There have been rapid improvements in the therapy of male infertility through the techniques that have emerged within the last decade. Microinjection technique, in particular, had given a chance of treatment to many infertile men...
Infertility can affect both women and men. About 15 to 20% of married couples apply to an IVF department because of infertility, and a male infertility factor is present in approximately half of these cases. Infertile couples receiving treatment in our department are evaluated by a team which includes a gynecologist, a urology / andrology specialist, an embryologist and genetic experts. All are experts in their fields and work in close collaboration with each other. Thorough investigations are made and necessary examinations and treatments are planned and carried out by doctors in the fields of their expertise.
The follicle stimulating hormone (FSH) and the luteinizing hormone (LH) are secreted from the pituitary glands. LH regulates the production of testosterone in the testes. FSH stimulates the development of spermatozoa.
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Hormones of male reproductive system |
Sperm cells produced in the testes travel through a series of ducts: the epididymis, the ductus deference (vas deference), the seminal vesicle and the ejaculatory duct.
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Sperm transmission channels |
Ejaculate is a whitish, mother of pearl-colored liquid containing sperm cells, called semen. The average volume of this fluid is 1.5 to 4 ml. Most of it is secreted from the testes, the prostate gland and the seminal vesicle.
This fluid includes substances which are important for sperm development and for keeping sperm alive until they reach the woman's egg (ovum). During sexual stimulation a little sticky liquid appears at the tip of the male sexual organ. This fluid is secreted from the gland around the urethra, and does not contain sperm. However, the first part of the ejaculate contains the greatest number of sperm cells.
“Azoospermia” is the absence of sperm in the ejaculate. It occurs for two reasons:
“Aspermia” is the absence of ejaculate. It may be due to obstructive azoospermia. It can also be caused by some systemic diseases, such as diabetes and diseases of the nervous system and by using certain medications.
The term “Hypospermia” means that the volume of ejaculate is smaller than normal. It may be due to obstruction or to abstaining from sexual activity for only short periods.
“Hemospermia” is the term for the presence of blood in the ejaculate. It is not usually considered to be a cause for concern in young men, and may be due to long term sexual abstinence or to infection.
There is a range of causes of infertility in men, including:
Causes are not found in around 20 to 30% of cases. This phenomenon is termed idiopathic infertility.
Varicocele is the varicous dilatation of testicular veins. It is the most common cause of male infertility, and is observed in around 20 to30% of infertile males. However, it can occur in 5 to10 % of the normal population.
The causes of varicocele are not known. However, it is more common in tall men, in obese men, in men who have chronic constipation, lung disease or a chronic cough, in men who work in a standing position for a long time and in men who do strenuous sports, such as weightlifting.
For anatomic reasons, varicocele is more common on the left side (90%). In 8 to 9 % of cases, it is bilateral; and in only 1 to 2% it is found on the right.
Scrotal pain and swelling on testis are the most common symptoms of varicocele. Over the long term, the testes may decrease in size.
Increased intratesticular temperature, decreased testicular blood flow and increased levels of toxic substances due to varicocele result in decreased sperm production.
It is diagnosed by physical examination. Scrotal Doppler ultrasonography is helpful for diagnosis.
It is treated surgically. However, an operation is not recommended in all cases It is advised if the patient has any of the following:
Testes develop in the abdomen of the unborn baby, just below the kidneys, and descend into the scrotum just before birth. In some babies they remain in a high position or outside the scrotum. This condition is called undescended testis/testes or cryptorchidism.
It is one of the most common congenital abnormalities, and is present in 2% to 5% of full-term newborn baby boys. However, it is more common in premature baby boys (around 30%).
Sperm production is negatively affected by the higher testicular temperature which results if the testes are undescended. While sperm production may be between 70% and 80% in cases of unilateral undescended testis, it is as low as 20%-30% in bilateral cases.
The testes may descend into the scrotum without medical intervention during the first year of life. If this does not happen naturally, it should be done surgically before the age of two. Sperm production is irreversibly affected after the age of 6.
