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Fertility preservation for people with cancer

Testicular biopsy

Clinical Question

In men and boys with cancer does the use of testicular biopsy result in pregnancy and live birth? Is there any evidence of harm from the harvesting procedure?

Chemotherapy, radiation and surgical treatments can result in temporary or permanent infertility for men. The collection of and cryopreservation of spermatozoa in semen is recommend in peri-pubertal and pubertal patients. However, options are unproven in pre-pubertal boys who are not yet making mature sperm. In this group cryopreservation of testicular tissue containing stem cells may be considered to provide hope for future fertility treatment options once these patients reach adulthood.[1]

Testicular spermatids may be recovered from testicular biopsies and used for intracytoplasmic sperm injection in azoospermic adults who have already undergone cancer treatments and are now desiring fertility treatment. The harvesting procedure itself is known as testicular sperm extraction or TESE. Spermatids may be extracted from fresh biopsies or cryopreserved tissues taken from post-pubertal boys before treatment, but this is still regarded as highly experimental.

Pre-pubertal boys

Spermatogonial stem cells are present in testicular tissue in pre-pubertal boys even when mature spermatids are not. Collection of testicular tissue from pre-pubertal boys under general anaesthetic is usually combined with other diagnostic or therapeutic procedures. This is a low risk approach[2][3][4][5][6] however, caution should be exercised as there is a potential risk of contamination with disruption of the blood testis barrier for boys with acute leukaemia.[7]

Testicular biopsy for fertility preservation in pre-pubertal boys remains an unproven procedure as it is not currently possible to use these stem cells in fertility treatment. There is a paucity of published research in this area, with a total of six studies included which address this part of the question and this patient group.[2][8][3][4][9][5] Cryopreservation of testicular tissue in this setting is therefore done with the expectation that future technology will allow in vitro maturation of these stem cells, or that in vivo transplantation would allow natural restoration of spermatogenesis and fertility. A recent publication regarding in vitro maturation in macaques resulting in livebirth provides encouragement for eventual success in humans.[10]

Evidence summary one

Evidence summaryLevelReferences
Extraction and use of stem cells from testicular tissue biopsies from pre-pubertal boys is currently experimental. Recent evidence showing successful live-births in a macaque monkey model is encouraging. This represents the only opportunity for future fertility in pre-pubertal boys whose fertility may be been compromised by cancer treatment. However, caution should be exercised as there is a potential risk of contamination with disruption of the blood testis barrier for boys with acute leukaemia.IV[2], [8], [3], [5], [4], [9]

Recommendation One

Evidence-based recommendationGrade
Health professionals should consider discussion about testicular tissue biopsy and cryopreservation in pre-pubertal boys, particularly if a general anaesthetic is planned as part of other diagnostic or therapeutic procedures. The surgical procedure is considered low risk (apart from boys with acute leukaemia) but there are no data on fertility outcomes. This treatment is currently regarded as experimental and should only occur within an established research/ethical framework. This invasive procedure should be balanced against the option of waiting until fertility is required, as recovery from testicular damage is possible and sperm extraction an option if natural fertility is not successful.D

Pubertal boys and post-pubertal men

In mid and late-pubertal boys with a testicular volume of ≥ 8 ml and men who are too unwell or otherwise unable to ejaculate, sperm can be harvested under general anaesthesia by testicular sperm extraction (TESE). There are several approaches to tissue collection including needle aspiration, open biopsy with random sampling of several sites or the more technically demanding microdissection testicular sperm extraction (microTESE) procedure using an operative microscope. Overall, microTESE has the highest yield of sperm from azoospemic patients in general (Bernie 2015, Deruyver 2014), but there are a limited number of surgeons trained and experienced in microTESE in Australia.

Depending on the clinical setting, sperm retrieval rates from cryopreserved testicular tissue are between 42-67%.[11][12][13][14][15][16] The majority of these studies are small case series, but larger studies were of 49 patients[11] and 66 patients.[15]

The risk of these procedures is low (reported at zero to ~5%), with adverse outcomes reported as; none,[2][11][8][3] one scrotal haematoma out of 175 patients,[17] one each of epididymo-orchitis and self-resolving torsion of the appendix testis out of 27 patients,[4] one scrotal wound dehiscence out of 11 patients (Ho 2017) and wound infection in two out of 78 patients.[9] Longer term outcomes include intra-scrotal haematomas in 10.9%, all completely resolving by six months, and very small fibrotic lesions remaining in 6.3% of boys by 12 months.[9] There was no impact seen in testicular growth in boys who underwent micro-TESE,[9] and no long-term risks for boys who had a testicular biopsy were detected during clinical follow-up (Borgstrom 2020). The effect of microTESE on serum testosterone levels was not assessed in any of the included studies.

