Authors: Daniel Green, MD and Leslie Appiah, MD

INTRODUCTION

Advances in cancer treatments have significantly changed the outcome for pediatric cancers with 5 year survival rates approaching 75-80%.  With improvements in treatment, of all cancer survivors, 1 in 25 will be of reproductive age [1].  Of these patients 8-12% will experience fertility compromise [2].  Manifestations of gonadal injury include disordered puberty, menopause-related health problems such as cardiac, skeletal and cognitive dysfunction in females and decreased reproductive potential.  Standard options for fertility preservation include sperm, oocyte, and embryo banking.  Investigational options include testicular, ovarian and immature oocyte cryopreservation.  Estimating risk prior to therapy allows determination and implementation of the appropriate fertility preserving therapy.  However, only ovarian tissue cryopreservation restores hormonal function, albeit temporary.  Minimizing risk prior to therapy will mitigate the need for invasive and costly fertility preserving therapies while preserving hormonal function after cancer treatment. 

ESTIMATING RISK

Assessment of the risk for impaired fertility after the completion of therapy should be undertaken prior to the start of therapy for optimal fertility preservation outcomes.  Surgical procedures, radiation therapy and chemotherapy can each produce impaired fertility.  Impaired fertility and hormone production are differentially sensitive to treatment exposures in males whereas these two functions are tightly linked in females.  The risk factors for impaired fertility differ for males and females.

Males

Females

MINIMIZING RISK

Several agents have been proposed as potentially fertoprotective, conferring protection against the damaging effects of chemotherapy and radiation.  Gonadotropin releasing hormone agonists (GnRHa) are the most studied, however results are conflicting.  Several newer agents are currently being evaluated which show some promise.  These agents include imatinib, bone marrow derived mesenchymal stem cells (BMMSC), sphingosine-1-phosphate (S1P), tamoxifen, granulocyte colony stimulating factor (G-CSF) and AS101.  GnRHa, Tamoxifen and G-CSF are the only agents that have been used in humans.  Other therapies have shown promise in rodent and primate studies however concerns remain about interference with chemotherapeutic efficacy and perpetuation of damaged DNA cell lines with resultant fetal loss and/or malformation.  Further studies are required to determine efficacy and safety in humans. 

Gonadotropin releasing hormone agonist

Imatinib

Bone marrow-derived mesenchymal stem cells

Sphingosine-1-phosphate (S1P)

Tamoxifen

AS101

Granulocyte-Colony Stimulating Factor (G-CSF)

SUMMARY

Cytotoxic agents act in specific ways on different cell populations within the ovary and more than one mode of treatment related gonadal injury may occur.  Consequently different fertoprotective agents may be tailored to cancer treatment regimens.  Rodent and primate studies that are safe and show efficacy need to be translated into human studies.  Agents currently used in humans for other indications need to be evaluated in prospective studies to better assess efficacy as a fertoprotective agent.  To adequately study these treatments, lessons from GnRHa studies are helpful: end-points must be accurately defined and reproductive and survival outcome measured.  Accurate end-points may include post-treatment follicular number and reliable and reproducible markers of ovarian reserve.  Lastly and most importantly, therapies must show that administration during cancer treatment does not affect treatment outcome or result in propagation of DNA damage leading to fetal loss and/or malformation.   Identification of successful fertoprotective agents will enhance therapeutic options to preserve fertility and restore hormonal function after cancer treatment.

 

 

References