Prostate infection (prostatitis) or sexually transmitted infections affect sperm function by increasing the number of white blood cells (leukocytes) in the ejaculate, and may result in male infertility.
Untreated gonorrhoea can lead to obstruction of sperm transmission channels. Tuberculosis affects the epididymis in the male reproductive system. Untreated tuberculosis can lead to obstruction.
Testicular infections, known as orchids, can lead to infertility by affecting the structure of the reproductive system and impairing sperm production. Mumps orchids developed after mumps infection are the most common cause of orchids. Before adolescence, mumps disease usually has no effect on sperm. However, after puberty, mumps orchids may develop in 40% of cases of unilateral or bilateral testicular infection.
The genetic structure of a normal male is 46, XY. This is made up of 22 pairs of autosomal chromosomes and one X and one Y sex chromosome.
There are several molecular mechanisms that affect sperm production, maturation and function. As yet, most of them have not been clearly identified.
Genetic disoders can cause male infertility by affecting sperm production in different ways:
1. Male sex chromosome disorders
a. number anomalies
b. structural abnormalities
2. Autosomal chromosome abnormalities in men
3. Abnormality in the genetic materials of the sperm
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Normal male chromosome structure |
Klinefelter syndrome is the most common disorder of the sex chromosome number. It occurs in between 1 in 500 and 1 in1,000 of baby boys. These babies have one extra X chromosome, so their genetic structure is 47,XXY. Men with this syndrome are tall, with longer arms and legs than normal. They have poorly developed gender-specific characteristics, and small testicles (less than 5ml in volume). They have high levels of FSH and LH levels and their testosterone level is lower than normal. Generally, these patients have azoospermia.
In Klinefelter cases, sperm can be obtained by microscopic testicular sperm extraction (Micro TeSe). Using this method, our success rate is 53%.
Three different regions on the male Y chromosome control sperm production: AZF-a, AZF-b and AZF-c. Deficiencies in any of these areas affect sperm production in varying degrees. Deficiencies in the AZF-c region are the most common abnormality and are associated with decreased sperm count. Deficiencies in the AZF-a and AZF-b regions are associated with severe problems in sperm production and maturation.
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Y Chromosome structure |
Some defects in the 22 pairs of chromosomes can cause male infertility.
Defects in the genetic structure of sperm lead to functionally and morphologically impaired sperm. Infections, varicocele, smoking, environmental toxic agents and fever can all be causes.
PLEASE CLICK HERE FOR DETAILED INFORMATION ABOUT GENETIC PROBLEMS AND DIAGNOSTIC METHODS IN MALE INFERTILITY.
Endocrine, or hormonal, disorders are present in around 3% to-5% of cases of male infertility. These problems are:
Hypogonadism is a clinical condition resulting from decreased testosterone production. It leads to male infertility and sexual dysfunction. There are two types of hypogonadism: “primary” and” secondary”.
In primary hypogonadism, also known as “primary testicular failure”, the serum testosterone level is low and FSH and/or LH levels are high.
In secondary hypogonadism, both testosterone and FHS/LH levels are low. This condition is one of the most common treatable endocrine abnormalities found in male infertility.
Testicular operations or any kind of operation in the inguinal region, such as hernia repair, or surgery for varicocele, can cause damage or injury to testicular vessels or sperm transmission channels, and can lead to infertility.
Surgical operations for lymph nodes in the back of the abdomen for cancer (retroperitoneal lymph node surgery), aorta surgery, colon surgery and spinal cord surgery can damage the neural mechanisms, affecting sperm transport, and leading to sperm escaping back into the bladder. Some prostate or bladder surgery can lead to a similar situation.
Smoking is the one of the main causes of damage to the genetic material of sperm.DNA damage. Moreover, smoking can result in the failure of assisted reproductive methods.
Alcohol consumption affects hormonal mechanisms, and can lead to a decrease in the production of testosterone over a long-term period.
