Stem Cells: A New Hope for the Treatment of Infertility

About one-third of infertility cases are caused by male problems, mainly due to sperm morphological and functional disorders, including hereditary diseases, genital damage or injury, as well as environmental and psychological factors. The rest are associated with female infertility, a mixture of female and male problems, or by unidentified causes. For female infertility, most cases of are caused by:

• Structural disorders of the fallopian tubes, uterus (adhesions, fibrosis, obstruction of the tubes, wrong structure, and thickness of the endometrium)
• Hormonal disorders (ovulation problems, menstrual problems, Polycystic Ovarian Syndrome (PCOS), premature ovarian failure (POF) or insufficiency (POI))
• Genetic disorders (balanced chromosomal abnormalities in the mother's karyotype, mutations in the oocytes)
• Immune-related disorders (Certain autoimmune diseases, antibodies to semen, increased activity of NK cells in the endometrium)

Currently, there are various ways to help couples with these fertility issues. The treatment options that are most suitable for every couple will depend on the cause of sterility. At times, only one person needs treatment, and there are times wherein both will use a combination of treatments to increase the possibility of having a baby. The treatment options available include hormonal therapy, surgical operations (removal of fibroids, restoration of tubal patency), or various assisted reproductive technology (ART), namely, intrauterine insemination (IUI), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI). These treatments have mostly been successful in addressing infertility.

In some cases, however, these treatments may further create problems rather than offer a solution. For instance, the surgical removal of adhesions and various formations in the uterine cavity and tubes does not always lead to the restoration of reproductive function due to the inflammatory processes that may accompany the surgical intervention. The inflammation caused by various infections, too, leads to an obstruction in the fallopian tubes and cannot be eliminated through mere surgery. Similarly, hormonal treatment could be harmful due to cancer-related side effects, while attempts to conceive using ART technologies do not always end up with pregnancy. Some couples who tried using ART experience recurrent implantation failure (RIF), an increasingly recognized clinical condition that occurs when embryos fail to implant after several IVF treatment attempts. RIF may be a consequence of the endometrium not ready for fetal attachment, excessive activity of NK cells, chronic infections, among others. But despite the likelihood of experiencing this problem, there are still some couples who are willing to go through up to 20 IVF cycles for pregnancy to occur.

How Mesenchymal Stem Cells Help?

On the onset and normal course of pregnancy, one of the factors that is essential for the pregnancy to be successful is the transformation of endometrial cells. This includes morphological and functional changes to form special decidual cells that provide embryo attachment and the maternal-fetal interface. As follows, disruption of formation processes and lack of decidual cells can lead to a concatenation of events, resulting in breakdown of the decidua in early gestation and miscarriage or, plausibly, accelerated aging of the maternal‐fetal interface and spontaneous preterm labor. That is why, for the 1-2% of couples who suffer from Recurrent Pregnancy Loss (RPL), or the loss of three or more consecutive pregnancies prior to 20 weeks of gestation, therapy with mesenchymal cells can help restore the normal number of decidual cells during the period of endometrial remodeling, which will increase the likelihood of embryo attachment and childbearing. It has been discovered that bone marrow-derived mesenchymal stem cells (the same type of cells as Kintaro Cells) normally circulating throughout the body – can give rise to a distinct decidual subpopulation.

With uterine fibrosis, various polyps, scars, and adhesions, these complications have the ability to deform the uterus, thereby making the implantation difficult. Uterine scarring and adhesions are usually caused by endometrial infections and surgeries such as dilatation and curettage (D&C). In relation to this, endometriosis, a disease characterized by the presence of ectopic endometrial lesions, also adversely affect fertility. In cases of moderate to severe endometriosis, the adhesive process is more pronounced and can interrupt the movement of the oocyte to the fallopian tube, leading to abnormal implantation and decreased fertility. The thinning of the normal layer of endometrial tissue, on the other hand, can be associated with surgery and previous infections that affect a woman’s reproductive health. For these conditions, MSC have shown a promising potential to effectively repair various endometrial damages due to:

• secretion of growth factors that stimulate the growth of microvessels
• activation of markers of endometrial receptivity
• enhancing the expression of estrogen receptor (ER) and progesterone receptor (PR)
• regulation of protein kinase B signalling
• downregulation of TNF-α and IL-1β

On average, pregnancy can occur without any additional medical intervention after treatment of adhesions of the endometrium with MSC. Some couples even combine MSC treatment with hormonal therapy and ART to increase their chances of getting pregnant.

Another common infertility problem is recurrent implantation failure due to excessive activity of NK cells in the endometrium. It is a distressing and frustrating condition for couples who are trying to conceive given the impossibility of the embryo to implant. For this kind of circumstance, the use of MSC could downregulate the activity of NK cells due to their immunosuppressive properties, which ultimately will have a positive effect on the likelihood of conceiving a child.

For premature ovarian failure (POF) and polycystic ovary syndrome (PCOS), these disorders are typically associated with an imbalance between the main hormones that regulate normal ovarian function and egg maturation. Treatments available for these conditions involve lifestyle changes and hormone replacement therapies. In some cases, however, hormone treatments are unsuccessful. There is also substantial evidence confirming that such therapy increases the risk of breast cancer.

On that account, more and more studies lead to the possibility of treating hormonal disorders using MSC. Mesenchymal stem cells have been found to secrete a number of cytokines and growth factors that reduce the loss of ovarian granulosa cells and restore their function. This, in turn, leads to the normalization of the balance of hormones responsible for folliculogenesis and the restoration of fertility.

In addition, the potential of MSC has been evident in one study where two out of 10 patients with POF resumed menstruation, and one even gave birth to a healthy child after MSC treatment without hormonal therapy. In the case of PCOS, MSC treatment has also reduced inflammation and regulated angiogenesis through the secretion of certain factors, which leads to the restoration of normal ovarian function.

Taken together, MSC therapy could be successfully applied in the treatment of infertility associated with certain structural and hormonal disorders. Therapy with mesenchymal cells in some cases can restore the function of the endometrium; help the successful implantation of the embryo; remove inflammatory processes in the uterus, tubes, and ovary, and; normalize the hormones that are necessary for the onset of pregnancy. With the monumental promise of MSC for the treatment of infertility, some experts are confident that the extensive introduction of MSC treatment can be recommended for combination therapy with other methods of fertility treatment in order to achieve better results. But as with all other medications, consultations with a qualified medical specialist are required prior the use of MSC.