Male factor infertility accounts for inability to conceive in up to one third of total couples facing difficulty in having a baby. Fortunately with the technological advancements, it is now possible to identify the cause and treat many such sub-fertile men thus ensuring their journey to parenthood is fruitful. It is, therefore, essential to understand various causes of male infertility and available treatment options for them.
Understanding the male reproductive system
The two essential contributors to male fertility are sperm production and sperm transport.
The process of sperm production or spermatogenesis is a long process that takes up to 3 months. It begins in the seminiferous tubules of the testis, where sperm cells undergo repeated cell division to finally produce a mature sperm. Sperm production is a continuous process with millions of sperms being produced daily after puberty. The sperms are then stored in the epididymis and it is here that the sperms finally mature and gain the ability to swim. The next passage of the sperms is in the vas deferens which is a tube connecting the epiphysis to the urethra via the ejaculatory duct. It is from the urethra that the sperms are ejaculated during coitus. The seminal fluid is formed with not only the sperms but also receives a lot of secretions from other gland like seminal glands, prostrate and Cowper’s gland. The secretion plays a vital role in the ability of the sperm to move and fertilize the egg.
In addition to healthy structures mentioned above, adequate levels of male hormone- testosterone and ambient temperature of the scrotum are also essential for sperm production and maturation. Testes play a vital role in production of testosterone. Therefore, testicular dysfunction can lead to disturbances in testosterone production also.
Causes of male infertility
There can be multiple reasons for male factor infertility. The important and correctable reasons are listed below for easy understanding.
1. Sperm production Problem– Problems in the production / development of sperms is the most cause of male infertility. The problems may range from oligospermia (low sperm Count) to azoospermia (nil sperm count) . The other issues commonly seen are defects in the morphology or motility of sperms. The various reasons which may impair the sperm production include:
- Infections- The common infectious conditions leading to infertility include mumps, tuberculosis, brucellosis, gonorrhea, typhoid, influenza, smallpox, and syphilis. These infections can cause testicular damage and atrophy leading to total arrest in sperm formation.
- Varicocele- Varicocele is a clinical condition in which the veins inside the scrotum get enlarged and bulky. It is more common on the left side and is usually seen among professionals whose jobs require prolonged standing- example long distance runners, bus conductors, policemen etc. Pooling of blood inside scrotum can potentially alter the temperature control around the testes and hence can negatively affect the sperm formation/ maturation. This can cause low sperm count and poor motility.
- Genetic Causes- The most common genetic causesare-
- Klinefelter’s Syndrome- It’s a genetic condition seen in the male partner, who has an extra pair of X chromosome (XXY) in his genetic makeup. The common clinical finding in these men is small testes and enlarged breasts. While this abnormality causes testicular atrophy, if treated timely with HCG (hormonal therapy), some spermatogenesis can be maintained and sperms can then be surgically retrieved using techniques like TESE and TESA and pregnancy can be achieved with ICSI.
- Y chromosome microdeletion- Another important genetic cause of reduced fertility in men is the deletion of a small region on the Y chromosome, which is responsible for spermatogenesis. Most of the men affected by this condition have low sperm count and some of them even suffer from total lack of sperm production (azoospermia). Testicular biopsy may yield some sperms in these patients and these can be the utilized for ICSI to achieve pregnancy.
2. Blockage of sperm transport– The obstruction to passage of sperms from the testes to the penis (called as obstructive azoospermia) is another major cause of infertility in men, and is responsible for up to 40% cases of male infertility. In these patients, spermatogenesis is generally normal. The common causes for obstructive azoospermia are:
- Congenital bilateral absence of the vas deferens (CBAVD)- CBAVD is mostly a genetic condition and is caused by a mutation in the cystic fibrosis trans-membrane conductance regulator (CFTR) gene.
- Infections- Blockage of the ejaculatory duct due to infections like tuberculosis can also result in subfertility.
- After vasectomy- Vasectomy performed as a family planning measure, resulting from complications of pelvic surgery or trauma will result in complete lack of transport of sperms.
Treatment– These patients will generally have functional testes (unless the testes are also affected by the infection) and can be managed with surgical techniques of sperm retrieval (such as TESE or TESA) followed by IVF/ ICSI. Surgical reconstruction of transacted Vas deferens (post-surgical/ trauma) is another option for carefully selected patients, but the chances of success of such repair remain very low even in experienced hands.
