Last updated date: 13-May-2023
Originally Written in English
The role of the male factor in marital infertility has increased enormously in recent years. Despite this advancement in identification, azoospermia remains the most difficult problem in infertility therapy. A variety of diseases that disrupt spermatogenesis and diminish sperm production and quality can result in azoospermia. Azoospermia can also be caused by a blockage in the reproductive system. A thorough understanding of the disease's genesis is required for optimal care of people with azoospermia.
What is Azoospermia?
Azoospermia, defined as the lack of sperm in the ejaculate, affects around 1% of all men and 10% to 15% of infertile men. To guide suitable therapeutic options and identify the related cost advantages, risks, and prognosis for treatment success, an accurate diagnosis of azoospermia and thorough examination of the patient are required. Clinicians should also offer enough counseling to the couple as well as ample assistance to patients suffering from severe male factor infertility.
The advancement of intracytoplasmic sperm injection (ICSI) as an effective treatment for severe male factor infertility has made it a viable option for the majority of male reproductive system abnormalities. Even males who have potentially curable reasons of infertility are often treated with assisted reproductive methods (ARTs) rather than particular treatment. However, once azoospermia is diagnosed, no sperm can be discovered in the ejaculate; as a result, assisted reproduction cannot be used due to the lack of sperm. As a result, knowing azoospermia is critical for urologists.
Grasp azoospermia requires at least a rudimentary understanding of how sperm is created and enters the ejaculate. The testicles, which are kept slightly outside of the body in the scrotum, are where sperm cells begin their trip. Because sperm is heat sensitive, the testicles are somewhat outside of the body. Sperm cells cannot live in a man's body temperature.
Sperm cells do not float in a pool of fluids in the testicles. Instead, they form within a network of microscopic tubes known as the seminiferous tubules.
Sperm cells do not begin in their tadpole-like shape, with a head and a tail. They start off as little spherical cells. They mature and grow into sperm cells only when exposed to reproductive hormones such as testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The pituitary gland and the testicles regulate and manufacture these hormones.
After reaching a specific degree of maturity in the seminiferous tubules, sperm cells travel into the epididymis, a lengthy, coiled tubal region. They will continue to grow here for several weeks.
Sperm cells travel into the vas deferens after passing via the epididymis. The seminal vesicle, commonly known as the seminal gland, transports sperm after the vas deferens. The bulk of the fluid that makes up sperm is generated here. This fluid feeds the sperm cells. The prostate gland is the next stage, when prostate fluids are added to the total semen mix.
The prostate gland is the last destination for sperm before they enter the urethra during ejaculation. The urethra runs from the bladder through the prostate gland and finally to the penis. The bulbourethral gland, also known as Cowper's Gland, is located just below the prostate gland. While sperm does not directly pass via these glands, they do discharge a fluid that neutralizes any acidity in the urethra left over from earlier urine before to ejaculation.
Although there are several causes of azoospermia, the etiologies of this condition may be divided into three categories: pretesticular, testicular, and post-testicular. Pretesticular causes of azoospermia include endocrine disorders that impair spermatogenesis. Testicular etiologies are caused by intrinsic spermatogenesis abnormalities inside the testes. Post-testicular causes of azoospermia include ductal system blockage in any site of the male reproductive tract.
Every cause of azoospermia has a distinct prognosis, ranging from normal sperm production to just detecting sperm in the reproductive canal. The pre- and post-testicular abnormalities that produce azoospermia are usually treated, which may make restoring reproductive potential easier. Testicular problems, on the other hand, are often irreversible, and the success rates for therapies related to intrinsic testicular abnormalities are substantially lower.
- Pretesticular causes
Pretesticular causes, often known as secondary testicular failure, are typically caused by pathological endocrine disorders. Although an infrequent cause of male infertility, endocrinopathy affects up to 3% of infertile men.
Kallmann's syndrome, pituitary trauma, pituitary tumors, and anabolic steroid usage are all common causes of hypogonadotropic hypogonadism (HGH). HGH is an uncommon cause of male infertility, and the condition can be hereditary or acquired.
