Triptorelin for Fertility Preservation in Adolescents Treated With Chemotherapy for Cancer

Meli, Mariaclaudia; Caruso-Nicoletti, Manuela; Spina, Milena La; Nigro, Luca Lo; Samperi, Piera; D’Amico, Salvatore; Bellia, Francesco; Miraglia, Vito; Licciardello, Maria; Cannata, Emanuela; Marino, Simona Domenica; Cimino, Carla; Puglisi, Fabrizio; Valvo, Laura Lo; Pezzulla, Agnese; Russo, Giovanna; Cataldo, Andrea Di

doi:10.1097/mph.0000000000001144

Cited by 14 publications

(11 citation statements)

References 54 publications

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“…High LH dosage could adversely alter factors required for fertility, as previously described ( Flaws et al , 1997 ), and reported for some drugs ( Bertoldo et al , 2020 ; Park et al , 2020 ). Administering gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy can improve reproductive outcomes in oncologic patients ( Blumenfeld et al , 2015 ; Meli et al , 2018 ; Sinha et al , 2018 ), but their efficacy as gonadoprotective agents is controversial ( Bildik et al , 2015 ; Horicks et al , 2018 ; Lambertini et al , 2018 ; Sofiyeva et al , 2019 ). The effects induced by our proposed LH treatment and the GnRHa therapies currently in use mainly differ in terms of treatment duration and cumulative dosage.…”

Section: Discussionmentioning

confidence: 99%

The cyto-protective effects of LH on ovarian reserve and female fertility during exposure to gonadotoxic alkylating agents in an adult mouse model

et al. 2021

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STUDY QUESTION Does LH protect mouse oocytes and female fertility from alkylating chemotherapy? SUMMARY ANSWER LH treatment before and during chemotherapy prevents detrimental effects on follicles and reproductive lifespan. WHAT IS KNOWN ALREADY Chemotherapies can damage the ovary, resulting in premature ovarian failure and reduced fertility in cancer survivors. LH was recently suggested to protect prepubertal mouse follicles from chemotoxic effects of cisplatin treatment. STUDY DESIGN, SIZE, DURATION This experimental study investigated LH effects on primordial follicles exposed to chemotherapy. Seven-week-old CD-1 female mice were randomly allocated to four experimental groups: Control (n = 13), chemotherapy (ChT, n = 15), ChT+LH-1x (n = 15), and ChT+LH-5x (n = 8). To induce primary ovarian insufficiency (POI), animals in the ChT and ChT+LH groups were intraperitoneally injected with 120 mg/kg of cyclophosphamide and 12 mg/kg of busulfan, while control mice received vehicle. For LH treatment, the ChT+LH-1x and ChT+LH-5x animals received a 1 or 5 IU LH dose, respectively, before chemotherapy, then a second LH injection administered with chemotherapy 24 h later. Then, two animals/group were euthanized at 12 and 24 h to investigate the early ovarian response to LH, while remaining mice were housed for 30 days to evaluate short- and long-term reproductive outcomes. The effects of LH and chemotherapy on growing-stage follicles were analyzed in a parallel experiment. Seven-week-old NOD-SCID female mice were allocated to control (n = 5), ChT (n = 5), and ChT+LH-1x (n = 6) groups. Animals were treated as described above, but maintained for 7 days before reproductive assessment. PARTICIPANTS/MATERIALS, SETTING, METHODS In the first experiment, follicular damage (phosphorylated H2AX histone (γH2AX) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay), apoptotic biomarkers (western blot), and DNA repair pathways (western blot and RT-qPCR) were assessed in ovaries collected at 12 and 24 h to determine early ovarian responses to LH. Thirty days after treatments, remaining mice were stimulated (10 IU of pregnant mare serum gonadotropin (PMSG) and 10 IU of hCG) and mated to collect ovaries, oocytes, and embryos. Histological analysis was performed on ovarian samples to investigate follicular populations and stromal status, and meiotic spindle and chromosome alignment was measured in oocytes by confocal microscopy. Long-term effects were monitored by assessing pregnancy rate and litter size during six consecutive breeding attempts. In the second experiment, mice were stimulated and mated 7 days after treatments and ovaries, oocytes, and embryos were collected. Follicular numbers, follicular protection (DNA damage and apoptosis by H2AX staining and TUNEL assay, respectively), and ovarian stroma were assessed. Oocyte quality was determined by confocal analysis. MAIN RESULTS AND THE ROLE OF CHANCE LH treatment was sufficient to preserve ovarian reserve and follicular development, avoid atresia, and restore ovulation and meiotic spindle configuration in mature oocytes exposed at the primordial stage. LH improved the cumulative pregnancy rate and litter size in six consecutive breeding rounds, confirming the potential of LH treatment to preserve fertility. This protective effect appeared to be mediated by an enhanced early DNA repair response, via homologous recombination, and generation of anti-apoptotic signals in the ovary a few hours after injury with chemotherapy. This response ameliorated the chemotherapy-induced increase in DNA-damaged oocytes and apoptotic granulosa cells. LH treatment also protected growing follicles from chemotherapy. LH reversed the chemotherapy-induced depletion of primordial and primary follicular subpopulations, reduced oocyte DNA damage and granulosa cell apoptosis, restored mature oocyte cohort size, and improved meiotic spindle properties. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION This was a preliminary study performed with mouse ovarian samples. Therefore, preclinical research with human samples is required for validation. WIDER IMPLICATIONS OF THE FINDINGS The current study tested if LH could protect the adult mouse ovarian reserve and reproductive lifespan from alkylating chemotherapy. These findings highlight the therapeutic potential of LH as a complementary non-surgical strategy for preserving fertility in female cancer patients. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by grants from the Regional Valencian Ministry of Education (PROMETEO/2018/137), the Spanish Ministry of Science and Innovation (CP19/00141), and the Spanish Ministry of Education, Culture and Sports (FPU16/05264). The authors declare no conflict of interest.

