Non-obstructive azoospermia (NOA) is generally considered a non-medically manageable cause of male infertility. These patients, who constitute up to 10% of all infertile men, have abnormal spermatogenesis as the cause of their azoospermia. The etiology affecting approximately 60% of azoospermic men, includes non-obstructive causes of azoospermia, including toxic exposures or abnormal testicular development. NOA results from either primary testicular failure (elevated Luteinizing Hormone (LH), Follicle stimulating hormone (FSH), small testes affecting up to 10% of men presenting with infertility), secondary testicular failure (congenital hypogonadotropic hypogonadism with decreased LH and FSH, small testes), or incomplete or ambiguous testicular failure (either increased FSH and normal volume testes, normal FSH and small testes, or normal FSH and normal testis volume). Prior to microsurgical testicular sperm retrieval techniques and IVF/ICSI, donor insemination was the only option available to men with NOA. The establishment of in vitro fertilization using intracytoplasmic sperm injection (ICSI) as a standard treatment modality has resulted in a number of these men successfully fathering a child through surgically retrieved sperm from the testis. The challenge, however, is to improve their spermatogenic function to enable the appearance of sperm in their ejaculate or to improve the chances of a successful retrieval from the testis for ICSI.
The initial evaluation aims at resolving the following issues: (1) confirming azoospermia, (2) differentiating obstructive from non-obstructive etiology, (3) assessing for the presence of reversible factors and (4) evaluating for the presence of genetic abnormalities. An elevated follicle-stimulating hormone (FSH) level or an absence of normal spermatogenesis by testicular histology in the presence of azoospermia is generally considered sufficient evidence of a non-obstructive etiology. The most common reversible factors that need to be ruled out include recent exogenous hormone administration, severe febrile illnesses, chemotherapy/radiation or prolonged antibiotic use.
During past few years a considerable progress in the derivation of male germ cells from pluripotent stem cells has been made. These studies provide a desirable experimental model for elucidating underlying molecular mechanism of male germ cell development and potential strategies for producing haploid germ cells for the treatment of male infertility. Spermatogenesis is a complex process by which spermatogonial stem cells (SSC) self-renew and differentiate into haploid spermatozoa. In mammals, this process takes place in the seminiferous tubules of testis, which provide a functional niche for male germ cells and involve three major stages: mitosis, meiosis, and spermiogenesis. Errors at any stage of spermatogenesis can result in subfertility and infertility.
Researchers are currently developing alternative treatment options for these men involving stem cells. It has been verified that mouse induced pluripotent stem cells (iPSCs) can form functional spermatozoa. Functional assays have shown that spermatozoa generated from iPSCs were capable of fertilizing the oocytes after intracytoplasmatic injection and giving rise to fertile offspring following embryo transfer. So far, functional male gametes from human iPSCs have not been obtained.
There are two possible approaches in generating of male germ cells from pluripotent stem cells: in vitro differentiation into advanced, haploid cell products or combined in vitro differentiation and in vivo transplantation. However, the originality of this study is illustrated in the transplantation of purified autologous CD34+/CD133+ and mesenchymal bone marrow stem cells (BMSCs) into infertile patients without in vitro breeding, culture, or manipulation thus avoiding in vitro cell propagation risks as genetic mutations and DNA changes. The cells are withdrawn and injected back into the patient on the very same day of the procedure, hence conferring the highest safety and efficacy parameters.
