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Stem cells can give new life to ovaries and potentially restore fertility

Stem cells enhanced ovarian function and egg retrieval in patients with premature ovarian insufficiency

Ivana Marisa da Costa Martins

Molecular Biology and Oncology

University of Coimbra

Premature ovarian insufficiency (POI) is a condition in which a person's ovaries stop working before the age of 40. Patients with POI experience ovarian dysfunction and irregular or absent menstrual periods long before the normal age of menopause, sometimes when they are still teenagers.

At birth, ovaries contain 1-2 million eggs, each one surrounded by a sac-like structure called a follicle. Every month, starting at puberty, a follicle fully develops, resulting in the release of a mature egg – ovulation.

However, people affected by POI present an unusually low number of follicles in their ovaries, and the follicles they do have are often dysfunctional and do not undergo normal maturation. Consequently, their ovaries stop producing sex hormones and releasing eggs regularly or even at all, greatly decreasing fertility. Although ovarian activity might occur sporadically, only 5-10% of people with POI are able to conceive spontaneously. Moreover the success rates of fertility treatments are low unless they use donor eggs. 

But research has found that that stem cells could be used to enhance the ovarian function of people with POI. And a recent study including 61 POI patients below the age of 35 who had an intention to get pregnant, published in the journal Cell Proliferation, indicates that injecting ovaries with these cells could be a safe treatment for POI.

Stem cells are promising for treating many diseases because they are able to renew themselves and to differentiate into several cellular types. In particular, growing evidence from pre-clinical and clinical studies indicates that stem cells could restore menstruation, hormone levels and, in rare cases, the ability to conceive. These cells seem to have a positive impact in ovarian function by producing substances that limit the death of ovarian cells, inhibit ovarian aging, and improve the formation of blood vessels. In addition, stem cells also have anti-fibrotic, anti-inflammatory and immunomodulatory effects. But despite these promising findings, further clinical results are needed to confirm the potential of stem cell therapies in treating POI. 

Overall, the patients treated with stem cells in this new study displayed improved ovarian function, seen in the increased number of follicles at different stages of development. The positive effect of the stem cells was particularly noticeable when the researchers realized that participants receiving an injection in only one of the ovaries developed follicles in that ovary but not in the other one. 

Remarkably, two patients even started menstruating again after having had missing or irregular periods for at least a year and a half. In addition, one of them developed several follicles in both ovaries long after the treatment, suggesting that the stem cells completely restored ovarian function in that participant.

The stem cell treatment also had a positive impact on fertility. In fact, after stem cell transplantation, some patients' ovaries contained mature follicles ready for ovulation. Furthermore, three of eight patients undergoing in vitro fertilization (IVF) were able to conceive, in addition to a patient who was even able to get pregnant through sex with partner. 

Despite these very promising results, the researchers noticed that some participants seemed to benefit from this therapy more than others. To understand what was causing this, they compared the clinical characteristics of patients who successfully developed mature follicles in response to the treatment and those who did not. They found that participnats who had some follicles in their ovaries prior to the stem cell transplant had better chances of presenting mature ones afterwards. These findings are an extremely important first step to define the subgroups of patients who are more likely to respond to this type of treatment.

Besides being able to improve ovarian function and fertility, this treatment did not trigger any serious side effects, indicating that stem cells, at least those derived from the umbilical cord as they were in this study, could be a promising and safe resource for the clinical treatment of POI in the future. However, some questions remain, such as how long the positive effects last and the ideal dose of stem cells. Although the findings suggested that subjects receiving more than one stem cell injection achieved higher follicle counts and thus, better ovarian function, several participants were lost to follow-up. 

This study is exciting for the scientific community because it provides evidence for another potential clinical application of stem cells. Several studies have explored the use of these cells to treat cardiovascular, metabolic and neurological diseases, among others. Still, to date, the FDA has only approved the use of  stem cell-based therapies to treat blood and immune disorders. As more and more studies provide evidence of these cells’ clinical benefits, it is likely that the number of registered stem cell therapies will increase in the near future.

Comment Peer Commentary

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Maiko Kitaoka

Cell Biology

UC Berkeley

This seems really cool, very promising for those with POI, especially if patients still have some follicles. How common is POI in the population, and what does this treatment plan look like (how many injections, how much time etc)? Also on a more molecular level, does the stem cell source matter? Why are umbilical cord stem cells the best source for this treatment, and would others be sufficient? 

Ivana Marisa da Costa Martins responds:

POI affects 1-3% of women before the age of 40. The participants received three injections, six months apart. Although the effects of the treatment were still visible months after the injections, the duration of the stem cells’ efficacy is something that needs to be further explored. Still, the participants that took part in all three injections  seemed to achieve better ovarian function and follicle counts. So, it seems that more than one intervention will be necessary.

Regarding the source of stem cells, although the authors do not explain why they are specifically testing umbilical cord-derived cells, I believe this could be due to availability and to the lower probability of being rejected by the recipient. However, studies that evaluate the use of bone marrow-derived stem cells to improve ovarian function are also available.

Xinwen Zhu

Systems Biology

Boston University

This is exciting news for reproductive medicine! I find it very interesting that umbilical cord stem cells derived through standard  procedures work well here, as opposed to bespoke treatment plans - I believe there is some preliminary evidence that umbilical cord stem  cells aren’t rejected by the recipient in the same ways that stem cells from other sources are. The present study makes no mention of mechanism of action, and I would be curious to know what exactly the introduced stem cells end up differentiating into. 

Ivana Marisa da Costa Martins responds:

Yes, I agree that these umbilical cord-derived stem cells might work well here because they are less rejected by the recipient than bone marrow cells, for example.
The effects of stem cells on ovarian function are complex, but it would definitely be very interesting to investigate what these cells differentiate into. For example, some studies have shown that stem cells are able to differentiate into granulosa-like cells

Margaux Lopez

Astronomy

Vera C. Rubin Observatory

This seems like a huge step forward for patients with POI, and it will be really interesting to see further research in this field. How is POI normally treated? Is the stem cell treatment used in this study more or less expensive/time intensive/invasive? Also, it’s mentioned that three of eight patients undergoing IVF treatment were able to conceive – compared to that what’s the success rate in the general population of  people trying to conceive without the prior stem cell treatment? That is, for patients with POI does this represent a huge jump or just a modest increase in the chance that the patient can become pregnant? 

Deanna MacNeil

Cell Biology

McGill University

You mentioned that these stem cells have anti-fibrotic, anti-inflammatory, and immunomodulatory effects as well as the potential usefulness of stem cells in treating cardiovascular, metabolic, and neurological diseases. Do you think stem cell treatments  could also be useful for treating other fibrotic conditions related to menstruation? I am thinking of endometriosis in particular, but I am also wondering about potential in treating polycystic ovarian syndrome.