Reducing Ovarian toxicity caused by Cyclophosphamide

Reducing Ovarian toxicity caused by Cyclophosphamide treatment which a main part of HSCT therapy (in doses 200mg/kg - 14 g for average female 70kg ) and in a much lower doses 750-900mg/m2 (which equals to about 1.2-1.5 grams for an average female).

The first step is the awareness of risks. I remember when I was very interested in HSCT treatment I was not properly informed. In fact, I was told by HSCT team  the risks are not signifcicant and I have  a risk like general populaton 1-2% of infertility. 

Neadless to say this is a complete nonsense.

Toxicity of cyclophosphamide for age 20-30, is 

age 30-40 is 7g

an 40+ is even 5 grams

Measure of ovarian age - although the age is the best predictor, AMH levels are very goo estimate too.   AMH is expected to be employed as a new index for assessment of ovarian toxicity of chemotherapeutics, as a sharp decline even larger than that of estradiol and inhibin B which are usually observed during chemotherapy [35]. Besides, the high sensitivity and specificity as well as the satisfying intraperiodic and interperiodic stability make AMH the only ovarian reserve marker that can be determined in both of follicular phase and luteal phase. 

 Also, these findings are considered as an indirect prove for the hypothesis that cyclophosphamide may lead to excessive activation of primordial follicles through over-activating this signaling pathway. 

 Our study reveals that CY increased phosphorylation of key proteins that play a critical role in regulating the proliferation of oocytes and granulosa cells in primodial follicles through the Pl3K signaling pathway. The specific mTORC1 inhibitor rapamycin can maintain the follicle reserve by preventing the over-activation of primordial follicle via Pl3K/Akt/mTOR signaling pathway. Our findings have revealed, for the first time, an effective protection of ovarian function during chemotherapy by rapamycin, and provide a new nonsurgical method to preserve primordial follicles for female cancer patients. These results may also have implications in ovarian reserve protection and POF prevention. 

 Anti-Mullerian hormone attenuates both cyclophosphamide-induced damage and PI3K signalling activation, while rapamycin attenuates only PI3K signalling activation, in human ovarian cortex in vitro  

 At the Brigham and Women's Hospital, our recommendation for women interested in this co-treatment is Depot-Lupron 3- month formulation 11.25 mg for two injections (total 6 months of therapy) started 3±4 weeks prior to the initiation of cyclophosphamide, and then pulse' Lupron with 7.5mg of the monthly formulation one month prior to and on the day of the pulse' cyclophosphamide. The ®rst Lupron injection may by necessity be given closer to the ®rst cyclopho- sphamide dose if the clinical situation is dire. Pretreatment BMD measurement is recommended, and repeated if the GnRH-a is to be continued for longer than 6 months. If a patient's bone density is below normal or the patient is on steroids, bispho- sphonate therapy may be offered, but concerns exist about effects on future fetuses from bone treated with biphosphonates. All patients are supplemented with calcium and vitamin D. 

https://pubmed.ncbi.nlm.nih.gov/31250176/

 Results: rAMH reached the ovary after intraperitoneal injection and demonstrated post-receptor bioactivity. Cy administration in mice caused primordial follicle activation, as shown by a decrease in primordial follicle population accompanied by an increase in early growing follicles and granulosa cell proliferation. Co-administration of rAMH reduced follicle activation, thereby protecting the primordial follicle reserve, and improving long-term fertility and reproductive outcomes. rAMH co-administration did not interfere with the cytotoxic actions of Cy in vitro on breast cancer cell line or in vivo in a model of human leukaemia. 

Chen X, Tang Z, Guan H, Xia H, Gu C, Xu Y, Li B, Zhang W. Rapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide-induced damage. J Reprod Dev 2022;68:287–294.

 Recent studies demonstrated that caloric restriction (CR) without malnutrition could prolong female fertility by preventing maternal age‐associated oocyte aneuploidy and meiotic spindle defects (Selesniemi et al., 2008, 2011). 

In conclusion, this work is among the first human data to demonstrate an effect of cyclophosphamide on both direct primordial follicle damage and PI3K signalling, and potentially primordial follicle activation. Furthermore, we have provided novel evidence supporting two different mechanisms for the chemoprotective efficacy of AMH in the human ovary; while rapamycin also prevented PI3K signalling, its effects on follicle protection were unclear. These data therefore suggest that administration of AMH alongside chemotherapy treatment may have significant benefit in protecting the ovarian reserve, and in fact there may be potential for benefit from both AMH and rapamycin as suggested by other rodent studies (Kashi et al., 2023).https://academic.oup.com/humrep/article/39/2/382/7468100

Targeting mTOR is a good strategy to pursue, Dr. Woodruff said. Research in mice, for example, has shown that other drugs that target the same pathway as mTOR, including the targeted therapy imatinib (Gleevec®), can also help to protect the reserve of primordial follicles.

But more research is needed, she stressed, to “identify all of the factors and the signaling pathways that may be involved in early activation” of primordial follicles.

In the study, the Langone team tested everolimus (Afinitor®)—which is approved by the Food and Drug Administration (FDA) for the treatment of some forms of pancreatic, kidney, and breast cancer—and sapanisertib (also known as INK128), an investigational second-generation mTOR inhibitor.