Kallmann's syndrome is a congenital cause of HGH that is connected with a midline cerebral structural abnormality. The etiology of this illness is a malfunction in hypothalamic release of gonadotropin-releasing hormone (GnRH) caused by the inability of GnRH-releasing neurons to migrate to the olfactory lobe during development. The most common form of congenital HGH is Kallman syndrome, which occurs in 1:10,000 to 1:60,000 infants.
Pituitary tumors, pituitary trauma, panhypopituitarism, and anabolic steroid usage are all acquired causes of HGH. Exogenous testosterone suppresses the hypothalamic-pituitary gonadal (HPG) axis and causes azoospermia by suppressing gonadotropins via the HPG axis feedback loop, resulting in hypogonadism and infertility. Excess exogenous androgens from anabolic steroid usage interfere with spermatogenesis by reducing FSH levels and decreasing intratesticular testosterone levels.
A pituitary MRI may be performed on individuals with suspected HGH to rule out a pituitary tumor. Pituitary tumors can induce anterior pituitary damage. Before beginning gonadotropin replacement treatment, the blood prolactin level should be tested, and hyperprolactinemia should be ruled out or treated. Treatment with exogenous gonadotropins or GnRH can generally restore normal spermatogenesis in patients with acquired HGH.
Hyperprolactinemia is a kind of HGH that results from excessive prolactin production. Prolactin excess suppresses GnRH hypothalamic production and has been linked to reproductive and sexual disorders. Routine hyperprolactinemia screening in infertile males has not been proved to be beneficial. Prolactin is generated in the anterior pituitary gland and has minor physiological effects in males.
Hyperprolactinemia suppresses both FSH and LH and may be caused by
- Concurrent medical illnesses,
- Tricyclic antidepressants,
- Some antihypertensives,
- Stress, or
- Pituitary tumors (macroadenoma or microadenoma)
Phenothiazines, imipramine, methyldopa, and reserpine are the most prevalent drugs that cause hyperprolactinemia. Prolactin-secreting microadenomas (10 mm) and prolactin-secreting macroadenomas (>10 mm) are the most prevalent causes of hyperprolactinemia. Infertility, low libido, galactorrhea, headache, lethargy, and erectile dysfunction are all symptoms of prolactinomas. Gonadotropin and testosterone levels are usually repressed in individuals with prolactin-secreting pituitary adenomas, although prolactin levels are raised.
Androgen resistance affects around 1 in every 60,000 births. The androgen receptor gene has been shown to contain over 300 mutations. Mutations in the gene promoter region have been identified in addition to well-known mutations in its 8 exons. Because of the many mutations, the disease is clinically heterogeneous, ranging from phenotypic females (total androgen insensitivity) to properly virilized yet sterile men (partial and minimal androgen insensitivity). Serum testosterone levels might be low, normal, or high depending on the severity of the abnormality. It has been suggested that as many as 40% of males with low or no sperm counts may be suffering from modest androgen receptor deficiencies.
Testicular etiologies, often known as primary testicular failure, are intrinsic spermatogenesis abnormalities. Varicocele-induced testicular injury, undescended testes, testicular torsion, mumps orchitis, gonadotoxic effects of medicines, genetic disorders, and idiopathic reasons can all cause direct testicular disease. Primary testicular failure with azoospermia, also known as nonobstructive azoospermia, is best handled by collecting testicular sperm for future ICSI. However, the precise cause should be recognized whenever feasible, and therapy may enhance sperm retrieval success rates.
There is currently compelling evidence in the literature that varicoceles cause a gradual deterioration in testicular function, and varicocelectomy has been demonstrated to prevent and reverse the damage. Furthermore, varicocele repairs have been shown to increase pregnancy rates and ART results. Identifying patients with varicocele who will benefit from varicocele therapy, on the other hand, remains a difficulty for andrologists.
Undescended testes are the most frequent genital deformity in boys, occurring in up to 0.8% of 1-year-olds and 2.7% of neonates. It is critical to distinguish cryptorchid testes from retractile testes, a condition characterized by overactive cremasteric muscles that cause the testes to dwell in the inguinal canal or upper scrotum on a regular basis. Testicular dysgenesis, an altered endocrine axis, immunologic damage, and blockage have all been proposed as reasons for cryptorchidism-induced infertility.
Early treatment may reduce the chance of infertility, and effectiveness is dependent on the initial location of the testicle. This disease should be treated hormonally and/or surgically before the child's first birthday; also, parents should be fully educated about the danger, especially because therapy before the age of 13 years does not appear to minimize the chance of malignancy.
