Genomic Consideration in Chemotherapy-Induced Ovarian Damage and Fertility Preservation

Chemotherapy-induced ovarian damage and fertility preservation in young patients with cancer are emerging disciplines. The mechanism of treatment-related gonadal damage provides important information for targeting prevention methods. The genomic aspects of ovarian damage after chemotherapy are not fully understood. Several studies have demonstrated that gene alterations related to follicular apoptosis or accelerated follicle activation are related to ovarian insufficiency and susceptibility to ovarian damage following chemotherapy. This may accelerate follicular apoptosis and follicle reservoir utilization and damage the ovarian stroma via multiple molecular reactions after chemotherapy. This review highlights the importance of genomic considerations in chemotherapy-induced ovarian damage and multidisciplinary oncofertility strategies for providing high-quality care to young female cancer patients.

Oncofertility care for newly diagnosed girls with cancer in a national pediatric oncology setting, the first full year experience from the Princess Máxima Center, the PEARL study

Background Childhood cancer patients often remain uninformed regarding their potential risk of gonadal damage. In our hospital we introduced a five step standard oncofertility care plan for all newly diagnosed female patients aiming to identify, inform and triage 100% of patients and counsel 100% of patients at high risk (HR) of gonadal damage. This observational retrospective study (PEARL study) evaluated the use of this standard oncofertility care plan in the first full year in a national cohort. Methods The steps consist of 1)timely (preferably before start of gonadotoxic treatment) identification of all new patients, 2)triage of gonadal damage risk using a standardized gonadal damage risk stratification tool, 3)informing all patients and families, 4)counseling of a selected subset of girls, and 5) fertility preservation including ovarian tissue cryopreservation (OTC) in HR patients using amended Edinburgh criteria. A survey of the medical records of all girls newly diagnosed with cancer the first year (1-1-2019 until 31-12-2019) was conducted. Results Of 261 girls, 228 (87.4%) were timely identified and triaged. Triage resulted in 151 (66%) low(LR), 32 (14%) intermediate(IR) and 45 (20%) high risk(HR) patients. Ninety-nine families were documented to be timely informed regarding gonadal damage risk. In total, 35 girls (5 LR, 5 IR, 25 HR) were counseled by an oncofertility expert. 16/25 HR patients underwent fertility preservation (1 ovariopexy + OTC, oocyte cryopreservation (1 with and 1 without OTC) and 13 OTC). Fertility preservation did not lead to complications or delay of cancer treatment in any patient. Conclusion We timely identified and triaged most girls (88%) with cancer with a high risk of gonadal damage to be counseled for fertility preservation. We aim to optimize the oncofertility care plan and the standardized gonadal damage risk stratification tool based on this experience and these may be of value to other pediatric oncology centers.

Anti-Müllerian Hormone as a Sensitive Marker of Ovarian Function in Young Cancer Survivors

We evaluated ovarian function by measuring the levels of anti-Müllerian hormone (AMH), estradiol, and gonadotropins in 83 young women treated for cancer during childhood and adolescence, and classified according to post-treatment gonadal toxicity versus 38 healthy females.Results. The mean AMH values were lower in the entire cohort independently of the risk group as compared to the control, whereas FSH was elevated only in the high risk group. The lowest AMH values were noted in patients after bone marrow transplantation (BMT) and those treated for Hodgkin lymphoma (HL). Nineteen patients (22.9%) had elevated FSH. They all had low AMH values. Lowered AMH values (but with normal FSH and LH) were observed in 43 patients (51.8%). There was no effect of age at the time of treatment (before puberty, during or after puberty) on AMH levels.Conclusion. Our results show the utility of AMH measurement as a sensitive marker of a reduced ovarian reserve in young cancer survivors. Patients after BMT and patients treated for HL, independently of age at treatment (prepuberty or puberty), are at the highest risk of gonadal damage and early menopause.

