A Look at Therapies For Men who cannot Produce Sperm

In the modern era, there are a host of avenues couples can pursue to initiate a pregnancy.

New technologies enable conception even in the setting of very few sperm and or eggs.  The most severe setting for male infertility occurs when no sperm at all is present in the ejaculate, a condition known as azoospermia.   Even in that situation, sperm can often be harvested from the epididymis  or testis to use in an IVF cycle with procedures known as epididymal sperm aspiration (MESA)  and Testicular Sperm Extraction (TESE).  However, even those procedures are insufficient when cells in the testis are not generating any sperm at all. 

There are two basic histologic patterns encountered when no sperm are present

 When considering the germ or sperm making cells of the testicles, there are two basic histologic patterns encountered when no sperm are present:  1) Sperm precursor cells (immature germ cells) are present, but no actual sperm.  This is referred to as “maturation arrest” as in the maturation of immature cells to becoming sperm is arrested. 2) No germ cells are present;, this is referred to as Sertoli “Cell Only” or “Germ Cell Aplasia”.  

Why would either of these situations occur?

For some men, it can happen as a consequence of exposure to chemotherapeutic agents.  For some, it may have been due to illness. Mumps is a classic example.  For some, there are genetic explanations, such as  a y chromosome microdeletion or abnormal karyotype.  However, for the majority of men, there is no explanation, or at least none that science has, to date, uncovered.

What can be done for Maturation arrest?

The answer is: “it depends”.  If the maturation arrest is due to an underlying condition, then sometimes medication can stimulate sperm precursors to become sperm.  The classic situation occurs in the setting of testosterone replacement where chronic administration of testosterone induces an arrest of sperm production.   I have seen this often in my practice and have been able restore sperm production for such patients.   Other systemic illness can induce a maturation arrest.  Renal failure, uncontrolled diabetes, and sarcoidosis with hypercalcemia, can all induce maturation arrest and treatment of the underlying disorder can often restore sperm production.  Even treatment of narcotic addition or alcoholism has sometimes restored sperm production.   Unfortunately, there are many cases of Maturation arrest with no identifiable cause.  Sometimes empiric medical therapy helps, but often it does not.

What can be done for Sertoli cell only?

 Sertoli cell refers to an absence of germ cells or sperm precursors.   Sometimes a diagnostic biopsy is performed on the testis as part of the 
evaluation for infertility. The problem with this approach is that if the biopsy comes back as Sertoli only, it is only certain that the cells in actual biopsy are Sertoli only.  It is possible for the remainder of the testis to harbor some sperm making cells.  Therefore in the setting of a diagnosis of Sertoli only based on a diagnostic biopsy, testicular microdissection can, in some cases find sperm in other parts of the testis.  Unfortunately, if no sperm are found (true Sertoli cell only), there is no way to create them, at least not currently.

What are options for true Sertoli only or untreatable Maturation arrest?

Currently, for patients trying to start a family, but who have exhausted options to try to create or retrieve sperm there are two options that remain:   the first is Donor insemination .  With donor insemination, a donor is usually chosen that has physical characteristics similar to the male partner wishing to become a father.  Photographs with a partial facial feature removed and a physical description are available from sperm banks.   Sometimes a directed donor (usually a sibling) is involved.  The second option is to pursue adoption.

What is the hope for the future for male patients who cannot make sperm?

New technologies are evolving in molecular and cellular biology and stem cell research to hopefully enable patients to actually generate their own sperm. How might this be done?   What has already been done?

One option to enable men to generate sperm comes from technology related to use of stem cells to grow tissue of different.  In this scenario, the idea would be to generate stem cells and then differentiate them into sperm precursors and ultimately into sperm.   This would ultimately require not only a means to generate new germ cells but also (ideally) a way to place them into a patient’s testes, again ideally, so that he could ejaculate sperm.   

What work currently touches closest to this area of research?   Currently , certain centers are offering services to prepubertal patients who need chemotherapy.    Protocols exist to harvest testicular cells which are sperm precursors (immature germ cells) and have them frozen.   The hope is that after treatment, these cells could be reintroduced into the testis and lead to the future natural production of sperm.   Of course, these cells are essentially normal cells and should respond accordingly as long as they are reintroduced into the right environment (the original patient’s testes).   In fact, this work has already been accomplished in animal models  including pigs, mice, and rats.   

If sperm precursor cells are not available from the patient, how can they be obtained or created?  What is being developed with respect to stem cell technology?

 

 There are currently two basic approaches:

1. Dedifferentiation of a somatic cell (a mature body cell)  back to a (pluripotent, immature) stem cell state, and then down a new cell pathway.

   This involves a reprogramming of adult somatic cells into embryonic stem cell like cells, which are then capable of differentiating along a new cell path way such as germ cell or sperm making cell pathway.  This has already been accomplished in the animal model using a combination of growth factors and proteins produced by oncogenes.   The resulting cells are called induced puripotent stem cells or iPSCS.   These iPSCs may be generated in the future from somatic cells of infertile male patients.  In the future, skin fibroblast cells obtained from a skin biopsy might serve as the origin of cells which would be eventually reprogrammed to produce sperm.    Several immediate concerns present themselves, however.  

a. Cell imprinting is a concern in this approach.  Imprinting refers to the conservation of epigenetic markers from mature somatic cells which may prevent  the sperm precursor cells from functioning normally.  

b. In addition, the use of oncogenes (genes which regulate cell growth)  gives concern as to the possible increased risk of cancer deriving from these induced cells. These concerns have encouraged attention in a different direction:

2. Creation of a new embryonic cell from a pre-embryo and  a nucleus from a patient cell:

   In this situation, a somatic cell nucleus could be transferred into a donor egg that  has had its original nucleus removed.  That donor egg-shell paired with the patient’s cell nucleus could create a new true embryonic cell which could then be guided down a germ cell pathway to eventually generate sperm.   If successful, this strategy would likely reduce some of the concerns involved with iPSCs: 

What actual animal work along these lines has been accomplished?    Hayashi demonstrated the transformation of mouse (epiblast) stem cells into priomordial germ cells in culture medium.  These cells were transferred into the testes of infertile mice and were reported to accomplish the generation of sperm.  These sperm, in turn were used to fertilize mouse oocytes using IVF with ICSI and the embryos were transferred and resulted in live births.  Unfortunately, the report also noted that some of the offspring developed malignant tumors.

CONCLUSION:

 Although clinical applications for use of induced stem cells or new embryonic cells are years away,   recent advances make the likelihood of practical uses seem almost certain  to become a reality.  This may be the last great bridge medicine needs to cross to help certain men become biological fathers.

The above synthesis is based on a review article from Fertility and Sterility, January  2014 by the following authors/institutions:  Charles Easley IVV, David Latof, Calvin Simerly and Gerald Schatten from Labortory of Translational Cell biology, Emory Univerisity School of Medicine,  Dept of OB/Gyn, Univeristy of Pittsburgh School of Medicine,  and Magee Women’s Research Institute, Pittsburgh Development Center, Pittsburgh.   In addition, the work of Hayashi et al is referenced:  Hayashi K et al: Reconstitution of the Mouse Germ Cell specification pathway in culture by pluripotent stem cells.  Cell 2011 146: 1-14

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