Heavy metals such as lead and mercury, pesticides, organic solvents, high ambient temperatures and electromagnetism have detrimental effects on sperm. Mobile phones, computer monitors and laptop computers affect sperm production through electromagnetic waves and the thermal effects. However, it is difficult to be precise about the length and intensity of exposure to environmental factors needed to bring about these adverse effects on human sperm.
Acidic fluids and lubricants are toxic to sperm.
Working in hot environments, such as furnaces or metallurgical plants, hot showers and frequent saunas can affect sperm quality.
Infectious diseases, scrotal trauma and surgery on the testes can result in disturbance of the testicular structure. This can lead to the human immune system being activated against sperm cells and a decrease in sperm motility. Reproductive techniques are recommended methods for immunologic infertility.
The drugs used in cancer treatment are toxic to all cells that are rapidly growing in number. In particular, the drugs used for Hodgkin's lymphoma and leukemia are extremely toxic. As a result, within eight to twelve weeks of starting chemotherapy, the production of sperm is interrupted. Depending on the dose and the duration, it may restart in only 15% to 30% of patients in one to five years after discontinuation of the treatment.
Radiotherapy has a similar effect. With applications above 600 Rad, azoospermia develops in 10 weeks.
Sperm freezing is advisable for all men in their reproductive years before cancer treatment, radiotherapy and/or chemotherapy.
Click here to get more detailed information about freezing sperm.
As well as cancer drugs, many other drugs can affect sperm production.
Diabetes, multiple sclerosis and spinal cord diseases can cause sperm transport problems, and lead to retrograde ejaculation, the ejaculation of semen backward towards the bladder instead of forward through the urethra.
Sperm production can be affected by hormonal imbalance in patients with liver and kidney failure. Immunosuppressive drugs taken after kidney or liver transplants may decrease sperm production.
Thyroid diseases can affect sperm production.
If the volume of the ejaculate is less than 1.5 ml, the most likely cause of azoospermia is obstruction of the sperm transmission channels. In these cases, sperm production in the testes and testicular size are normal. However, the sperm cannot flow out because of anatomical or functional problems of the sperm transmission channels. Some causes of obstructive azoospermia can be treated surgically.
In some infertile men, the vas deferens is absent. This condition is associated with a genetic disorder called cystic fibrosis. Additional genetic tests should be performed in this condition.
Masses such as epididymal cysts, spermatocele or a cystic mass on the urethra can block the passage of sperm.
Infections such as untreated gonorrhea and tuberculosis, surgery in the inguinal area, such ashernia repair or varicocele surgery, and some diagnostic techniques for male infertility such as vasography, can cause the obstruction of sperm channels. In some cases, reconstructive surgery is possible.
During ejaculation, bladder muscles contract, pushing ejaculate through the urethra into the penis. If there are any defects in the structure of these muscles, they fail to contract, and ejaculate flows back into the bladder.
Retrograde ejaculation results from:
a. Diseases of the nervous system, such as diabetes, and spinal cord diseases.
b. Previous surgery, such as prostate or bladder neck surgery, some abdominal operations and oncologic operations.
c. Some medications, such as those prescribed for prostate disease or psychiatric disorders.
In this section you will find information on the steps involved in diagnosing male infertility:
• Initial Assessment
• Medical History
• Clinical Examination
- Physical Appearance
- Testicular Examination
- Penile Examination
• Laboratory Tests (Routine)
- Semen Analysis and Providing a Semen Sample
• Macroscopic analysis
• Microscopic analysis
• Further Tests
- Motile sperm organelle morphologic examination (MSOME)
- DNA fragmentation test
- Sperm FISH test
- Electron microscopic examination of sperm
- Hormone Tests
- Ultrasonography
- Testicular biopsy
• INITIAL ASSESSMENT
Both partners should be evaluated together in the initial assessment.
The first step towards the successful diagnosis and treatment of male infertility is a detailed evaluation of the husband’s medical history. This can include:
•Previous treatments for infertility:
Types, number and dates of any previous treatments such as surgery (varicocele, orchidopexy, TeSe/Micro TeSe, etc…).
