Novel approaches to fertility restoration in women with premature ovarian insufficiency.

Summary

Recently, Rosario et al [1] have published an interesting review on novel approaches aimed at restoring fertility in women with premature ovarian insufficiency (POI) [1]. This entity is characterized by oligo/amenorrhea, high follicle stimulating hormone (FSH) (over 25 IU/L or 40 IU/L), low estradiol (<50 pmol/L) in women younger than 40 years of age. Some authors have found that 5% of them will conceive naturally [2]. Fraison et al [3] confirmed that approximately 1,000 follicles remain in the ovary one year after the last menstruation. Follicles can be found in the post-natal period following neo-oogenesis. Rosario et al [1] discuss in their review emerging approaches that may provide new opportunities, mostly based on the activation of residual primordial follicles and therapy with platelet enriched plasma. Folliculogenesis and normalization of hormonal levels were detected in women with POI treated  with mesenchymal stem cells extracted from bone marrow, peripheral blood mononuclear cells [4], adipose tissue [5], placenta, umbilical cord and/or menstrual blood. Activation of  remaining primordial follicle is being explored through regulatory pathways, phosphoinositide 3-kinase (PI3K) Akt/mammalian target of rapamycin (mTOR) and  hippo pathways [6]. Collagen can also be added.  Despite this, most of the clinical data are uncontrolled and small numbers of POI patients were recruited. Authors conclude that clinical data are largely preliminary and controlled clinical studies are needed.

Commentary

Novel modern technologies that improve fertility rate in POI patients are well described. Clinical approach with empathy and appropriate hormonal therapy are needed for all women with POI. Possible mechanisms of the origin of POI can be decreased number of follicles at birth, increased atresia and altered follicle maturation. Estradiol and progesterone therapy has to be individually well tailored trying to decrease FSH levels below 15 IU/L [7], when ovulation can be expected. Estradiol sensitizes and differentiates granulosa cells, down regulates FSH and LH receptors, increases response of FSH and the number of LH receptors previously induced by FSH.  In addition, it deceases LH, stimulates endometrial proliferation and the production of cervical mucus. Estradiol regulates key enzymes involved in mitochondrial bioenergetics including glucose transporters. DHEAS is added due to the conversion to estradiol and it induces antral follicle growth. Thyroid hormones influences steroidogenesis, especially DHEAS, through cytochrome P450 and sulfotransferase. Optimal levels of TSH has to be 1-2.5. Insulin levels have to be tested with oral glucose tolerance test in order to detect insulin sensitivity. Hyperinsulinism decreases glycodelin leading to follicle growth retardation and decreased uterine vascularization. It increases plasminogen activator inhibitor activity (PAI). Metformin, can be added in order to block insulin receptors and induce GLUT4 expression. Uterine glucose metabolism plays an important physiological role during follicle development, implantation, embryo development and pregnancy. Sleeping habits have to be corrected and melatonin added [8 ] because it inhibits gonadotropin releasing hormone, increases gamma-amino butyric acid, inhibits thyroid releasing hormone and growth hormone. Thrombophilia status has to be checked (Leyden V, MTHFR, factor II and PAI mutations).  PAI-1 is a major inhibitor of fibrinolysis. Increased PAI-1 activity results in placental bed thrombosis and vascular insufficiency, promoting recurrent pregnancy loss. Methyl folate and aspirin are advised. Emotional status of every patient with POI is crucial. Sometimes anxiolytics can be added and psychotherapy can be advised including lifestyle changes with focus on achieving optimal body mass index.

When all these goals are achieved pregnancy rate in POI can increased to 18%. In a case that no dominant follicles are obtained during 6-12 months, with FSH 10-15 IU/L, in women who are well prepared from a endocrinological, hematological, immunological and psychological point of view, modern technological approaches can be performed with more successful pregnancy rates than the expected now.

Prof. Dr. Svetlana Vujović
Head of the Department of Endocrinology of Gender
Faculty of Medicine, University of Belgrade, Belgrade Serbia
President of the Serbian Menopause Society

References

1. Rosario R, Anderson RA. Novel approaches to fertility restoration in women with premature ovarian insufficiency. Climacteric. 2021 Jan 11;1-13.
   https://pubmed.ncbi.nlm.nih.gov/33427510/
2. Fraison E, Crawford G, Casper G, Harris V, Ledger W. Pregnancy following diagnosis of premature ovarian insufficiency: a systematic review. Reprod Biomed Online. 2019;39(3):467–76.
   https://pubmed.ncbi.nlm.nih.gov/31279714/
3. Faddy MJ, Gosden RG. A model conforming the decline in follicle numbers to the age of menopause in women. Hum Reprod. 1996;11(7):1484–6.
   https://pubmed.ncbi.nlm.nih.gov/8671489/
4. Huang Q, Liu B, Jiang R, et al. G-CSF-mobilized peripheral blood mononuclear cells combined with platelet-rich plasma accelerate restoration of ovarian function in cyclophosphamide-induced POI rats. Biol Reprod. 2019;101(1):91-101.
   https://pubmed.ncbi.nlm.nih.gov/31034039/
5. Vural B, Duruksu G, Vural F, Gorguc M, Karaoz E. Effects of VEGF + Mesenchymal Stem Cells and Platelet-Rich Plasma on Inbred Rat Ovarian Functions in Cyclophosphamide-Induced Premature Ovarian Insufficiency Model. Stem Cell Rev Rep. 2019;15(4):558–73.
   https://pubmed.ncbi.nlm.nih.gov/31037585/
6. Ford EA, Beckett EL, Roman SD, McLaughlin EA, Sutherland JM. Advances in human primordial follicle activation and premature ovarian insufficiency. Reproduction. 2020;159:R15–R29.
   https://pubmed.ncbi.nlm.nih.gov/31376814/
7. Vujović S, Ivovic M, Tančić-Gajić M, Marina L, Ljubic A, Dragojević-Dikić S, Genazzani AR. Endometrium receptivity in premature ovarian insufficiency – how to improve fertility rate and predict diseases? Gynecol Endocrinol. 2018;34(12):1011-1015.
   https://pubmed.ncbi.nlm.nih.gov/30044147/
8. Dragojević Dikić S, Vasiljević M, Jovanović A, et al. Premature ovarian insufficiency: novel hormonal approaches in optimizing fertility. Gynecol Endocrinol. 2019;36(2):162-165. https://pubmed.ncbi.nlm.nih.gov/31311350/

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