Azoospermia, which means no sperm in the semen, is seen in 1% of men and 10-15% of men with infertility problems. It is important to distinguish between severe oligospermia with very few sperm in the semen and azoospermia. Because, in severe oligospermia, it is possible to use the small number of sperm that can be obtained by centrifugation of the semen for microinjection. Thus, additional tests or attempts to obtain sperm may be unnecessary. For this purpose, the World Health Organization states that the diagnosis of azoospermia cannot be made without microscopic examination after centrifugation in at least two semen samples.
In most azoospermic men, the problem is that there is not enough mature sperm production in the testicles (nonobstructive azoospermia) even though the sperm carrier ducts are open. This condition, called testicular failure, may be due to defects in the testicles themselves or diseases of the pituitary gland, in which hormones that stimulate the testicles to produce sperm are secreted. In approximately 40% of patients, the cause of azoospermia is not a production defect in the testicles but the process of expulsion of the mature sperm produced from the body through the evacuating channels (obstructive azoospermia).
In men diagnosed with azoospermia, a detailed history should be taken, a physical examination should be performed, and the doctor should find the cause of azoospermia with necessary laboratory tests. The basic tests to be done when evaluating azoospermic men are determining the levels of FSH and testosterone hormones.
The presence of collecting ducts called vas deferens should be checked in the physical examination. In patients with congenital bilateral absence of the vas deferens, the kidneys should be checked with ultrasonography since congenital kidney defects may accompany this condition. In addition, two-thirds of men without vas deferens have a gene defect (CFTR mutation) that can cause cystic fibrosis. Suppose the expectant mother also carries this mutation. In that case, screening for the CFTR mutation should be recommended for the mother-to-be since the child can be born to have cystic fibrosis. In these patients, sperm production in the testicles is normal, and sperm can be obtained with PESA, TESA or TESE.
The second point to be considered during the physical examination is the size of the testicles. If the testicles are smaller than normal (atrophic), the source of the problem can be determined by the hormonal tests performed at the beginning. If atrophic testicles are accompanied by high FSH and normal or low testosterone levels, the problem is considered in the testicles. A genetic examination should be recommended because chromosomal defects, called primary testicular failure, may accompany this condition. If FSH and testosterone levels are low along with atrophic testicles, a condition called hypogonadotropic hypogonadism is present. These patients may also have low levels of LH hormone. Hypogonadotropic hypogonadism is caused by defects in the hypothalamus or pituitary glands. These defects may be congenital (Kallmann’s syndrome) or tumours that develop later in the pituitary gland. Prolactin measurement and pituitary imaging are required to elucidate this situation.
When vas deferens and testicular size are normal, semen volume and serum FSH level guide in determining the cause of azoospermia. In patients with normal semen volume, the problem may be in the discharge ducts (obstructive azoospermia) or sperm production in the testicles (nonobstructive azoospermia). If the FSH level is twice the normal value, the problem is in sperm production (nonobstructive azoospermia). In this case, although some recommend a diagnostic testicular biopsy to determine the level of impaired sperm production in the testicles, the value of diagnostic biopsy is controversial. Even if sperms suitable for microinjection are found in the first-cause diagnostic biopsy, there is no guarantee that sperm will be found when re-biopsy is performed for real practice. Although there are studies on the later use of sperm that can be found during a biopsy, it has not yet been fully proven that pregnancy rates after microinjection with frozen sperm in nonobstructive azoospermia cases are equivalent to pregnancy rates obtained with fresh sperm. Another issue related to diagnostic biopsy is that the absence of sperm in the diagnostic biopsy does not mean that sperm cannot be found in subsequent biopsies. For this reason, patients should not be told that having a child is impossible because sperm cannot be found in a biopsy. For this reason, we recommend our patients perform testicular biopsy after preparing their spouses for microinjection. Suppose sperm are found, microinjection with fresh sperm. In patients with normal testicular volume and semen volume and normal FSH levels, the problem will most likely be a blockage in the excretory system. In this case, sperm can be obtained in testicular biopsy with approximately 100% success. In this case, we recommend performing a testicular biopsy following the spouse’s preparation for microinjection and performing the procedure with fresh sperm if sperm are found. As a result, in these two cases, if sperm is obtained by performing a biopsy for both diagnostic and therapeutic purposes after preparation for microinjection instead of a diagnostic testicular biopsy, it is a reasonable choice for me to complete the procedure with fresh sperm. The main difference in terms of treatment between the two conditions is the possibility of obtaining sperm after a biopsy. While the probability of finding sperm in obstructive azoospermia is close to 100%, this rate is around 65% in nonobstructive azoospermia.
When we turn to the genetic tests that should be done in azoospermic men, in addition to screening for the mutations in the CFTR gene related to cystic fibrosis and vas deferens agenesis in the obstructive azoospermia men mentioned above, the genetic problems that may be found in nonobstructive azoospermic patients are chromosomal abnormalities that can impair testicular functions and Y chromosome microdeletions that can only affect sperm production.
7% of men with infertility problems have chromosomal defects detected by chromosome analysis in white blood cells. The frequency of chromosomal defects is inversely proportional to the sperm count, and this rate is 10-15% in azoospermic men, while it is less than 1% in men with normal sperm count. Two-thirds of the chromosomal abnormalities observed in men with infertility problems belong to the sex chromosome (Klinefelter syndrome). The family should be told that when the male has major chromosomal defects, the couple’s pregnancies are more likely to result in miscarriage, and the risk of having children with chromosomal defects or congenital disabilities is also increased. In this case, genetic examination of embryos that can be obtained after microinjection before transfer to the uterus (preimplantation genetic diagnosis (PGD)) and transferring only normal embryos may be recommended to the family.
