Προοπτικές γονιμότητας σε ασθενείς με διάγνωση καρκίνου του όρχι.

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1 Προοπτικές γονιμότητας σε ασθενείς με διάγνωση καρκίνου του όρχι. Δημητριάδης Φώτης τ.λέκτορας Ουρολογίας Πανεπιστημίου Tottori Ιαπωνίας Δήλωση συμφερόντων ΚΑΜΙΑ 1

2 Αίτια χαμηλών ποσοτικών παραμέτρων των σπερματοζωαρίων πριν την ορχεκτομή Πιεστικά φαινόμενα, τα οποία ασκούνται στον φυσιολογικό ιστό του όρχι από τον όγκο. Αίτια χαμηλών ποσοτικών παραμέτρων των σπερματοζωαρίων πριν την ορχεκτομή Πρωτοπαθής βλάβη του σπερματικού επιθηλίου (σύνδρομο ορχικής δυσλειτουργίας) 2

3 Αίτια χαμηλών ποσοτικών παραμέτρων των σπερματοζωαρίων πριν την ορχεκτομή Είδος, ιστολογικός τύπος και προέλευση του όγκου. Τα σεμινώματα συνοδεύονται από καλύτερο σπερμοδιάγραμμα σχετικά με τους μη σεμινωματώδης όγκους (Botchan 1997) Αίτια χαμηλών ποσοτικών παραμέτρων των σπερματοζωαρίων πριν την ορχεκτομή Ανοσολογική αντίδραση στα σπερματοζωάρια λόγω καταστροφής του αιματοορχικού φραγμού από τον καρκίνο του όρχι. 3

4 Αίτια χαμηλών ποσοτικών παραμέτρων των σπερματοζωαρίων πριν την ορχεκτομή Οι όγκοι του όρχεως που παράγουν hcg στον ορό του αίματος συνοδεύονται από υψηλότερα επίπεδα Ε2 στο αίμα συγκρινόμενοι με τους όγκους αρνητικούς για hcg στον ορό. Αίτια χαμηλών ποσοτικών παραμέτρων των σπερματοζωαρίων πριν την ορχεκτομή Οι όγκοι του όρχεως που παράγουν hcg στον ορό, σχετίζονται με καταστολή της απάντησης γοναδοτροπινών στις διεγερτικές ώσεις GnRH στο επίπεδο της υπόφυσης, έχοντας ως αποτέλεσμα την αναστολή έκκρισης LH και FSH. 4

5 Αίτια χαμηλών ποσοτικών παραμέτρων των σπερματοζωαρίων πριν την ορχεκτομή Επιπρόσθετα η hcg που εκκρίνεται στο αίμα από τον ορχικό όγκο ίσως να κατάστέλλει την σπερματογένεση και να προκαλεί την παραγωγή ανδρογόνων και οιστραδιόλης από τους όρχεις. Oncofertility Μία δια-επιστημονική προσέγγιση με σκοπό τη μεγιστοποίηση της αναπαραγωγικής ικανότητας ασθενών με καρκίνο και που προσφέρει διάφορες τεχνικές διατήρησης της γονιμότητας Tournaye et al. Lancet

6 Cytotoxic treatment Impairs spermatogenesis temporarily or permanently. The differentiating spermatogonia are most sensitive to chemotherapy In testicular cancer chemotherapy, the combination of bleomycin, etoposide, and cisplatin has an intermediated risk of sterility of 20%. Meistrich ML Fertil Steril 2013 Behringer K, et al. J Clin Oncol 2013 Romerius P et al. Int J Androl 2011 Chemotherapy Severe oligozoospermia and azoospermia often arise in the first 6 months after the start of chemotherapy Recovery depends on the amount of stem-cell loss and their regeneration and can take up to 5 years. Tournaye et al. Lancet

7 Fertility and Radiation High levels of radiation aimed directly at the testicle (20 Gy for carcinoma in situ) will render it completely sterile. Adjuvant radiation used to prevent relapses of seminoma (0.6 Gy) Doses of 1-2 Gy may produce a temporary decrease in sperm counts, but no permanent damage. Waiting period from 6 months to 1 to 2 years before attempting to conceive Συνέπειες χημειοθεραπείας και ακτινοβλίας Chemotherapy and radiation therapy can result in DNA abnormalities of germ cells and potentially increase the risk of disturbed growth, childhood diseases, congenital abnormalities, and cancer in the children of individuals who have had cancer. Conflicting results. Further detailed studies of offspring from patients with cancer are necessary. Tournaye et al. Lancet

8 Prevention of germ cell loss in men Μain strategy to minimize germ cell loss: Choose treatment and combinations that have a less severe effect on spermatogenesis. GnRH analogues or antagonists that temporarily suppress the production of gonadotropins have been used to preserve spermatogenesis, and although some promising data exist in non-human primates, this treatment is not recommended by the American Society of Clinical Oncology. Shetty G, Andrology 2013 Loren AW, J Clin Oncol 2013 Prevention of germ cell loss in men Cryopreservation and the subsequent storage of semen samples is the main option for fertility preservation in men who are undergoing chemotherapy or radiotherapy Ideally, several semen samples should be collected 48 h apart, but because time is always a concern, patients should provide samples without delay, which can mean obtaining more than one sample in a day Electro-ejaculation or TESE might be appropriate for some patients that have difficulty producing semen because of stress, severe illness Hovav Y, Fertil Steril 2001 Schrader M, Urology