Examination begins with the assessment of the general appearance: height, weight, distribution of body hair, genital organs, whether there is evidence of the growth of breast tissue.
• Testicular examination
This is done in a standing position at a room temperature of 22°C. First, the position and size of the testicles are checked.
The doctor also checks to see whether other structures in the scrotum such as epidydimis and vas deferens are present and normal, and whether there is evidence of varicocele.
• Penile examination
The size and shape of the penis may be significant. If the penis is unusually small, the doctor will recommend a detailed hormonal evaluation. Penile curvature and hypospadias may affect the transport of ejaculate into female genital system.
• Semen analysis
Semen analysis is an inexpensive test which provides valuable information about the quality and quantity of spermatozo, and is one the most important laboratory tests for evaluating male infertility. At the Memorial Andrology Laboratoty, semen analysis is perfomed according to WHO 2010 guidelines.
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Semen analysis giving room |
Important points to remember when providing a semen sample are:
Semen is analysed both “macroscopically “ and “microscopically”.
1. Volume: The volume of the ejaculate should be more than 1.5 ml. The absence of ejaculate is termed aspermia.
2. Acidity: The acidity level (pH) should be between 7.2 and 7.8.
3. Colour: The normal colour of semen is whitish gray or pearl-white
4. Liquefaction: Fresh ejaculate has a coating consistency. It coagulates liquefies in 20 minutes.
5. Viscosity: The fluidity of ejaculate is checked.
Microscopic analysis gives information about the number (sperm count), motility, morphology and viability of sperm..
A normal sperm count is more than 15 million per ml and more than 39 million in the whole ejaculate. A sperm count of less than this, is termed “oligozoospermia”.
This evaluates the ability of sperm to propel themselves forward. Normal sperm show “progressive” rapid motility. Motility is divided into four grades:
Grade a: Sperm with progressive motility. These are the strongest and swim fast in a straight line. Sometimes it is also denoted motility IV.
Grade b: (non-linear motility): These also move forward but tend to travel in a curved or crooked motion. Sometimes also denoted motility III.
Grade c: These have non-progressive motility because they do not move forward despite the fact that they move their tails. Sometimes also denoted motility II.
Grade d: These are immotile and fail to move at all. Sometimes also denoted motility I.
Motility is calculated per 100 sperm. The percentage of normal sperm (grades a and b) should be over 32%. Less than this is termed “asthenozoospermia” (reduced sperm motility).
Evaluation of sperm motility |
Sperm morphology
This is carried out using special dyes under a microscope of x400 magnification. The form and structure of the sperm and are evaluated using the Kruger criteria. The percentage of morphologically normal sperm should be more than 4%. Less than this is termed “teratozoospermia”.
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Nomal sperm morphology |
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Round head |
Free head |
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Multiple head and tail |
Broken neck |
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Multiple tail |
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Pinhead |
Tail-Stump |
Sperm vitality
If the percentage of grade “a” and “b” progressively motile sperm is less than 30%, further tests are done to evaluate sperm vitality. Eosin Y test and HOS test can be used for the evaluation of sperm viability.
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Sperm cells after eosin-Y staining |
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Cells that swell under hypoosmotic conditions (those with a coiled tail) are alive whereas those with straight tails are dead |
Other cells found in the ejaculate
White blood cells, early stage sperm cells and epithelial debrides can be found in the ejaculate. All of these are identified using special dyes.
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Leucocyte in the ejeculate |
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Inmature germ cells in the ejeculete |
Further sperm tests
In some cases, we need to do a more detailed evaluation of the sperm using further tests:
None of these tests are performed routinely, but only for patients with any of the following:
MSOME test: Motile sperm can be examined under x6600-8050 magnification. This provides more detailed information about sperm morphology than routine semen analysis. It enables the detection of vacuoles in the sperm heads, which can be associated with sperm DNA damage. These sperms can result in unsuccessful attempts at assisted reproduction. Using MSOME evaluation, normal sperms without vacuoles can be selected for ART.