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Section: Discussionmentioning

confidence: 99%

The cyto-protective effects of LH on ovarian reserve and female fertility during exposure to gonadotoxic alkylating agents in an adult mouse model

et al. 2021

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“…The study found that GnRHa co-treatment may significantly decrease the POF rate from 82–33% in patients with lymphomas. Moreover, a recent single-center retrospective study on postmenarchal adolescent patients (median age 14, range 11 to 18) showed that GnRHa preserved ovarian function and fertility in adolescents treated for acute lymphoblastic leukemia, acute myeloid leukemia, Hodgkin lymphoma, or other cancers ( 100 ). On the last clinical visit, 29 patients (81%) had a regular menstrual cycle, three (8%) oligomenorrhea, and four (11%) amenorrhea.…”

Section: The Clinical Perspective: Concluded and Ongoing Trialsmentioning

confidence: 99%

Fertility Preservation in Female Pediatric Patients With Cancer: A Clinical and Regulatory Issue

et al. 2021

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Fertility preservation represents one important goal of cancer patients’ management due to the high impact on health and quality of life of survivors. The available preventive measures cannot be performed in all patients and are not feasible in all health-care facilities. Therefore, the pharmacological treatment with GnRHa has become a valuable non-invasive and well-tolerated alternative, especially in those who cannot access to cryopreservation options due to clinical and/or logistic issues. Supporting data demonstrate a significant advantage for the survivors who received GnRHa in the long-term maintenance of ovarian function and preservation of fertility. The prevention of the risk of ovarian failure with GnRHa is a typical off-label use, defined as the administration of a medicinal product not in accordance with the authorized product information. Italy has officially recognized the off-label use of GnRHa in adult women at risk of premature and permanent menopause following chemotherapy. However, fertility preservation still represents an unmet medical need in adolescents who cannot access to other treatment options.

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“…Ovarian suppression with gonadotropin releasing hormone (GnRH) analogs —Numerous trials and meta-analyses have demonstrated a correlation between the use of GnRH analogs before and during chemotherapy treatment and lower incidence of premature ovarian insufficiency in young girls facing cancer [ 64 , 65 , 66 , 67 , 68 , 69 ] GnRH indirectly suppresses ovarian function by suppressing gonadotropin secretion from the pituitary gland [ 70 , 71 ]. The use of GnRH analogs in most cases does not protect against gonadotoxic effects of radiotherapy, especially if treatments associated with a high risk of gonadotoxicity are used such as preparation for hematopoietic stem cell transplantation [ 43 , 69 ]. Their usage in fertility preservation is still debatable.…”

Section: Fertility Preservation Methodsmentioning

confidence: 99%

Fertility Preservation and Long-Term Monitoring of Gonadotoxicity in Girls, Adolescents and Young Adults Undergoing Cancer Treatment

Michalczyk

Cymbaluk‐Płoska

2021

Cancers

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Chemo- and radio-therapy can often affect reproductive organs impairing hormonal regulation, fertility, and sexual function. As cancer treatments become more effective and many patients have long term survival, concerns related to patient’s quality of life and reproductive health become relevant. It is especially important for girls and young females facing cancer therapy who have not yet started family planning. Chemotherapy protocols using alkylating agents and abdominal radiotherapy, which are frequently used in the treatment of childhood and adolescent cancer, can cause gonadal injury. The most common clinical manifests are ovarian hormone insufficiency, premature ovarian insufficiency, early menopause and infertility. In this review we assess current literature and summarize current recommendations on the reproductive function of girls and young females undergoing cancer treatment and their follow-up. Fertility preservation methods are discussed, including psychological and ethical considerations and barriers. Improvement of reproductive health and quality of life of adolescents and young adults (AYA) undergoing cancer treatment is an important issue. Further research should be continued to develop efficient and accessible methods for fertility preservation in young patients. An expert panel including oncologists, radiation oncologists, endocrinologists and gynecologists should always consider fertility preservation in pediatric, adolescent and AYA cancer patients, minding patients’ medical condition, cancer staging and potential risk of treatment-related gonadotoxicity.

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Triptorelin for Fertility Preservation in Adolescents Treated With Chemotherapy for Cancer

Cited by 14 publications

References 54 publications

The cyto-protective effects of LH on ovarian reserve and female fertility during exposure to gonadotoxic alkylating agents in an adult mouse model

The cyto-protective effects of LH on ovarian reserve and female fertility during exposure to gonadotoxic alkylating agents in an adult mouse model

Fertility Preservation in Female Pediatric Patients With Cancer: A Clinical and Regulatory Issue

Fertility Preservation and Long-Term Monitoring of Gonadotoxicity in Girls, Adolescents and Young Adults Undergoing Cancer Treatment

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