Fresh sperm retrieved from testicular tissue of cancer patients has been reported to achieve between 42%[18] and 59% (Dar 2018) live birth rates, in large centres experienced in microTESE. While sperm extracted from the testicular tissue of cancer patients, and used for ICSI results in fertilisation rates of approximately 30-65%,[17][14][19][15][16][20] there is a paucity of data with regard to pregnancy and live birth rates. Seven studies included data on pregnancy rates,[12][13][17][14][15][16][20] and there was one additional case study with n = 1.[19] Five studies included live birth rates,[17][14][15][16][20]), one study combined the outcomes of ongoing pregnancy and birth rates[12] and there was one additional case report with n=1.[19] In those cases with n > 1, and assuming that the two patients in Damani et al. both had a live birth, there was an overall pregnancy rate of 30%, and live birth rate of 63/315 (20%).[12]

In a cancer context, sperm are often frozen for use some many years later, which adds a further degree of complexity to conducting research in this area. Despite the relative paucity of data, consistent clinical observations show that sperm extracted from testicular tissue works effectively with ICSI and that there is relatively low risk from surgery. This approach serves as a mean to circumvent later childlessness associated with gonadal damage from cancer treatments.

This is an area with very little evidence base to guide clinical practice. Larger studies are needed, and the main focus of research needs to shift to clinically relevant outcomes, particularly pregnancy and live birth rates.

Evidence summary two

Evidence summaryLevelReferences
Testicular sperm extraction for post-pubertal males prior to chemotherapy where production of a semen sample is not possible is an established fertility preservation option with few risks and excellent success rates.IV[12], [13], [17], [14], [15], [16], [20]

Recommendation Two

Evidence-based recommendationGrade
Health professionals should discuss the option of testicular sperm extraction and sperm cryopreservation in post pubertal boys and men who cannot produce a semen sample.D

Consensus based recommendation

Consensus-based recommendation
Health professionals should discuss the option of testicular sperm extraction and sperm cryopreservation with mid- and late pubertal boys (testis volumes ≥ 8 ml) and men who are unable to provide a semen sample and who are embarking on gonadotoxic cancer treatments, and in azoospermic men who have had gonadotoxic cancer treatments and are desiring fertility treatment.


References

  1. Anazodo A, Laws P, Logan S, Saunders C, Travaglia J, Gerstl B, et al. How can we improve oncofertility care for patients? A systematic scoping review of current international practice and models of care. Hum Reprod Update 2018 Nov 20 Available from: http://www.ncbi.nlm.nih.gov/pubmed/30462263.
  2. Babayev SN, Arslan E, Kogan S, Moy F, Oktay K. Evaluation of ovarian and testicular tissue cryopreservation in children undergoing gonadotoxic therapies. J Assist Reprod Genet 2013 Jan;30(1):3-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23242649.
  3. Ginsberg JP, Li Y, Carlson CA, Gracia CR, Hobbie WL, Miller VA, et al. Testicular tissue cryopreservation in prepubertal male children: an analysis of parental decision-making. Pediatr Blood Cancer 2014 Sep;61(9):1673-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24777742.
  4. Ming JM, Chua ME, Lopes RI, Maloney AM, Gupta AA, Lorenzo AJ. Cryopreservation of testicular tissue in pre-pubertal and adolescent boys at risk for infertility: A low risk procedure. J Pediatr Urol 2018 Jun;14(3):274.e1-274.e5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29571658.
  5. Ho WLC, Bourne H, Gook D, Clarke G, Kemertzis M, Stern K, et al. A short report on current fertility preservation strategies for boys. Clin Endocrinol (Oxf) 2017 Sep;87(3):279-285 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28504866.
  6. Borgström B, Fridström M, Gustafsson B, Ljungman P, Rodriguez-Wallberg KA. A prospective study on the long-term outcome of prepubertal and pubertal boys undergoing testicular biopsy for fertility preservation prior to hematologic stem cell transplantation. Pediatr Blood Cancer 2020 Sep;67(9):e28507 Available from: http://www.ncbi.nlm.nih.gov/pubmed/32649054.
  7. Chong C, Logothetis CJ, von Eschenbach A, Ayala A, Samuels M. Orchiectomy in advanced germ cell cancer following intensive chemotherapy: a comparison of systemic to testicular response. J Urol 1986 Dec;136(6):1221-3 Available from: http://www.ncbi.nlm.nih.gov/pubmed/3022018.
  8. Ginsberg JP, Carlson CA, Lin K, Hobbie WL, Wigo E, Wu X, et al. An experimental protocol for fertility preservation in prepubertal boys recently diagnosed with cancer: a report of acceptability and safety. Hum Reprod 2010 Jan;25(1):37-41 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19861330.
  9. Uijldert M, Meißner A, de Melker AA, van Pelt AMM, van de Wetering MD, van Rijn RR, et al. Development of the testis in pre-pubertal boys with cancer after biopsy for fertility preservation. Hum Reprod 2017 Dec 1;32(12):2366-2372 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29040511.
  10. Fayomi AP, Peters K, Sukhwani M, Valli-Pulaski H, Shetty G, Meistrich ML, et al. Autologous grafting of cryopreserved prepubertal rhesus testis produces sperm and offspring. Science 2019 Mar 22;363(6433):1314-1319 Available from: http://www.ncbi.nlm.nih.gov/pubmed/30898927.
  11. Berookhim BM, Mulhall JP. Outcomes of operative sperm retrieval strategies for fertility preservation among males scheduled to undergo cancer treatment. Fertil Steril 2014 Mar;101(3):805-11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24424372.
  12. Damani MN, Master V, Meng MV, Burgess C, Turek P, Oates RD. Postchemotherapy ejaculatory azoospermia: fatherhood with sperm from testis tissue with intracytoplasmic sperm injection. J Clin Oncol 2002 Feb 15;20(4):930-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11844813.
  13. Furuhashi K, Ishikawa T, Hashimoto H, Yamada S, Ogata S, Mizusawa Y, et al. Onco-testicular sperm extraction: testicular sperm extraction in azoospermic and very severely oligozoospermic cancer patients. Andrologia 2013 Apr;45(2):107-10 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22690948.
  14. Meseguer M, Garrido N, Remohí J, Pellicer A, Simón C, Martínez-Jabaloyas JM, et al. Testicular sperm extraction (TESE) and ICSI in patients with permanent azoospermia after chemotherapy. Hum Reprod 2003 Jun;18(6):1281-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12773459.
  15. Shin T, Kobayashi T, Shimomura Y, Iwahata T, Suzuki K, Tanaka T, et al. Microdissection testicular sperm extraction in Japanese patients with persistent azoospermia after chemotherapy. Int J Clin Oncol 2016 Dec;21(6):1167-1171 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27306218.
  16. Shiraishi K, Matsuyama H. Microdissection testicular sperm extraction and salvage hormonal treatment in patients with postchemotherapy azoospermia. Urology 2014 Jan;83(1):100-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24269225.
  17. Küpker W, Schlegel PN, Al-Hasani S, Fornara P, Johannisson R, Sandmann J, et al. Use of frozen-thawed testicular sperm for intracytoplasmic sperm injection. Fertil Steril 2000 Mar;73(3):453-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10688995.
  18. Hsiao W, Stahl PJ, Osterberg EC, Nejat E, Palermo GD, Rosenwaks Z, et al. Successful treatment of postchemotherapy azoospermia with microsurgical testicular sperm extraction: the Weill Cornell experience. J Clin Oncol 2011 Apr 20;29(12):1607-11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21402606.
  19. Res U, Res P, Kastelic D, Stanovnik M, Kmetec A, Merlo A. Birth after treatment of a male with seminoma and azoospermia with cryopreserved-thawed testicular tissue. Hum Reprod 2000 Apr;15(4):861-4 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10739833.
  20. Zorn B, Virant-Klun I, Stanovnik M, Drobnic S, Meden-Vrtovec H. Intracytoplasmic sperm injection by testicular sperm in patients with aspermia or azoospermia after cancer treatment. Int J Androl 2006 Oct;29(5):521-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16524365.