3. Sperm Antibodies/ immunologic causes- Anti-sperm antibodies occur in about 7% of infertile women and in a little higher proportion of infertile men. It is an important cause of subfertility among men, especially among those with history of previous surgery such as vasectomy or vasectomy reversal, pelvic trauma or reproductive tract infections- all conditions which breach the blood-testes barrier, thus bringing sperms in direct contact with blood. Anti-sperm antibodies are generally not an absolute cause of infertility by themselves. But, presence of anti-sperm antibodies does reduce fertility in a graduated manner. This means that the higher the immunologic response of the body, the less likely it is that a pregnancy will occur.
Any condition causing breach of blood-testes barrier exposes the proteins present on the surface of sperms to blood. These proteins can be identified by the body as antigens, thus activating body’s immunogenic response leading to formation of anti-sperm antibodies. Similarly, when the sperms come in contact with female immune cells (this contact is normally prevented by vagina), sperms are identified by the immune system of the woman as foreign cells and this activates immunological response of the female body resulting in formation of antibodies.
Once sperm antibodies have formed, they can affect sperm in several different ways.
- Some antibodies will cause sperms to stick together (agglutinating antibodies). Agglutinated sperms clump together in huge masses and are unable to migrate through the cervix and uterus.
- Other antibodies mark the sperm for attack by Natural killer (NK) cells of the body’s immune system (opsonizing antibodies).
- Some antibodies cause reactions between the sperm membrane and the cervical mucus preventing the sperm from swimming through the cervix (immobilizing antibodies).
- Antibodies can also block the sperm’s ability to bind to the outer membrane (known as zona pellucida) of the egg, a prerequisite for fertilization.
- Also, there is some evidence that the fertilized egg shares some of the same antigens that are found on the sperm. It is possible that sperm antibodies present in the mother can react with the early embryo, resulting in its destruction by phagocytic cells.
Diagnosis- There are a number of diagnostic tests available to detect the presence of sperm antibodies. These tests include flow cytometry, ELISA (enzyme-linked immunoabsorbent assay), Franklin-Dukes sperm agglutination assay and Immunobead Binding Test (IBT) to name a few.
Like the source of some antibodies, the critical levels of sperm antibodies are also debatable. As a broad cut off, serum antibody level of above 40% by the IBT is generally associated with significant fertility problems.
Treatment- Once an immunological cause has been identified as the cause of infertility, there are 3 treatment options for the couple:
- Intracytoplasmic Sperm Injection (ICSI)- ICSI involves fertilization of an egg with a single sperm under direct vision and produces high pregnancy rate. ICSI is the preferred treatment option for patients with identified immunological infertility. According to accumulated scientific evidence, ICSI has optimized IVF pregnancy in cases of male immunologic infertility so much so that that pregnancy rate is actually unaffected by the anti-sperm antibodies.
- Steroid therapy- In some patients, the corticosteroids (prednisone) does temporarily suppress antibody production. But, pregnancy rate with steroid treatment is not very encouraging. Moreover, steroid treatment can lead to significant side effects such as spontaneous fractures in up to 2 – 4% cases. As such, we do not routinely recommend steroid therapy to our patients.
- Other treatment options- These include prolonged use of condoms or antibiotic therapy. But all these methods have low scientific basis and do not as such increase the chances of pregnancy in cases with proven immunological infertility.
4. Sexual Problems – Erection pf penis is essential for penetration and ejaculation is process of release of semen from the penis when the man has orgasm. Erectile and ejaculatory dysfunctions can therefore cause infertility.
A variety of physical and psychological problems can cause such sexual dysfunctions. These conditions include illnesses like diabetes, infections, certain medications, stress, anxiety and depression. Very significantly, disharmony in relationship can also cause erectile or ejaculatory disorders.
The common manifestations of ejaculatory dysfunctions include:
- Premature ejaculation: It is a common problem affecting men of all ages. It is a distressing problem for both partners as the man seems to lose control over ejaculation and ejaculation happens “too soon”. Some men may acquire it later in life as a manifestation of some disease like diabetes or as an outcome of excessive stress or certain medications.
- Retrograde ejaculation- Under normal circumstance the semen is propelled through the urethra and the penis and prevented from going in the bladder by the contraction of circular muscle present at the bladder neck, however in retrograde ejaculation due to some problem in the nerves in the bladder and the bladder neck the sperms flow backward in the bladder. This is commonly seen in males with long standing and/or uncontrolled diabetes or after operations of prostrate or urinary bladder neck.