Testicular torsion affects around 1 in every 4,000 guys before the age of 25. The hazards of nonoperative therapy are well recognized, and this disease need rapid surgical examination. If surgical exploration is conducted within 6 hours of the beginning of symptoms, testicular preservation is frequently obtained. Other parameters, such as the degree of rotation, have been linked to testicular salvage in addition to length.
The most serious consequence of testicular torsion is testicular loss, which can impede fertility. Although severe oligospermia or azoospermia are uncommon following unilateral testicular torsion, they are feasible if the contralateral testis has previously had any abnormalities, such as orchiopexy for an undescended testis.
Chromosomal abnormalities are more common in the infertile population than in the fertile population. These chromosomal abnormalities, which affect 15% of azoospermic and 5% of oligospermic men, are one of the most frequent genetic disorders in infertile males. As a result, it is critical that these men undergo genetic testing prior to using their sperm for ART.
2. Post-testicular causes of azoospermia
Post-testicular azoospermia is caused by either sperm delivery restriction or ejaculatory malfunction. The clinical care of obstructive azoospermia is determined by the etiology, as well as any associated infertility issues in the female spouse. As a result, before making any therapy recommendations, both partners should be thoroughly assessed.
Men with obstructive azoospermia can father children in two ways: surgical repair of the blockage, which may allow the couple to conceive naturally, or retrieval of sperm straight from the epididymis or testis, followed by ART. The surgical therapy of obstructive azoospermia differs depending on the location of blockage and the presence of pathological diseases such as vasal obstruction and ejaculatory duct obstruction. These conditions are described separately below.
Absence of the vasa deferentia
Congenital bilateral vas deferens absence (CBAVD) affects 1% of infertile males and up to 6% of those with obstructive azoospermia. There are two proposed causes of this condition:
- Mutations in the cystic fibrosis transmembrane regulator gene (CFTR) and
- Anomalies in mesonephric duct differentiation.
Medication Side Effects
The most prevalent cause of azoospermia as a side effect of medicine is testosterone supplementation. Athlete usage of anabolic steroids, as well as chemotherapy medicines, can induce azoospermia. Some medicines that produce azoospermia have a temporary effect, while others might cause long-term azoospermia. Other drugs that can cause non-obstructive azoospermia include:
- Colchicine (used to treat gout)
- Chlorambucil (cancer medication)
- Cyclophosphamide (cancer medication)
- Procarbazine hydrochloride (treatment for Hodgkin’s disease)
- Vinblastine sulfate (cancer medication)
- Everolimus (cancer drug and also used to prevent organ rejection after transplants)
- Sirolimus (used to prevent organ rejection after transplant)
Azoospermia does not have any distinct symptoms. Couples attempting to conceive will face infertility if the male partner has a sperm count of zero. If a couple does not become pregnant after one year of unprotected intercourse, they are considered to be coping with infertility. Infertility is often the sole indication that anything is amiss.
Some causes of azoospermia can cause visible signs and symptoms. The following signs or symptoms may suggest that you are at risk for azoospermia:
- Low ejaculate volume or “dry” orgasm (no or little semen)
- Cloudy urine after sex
- Painful urination
- Pelvic pain
- Swollen testicles
- Small or undescended testicles
- Smaller than normal penis
- Delayed or abnormal puberty
- Difficulty with erections or ejaculation
- Low sex drive
- Reduced male hair growth
- Enlarged breasts
- Muscle loss
Diagnosis of Azoospermia
Azoospermia is described as the lack of all sperm in the ejaculate. A semen samples must be centrifuged for 15 minutes at room temperature with a high-powered microscopic inspection of the pellet and a centrifugation speed of at least 3,000 g to confirm this diagnosis. At least two semen samples acquired more than two weeks apart should be evaluated during the semen analysis.
The presence of even trace amounts of sperm in the centrifuged samples rules out full ductal occlusion and opens the door to prompt sperm cryopreservation for ICSI cycles. When a rigorous routine study of a centrifuged sperm specimen was done, sperm was found in 35% of the men who were deemed to have nonobstructive azoospermia.