9 Prevention of germ cell loss in men Sperm banking should be done before orchiectomy TESE should be offered during scrotal surgery in cases of azoospermia. Williams DH J Urol 2009 van Casteren NJInt J Androl 2010 Hotaling JM Fertil Steril 2013 Prevention of germ cell loss in men Cryopreservation adversely affects the quality of samples of men with testicular cancer. (more samples should be stored) Rives N J Androl 2012 Hotaling JM Fertil Steril

10 Prevention of germ cell loss in men Take home Massages Sperm storage should be done before chemotherapy and radiotherapy Whether sperm DNA damage is increased in men with cancer is controversial Whether cryopreservation itself induces DNA damage remains controversial. Loren AW, J Clin Oncol 2013 O Flaherty C Hum Reprod 2008 Smit M, Hum Reprod 2010 Prevention of germ cell loss in men Take home Massages Men should be warned of a potentially increased risk of genetic damage in sperm collected after initiation of chemotherapy or radiotherapy Radiotherapy is associated with a permanent increase in sperm DNA damage compared with the DNA fragmentation of patients who have received only chemotherapy Smit M, Hum Reprod 2010 Choy JT, Fertil Steril 2013 Ribas-Maynou J, Andrology

11 Treatment options with cryopreserved samples ART is often needed after cancer treatment in men with azoospermia, when the only semen available has been cryopreserved before cytotoxic treatment. ICSI has the advantage of allowing assisted reproduction even if only one semen sample of poor quality has been cryopreserved. Chow EJ, Arch Pediatr Adolesc Med 2009 Hourvitz A, Fertil Steril 2008 Treatment options with cryopreserved samples ICSI is the most successful Technique ICSI IVF IUI Average No of cycles Pregnancy Rate (%) Kelleher S, Hum Reprod 2001 Bizet P, Reprod Biomed Online

12 Treatment options with cryopreserved samples If spermatogenesis recovers after cancer treatment, fresh semen is usually used for ART if no spontaneous pregnancy has happened. <10% use their cryopreserved samples Up to now, follow-up information applies to children born after spontaneous conception, and might be different for children born after ART. Eiser C, Hum Reprod 2011 Peripubertal options for prevention of germ cell loss Spermarche starts at puberty, but it is not exactly known in what stage of pubertal development spermatozoa are produced Electro-ejaculation can be offered in boys and adolescents, unable to produce sperm However, this method of sperm harvesting is not widely used in children because it requires general anesthesia. Alternatively TESE especially for boys at high risk to become sterile after cancer treatment Mόller J, Int J Androl 1983 Berookhim BM, Fertil Steril

13 Preservation of stem cells in prepubertal boys Before puberty, spermatogenesis is absent and cryopreservation of spermatozoa is not an option Some oncofertility programmes collect and freeze testicular stem cells to preserve fertility of survivors of childhood cancer McCook A. Nat Med 2013 Preservation of stem cells in prepubertal boys Stem cell transplantation Testicular stem cells from the mouse can be transplanted into seminiferous tubules devoid of germ cells and reinitiate spermatogenesis Recently, spermatozoa able to fertilize oocytes were obtained by this procedure in both prepubertal and adult recipient macaques Brinster RL, Proc Natl Acad Sci USA 1994 Hermann BP, Cell Stem Cell

14 Preservation of stem cells in prepubertal boys Stem cell transplantation Freezing tissue allows subsequent transplantation either by infusion of a testicular cell suspension into the seminiferous tubules or intratesticular grafting of tissue Orthotopic intratesticular grafting has the advantage of conserving the stem cell niche, but is inappropriate whenever a risk of testicular malignant contamination exists Baert Y, Hum Reprod 2013 Ning L, Fertil Steril 2012 Preservation of stem cells in prepubertal boys Stem cell transplantation Because both testicular stem-cell cryopreservation and transplantation are still under investigation, this preventive strategy remains controversial Testicular germ cell transplantation might be restricted to children that have a high risk (>80%) of becoming sterile because a testicular biopsy in a young child with small testes might diminish future spermatogenesis after recovery from cancer treatment Ruutiainen T, Am J Bioeth 2013 Wallace WH, ancet Oncol

15 Preservation of stem cells in prepubertal boys Stem cell in-vitro culture In-vitro spermatogenesis would: - circumvent the risk of cotransplanting cancer cells - allow the production of male gametes in boys or men who had bilateral orchiectomy Stukenborg JB, Mol Hum Reprod 2009 Preservation of stem cells in prepubertal boys Stem cell in-vitro culture Haploid cells could be produced in-vitro from blastomeres isolated from mice embryos (but sterile offspring) Primordial germ cell-like cells were produced from both embryonic stem cells and induced pluripotent stem cells in mice Once transplanted to the testis of an otherwise sterile recipient mouse, these in-vitro derived cells developed into spermatozoa that could fertilize oocytes, and eventually produced fertile offspring Geijsen N, Nature 2004 Hayashi K, Cell 2011 Li Y, Stem Cell Res (Amst)

16 Preservation of stem cells in prepubertal boys Stem cell in-vitro culture However, any clinical application in human beings remains speculative, not just because of the need to extrapolate this research in human beings, but also because of uncertainties about genetic and epigenetic consequences for the offspring. Tournaye et al. Lancet 2014 Conclusions In adult men, fertility can be preserved by cryopreservation of mature spermatozoa. Even storing one poor quality semen sample is worthwhile Cancer survivors have a slight increased risk for congenital malformations in their offspring; thus, banking semen before starting any gonadotoxic treatment has become a general guideline. 16

17 Conclusions Prepubertal boys harbour stem cells in their testes that can be cryopreserved Prepubertal testicular stem cell banking should be regarded as experimental Creation of spermatozoa from stem cells other than spermatogonial stem cells is still under research 17