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Grading of sperm cells under high magnification (8050x) |
DNA fragmentation Test: The causes of sperm DNA damage are not clear. Smoking, infections, high fever, varicocele, genetic factors, air pollution, long term sexual abstinence have all been named as possible causes.
There is a close relationship between damage to sperm genetic material (DNA) and male infertility. Increased sperm DNA damage results in repeated miscarriages as well as a reduction in fertilization.
For patients with elevated levels of sperm DNA damage, using testicular sperm instead of ejaculated sperm is recommended for ART/IVF techniques.
The acridine orange test and the Tunnel test are used for the evaluation of sperm DNA damage.
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The Acridine orange test | The Tunnel test |
Sperm FISH test: This test is used for the evaluation of sperm genetic material.
Electron microscopic examination: This test is used only for diagnostic purpose in cases having severe morphological abnormalities.
In the basic evaluation, serum FSH and total testosterone levels are recommended. Blood tests should be done between 8 and 10 am in the morning. This is because serum testosterone level is higher in the morning, and lower in the afternoon.
If there is a sexual problem or any findings of endocrinologic disorders, detailed hormonal evaluation should be performed. Patients having any kind of hormonal treatment may also be advised to have these tests.
erum prolactin, estrogen and thyroid hormone levels can be measured if necessary.
Ultrasonography is recommended only in certain cases:
Diagnostic biopsies are not normally advised for infertile patients. However, a biopsy can be performed following Micro TeSe, as it allows, testicular histology to be evaluated. Furthermore, testicular tumors are more common in infertile men and biopsy can allow early stage tumors to be detected..
If sperm counts are less than 1 million/ml, chromosome analysis is recommended. Chromosome analysis provides information about the number and genetic structure of chromosomes.
If azoospermia has been diagnosed, a Y chromosome analysis should be performed. The Y chromosome is related to the male gender, and also includes some genes related to sperm production.
In cases of obstructive azoospermia, especially when there is a congenital absence of channels, the possibility of a cystic fibrosis gene mutation should be investigated. Even if neither partner has symptoms of the disease, but both are carriers, their child is at risk of being born with severe cystic fibrosis. In such cases, preimplantation genetic diagnosis is recommended.
Please click here for detailed information about genetic tests and preimplantation genetic diagnosis.
Klinefelter syndrome is a condition in which there is an extra X chromosome: the genetic structure is 47 XXY. It is the most common genetic abnormality in infertile men and is observed in 10-15% of cases of azoopsermia. . Micro TeSe is recommended for these patients and a sperm retrieval rate of around 55% is achieved in our department.
There are three regions on chromosome Y which affect sperm production. These are AZF-a, AZF-b and AZF-c. There may be complate or partial deletions of these regions. All azoospermic men should have a Y chromosome investigation because micro TeSe is not advisable for patients who have complete AZF-a and/or AZF-b deletion, whereas, if there are partial deletions of these regions or partial or complete deletions of the AZF-c region, Micro TeSe can be performed. However, the male offspring of these men may be infertile in adulthood.
General advice for all infertile men
All patients are advised to:
For some conditions, you may be prescribed medication:
In some cases, varicocele is treated surgically. However, surgery is not necessary for all patients. It is recommended for patients who have any of the following:
Sperm can be retrieved from the testes of azoospermic men either by
Micro TeSe is done under general anesthesia using an operation microscope to find mature sperm. It can take two hours or more.
The main advantages are;
Disadvantages of Micro TeSe are;
Wound infection, hematoma and pain are the most common complications of Micro TeSe. However, these are observed very rarely (less than 1%). During the first three months after the operation, there can be a decrease in testosterone production, but it returns to a normal level at the end of the first year. However, patients who already have low testosterone levels are advised to have hormonal treatment to increase it before having surgery.
Micro TeSe is a standard treatment for azoospermia and can be performed for patients who have previously had TESE . However, we do not recommend repeated attempts to find sperm using Micro TeSe.
TESA is performed under local anesthesia. Sperm are aspirated with a thin needle..
TESA is very a simple method, with no serious complications. Pain and hematoma may occur only rarely.