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For conception of a healthy child, it is important for a couple to have high-quality gametes. As it is well known, egg cells (oocytes) in women do not regenerate over time and are constantly depleted. Typically, female fertility begins to decrease significantly after the age of 35, but it often happens that the egg reserve formed from birth is lower than normal, and by the time of conception planning, it may be insufficient or exhausted.
What is premature ovarian reserve decline?
Premature ovarian reserve decline is a condition in which the number and quality of egg cells in a woman’s body decline faster than expected during a particular reproductive period. However, the reproductive function and menstrual cycle are not yet fully disrupted.
What is premature ovarian insufficiency (POI)?
Premature ovarian insufficiency (POI) is a condition in women where the functional reserve of egg cells decreases by the age of 40. Such a decline in both quantity and quality of eggs can lead to infertility, disruption of the menstrual cycle, and symptoms similar to menopause.
What are the key facts about the egg reserve?
- It is important to know that the egg reserve does not regenerate and is continually depleted from birth.
- During the reproductive period, a woman’s body experiences only 300-500 ovulations.
- At birth, the ovarian reserve consists of 1-2 million eggs.
- By the time of the first menstruation, approximately 300-500 thousand eggs remain in the ovaries.
- For each menstrual cycle, several hundred follicles are used, and only one (or occasionally two) ovulates.
- By menopause, only a few thousand follicles remain in the ovaries, most of which are inactive. It has been calculated that women in menopause have an average of 1000-1500 follicles remaining.
One of the directions in our infertility treatment department for those with low ovarian reserve involves the use of innovative and effective methods: two of them are exosomes and stem cells.
What are exosomes?
Exosomes are microscopic vesicles that carry important signals between cells and affect regeneration. This effect is applied in infertility treatment to improve communication between cells in cases of premature ovarian reserve decline and improper endometrial growth (endometrial hypoplasia). Exosomes are also important for treating autoimmune diseases and chronic endometritis that are resistant to standard treatment methods (through immune response modulation).
Due to their unique properties, exosomes are used in modern medicine in various fields: cardiovascular diseases (for the regeneration of damaged myocardium after a heart attack), in burn treatment, for joint recovery, oncology, immunotherapy (to stimulate the immune system against tumors and infections). An important direction of exosome use is as natural platforms for drug delivery, DNA, and RNA therapeutic molecules to target cells.
What are mesenchymal stem cells (MSCs)?
MSCs (mesenchymal stem cells) are multipotent cells capable of differentiating into various types of cells. They have regenerative and immunomodulatory properties. Since these cells can transform into different tissue types, they have become promising for treating various diseases and regenerating tissues.
Who can benefit from the use of MSCs and exosomes?
Primarily women with premature ovarian reserve decline and poor response to follicle stimulation:
- If premature ovarian reserve decline or premature ovarian reserve depletion has been diagnosed, or if low AMH is found after ovarian tissue surgery, or after medications that led to decreased egg count, or in cases of a congenital small egg reserve.
- If low-quality oocytes were obtained during previous stimulation or if there were issues with egg maturation.
- To restore the endometrium in cases of atrophy, improving embryo implantation during IVF.
- In the treatment of male infertility (to restore damaged testicular cells such as spermatogonia, Sertoli cells, and Leydig cells).
In these cases, the use of mesenchymal stem cells (MSCs) and exosomes can improve the success of infertility treatment, enhance the response to stimulation, improve egg quality, and result in a larger number of embryos.
What are the benefits of using MSCs and exosomes?
- Potential improvement in egg quality.
- Activation of residual primordial follicles, promoting their maturation.
- Restoration of hormonal balance.
- Increased chances of obtaining own eggs without using donor oocytes.
- Safety: MSCs have an immunomodulatory effect, so there is a low risk of rejection.
How is treatment performed with MSCs and exosomes?
MSCs and exosome therapy is a minimally invasive method, typically performed on an outpatient basis. Under sedation, which lasts about 20 minutes, the cells are introduced into the ovarian tissue using a special needle under ultrasound control. Afterward, the patient should rest for about an hour. Possible sensations include slight tingling in the ovarian area for one day.
For treating endometrial atrophy in IVF programs, exosomes are used during the early proliferative phase of the menstrual cycle (days 7-10 of the menstrual cycle). When using stem cells for the endometrium, first, a pipelle biopsy is performed to collect endometrial cells during the early or mid-proliferative phase of the cycle. The stem cells are cultured for about three weeks, and then the endometrial cells are prepared for implantation.
How do MSCs and exosomes affect the ovaries and fertility?
- Exosomes transmit signals between granulosa cells (cells that line the follicles and form the environment for egg cells, playing an essential role in follicle development and egg maturation), theca cells (important for hormonal regulation of the female cycle, ensuring follicle development, and interacting with granulosa cells), and the oocytes themselves. This means that exosomes serve as intermediaries between cells, delivering signals and ensuring cellular activity (proliferation and differentiation).
- MSCs improve the microenvironment of follicles, aiding their maturation.
- Exosomes promote angiogenesis – the formation of new blood vessels, which is crucial when the ovarian reserve is low or exhausted. Proper blood supply, oxygen, and nutrient transport are needed for a proper response to follicle growth stimulation and egg maturation.
- Exosomes reduce apoptosis (programmed cell death), supporting cell survival, which is essential in cases of premature ovarian insufficiency.
- Exosomes carry micro-RNAs that are crucial for regulating gene expression that controls follicle growth and female hormone levels.
- Exosomes have an antioxidant effect on cells.
- MSCs’ ability to activate local stem cells is important for ovarian function in cases of low ovarian reserve and conditions like thin endometrium, facilitating embryo implantation.
- The immunomodulatory effect of exosomes helps create a more favorable environment for tissue regeneration, regulating inflammation and preventing excessive immune responses.
Exosome-based treatment improves tissue remodeling and is used to regenerate damaged tissue by influencing the extracellular matrix. This property is used to enhance endometrial growth and its quality, which is necessary for successful embryo implantation.
This effect of exosomes is applied in the treatment of patients with thin endometrium (hypoplasia, endometrial atrophy, Asherman’s syndrome) when standard treatments are ineffective. Exosomes improve the effectiveness of stem cell treatments in these cases.
How are MSCs obtained?
Sources of MSCs include bone marrow, adipose tissue, umbilical blood or tissue, and endometrium (endometrial stem cells). For ovarian activation, we recommend using stem cells cultured from the patient’s own adipose tissue. For stimulating endometrial growth in cases of hypoplasia, we use cultured stem cells from the endometrium.
The use of exosomes and mesenchymal stem cells (MSCs) is a promising approach in the treatment of infertility due to premature ovarian reserve decline. This method significantly improves the potential for endometrial growth in cases of endometrial hypoplasia or Asherman’s syndrome. These methods can only be used on an individualized basis, with their use determined by a fertility specialist with extensive experience in treating infertility caused by premature ovarian insufficiency and endometrial hypoplasia/atrophy.
Our infertility treatment department for premature ovarian insufficiency successfully uses stem cells and exosomes. Their use can be evaluated individually, based on the results of a reproductive health assessment.