Stem Cell Therapy for Non-Obstructive Azoospermia (NOA)

Non-obstructive azoospermia (NOA) is a medical term used when the sperm count is low due to abnormal sperm production by the testicles. Inadequate gonadotropin production or a defect in the testes themselves are the root causes of NOA. These abnormalities may be as a result of;

  1. Genetic defects
  2. Hormonal imbalances
  3. Radiation therapy or toxins
  4. Certain type of medications
  5. Varicocele

There are several techniques to overcome NOA. It is a highly sensitive subject because the treatment greatly differs with the cause of the disease. In most cases,  restoring the spermatogenic function impaired due to NOA to produce sperm high enough to support natural pregnancy is not possible. So, sperm retrieval methods, like micro-TESE, are applied for in vitro fertilization with intracytoplasmic sperm injection (ICSI). However, advanced technologies offer new promises to those who are suffering from infertility due to NOA. One of these promising technologies is stem cell therapy, which might be a future approach to overwhelming procedures of traditional methods.

What is Azoospermia?

According to a study published in Clinics Journal, about 10% of male infertility cases are due to non-obstructive azoospermia. It is important to diagnose azoospermia to come up with the best treatment, since spermatogenesis cannot be restored in the vast majority of cases of NOA.

Normally, sperm is produced through the tubules in the testicles, then moves to the sperm duct, where it is mixed with the fluid in the seminal duct, which forms the semen and finally released through ejaculation.

This process is impaired in men diagnosed with azoospermia. Azoospermia can be obstructive (OA) or non-obstructive (NOA). In obstructive azoospermia, sperm is produced as described above, but blocked in the ducts before ejaculation. In non-obstructive azoospermia, on the other hand, sperm production doesn’t occur in the first place due to a defect in testes or inadequate gonadotropin production.

Diagnosis of Non-Obstructive Azoospermia

NOA diagnosis is required when there is no sperm in the ejaculate. It starts with 2 different samples submitted by the patient. For the best result, samples should be the result of ejaculation which is refrained for 3 to 5 days. Absence of sperm in the ejaculate confirmed by semen analysis. During the semen analysis, several drops from the sediment of centrifuged semen are examined under a microscope. Initial results show the presence of viable sperm in the semen of 35% of men diagnosed with NOA.

It is called cryptozoospermia when just a small number of sperm, also called hidden sperm, are recovered after centrifugation. Although greater implantation rates have been recorded utilizing testicular sperm compared with sperm from ejaculates, testicular sperm extraction (TESE) is not generally recommended while performing intracytoplasmic sperm injection (ICSI) in these patients.

If no sperm is found, the doctor further examines the sample to find out which type of azoospermia is the concern. Diagnosis of the type of azoospermia includes the patient's history evaluation, further physical examination, hormone levels assessment, and genetic testing analysis. It is possible to diagnose the lack of spermatogenesis if the patient has a history of conditions like undescended testis or chemotherapy for cancer.

In order to diagnose NOA, it is necessary to measure testicular volume, either with an orchidometer or with ultrasound. In men, spermatogenesis is reflected in the size of the testes; hence, underdeveloped testes signal sperm production issues. The testes of a man with NOA often have a testicular volume of less than 15 cc and have a flat epididymis.

Varicocele, which is a disease associated with the enlargement of the veins in the scrotum, is a common condition which might be the reason for NOA. A varicocele can induce spermatogenesis impairment or even azoospermia, even though only 20% of men with a diagnosed varicocele experience fertility issues. Therefore, during the diagnosis of individuals with NOA, it is important to check for the presence of a varicocele.

Hormonal evaluation is another diagnosis method for NOA, where follicle‐stimulating hormone (FSH), luteinizing hormone (LH), and testicular volume are evaluated.

Causes of male infertility associated with Non-Obstructive Azoospermia

NOA is associated with the impairment of sperm production due to testicle abnormalities or inadequate gonadotropin production. According to an article published in Reproductive Medicine and Biology, these two main causes may be the result of several conditions described below:

  • Undescended testes

  • Varicocele

  • Testicular tumor

  • Klinefelter syndrome

  • XX male

  • Primary hypogonadism of unknown cause

  • Kallmann syndrome

  • Idiopathic hypogonadotropic hypogonadism

  • Pituitary surgery

  • Systemic disease

  • Obesity

  • Obstruction

  • Idiopathic

All these conditions commonly cause Hypogonadotropic hypogonadism (HH), which is associated with the decrease in the secretion of gonadotropins (FSH, LH) and hence resulting in NOA.

