The Future of Fertility Treatments for Men

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The fertility space has seen a surge of interest in recent years, with many recognizing the unmet need that millions of couples around the world face. It is estimated that about 1 in 7 couples worldwide will struggle with infertility, and the industry that has arisen to treat them is now valued at the tune of $17 billion dollars. The potential of new technologies holds the promise of upending the status quo – these are some of the most promising.


Stem Cell Therapies

Stem cell therapies have been a huge topic of interest in recent years, as their potential to treat a number of illnesses and conditions is unparalleled. To understand stem cell therapies for infertility, we must first understand how sperm cells are created. Sperm cells are produced through a process known as spermatogenesis, which occurs in the testis. This process starts with a small pool of spermatogonial stem cells (SSC’s), which divide and differentiate into spermatocytes – cells that will eventually become mature sperm. This is one of the great advantages to using stem cells – they can differentiate into the cells you need to restore normal function. But how do we take advantage of this?

Testicular Tissue Freezing and Spermatogonial Sperm Cell Transplantation

Since these SSC’s are found in the testis, many pre-pubertal patients who are about to undergo cancer treatments are opting to undergo a process known as testicular tissue freezing – a small amount of testicular tissue is removed and stored for later utilization of the SSC’s. Previous research has shown that, when testicular tissue obtained from healthy mice was transplanted to infertile mice, normal fertility could be restored after a few months. This is due to the activity of the healthy SSCs restoring normal function in the infertile mice. Furthermore, they discovered that SSCs retain their biological activity after being frozen and later thawed. Researchers hope to utilize the same idea in humans. Healthy SSCs found in testicular tissue obtained from pre-pubertal boys prior to cancer treatment can be transplanted back to the patient once treatment is done, hopefully restoring normal functioning of the testes and preserving fertility.

Testicular Tissue Grafting

Although rather unconventional, this approach may be considered in specific medical cases where “malignant contamination” may be an issue – more on this later. Research has shown that testicular tissue can be “grafted” (implanted) under the skin of immune-impaired mice, and that these grafts will eventually mature and produce complete spermatogenesis. It may be possible to use these grafts in a variety of animals, such as mice, rats, or pigs. The most important characteristic of grafting is that it circumvents the issue of malignant contamination– important in cases such as leukemia where returning testicular tissue back to the patient may be unsafe. If this is not a concern, the grafts can be implanted almost anywhere back into the patient – convenient for cases where normal transplantation back into the testes is not possible (for example, in the case of bilateral removal of the testes to treat testicular cancer).

Although testicular tissue grafting would not actually restore full fertility, it may produce enough sperm that can be used to fertilize eggs through ICSI.

Pluripotent Stem Cells

One of the most exciting treatments in the research pipeline, the use of induced pluripotent stem cells (iPSCs) could be a paradigm shift in treating infertility. By utilizing a cocktail of reprogramming factors, researchers can take any cell in the body and transform them into iPSCs, a sort of “clean-slate” cell that is capable of differentiating into a number of different cells. These iPSCs can be transformed into germ cells (reproductive cells) that when transplanted into the testes, restore normal function and spermatogenesis. This process could be utilized by any patient who cannot preserve or produce functional sperm. However, more research is needed to guarantee the safety and viability of this method.

Gene Therapies

Gene therapies work by directly modifying the genetic information of a cell. Thus, genetic defects that are the cause of infertility can be treated directly at the source, potentially restoring natural fertility with a single treatment. However, these therapies are either highly experimental or mired in ethical concerns, and much more research is needed before they are widespread.

Germline Gene Therapy

Germline cells have somewhat of misleading name, as they have nothing to do with germs. Rather, these are the “reproductive cells” that include the male and female gametes; egg and sperm, respectively. They also include all their developmental precursors. Genetic modification of germline cells is an often-used method in basic research and has a well-established methodology. This makes it technically possible to do in human germ cells, yet there are great ethical concerns that genetic modifications to the germline would not only treat the patient, but also their progeny, and in turn all subsequent generations. There is much active discussion on the issue, but as of now it remains forbidden to directly modify human germ cells in clinical practice.

Sertoli Cell Gene Therapy

This type of gene therapy holds the potential of treating the genetic basis of infertility without directly modifying the germline, thus ensuring the therapy affects only the patient and not necessarily their progeny. Sertoli cells are somatic cells – any cell besides germline cells falls into this category. Somatic cells can be seen as the “building blocks” of the body. These Sertoli cells are found in the testis; they are essential for spermatogenesis and also keep the germline cells healthy and nourished. New mutations in Sertoli cells that can lead to infertility are being explored, and research suggests that these cells can be modified without risking germline transmission. However, not all causes of genetic infertility are attributable to Sertoli cells, so the potential of the therapy remains rather limited.

 

Ectogenesis

This idea may seem like it was lifted straight out of science fiction; ectogenesis, the process of growing a baby in an artificial womb. However, technological advances have made this a very real possibility in the near future. In 2017, researchers at the Children’s Hospital of Philadelphia managed to keep lamb fetuses alive in “bio-bags” – nutrient rich bags of fluid – for 4 weeks. 

The key to functional ectogenesis is reproducing the conditions inside the womb as closely as possible. Much research is already ongoing in this direction, as scientists approach the problem in two directions; how to keep embryos alive as long as possible before implantation, and how to keep fetuses viable in progressively earlier deliveries. When these two approaches meet in the middle, we may be on the way to a truly functional artificial womb, capable of growing a fully developed human.

The consequences of developing such a technology are enormous. It poses a plethora of new issues to tackle – will this become a new advantage for the privileged? How will insurance approach these new developments? What new dimensions will we have to think about on abortion rights? Nonetheless, the potential for good is equally powerful. Gender equality would advance as parental roles are equalized. New opportunities for genetic parenthood would be opened for gay and trans individuals. It may also provide a safer alternative for traditional pregnancy by eliminating risks posed by external factors such as nutritional imbalances or drug usage. The potential of such technology is immense, and the many transformative changes it could have in society highlight the need to have discussions about it before it arrives.