Both in vivo FSH depletion and follicular exposure to Gonadotrophin-releasing hormone analogues in vitro are not effective to prevent follicular depletion during chemotherapy in mice
Notice bibliographique
Résumé
STUDY QUESTION: Does fertility preservation using gonadotrophin-releasing hormone (GnRH) analogues during chemotherapy act through a direct effect on the ovary or through inhibition of FSH secretion? SUMMARY ANSWER: The absence of FSH in vivo and the direct exposition of ovarian follicles to GnRH analogues in vitro did not prevent chemotherapy-induced ovarian damage. WHAT IS KNOWN ALREADY: The potential mechanisms of action of GnRH analogues in protecting ovaries against chemotherapy damage remain poorly understood. We previously showed that GnRH analogues have a limited inhibitory effect on gonadotropin secretion and follicular growth in mice. STUDY DESIGN SIZE, DURATION: Mouse models were developed to independently evaluate (i) the indirect effect of FSH depletion on chemotherapy-induced ovarian damage using Fshb-deficient (-/-) mice to mimic the profound inhibition of FSH secretion during GnRH analogues treatment and (ii) the direct in vitro effect of GnRH agonist and antagonist in follicles exposed to chemotherapy using a follicular culture system. PARTICIPANTS/MATERIALS, SETTING, METHODS: To assess the indirect effect of GnRH analogues through FSH inhibition, Fshb-/- mice were treated with 1 IU pregnant mare serum gonadotropin (control group) or saline (study group) for 7 days and with cyclophosphamide (200 mg/kg) on Day 5. Ovaries were collected 48 h post-cyclophosphamide to evaluate ovarian reserve, cellular apoptosis and proliferation. To evaluate the direct effects of GnRH analogues on growing follicles, isolated preantral follicles from prepubertal mice were cultured in vitro for 13 days with 1 μM GnRH analogues and 20 μM of 4-hydroperoxycyclophosphamide or not at Day 4. Oocytes were matured by adding epidermal growth factor (EGF)/hCG on Day 12. Follicular development, follicular survival, oocyte maturation rates, cAMP production, and steroidogenesis were evaluated. To assess the direct GnRH analogues effects on follicular reserve, whole neonatal ovaries were cultured in vitro under the same conditions for 2 days. Ovaries were processed 24 h post-chemotherapy for ovarian reserve, cellular apoptosis and proliferation analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Cyclophosphamide induced a significant follicular loss of more than 50% in Fshb-/- mice regardless of previous treatment with gonadotropins and no difference was observed in cell proliferation or apoptosis. In vitro experiments on growing follicles showed that 4-hydroperoxycyclophosphamide significantly decreased preantral follicle survival and maturation rates (55% and 37%, respectively) and delayed follicular development, regardless of the presence of GnRH analogues. Chemotherapy reduced granulosa cell numbers in all groups, while no change in cAMP production/106 granulosa cells was observed. Similarly, 4-hydroperoxycyclophosphamide induced apoptosis and significant follicular loss in cultured neonatal ovaries irrespective of GnRH analogues exposure. LIMITATIONS REASONS FOR CAUTION: As ovarian GnRH receptors expression differs in humans and mice, further studies are needed to validate our results in human ovaries. WIDER IMPLICATIONS OF THE FINDINGS: Our findings demonstrate that ovarian damage occurred even in the absence of FSH, suggesting that inhibition of the pituitary-gonadal axis is not involved in ovarian protection during GnRH analogues treatment. Using in vitro models, no evidence for direct protective effect of GnRH analogues against cyclophosphamide metabolite damage was observed. At present, clinical efficiency of GnRH analogues to prevent chemotherapy-induced ovarian damage remains highly debated and these experimental results reinforced the question as they did not bring evidence of direct or indirect mechanisms of protection. LARGE SCALE DATA: N/A. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by the Belgian FNRS, 'Le Fonds Emile DEFAY', and 'La Fondation Rose et Jean Hoguet'. Authors have no conflict of interest to declare.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».