Prevention of chemotherapy-induced ovarian damage Hadassa Roness, Ph.D., Oren Kashi, M.Sc., Dror Meirow, M.D.  Fertility and Sterility  Volume 105, Issue 1, Pages 20-29 (January 2016) DOI: 10.1016/j.fertnstert.2015.11.043 Copyright © 2016 Terms and Conditions

Figure 1 Cyclophosphamide induces dormant follicle activation and loss. (A) During normal follicular development, the primordial follicles are under balanced regulation by the PI3K/PTEN/Akt pathway, and suppressive factors produced by growing follicles ensure that the vast majority of primordial follicles are maintained in a state of dormancy and very few are activated into growth. (B) Exposure to chemotherapy disturbs the balance, up-regulating the PI3K/PTEN/Akt follicle activation pathway and causing growing follicles to undergo apoptosis. The loss of growing follicles reduces the secretion of inhibitory factors responsible for maintaining the dormancy of the primordial follicle reserve. As a result, more primordial follicles are recruited into growth, develop, and die, causing the reservoir to burn out. (Adapted and reprinted, with permission, from Kalich-Philosoph, 2013 [17]). Fertility and Sterility 2016 105, 20-29DOI: (10.1016/j.fertnstert.2015.11.043) Copyright © 2016 Terms and Conditions

Figure 2 AS101 co-treatment rescues fertility in mice treated with cyclophosphamide (Cy). Three successive mating rounds were conducted in mice that received phosphate buffered saline, Cy (75 mg/kg × four weekly injections), AS101 (10 mg), or Cy + AS101. (A) Mean litter size per pregnant mouse in each treatment group. (B) Total number of pups born to all mice within each group over the entire mating period. (C) Midline histological sections of ovaries removed after the mating rounds and stained with hematoxylin and eosin (H&E) showing corpora lutea (examples of corpora lutea in each section are marked with arrows). Data presented as mean ± SEM; n = 6 per group; *P<.05; **P<.01; Scale bars = 400 mm. (Reprinted, with permission, from Kalich-Philosoph, 2013 [17]). Fertility and Sterility 2016 105, 20-29DOI: (10.1016/j.fertnstert.2015.11.043) Copyright © 2016 Terms and Conditions

Figure 3 Molecular pathways in the oocyte in response to cytotoxic injury. DNA damage activates c-Abl, which, depending on the type and severity of the damage, can shift the balance between DNA repair, proliferation and/or activation of cell death. Moderate or low activation of c-Abl promotes DNA repair via Rad51, while at high levels c-Abl activates TAp63 mediated cell death. Tap63 is responsible for inducing transcription of proapoptotic family members PUMA and NOXA, which then bind to BAX/BAK and trigger apoptosis. Tap63 also affects the PTEN-PI3K follicle activation pathway by increasing PTEN levels, thereby reducing PIP3 mediated AKT phosphorylation, and inhibiting proliferation. BAK = Bcl-2 homologous antagonist killer; BAX = Bcl-2-associated X protein; NOXA = phorbol-12-myristate-13-acetate-induced protein 1; PUMA = p53 upregulated modulator of apoptosis. (Adapted and reprinted, with permission, from Roness, 2014 [100]). Fertility and Sterility 2016 105, 20-29DOI: (10.1016/j.fertnstert.2015.11.043) Copyright © 2016 Terms and Conditions