These findings are noteworthy since patients frequently arrive with one or more sperm analyses that were previously completed without the use of standardized centrifugation methods. To consistently confirm the diagnosis of azoospermia, urologists must constantly evaluate the necessity to repeat the seminal analysis.
Evaluation of Azoospermic Patients
A detailed medical and surgical history, a history of childhood disorders (such as viral orchitis or cryptorchidism) and genital injuries, medicines and allergies, and an examination of prior infections, such as sexually transmitted diseases, should all be part of a thorough review. It is critical to evaluate gonadotoxin exposures as well as past radiation treatment or chemotherapy. Furthermore, around 1% of male infertility cases are the result of a serious or potentially deadly illness. As a result, it is critical to understand that infertility may be the first sign of a serious medical issue.
A thorough physical examination is an important element of evaluating an azoospermic male, and the patient should be evaluated in a warm environment while supine and standing. A chilly environment causes the dartos to constrict, making the inspection difficult.
Clinical varicocele should be studied and appropriately classified, as some recent research have revealed that varicocele grade is connected to treatment prognosis. These data imply that high-grade varicocele may be more commonly associated with azoospermia, although varicocele grade I does not explain the complete illness etiology.
Appropriate sexual development should be evaluated. In the case of decreased body hair distribution, gynecomastia, or eunuchoid proportions, androgen insufficiency should be investigated. During a physical examination, males who are incompletely masculinized can be detected by unusually long extremities caused by a lack of proper epiphyseal closure during puberty; this trait is seen in men with Kallmann's or Klinefelter's syndrome.
The thyroid should be palpated, as well as the heart and lungs. Gynecomastia, which can be caused by estrogen-secreting testicular tumors or adrenal tumors, should be monitored and palpated in the breasts. The abdomen must be palpated with caution. In addition to the standard physical examination, the genitalia must be given special attention.
It is necessary to palpate the testes and assess their size. Adult testicular measures of at least 4.6 cm in length and 2.6 cm in breadth have been determined, resulting in a volume ranging from 18 to 20 cm3. Because sperm production accounts for 85% of testicular volume, a reduction in testicular size suggests diminished spermatogenic capacity.
Patients with nonobstructive azoospermia have testes that are less than 15 cm3 in volume and an epididymis that is flat. Through a thorough investigation of clinical diagnostic characteristics, obstructive azoospermia may be clearly separated from nonobstructive azoospermia in the great majority of patients.
In a wide population of infertile males, an endocrinologic examination of individuals with severe male factor infertility leads to precise diagnosis and treatment modalities. Although some authors advocate routine screening of the male hypothalamic-pituitary-gonadal axis in all patients, endocrine screening of men with sperm counts less than 10 million/mL using serum testosterone and FSH levels alone will detect the vast majority of clinically significant endocrinopathies.
In addition to cases of seminal parameter abnormalities, individuals who come with poor sexual function or other clinical symptoms suggestive of endocrinopathy, such as a significant reduction in testicular size or gynecomastia, should be investigated.
If the testosterone level is low, a more thorough examination will be required to assess total and free testosterone, luteinizing hormone (LH), prolactin, and estradiol levels.
Azoospermic individuals with normal ejaculate volume may have reproductive system blockage or spermatogenesis disorders. Azoospermic males with normal-sized testes and poor semen volume may have ejaculatory dysfunction or duct occlusion. All patients who report with missing ejaculation or low-volume ejaculation (1.5 ml) should have the semen analysis repeated and a postejaculation urine test collected.
It is critical to remember that the seminal vesicle contributes the vast bulk of seminal fluid. The ejaculated volume is an important tool in the evaluation of an azoospermic patient, and using a diagnostic method may help to avoid errors.
Diagnostic testis biopsy
The only sure approach to detect azoospermia is by testicular histology. However, because the pattern of the testis tissue is variable and spermatogenesis occurs most commonly in focused locations, a biopsy is rarely employed as a diagnostic tool. Nonobstructive azoospermia is usually indicated by testicular features and laboratory results. Thus, at a specialist assisted reproduction clinic, testicular sperm extraction (TESE) can be performed concurrently with ART, allowing for sperm cryopreservation during the surgery and avoiding a testicular biopsy.
How Azoospermia is treated?