Hypogonadotropic hypogonadism (HH)

Gonadotropins are FSH and LH hormones that have a fundamental role in regulating testicular function and therefore in male reproduction.

Hypogonadotropic hypogonadism (HH) is a secondary testicular dysfunction, where decrease in the secretion (hypersecretion) of the gonadotropins results in low testosterone production by the testes, and therefore impairs spermatogenesis. This type of impairment is counted as non-obstructive azoospermia.

HH might be congenital or acquired. The Kallmann syndrome, the Prader-Willi syndrome, and the Laurence-Moon syndrome are the congenital types of the condition. The breakdown of normal pituitary function, which can occur as a result of radiotherapy, trauma, or a pituitary tumor, is typically what causes acquired HH in adults. The presence of an excessive amount of exogenous androgens or steroids is also a cause of acquired HH.

Treatment for Non-Obstructive Azoospermia

Treatment for NOA changes greatly depending on the cause of it. If it is because of chemotherapy or radiation therapy, for example, your body will recover after a certain period of time. Here are several treatments for different causes.

Sperm Retrieval

Unless there is secondary testicular dysfunction such as HH, it is not always easy to restore the spermatogenic function impaired due to NOA to produce sperm high enough to support fathering a child. In most cases when infertility is associated with NOA, surgical removal of the sperm is advised. Sperm retrieval can be done by microscopic testicular sperm extraction (micro-TESE) OR fine needle aspiration (FNA). FNA is considered to be less invasive compared to TESE, however sperm retrieval rate (SRR) is reported considerably lower in FNA. The average success rate of sperm retrieval with micro-TESE is 40–50%.

IVF is then can be performed by intracytoplasmic sperm injection (ICSI), where viable sperm is directly injected into the egg by an embryologist.

Treatment for NOA with Varicocele

Varicocele treatment is considerably easy, including either by percutaneous embolization or varicocelectomy. Although these operations may restore spermatogenesis to some extent, sperm concentrations in the ejaculate might still be low enough to require assisted reproductive treatment. Therefore, it is essential to determine whether to provide these patients with a varicocelectomy or a sperm retrieval procedure that does not involve varicocelectomy.

Treatment for NOA with HH

HH is one of the few causes of NOA that have shown a consistent response to medical management. The hormonal treatment with gonadotropins is the conventional method for cases in which fertility is a problem. This treatment can increase sperm production high enough to support natural pregnancy. If there is no longer a problem with fertility, a therapy strategy that involves the administration of testosterone rather than gonadotropins can be considered.

Advanced treatments for NOA: Stem Cell Therapy

Recent developments in the biotechnological field have shown new promises to treat NOA. One of these advanced technologies is stem cell therapy.

The human body contains a wide variety of distinct types of stem cells in its tissues. The use of mesenchymal stromal/stem cells, also known as MSCs, which may be obtained from a variety of tissues, including bone marrow and adipose tissue, has been regarded as one of the most promising applications for cell therapy. They have many special functions that aren’t found in any other cells. These are;

  • multilinear differentiation potential,

  • low immunogenicity,

  • their active engagement in tissue repair and regeneration after migration to injured locations. 

MSCs have the ability to differentiate into a variety of cell types, including chondrocytes, fibroblasts, osteoblasts, and adipocytes. They have a therapeutic effect thanks to their ability to release various signaling molecules, which replicate the functional activity of numerous targets inside the body.

According to a 2021 study, there are various mechanisms to restore testicular function via MSC therapy. These include:

  • antisperm antibodies suppression

  • reduction of apoptosis

  • reduction of oxidative stress 

  • stimulation of testosterone production through its differentiation into Leydig cells

  • differentiation into into target cell

  • secretion of growth factors, which will restore cellular function

  • connection with endogenous cells, which will restore the function of damaged cells

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