- Anejeculation– Anejeculation is the inability to ejaculate semen despite stimulation. It can be caused by psychological causes or stress and also due to certain hormonal imbalances.
- Painful ejaculation- Painful ejaculation can be encountered in presence of certain infectious conditions of the penis or tests.
5. Life style- Male infertility can also be an outcome of poor lifestyle habits, which have a negative impact on sperm formation, maturation and/ or transportation. Some important life style conditions which negatively affect sexuality and fertility include:
- Smoking- Lowers the sperm count and motility
- Chronic alcohol abuse
- Intake of Anabolic steroids- Causes testicular shrinkage and infertility
- Excessive exercise- This can produce excessive adrenal hormones, which causes testosterone deficiency.
- Overheating the scrotum- Normal scrotal temperature is 2 degrees less than the normal body temperature. Certain personal habits such as frequent hot baths, sauna, wearing tight underwear etc. can increase the scrotal temperature, which in turn can impair spermatogenesis.
- Stress- Chronic stress can lead to increase adrenal hormone secretion which interferes with sex hormone production.
- Obesity- Fat cells produce estrogen, which adversely affects testosterone production.
- Hazards in workplace- Some men may be working in and around toxic substances, heavy metals, lead etc which can damage the sperms.
6. Hormonal Problems- Hormonal imbalance in form of hypothyroidism, low testosterone, Kallaman’s syndrome etc may present with male sexual dysfunction and oligospermia .
Evaluation of Male Infertility
Male infertility has many causes ranging from hormonal imbalances, to physical problems, to psychological and/or behavioral problems. The evaluation of the male partner begins with history, physical examination and semen analysis.
Semen Analysis: It is a laboratory assessment of the quality and quantity of sperms present in the semen. It is one of the initial tests done to assess if the male has any fertility issues. The semen analysis is done according to certain set guidelines to determine if it is normal. Generally the male collects a semen sample in a sterile container by masturbation after an abstinence of 3-5 days. The sample is than left to liquefy for about 30 min as semen is a viscous liquid. Later a slide is made of the liquefied semen and then the count, motility and morphology of the sperms is assessed under microscope.
At least 2 semen analyses performed at least 6 weeks apart are essential for proper evaluation and arriving at a diagnosis.
Normal Sperm parameters:
- Sperm concentration- often referred to as a sperm count, it is the number of sperm present in each ml of fluid. A normal concentration is 15 million per ml.
- Sperm motility- This is the percentage of sperms which are mobile. At least 40% of the sperms in an ejaculate should be motile and 32 % sperms should be progressively motile.
- Semen volume- This refers to the total amount of fluid collected in the sperm sample. Semen volume between 1.5- 5 ml per ejaculate is considered normal.
- Total motile sperm count- This is the count of total number of moving sperm in the sample. Normally, there are at least 15 million motile sperm in the sample.
- Sperm morphology- This refers to the shape of the sperm. Surprisingly, abnormally shaped sperm are common. As per the latest World Health Organization (WHO) criteria for assessing morphology of sperms, the sample is considered normal if more than 4% sperms are normal.
- Viscosity- Viscosity refers to thickness of the sperm fluid. Low or moderate viscosity is considered normal.
- Leukocytes- Leukocytes are the white blood cells, presence of which in semen is a sign of inflammation or infection. A small number of leukocytes can be present in normal semen also. But, presence of more than one million leukocytes per ml of semen is considered abnormal.
For more information about the semen analysis and its interpretation, please read here-
Advanced techniques of sperm assessment:
- Vitality Testing- vitality testing is of importance when all the sperms are immotile. This test helps in differentiating dead immotile sperms from viable immotile sperms. The viable immotile sperms can be picked and used for fertilizing the eggs with ICSI.
- Sperm DNA fragmentation- Sperm DNA fragmentation refers to the breakage in the DNA of the sperm and indicates the damage to the genetic material of the sperm. The DNA damage can occur at any time from the stage of sperm manufacture when the immature sperms may be exposed to hostile conditions or during the storage time in the epididymis by the reactive oxidative species which react with the DNA of the sperms and produce breakage and fragmentation in the DNA. The presence of Increased DNA fragmentation has been found to correlate with ICSI failures, recurrent miscarriage and poor pregnancy outcomes. Some tests have now been developed which detect the percentage of sperms in the semen sample have DNA fragmentation which is expressed as DNA fragmentation Index (DFI), though there is still some controversy about what level of DNA fragmentation should be regarded as the threshold for threat to DNA integrity.