Fertility treatment will be determined by the type of azoospermia and the underlying cause of the problem. Treatment options will also be influenced by the female partner's reproductive state.
Treatment of Any Lingering Infections
If there is an active infection, it should be treated before any additional therapies are explored. While some men will have infection-related symptoms (such as painful urinating), up to one in four men will not. Even if there are no visible signs, the infection can impair fertility and cause lasting damage to the reproductive system.
Microsurgical therapy can be used to correct blockages and damaged (or missing) connections in some cases of obstructive azoospermia. A varicocele can be removed or treated surgically, and retrograde ejaculation can also be treated.
When surgery may treat obstructive azoospermia, natural pregnancy may be achievable. Surgical procedures, on the other hand, do not solve the problem overnight. Three to six months after surgery, a sperm study will be ordered.
If sperm counts are normal and the female spouse has no reproductive issues, the pair may be able to try to conceive naturally. Other methods might be tried if sperm counts remain abnormal following surgery.
Medication or Hormonal Support
Azolospermia can be treated with medicine in some circumstances. Retrograde ejaculation, for example, can occasionally be cured with drugs, allowing for natural conception. Clomid, Letrozole, FSH injections, or hCG injections are examples of hormones or hormonal medicines used to treat male fertility.
In certain azoospermic males, hormone therapy can be utilized to increase sperm formation. In rare situations, hormonal assistance can help sperm cells return to the sperm. In other situations, it will allow adequate sperm growth to allow for the extraction of healthy sperm cells from the testicle via a testicular biopsy.
Sperm Extraction from Post-Ejaculate Urine
If treating the retrograde ejaculation itself is not possible, your doctor may be able to extract sperm from post-ejaculate urine. Then, depending on the number of sperm available and any female reproductive concerns, either IUI or IVF therapy is performed.
Lifestyle Change or Discontinuation of Medications
If a certain medicine is associated to azoospermia, the first step is to stop using it or to wait until treatment is finished. Chemotherapy, for example, may produce azoospermia, although sperm may recover months (or years) later. Alternatively, if testosterone supplements are causing azoospermia, stopping testosterone may be advised. Never stop using any drugs or supplements without first seeing your doctor.
If harmful chemicals or high heat at work are suspected of causing azoospermia, shifting jobs may be advised (if possible.) Long-term exposure to chemicals can sometimes result in lasting harm. In other circumstances, sperm development may resume or improve, increasing the chances of success when combined with other reproductive therapies.
Testicular Sperm Extraction with IVF and ICSI
TESE, or testicular sperm extraction, can be utilized to remove sperm cells straight from the testes. Before the operation, you will be sedated or given general anesthetic. The doctor will make a tiny incision in your scrotum and retrieve testicular tissue. That tissue will be checked for sperm cells and cryopreserved if not utilized immediately.
When obstructive azoospermia prevents sperm cells from entering the ejaculate, TESE can be employed. In situations of nonobstructive azoospermia, TESE may be utilized to seek for useable, mature sperm cells that may be created but not enough to enter the sperm.
Sperm cells retrieved using TESE can only be used in IVF and ICSI procedures. ICSI, which stands for intracytoplasmic sperm injection, is the injection of a single sperm cell into an egg. If fertilization is successful, the embryo is transported to the woman's uterus.
There is an increased chance of passing on infertility to a male kid with IVF-ICSI and TESE. This is something you should talk about with your doctor.
In the treatment of infertile males, it is common to encounter the misperception that infertility is generally associated with women. It is unusual for a patient to arrive for an infertility examination with an abnormal sperm analysis report before undergoing a complete female companion workup. Furthermore, without a physical test, a guy is frequently judged fertile based only on seminal characteristics. This conduct may cause a delay in both the precise diagnosis and any particular infertility therapy. Furthermore, male factor infertility might be caused by an underlying medical problem that is generally curable but may be life-threatening.
Receiving an azoospermia diagnosis can be quite upsetting. When this diagnosis is accompanied by other information, such as the discovery of a genetic problem or the possibility of passing on an inheritable disease to your future children, it can be even more upsetting. Some men may be humiliated or embarrassed about their illness, and as a result, they may not disclose their male infertility diagnosis to their primary care practitioner. However, due of the increased risk of general health concerns, it is critical to be open and honest with your doctor.