Abstract
Context: The increase in malignancy of young women in the recent decades, combined with a significant improvement in long term survival after gonadotoxic chemotherapy, have brought about a ubiquitous interest in preservation of fertility in these young patients. The present study examines the effects of Sphingosine-1-Phosphate (S1P) on primary human granulosa cell cultures in-vitro as a possible protecting factor against Doxorubicin (DOX) and Cyclophosphamide associated toxicity. Understanding cytotoxic effects and gonadotoxicity in human luteinized Granulosa Cells (GC) may contribute to our understanding and preventing follicle loss. Study objective: To examine the possible protective effect of S1P on chemotherapy induced gonadotoxicity, in human luteinized Granulosa Cells (GCs). Design: Human GC’s were donated by women undergoing follicular aspiration for in vitro fertilization (IVF), after informed consent and institutional approval by ethics committee (IRB, Helsinki). The GCs were separated from RBC’s by centrifugation on ficoll and plated on multiwell plates for Lactate Dehydrogenase (LDH) assay, and on 6 well plates for flow cytometry. Each experiment was conducted in triplicates and repeated at least three times. Results: S1P significantly protected GCs against Doxorubicin (DOX) toxicity, but inconsistently against Cyclophosphamide. Conclusion: S1P may minimize the gonadotoxic effect of chemotherapy on human luteinized granulosa cells.
Highlights
In the last decades, the survival rates for many malignant diseases that affect young adults have increased to 80-90% [1,2]
Since S1P may decrease the gonadotoxic effects of chemotherapy [9,10] and prevent ova destruction by doxorubicin, we have investigated its effect on human Granulosa Cells (GC)
S1P may protect GCs from DOX induced chemotoxicity: After determining that low S1P concentrations were not cytotoxic we examined the optimal DOX concentration for our experiments, the highest DOX concentration that S1P can protect against (Figure 1)
Summary
The survival rates for many malignant diseases that affect young adults have increased to 80-90% [1,2]. The advance in treatment results in improved childhood, adolescent and young adults cancer long-term survival [3]. From 14% to almost 100% of the adult female cancer survivors may suffer premature ovarian failure (POF) - early menopause [4,5,6,7] while only 8-13% of pre-pubertal girls who were treated for malignant diseases will experience POF [5,8]. Chemotherapy induced amenorrhea may occur in 30-76% of women depending on the treatment protocol and age [9]. Dramatic increase in success rates has been reported following various preservation techniques [1,4,5] none of these methods can completely guarantee future fertility, and it is recommended to consider all the available methods in order to maximize the chance of fertility preservation
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