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The treatment and our European Affiliates

Female infertility is a global health issue with significant medical and psychological suffering among women throughout the world. It is a disease condition in which the female counterpart of a couple fails to achieve pregnancy in 12 months of unprotected sexual relationship without using any contraceptives.[1] According to a study published in 2007, 72.4 million women aged between 20-44 years suffered from primary or secondary infertility worldwide.[2] Defective ovulation, transport, and implantation are the three broadly categorized causes of female infertility by the Center for Disease Control (CDC).[3] However, the defect or complete cessation of ovarian function such as ovulation is the leading cause of female infertility.

Premature Ovarian Failure, which is also referred to as Ovarian Insufficiency, is the condition in which the ovaries cease to produce eggs and observe the decline in follicle count has the main influence on rendering infertility.[4-5] It was believed that women have a limited number of eggs that emerge from a finite number of primordial follicles produced during fetal development. Only these follicles were thought to develop to the grafian stage, in which the eggs ovulate. However, the revolutionary work of Dr. Tilly and his colleagues proved contrary to the landmark discovery of Female Germline Stem Cells (FGSCs) in postnatal mammalian ovaries.[6]. Notably, these undifferentiated FGSCs were shown to differentiate and form oocytes or egg cells which challenged the belief of limited Ovarian Reserve. [7]. Secondly, ovarian aging disrupts the ovulation cycle that leads to hormonal disparity and establishes the basis of female infertility. Moreover, the increased follicle-stimulating hormone (FSH) level > 25 IU/l is an important diagnostic factor for premature ovarian failure. Consequently, Premature Ovarian Failure and Menopause cause a decline in the overall wellbeing of women aged 35 and above 40 years respectively.

The  program in conjunction with our European affiliates consists of a comprehensive treatment plan for infertility involving baseline blood testing, evaluation, stem cell treatment, energy mitochondria boosting, growth factor PLRP therapy, and Ovarian In-Vitro activation.

This European stem cell treatment uses the autologous injection of mesenchymal stem cells derived from the patient’s own body to the ovaries to promote the differentiation of Germline Stem Cells into healthy follicles. The autologous nature minimizes any chances of infections and restores ovarian function. [8-9] The mesenchymal stem cells have been proven to restore fertility through the reduction of apoptosis in stromal and oocytes, promote folliculogenesis and improving ovarian microenvironment.[10]

Energy mitochondrial boosting involves High Intensity Interval Training, a specific anaerobic fitness regime that boosts mitochondrial energy production in gonadal cells. [11]

Growth factor PLRP Therapy utilizes the potential of concentrated growth factors derived from the patient’s own blood as they play a key role in the regulation of ovarian function.[12] The regulation involves controlling the growth and production of eggs and surrounding stromal cells in the ovaries responsible for hormonal balance.[13-14] PLRP is extracted from the whole blood derived from the patient using a specialized clinical method to obtain the concentrated source of growth factors found in plasma. PLRP has 3-5 times higher concentration of these growth factors than whole blood plasma. These growth factors play a role in the promotion of cell proliferation, chemotaxis, angiogenesis, etc. [15-16]

Ovarian In-vitro activation (OVA) involves activation of the autologous ovarian tissue (derived from the patient’s own ovary through clinical biopsy) in a controlled medium using the growth factors derived from activated PLRP following orthotopic re-transplantation. It restores the ovarian function previously depleted due to the disruption of genetic signaling.  The HIPPO signaling pathway controls the size of the organ and the AKT pathway plays a key role in the initiation of follicular growth, the in vitro activation of these pathways restore the gonadal and endocrine function of ovaries. [17-18] Therefore, Ovarian In-vitro Activation (OVA) represents a safe autologous genetic treatment for ovarian failure and restoration of youthful hormone levels.

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Procedure

This is a multi-phase procedure, and it is carried out after a complete examination of possible patterns of omission of the ovarian function, treatment of hereditary, hormonal and immunological factors.

The first phase involves the extraction of an adequate amount of blood, which depends on the patient’s constitution and the degree of oxygen deprivation, clinical picture, and prognosis, as well as the desired composition of the factors that are injected into the ovary.

The second phase, laboratory, implies the application of complex technology, by which special systems are separated and purified by the corresponding cells, prepared and then activated.

The third stage involves inserting an active substance, derived from its own blood by a special treatment method, into the tissue of the ovary, outside the blood vessels.


The effects relate to the growth of follicles and the production of egg cells in a spontaneous and stimulated cycle, as well as repairing the hormonal function of the ovaries. This allows for their fertilization and leads to more pregnancies. The first effects are expected in a month or two. For the next six months, the standard procedures of IVF in a natural, modified and stimulated cycle are carried out.

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Case Results

The sample of 73 patients with sonographic follow-ups, and 50 patients who finished one-year hormone change monitoring showed that the procedure has a favorable effect on the endocrine status and on the reproductive outcome of patients in post-menopause.

