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Zicchina, Cecilia (2015) Dosaggio sierico e follicolare di stem cells factor in pazienti poor responder sottoposte a trattamenti di procreazione assistita: evidenze e future applicazioni. [Ph.D. thesis]

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Abstract (english)

Objective
The aim of the study was to detect and quantify the growth factor stem cell factor (SCF) in follicular fluid and serum of patients "poor responders" undergoing to in vitro fertilization (IVF) cycle both after conventional treatment (rFSH) and after non-conventional treatment (rFSH + RLH) in order to understand its role in human gametogenesis and future applications in clinical practice.
Materials and Methods
We conducted a cross-matched observational cohort study in patients "poor responder" addressed to Physiopathology Reproduction Unit of Padua University-Gynecology and Obstetrics Clinic-Department of Women and Child Health, in the time interval between January 2012 and December 2014.
All eligible patients (28) received both ovarian hyper-stimulation protocols, specifically: treatment-A using conventional long protocol stimulation with rFSH and treatment-B using long protocol stimulation with rFSH and rLH. At ultrasound imaging of at least 3 follicles with a mean diameter ≥ 16 mm (or at least 1 follicle greater than 18 mm), 250 g rhCG was administered for ovulation induction; oocyte retrieval, under ultrasound guide, was performed 36 hours after hCG administration. For each patient before the oocyte pick up it was collected a blood-serum sample and subsequently for each oocyte pick up it was recovered a sample of follicular fluid.
The follicular fluids were centrifuged at 250 g for 10 minutes and then were transferred to sterile polypropylene tubes and frozen at -70° C until further analysis. Similarly, samples of blood were centrifuged for 15 minutes at 1000 g after 30 min of collection and serum were transferred to sterile polypropylene tubes and frozen at -70° C. Before storage, the tubes were appropriately marked with an alphanumeric code corresponding to the identification of the patient.
Subsequently, SCF factor was measured quantitatively by ELISA-kit. After the removal of the cumulus complex and corona radiate, only mature oocytes-MII were inseminated by ICSI (Intra Cytoplasmatic Sperm Injection). For all patients, were collected clinical data regarding ovarian reserve, trend of the ovarian response to hyper-stimulation and quantitative and qualitative data of oocytes and embryos. Data were collected regarding the dosage of serum and follicular SCF for each patient, for both treatments.
Primary endpoint was to compare the two treatments in terms of clinical response and biochemical assay of serum and follicular SCF.
Secondary endpoint was to compare the values of follicular SCF with serum SCF, in order to assess whether the value could reflect the serum follicle.
Tertiary endpoint was to correlate the serum SCF values, with the clinical outcome, in order to evaluate its use as a predictive parameter of clinical response to hormonal stimulation.
Results
Based on our inclusion criteria, 28 patients resulted eligible for the study (56 treatments). The comparison between the two treatment groups considering clinical response demonstrated significant differences, higher with the addition of rLH (treatment B), in terms of 17β estradiol at the time of ovulation induction [p <0.05], endometrial thickness [p <0.001], number of follicles <16 mm [p <0.05], total number of oocytes retrieved at pick up [p <0.05], oocytes MII [p <0.001] and embryos quality [p <0.05]. However, the analysis of serum and follicular SCF concentrations between the two treatment groups, showed no statistically significant difference. (primary endpoint).
From the correlation between the values of serum and follicular SCF emerged a strong linear association [p <0.001; r2 0.998] (secondary endpoint).
From the comparison of clinical and biochemical parameters of SCF, emerged a significative correlation between the SCF serum value and number of oocytes MII, and specifically: for values between 1200 and 1400 pg / mL there was a likelihood of 50% to recover 3 MII oocytes and for values greater than or equal to 1400 pg / mL there was a likelihood of 95% to recover 1 MII oocyte. Finally, for values lower than 350 pg / mL, it was observed a probability of 95% to not retrieve any oocyte. (tertiary endpoint)
Conclusions
In controlled ovarian hyper-stimulation protocols of "poor responders" patients, the administration of rLH showed significant improvements in terms of clinical response, both quantitative and qualitative. However this improvement induced by rLH, seems to not affect the pathway of SCF (probably influenced only by FSH). The detection of SCF serum values comparable to SCF follicular ones, opens the possibility of predicting the SCF follicular values before the oocyte pick-up. Since SCF follicular value is predictive of the number of MII oocytes recruitable, we can hypothesize that in the next future SCF could be used as a pre pick-up marker to predict the ovarian response to hormonal hyper-stimulation avoiding oocyte pick up in the absence of oocytes.

Abstract (italian)

