The production of eggs – oogenesis, is dependent on proper genetic control. Hippo signaling pathway is essential for maintaining optimum organ size. It contains several negative growth regulators. The AKT signaling pathway has a key role in the initiation of follicle growth. The ovarian in Vitro Activation(IVA) represents the autologous genetic treatment of the ovarian tissue in order to restore both reproductive and endocrine functions of the ovary.
Ovarian function is realized by creating the egg, which relates to the determinate hormonal activity. Primordial follicles enter the further development by process of follicular activation and then undergo a series of developmental changes, until reaching maturity.
During this process, many follicles enter atresia, programmed apoptosis. Part of the follicles survives by making the cell cycle slower. Their dormant status is characterized by communication with surrounding granulosa cells and numerous mechanical and chemical factors controlling progression of their cell cycle. These factors control signaling activation of the pathways included in the primordial follicle dormant status regulation, like the Hippo and the Akt signaling.
Reduction of the number of primordial follicles leads to failure of ovarian function and, ultimately, to menopause. Reduction of the number of primordial follicles is associated with cellular and molecular damage of the ovarian tissue, which gradually reduces the possibility of tissue to perform its functions. Removal or correction of these negative effects by biotechnological regenerative processes leads to recovery of ovarian function.
On the other hand, cryopreservation of ovarian tissue, with re-transplantation has long been used for the purpose of preservation of fertility in patients who must undergo gonad toxic therapy. On that occasion, the ovarian cortex is routinely fragmented for more efficient vitrification and grafting. Wedged resection has been used for a century as a treatment of PCOS(Polycystic ovary syndrome) in order to induce follicle growth.
A newer version of this therapy is ovarian drilling, by diathermy or laser. Other authors suggest transvaginal ovarian trauma puncture in order to restore the ovary function. These papers indicate potential change of conditions of folliculogenesis by using physical methods.
Japanese group showed that the fragmentation of mouse ovaries leads to actin polymerization and interruption of Hippo signal. Disruption of this signaling pathway leads to the increased expression of downstream growth factors, promotion of follicle growth and maturation of oocytes. After laparoscopic ovariectomy, parts of the ovarian cortex were vitrified. After thawing, in the framework of preparation for autografting into mesosalpinx, the fragmentation and exposure of AKT by simulating substances (Stanford based) was done, during two days. Laparoscopic auto-transplantation of activated tissue in mesosalpinx was done in this study. After the transfer three pregnancies occurred, one of which ended in miscarriage, while the two children born with normal outcome, until the year 2015.
The SEGOVA program has several essential advantages over the Kawamura’s approach.
First, conservative surgery with partial decortication instead of ovariectomy is performed, allowing orthotopic instead of heterotopic approach during re-transplantation. Besides that, instead of chemical stimulation of the Akt pathway, autologous PLRP growth factors are used.
The second laparoscopic operation is avoided, using needle injection under colour 3D colour Doppler guidance.
PROCEDURE DESCRIPTION
OVA program has several steps. Laparoscopy with partial ovarian decortication is the first step.
1. Laparoscopy with ovarian partial decortication
Using minimally invasive surgery (NOS/one hole laparoscopy). Biologic fibrin is used instead of suturing the tissue.
2. Blood sampling for PLRP and BRF
The blood sample is processed for growth factors extraction
3. Ovarian tissue fragmentation
Microfragmentation of the tissue is performed under the autologous activated hcPLRP.
4. Ovarian tissue incubation with PLRP growth factors
Sequential growth factors concentration is used.
5. Laparoscopic-monitored orthotopic ovarian tissue re-transplantation with BRF scaffold
We introduced a unique way for re-transplantation of the tissue, as the tissue is microfagmented to that extent that can pass through lumen of the instruments.
TIMING OF THE PROCEDURE
Procedure is not related to the phase of the cycle.
POSSIBLE COMPLICATIONS
Possible complications are related to the laparoscopy and injection of blood and tissue elements into the ovary. The complication rate is less than 5% and can involve infection, bleeding, punctures or injuries to the surrounding organs and complication with anaesthesia. Serious complications requiring hospital treatment are significantly less frequent.
TREATMENT EFFECTS
First results are to be expected in a few months and full effects are expected within 6 months. In the period following the treatment, if sterility is the case, standard in vitro fertility treatments are performed in a natural, modified and stimulated cycle. We track all changes in hormonal, immunological and reproductive parameters and closely follow and assess the results of the treatment.
REFERENCES:
- Kawamura K, Kawamura N et al, Activation of dormant follicles: a new treatment for premature ovarian failure? Current Opinion in Obstetrics&Gynecology 2016, 28(3):217-22
https://www.ncbi.nlm.nih.gov/pubmed/?term=Activation+of+dormant+follicles%3A+a+new+treatment+for+premature+ovarian+failure%3F+Curr+Opin+Obstet+Gynecol.+2016 - Callejo J, Salvador C et al, Live birth in a woman without ovaries after autograft of frozen-thawed ovarian tissue combined with growth factors. Journal of Ovarian Research 2013, 6(1):33
https://www.ncbi.nlm.nih.gov/pubmed/?term=Live+birth+in+a+woman+without+ovaries+after+autograft+of+frozen-thawed+ovarian+tissue+combined+with+growth+factors.+J+Ovarian+Res.+2013 - Revelli A, Gianluigi M et al, Live birth after orthotopic grafting of autologous cryopreserved ovarian tissue and spontaneous conception in Italy. Fertility and Sterility 2013, 99(1):227-30
https://www.ncbi.nlm.nih.gov/pubmed/?term=Live+birth+after+orthotopic+grafting+of+autologous+cryopreserved+ovarian+tissue+and+spontaneous+conception+in+Italy.+Fertil+Steril.+2013 - Donnez J, Dolmans MM et al, Restoration of ovarian function after orthotopic (intraovarian and periovarian) transplantation of cryopreserved ovarian tissue in a woman treated by bone marrow transplantation for sickle cell anaemia: case report, Human Reproduction 2006, 21(1):183-8
https://www.ncbi.nlm.nih.gov/pubmed/?term=Restoration+of+ovarian+function+after+orthotopic+(intraovarian+and+periovarian)+transplantation+of+cryopreserved+ovarian+tissue+in+a+woman+treated+by+bone+marrow+transplantation+for+sickle+cell+anaemia%3A+case+report.+Hum+Reprod.+2006