Percentage change compared to the baseline value (%)

Hormone3 months6 months12 months
FSH2.68 % ˃25.82 %˂23.95% ˂
LH7.29 % ˂25 % ˂18.58 % ˂
E226.6 % ˃13.35 % ˂8.54% ˃
PG12.5 % ˂56.25% ˂12.5% ˂

The results show that the first effects of the intervention on FSH levels could be seen after 6 months when FSH starts significant declining (25.8%). (Table 1) The effects of the intervention on LH could be seen already after 3 months, when its concentration starts declining, while a decrease is the most pronounced at six months post-intervention (25%).

The rise in estradiol (E2) levels were recorded at 3 months post-intervention (26.6%). The decrease in progesterone levels was recorded at 3 months post-intervention, being the most pronounced at six months (56.2%).

The total results of ultrasonography for 73 patients that completed the one-year follow-up show during 12 months period after the re-transplantation 64% of patients had the presence of a follicle. Attempts to perform oocyte retrieval resulted in aspirated oocytes in 39.1% follicle positive women (24.6% out of the total number of patients). The fertilization rate of the aspirated oocytes was 83 %, resulting in embryos in 20.54 % of women out of the total number of patients. Embryo transfers were performed in 60 % embryo positive women (12.32% out of the total number of patients), while 66.6% embryo positive women had vitrified embryos (13.69% out of the total number of patients had embryos vitrified). Two patients spontaneously conceived after transplantation, while two pregnancies were conceived with IVF (one of them Gemelli pregnancy), resulting in 5 newborns.

References

  1. Gurunath S, Pandian Z, Anderson RA, Bhattacharya S. Defining infertility—a systematic review of prevalence studies. Human reproduction update. 2011 Apr 14;17(5):575-88.
  2. Boivin J, Bunting L, Collins JA, Nygren KG. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Human reproduction. 2007 Jun 1;22(6):1506-12.
  3. Centers for Disease Control and Prevention. Infertility FAQs. 2013. 
  4. Fortuño C, Labarta E. Genetics of primary ovarian insufficiency: a review. Journal of assisted reproduction and genetics. 2014 Dec 1;31(12):1573-85.
  5. Rudnicka E, Kruszewska J, Klicka K, Kowalczyk J, Grymowicz M, Skórska J, Pięta W, Smolarczyk R. Premature ovarian insufficiency–aetiopathology, epidemiology, and diagnostic evaluation. Menopause Review/Przegląd Menopauzalny.;17(3):105-8.
  6. Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004 Mar;428(6979):145.
  7. White YA, Woods DC, Takai Y, Ishihara O, Seki H, Tilly JL. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Nature medicine. 2012 Mar;18(3):413.
  8. Fazeli Z, Abedindo A, Omrani MD, Ghaderian SM. Mesenchymal stem cells (MSCs) therapy for recovery of fertility: a systematic review. Stem Cell Reviews and Reports. 2018 Feb 1;14(1):1-2.
  9. Sheikhansari G, Aghebati-Maleki L, Nouri M, Jadidi-Niaragh F, Yousefi M. Current approaches for the treatment of premature ovarian failure with stem cell therapy. Biomedicine & Pharmacotherapy. 2018 Jun 1;102:254-62.
  10. Fu XF, He YL, Xie CH, Liu W. Bone marrow mesenchymal stem cell transplantation improves ovarian function and structure in rats with chemotherapy-induced ovarian damage. Cytotherapy. 2008 Jan 1;10(4):353-63.
  11. Ndlovu P, Ackerman SA, Davis WH, Wise A. The effect of high intensity interval training and detraining on the health-related outcomes of young women.
  12. Erickson GF, Shimasaki S. The physiology of folliculogenesis: the role of novel growth factors. Fertility and Sterility. 2001 Nov 1;76(5):943-9.
  13. Otsuka F, McTavish KJ, Shimasaki S. Integral role of GDF-9 and BMP-15 in ovarian function. Molecular Reproduction and Development. 2011 Jan;78(1):9-21. 
  14. Spicer LJ, Aad PY, Allen DT, Mazerbourg S, Payne AH, Hsueh AJ. Growth differentiation factor 9 (GDF9) stimulates proliferation and inhibits steroidogenesis by bovine theca cells: influence of follicle size on responses to GDF9. Biology of Reproduction. 2008 Feb 1;78(2):243-53.
  15. Sanchez AR, Sheridan PJ, Kupp LI. Is platelet-rich plasma the perfect enhancement factor? A current review. International Journal of Oral & Maxillofacial Implants. 2003 Jan 1;18(1).
  16. Lyras DN, Kazakos K, Agrogiannis G, Verettas D, Kokka A, Kiziridis G, Chronopoulos E, Tryfonidis M. Experimental study of tendon healing early phase: is IGF-1 expression influenced by platelet rich plasma gel?. Orthopaedics & Traumatology: Surgery & Research. 2010 Jun 1;96(4):381-7.
  17. Kawamura K, Cheng Y, Suzuki N, Deguchi M, Sato Y, Takae S, Ho CH, Kawamura N, Tamura M, Hashimoto S, Sugishita Y. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proceedings of the National Academy of Sciences. 2013 Oct 22;110(43):17474-9.
  18. Halder G, Johnson RL. Hippo signaling: Growth control and beyond. Development. 2011 Jan 1;138(1):9-22.