Y chromosome microdeletions can be detected in 15% of azoospermic men. Since these defects are too small to be detected by normal karyotype determination, they can be found with a genetic test called polymerase chain reaction (PCR). Microdeletion to be detected by PCR is important for informing the family, as it can determine the chance of finding sperm with testicular biopsy methods of the couple. Especially in the presence of microdeletions affecting AZFa and all AZFb regions on the Y chromosome, the probability of finding sperm is seriously reduced. In summary, patients with nonobstructive azoospermia should be given detailed information about the genetic defects they may have, and helpful genetic studies should be offered.
Obtaining sperm from testicles or epididymis in azoospermic men and using them in microinjection does not provide a permanent solution to their problems. Still, it helps to achieve pregnancy with that application. These men do not have the opportunity to conceive on their own later on. In nonobstructive azoospermia cases, when the problem is due to the hypothalamus or pituitary gland defects mentioned above, it may be possible to correct the underlying disease, gain masculine physical characteristics and even provide sperm production in some patients by applying treatment with GnRH, FSH and testosterone hormones. However, these treatments take a very long time to produce results. In addition, the only problem that causes infertility in the couple must be azoospermia in the male. When a woman has a problem and already needs in vitro fertilization, these alternative treatments cannot be seen as valid options for eliminating infertility. In addition, since the woman’s age will increase in this long period, the probability of pregnancy will gradually decrease even with microinjection. For this reason, these treatment methods should only be considered for eliminating problems other than sperm production in men.
In cases of primary testicular failure where the main problem is sperm production in the testicles, the testicular problem is either congenital or developed due to external factors such as viral infections, radiation, chemotherapy, and trauma. Sperm production disorders can be caused by Sertoli cell-only (SCO) syndrome, maturation arrest (stuck at various stages of sperm production), and tubular sclerosis (damage to the tubes where sperm production takes place). None of these conditions has a permanent cure today, and the only option is to obtain sperm from the testis by surgical methods and use it in microinjection.
Is it possible to surgically remove the obstruction in obstructive azoospermia, where sperm production is normal in the testicles and due to obstructions in the carrier channels? Correction of carrier canals with microsurgery is a procedure that requires advanced training and high experience. Even in the most experienced centres in the world, the rate of pregnancy after microsurgery is 25-40%, and the average duration of pregnancy is reported as 12 months in successful cases. When considering this option, the woman should have no fertility problem, and the infertility problem should be overcome by removing the azoospermia. Another factor against microsurgery is that the woman’s age will progress in this process and decrease the chance of pregnancy with microinjection if the surgery is unsuccessful.
All surgical sperm retrieval methods can be performed under local or general anaesthesia. Unless there is an obstacle, general anaesthesia can be preferred for the patients’ comfort. All of them are outpatient procedures without the need for hospitalization. Processes often take between ten minutes and half an hour. After the procedures, daily life can be continued.
All procedures are done in the IVF centre, and the samples taken are examined in the laboratory simultaneously to see if there are sperms. When sperm is found, the process is terminated.
Surgical sperm retrieval methods are explained below.
PESA: Percutaneous Epididymal Sperm Aspiration.
It is a method of pulling the sperm inside the testicles by entering the epididymis with a thin needle. It is applied with a needle inserted through the skin without opening the scrotum sac where the testicles are located. It can only be applied in cases of obstructive azoospermia. If sperm cannot be obtained with this method, methods of obtaining sperm from the testis are used.
PTSA: Percutaneous Testicular Sperm Aspiration.
It is the sampling of testicular tissue by entering the testicles with a needle inserted through the skin without opening the sac where the testicles are located. If sperm cannot be obtained with this method, TESE is performed.
TESE: Testicular Sperm Extraction.
The sac containing the testicles and the tunica albuginea sheath surrounding each testis is opened with a small incision. Small pieces of testicular tissue are taken. The cut sections are stitched, and the process is terminated.
Micro TESE: Testicular Sperm Extraction under the Microscope.
The sac containing the testicles and the tunica albuginea sheath surrounding each testis is opened with a small incision. The testicular tissue is examined with a microscope, and samples are taken from the large parts. The cut sections are stitched, and the process is terminated. Publications are suggesting that this method causes less damage to testicular tissue.
With surgical sperm retrieval methods, sperm can be found in 100% of obstructive azoospermia cases and 65% of nonobstructive azoospermia cases.
In cases of obstructive azoospermia, the viability rates of the sperms after freezing and thawing and the pregnancy rates obtained with these sperms are quite good.
However, freezing and reusing the sperm obtained in nonobstructive azoospermia cases is controversial. A significant portion of the sperm obtained from these patients have structural defects and may not be able to handle the stress of the freezing and thawing process. However, in case of not finding sperm in later procedures, it may be recommended to freeze and store suitable sperm selectively. Using fresh sperm as much as possible in this group increases success.
For obstructive azoospermia cases, patients who have been applied up to seven times have been reported in the literature and sperm were obtained each time of these procedures.
Patients with nonobstructive azoospermia who have undergone TESE up to six times and obtained sperm are reported, provided sperm were found in previous TESEs.
Pregnancy rates obtained with repeated TESE applications are not different from the pregnancy rates obtained in the first application.
It has been reported that 25% of patients with nonobstructive azoospermia who could not find mature sperm in the first TESE had sperm in the second application.
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