Scopo
Scopo dello studio è rilevare e quantificare il fattore di crescita Stem Cell Factor (SCF) nel liquido follicolare e nel siero di pazienti "poor responder" sottoposte a trattamenti di fertilizzazione in vitro (IVF) sia dopo trattamento convenzionale (rFSH) che dopo trattamento non-convenzionale (rFSH+rLH) al fine di comprendere il suo ruolo nella gametogenesi umana e le sue eventuali future applicazioni nella pratica clinica.
Materiali e Metodi
E' stato condotto uno studio osservazionale cross-matched di coorte in pazienti "poor responder" afferite presso il Centro di PMA della Clinica Ostetrica e Ginecologica di Padova - Dipartimento di Salute della Donna e del Bambino - Università  degli Studi di Padova nell'intervallo temporale compreso tra Gennaio 2012 e Dicembre 2014. Le pazienti eleggibili per lo studio (28) hanno ricevuto tutte 2 trattamenti di stimolazione ovarica e nello specifico: Trattamento A mediante protocollo lungo di stimolazione convenzionale con solo rFSH e Trattamento B mediante protocollo lungo di stimolazione con rFSH con l'aggiunta rLH. Al riscontro ecografico di almeno 3 follicoli di diametro medio ≥ di 16 mm (o di almeno 1 follicolo più grande di 18 mm), è stato somministrato rhCG 250 µg per l'induzione dell'ovulazione; il recupero ovocitario, sotto guida ecografica, è stato eseguito 36 ore dopo la somministrazione dell'hCG. Ad ogni paziente prima del pick up ovocitario è stato eseguito un prelievo di plasma e, successivamente nello stesso soggetto, al prelievo ovocitario, è stato recuperato un campione di liquido follicolare.
I liquidi follicolari sono stati centrifugati a 250 g per 10 minuti e successivamente sono stati trasferiti in provette di polipropilene sterili e congelati a -70 ° C fino ad ulteriore analisi. Analogamente, i campioni di sangue sono stati centrifugati per 15 minuti a 1000 g entro 30 min dalla raccolta ed i sieri sono stati anch'essi trasferiti in provette sterili di polipropilene e congelati a -70 ° C. Prima dello stoccaggio, le provette sono state opportunamente contrassegnate con un codice alfanumerico corrispondente all'identificazione della paziente. Successivamente, il fattore SCF è stato dosato quantitativamente mediante apposito kit, usando il test biochimico ELISA. Tutti gli ovociti recuperati sono stati decoronizzati e solo gli ovociti maturi inseminati mediante tecnica ICSI (Intra Cytoplasmatic Sperm Injection). Di tutte le pazienti sono stati raccolti dati clinici inerenti la riserva ovarica, l'andamento della risposta ovarica alla iper-stimolazione controllata ed la resa quantitativa e qualitativa del trattamento, in termini di ovociti ed embrioni. Sono stati raccolti dati inerenti il dosaggio sierico e follicolare di SCF di ogni paziente per entrambi i trattamenti.
Endpoint primario è stato confrontare i due trattamenti in termini di risposta clinica e dosaggio biochimico di SCF follicolare e sierico.
Endpoint secondario è stato confrontare i valori di SCF follicolare con quello sierico al fine di valutare se il valore sierico potesse rispecchiare quello follicolare.
Endpoint terziario è stato correlare i valori sierici di SCF con l'esito clinico del trattamento al fine di valutare la potenzialità  del suo utilizzo come parametro predittivo di risposta clinica alla stimolazione ormonale.
Risultati
Sulla base dei criteri di inclusione sono risultate eleggibili per lo studio 28 pazienti (56 trattamenti). Il confronto tra i due gruppi di trattamento in termini di risposta clinica ha mostrato differenze significative per quanto riguarda il 17β estradiolo al momento dell'induzione [p<0.05], lo spessore endometriale [p<0.001], il numero di follicoli < 16 mm [p<0.05], il numero totale di ovociti recuperati al prelievo ovocitario [p<0.05], gli ovociti in Metafase II [p<0.001] e la qualità  degli embrioni [p<0.05], risultati significativamente superiore con l'aggiunta di rLH (trattamento B).
Tuttavia l'analisi delle concentrazione sieriche e follicolari tra i due gruppi di trattamento non ha mostrato differenze statisticamente significative. (endpoint primario)
Dalla correlazione tra i valori follicolari e sierici di SCF è emersa forte associazione lineare [p <0.001; r20.998] (endpoint secondario).
Dal confronto tra i parametri clinici ed i valori di SCF è emersa significatività statistica tra il valore sierico di SCF ed il numero di ovociti maturi (MII).
Nello specifico, per valori di SCF compresi tra 1200 e 1400 pg/mL è stata riscontrata una probabilità  del 50% di recuperare 3 ovociti MII e per valori pari o superiori a 1400 pg/mL una probabilità  del 95% di recuperare 1 ovocita MII.
Infine per valori inferiori a 350 pg/mL, è stata riscontrata una probabilità  del 95% di non recuperare nessun ovocita. (endpoint terziario)
Conclusioni
L'aggiunta di rLH nel protocollo di stimolazione ovarica controllato di pazienti "poor responders" ha mostrato significativi miglioramenti in termini di risposta clinica, sia quantitativa che qualitativa. Tuttavia tale miglioramento indotto dall'rLH sembra non influenzare il pathway di SCF (probabilmente influenzato solo da FSH). Il riscontro di valori sierici di SCF, comparabili a quelli follicolari, apre la possibilità  di predire prima del pick up i valori follicolari di SCF. Essendo il valore follicolare di SCF predittivo del numero di ovociti MII reclutabili, lascia ipotizzare che nel prossimo futuro SCF potrebbe essere utilizzato come marker predittivo della risposta ovarica alla stimolazione suggerendo aggiustamenti nei dosaggi di rFSH o suggerendo l'inutilità  di giungere al prelievo ovocitario.

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EPrint type:Ph.D. thesis
Tutor:Gangemi, Michele
Supervisor:Gizzo, Salvatore
Ph.D. course:Ciclo 27 > scuole 27 > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE > "EMATOONCOLOGIA, GENETICA, MALATTIE RARE E MEDICINA PREDITTIVA"
Data di deposito della tesi:30 January 2015
Anno di Pubblicazione:30 January 2015
Key Words:SCF, rLH, IVF, poor responder, AMH
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/40 Ginecologia e ostetricia
Struttura di riferimento:Dipartimenti > Dipartimento di Salute della Donna e del Bambino
Codice ID:7801
Depositato il:10 Nov 2015 13:00
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Bibliografia

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