperm cells directly from the testicle or Epididymis .

Uses in pharmacology and physiology

The vas deferens has a dense sympathetic innervation (Sjöstrand, NO (1965). The adrenergic innervation of the vas deferens and the accessory male genital organs. Acta Physiologica Scandinavica 257:S1–82), making it a useful system for studying sympathetic nerve function and for studying drugs that modify neurotransmission.^[2]
It has been used:

• as a bioassay for the discovery of enkephalins, the endogenous opiates.^[3]
• to demonstrate quantal transmission from sympathetic nerve termianals.^[4]
• as the first direct measure of free Ca²⁺ concentration in a postganglionic nerve terminal.^[5]
• to develop an optical method for monitoring quantal transmission.^[6]

Other animals

Most vertebrates have some form of duct to transfer the sperm from the testes to the urethra. In cartilaginous fish and amphibians, sperm is carried through the archinephric duct, which also partially helps to transport urine from the kidneys. In teleosts, there is a distinct sperm duct, separate from the ureters, and often called the vas deferens, although probably not truly homologous with that in humans.^[7]
In cartilaginous fishes, the part of the archinephric duct closest to the testis is coiled up to form an epididymis. Below this are a number of small glands secreting components of the seminal fluid. The final portion of the duct also receives ducts from the kidneys in most species.^[7]
In amniotes, however, the archinephric duct has become a true vas deferens, and is used only for conducting sperm, never urine. As in cartilaginous fish, the upper part of the duct forms the epididymis. In many species, the vas deferens ends in a small sac for storing sperm.^[7]
The only vertebrates to lack any structure resembling a vas deferens are the primitive jawless fishes, which release sperm directly into the body cavity, and then into the surrounding water through a simple opening in the body wall.
See also

• Infertility