Testicular Recovery Effects of Folinic Acid on Cyclophosphamide Induced Damage in Rat

Background: Cyclophosphamide is a cytotoxic drug and used as anti-neoplastic agent. It produces gonadal damage leading to infertility. On the other hand Folinic acid is essential in purine synthesis, prevents DNA beak down and essential for spermatogenesis. Therefore, the present study was designed to observe the recovery role of Folinic acid on Cyclophosphamide induced testicular damage. Objective: To observe the recovery effects of Folinic acid on Cyclophosphamide induced testicular damage in Long Evans rats. Methodology: This experimental study was carried out from July 1998 to June 1999 in the Department of Pharmacology, IPGM & R (Under Dhaka University) Dhaka. Twenty four adult Long Evans male rats were pre-treated with Cyclophosphamide, then divided into two groups (A and B).Group of no drug was compared with Folinic acid treated group in 14 day and 28 days. Cytotoxic damage and recovery was assessed by measuring of body weight, testicular weight and volume and the histological findings likely- number of seminiferous tubules, spermatozoa containing tubules, and mean diameter of seminiferous tubules per microscopic field (10X). Serum Testosterone was estimated by Radio Immunoassay to assess if there any Leydig cell damage of rat testes during Cyclophosphamide treatment. Results: After Cyclophosphamide induced toxicity, treatment with Folinic acid produced significant increased in the histological parameters likely- number of seminiferous tubules, spermatozoa containing tubules and mean diameter of seminiferous tubules in 14 days ( p < 0.001) and 28 days (p <0.05). Conclusion: Folinic acid provides significant recovery effects after cyclophosphamide induced gonadal damage in Long Evans rats. J Shaheed Suhrawardy Med Coll, 2011;3 (2): 31-34 DOI: http://dx.doi.org/10.3329/jssmc.v3i2.12074

Ifosfamide versus cyclophosphamide: Long term gonadal effects in 166 male survivors of childhood cancer

9515 Background: Alkylating agents are associated with a risk of male gonadal damage, even in patients treated during childhood. The purpose of this work was to compare this risk after treatment by ifosfamide vs cyclophosphamide during childhood. Methods: Evaluation was based on basal FSH measurement known for its correlation with spermatogenesis. LH and testosterone were also measured in most of the patients. 159 males were evaluated after treatment of a soft tissue sarcoma (79), osteoasarcoma (39), ewing (10), lymphoma (28), other (3). 100 patients received ifosfamide as unique alkylating agent and the other 59 received cyclophosphamide as the other unique alkylating agent between 1973 and 2000. Median age at treatment was 11.2 years (0–18 yrs). Median interval after the end of the treatment was 10.7 years (4.1–20.2 yrs), median age at evaluation was 21.4 years (17.5–36.1 yrs). Median dose of ifosfamide was 54 g/m2 (18- 114), median dose of cyclo was 8.3 g/m2 (4.6–22). Age at treatment and at evaluation were similar in both groups. Results: All males but two (17.5 and 26.5 yrs) had normal testosterone levels. LH was elevated in 14% of the patients. FSH was above laboratory upper limit in 28 of the 59 males (47.5%) treated with cyclophosphamide and was within the normal range in 94 of 100 patients (94%) treated with ifosfamide. Eight patients treated with cyclophosphamide fathered children. The median dose of cyclo was 5.6 g/m2 (4.8 - 10.8 g/m2). Six patients who received 51 to 54 g/m2 fathered children. The risk of abnormal FSH increased with the cumulative dose of cyclophosphamide: only 2/16 boys (12%) who received more than 12 g/m2 had a normal dosage of FSH, while 29/43 (67%) of the boys who received lower doses of cyclo did so. Conclusions: These results show a low risk of gonadal dysfunction in men exposed to ifosfamide (median dose 54 g/m2) compared to the results for males treated with cyclophosphamide. The risk of abnormal FSH increased with the cumulative dose of cyclophosphamide. No significant financial relationships to disclose.