Azoospermia Research

What are fertility problems?

Today men fertility problem is about 20% to 30% of the time. And discovering these fertility problems early in men could help in better treatment and successful pregnancy.
Some of men fertility could be cure in simple ways using drugs and some of them could be more complicated and need surgery involved.

Sperm Production (Spermatogenesis)

The male testes have tiny tubules containing diploid cells called spermatogonium that mature to become sperm. The basic function of spermatogenesis is to turn each one of the diploid spermatogonium into four haploid sperm cells. During interphase before meiosis I, the spermatogonium’s 46 single chromosomes are replicated to form 46 pairs of sister chromatids, which then exchange genetic material through synapsis before the first meiotic division.

In meiosis II, the two daughter cells go through a second division to yield four cells containing a unique set of 23 single chromosomes that ultimately mature into four sperm cells. Starting at puberty, a male will produce literally millions of sperm every single day for the rest of his life [1,2].

Non-Obstructive Azoospermia
Non-Obstructive Azoospermia

In non-obstructive azoospermia the testes are abnormal, atrophic, or absent, and sperm production severely disturbed to absent. FSH levels tend to be elevated (hypergonadotropic) as the feedback loop is interrupted. The condition is seen in 49-93% of men with azoospermia [3].

Testicular failure includes absence of failure production as well as low production and maturation arrest during the process of spermatogenesis. Causes for testicular failure include congenital issues such as in certain genetic conditions (e.g. Klinefelter syndrome), some cases of cryptorchidism or Sertoli-cell-onlysyndrome as well as acquired conditions by infection (orchitis), surgery (trauma, cancer), radiation [4] or other causes that we don’t know yet.

Until recently, it was assumed that men with non-obstructive azoospermia were untreatable. The only options offered to these couples to have children were the use of donor spermatozoa or adoption. Several clinically relevant findings have changed our approach to this condition [5].

Azoospermia and Testosterone

Azoospermic males have only a few spermatogonia stem cells. These cells are the source of all germ cells and sperm in the testis. Azoospermic men usually have normal testosterone levels [6,7].

Studies have shown that testosterone is critical for the late stages of spermatogenesis [8,9,10]. This means that the spermatogonia stem cells in the seminiferous tubules do not need testosterone to divide. Researchers have also found that testosterone is involved in the blockage of spermatogonial stem cells in abnormal conditions such as azoospermia [11]. In 2003, the Journal of Andrology published a review describing a variety of pathological conditions on rodents, such as chemotherapy and radiation that resulted in a loss of germ cells in the testis (azoospermia).

Suppression of gonadotropins and testosterone restores the spermatogenesis process, and in some cases, spermatogenesis was maintained after the cessation of hormonal treatment and fertility restoration [11].

This group has shown that hormones are responsible for the maintenance of sperm production in normal conditions; however, in abnormal conditions the testosterone inhibits the spermatogonial differentiation [12,13,14,15,16].

The picture below explains all of the data from various researchers in a simple manner. In normal conditions (A), the testosterone is present and required for the spermatogenesis, especially for the formation of sperm cells. In a pathological condition (B), the condition causes a disorder with arrest at various stages of spermatogenesis (usually the subjects have normal testosterone levels). In (C), reducing the testosterone levels in these pathological conditions helps the stem cell to differentiate. Testosterone is usually required for the last stages in the spermatogenesis process.

 The Prolistem Idea
The Prolistem Idea 

Children have early stages of undifferentiated cells and low testosterone levels [17]. Children’s testis can produce only undifferentiated cells and zero sperm. We call this process “stem cells divide mode.”

In adults, the testosterone levels increase and the undifferentiated cells start to differentiate and transform their morphology to sperm. The high levels of testosterone will maintain the sperm production. We call this process “sperm production mode.” Sometimes in pathological conditions, such as when the sperm count becomes low, testosterone levels also become low.

This happens because our body is trying to fix the problem by producing more undifferentiated cells by activating the “stem cells divide mode.” This lowers the testosterone levels, allowing the spermatogonial stem cells in the seminiferous tubules to divide and produce more cells that differentiate the sperm. After the sperm count becomes normal, the “sperm production mode” will become active and testosterone levels will increase to a more normal level.

“In normal males, both modes are active at the same time, but the sync between the two modes in not fully understood yet.”

Azoospermic men have only spermatogonial stem cells and/or few differentiated cells in the seminiferous tubules [18]. This could happen for many reasons: genetic, trauma, radiation, chemotherapy, and toxic materials. This condition is not normal because the testes have a few undifferentiated cells and yet the body has normal testosterone levels.

This is abnormal because the “sperm production mode” is active while no differentiated cells in seminiferous tubules are present. The body cannot recognize this problem for reasons we are not aware of yet. In order to fix this problem, we can inactivate the “sperm production mode” as well as active the “stem cells divide mode” by reducing the testosterone levels.

Prolistem can do this by lowering testosterone levels naturally and increasing spermatogonial stem cells growth factors such as glial cell line-derived neurotrophic factors (GDNF).

 

New Discoveries


The levels of follicle-stimulating hormone (FSH) tend to elevate (hyper-gonadotropic) when the feedback loop is interrupted. This condition is found in 49%–93% of men with azoospermia. High levels of FSH show only testicular failure, which includes absence or failure to produce, low production, and maturation arrest during the process of spermatogenesis.

In 2010 study showed that Non-Obstructive Azoospermia patients have little number of spermatogonia stem cells and these cells can be culture in the lab and the cells can divide [19]: The problem is not in the spermatogonia stem cells, the problem is in the environment that surrounds these cells.

In 2012 [20], the Department of Urology in Presbyterian Hospital (New York) published new article about the hormone treatments before the TESE, The conclusion was: “Men with non-obstructive azoospermia and hypogonadism often respond to hormonal therapy with an increase in testosterone levels, but neither baseline testosterone level nor response to hormonal therapy appears to affect overall sperm retrieval, clinical pregnancy or live birth rates.”

High number of spermatogonia stem cells increases the success rate of the treatment [21].

Hormones Changes after Treatment (Example) 

Success Rate

This study include 89 patients with non obstructive Azoospermia (NOA), the success rate (48%) include 23% patients that found sperm in their semen (few sperm for IVF) and 25% patients performed success TESE or micro-TESE after taking the six months treatment. There is no effect in 52% of the patients that used our treatment for six months, this could be related to serious genetic issues.

Success 48%
No Effect 52%