Body of evidence

In male cancer patients does the use of cryopreserved testicular tissue result in pregnancy and live birth? Is there any evidence of harm from the harvesting procedure?

CitationLevel of EvidenceQuality of EvidenceSize of EffectNumber of PatientsRelevance of Evidence
Babayev SN, Arslan E, Kogan S, Moy F, Oktay K. Evaluation of ovarian and testicular tissue cryopreservation in children undergoing gonadotoxic therapies. J Assist Reprod Genet 2013 Jan;30(1):3-9 Available from:http://www.ncbi.nlm.nih.gov/pubmed/23242649IVLow545
Berookhim BM, Mulhall JP. Outcomes of operative sperm retrieval strategies for fertility preservation among males scheduled to undergo cancer treatment. Fertil Steril 2014 Mar;101(3):805-11 Available from:http://www.ncbi.nlm.nih.gov/pubmed/24424372IVLow5491
Chan PT, Palermo GD, Veeck LL, Rosenwaks Z, Schlegel PN. Testicular sperm extraction combined with intracytoplasmic sperm injection in the treatment of men with persistent azoospermia postchemotherapy. Cancer 2001 Sep 15;92(6):1632-7 Available from:http://www.ncbi.nlm.nih.gov/pubmed/11745242IVLowN/A20N/A
Damani MN, Master V, Meng MV, Burgess C, Turek P, Oates RD. Postchemotherapy ejaculatory azoospermia: fatherhood with sperm from testis tissue with intracytoplasmic sperm injection. J Clin Oncol 2002 Feb 15;20(4):930-6 Available from:http://www.ncbi.nlm.nih.gov/pubmed/11844813IVLow561
Dar S, Orvieto R, Levron J, Haas J, Gat I, Raviv G. IVF outcome in azoospermic cancer survivors. Eur J Obstet Gynecol Reprod Biol 2018 Jan;220:84-87 Available from:http://www.ncbi.nlm.nih.gov/pubmed/29179011IVLowN/A36N/A
Furuhashi K, Ishikawa T, Hashimoto H, Yamada S, Ogata S, Mizusawa Y, et al. Onco-testicular sperm extraction: testicular sperm extraction in azoospermic and very severely oligozoospermic cancer patients. Andrologia 2013 Apr;45(2):107-10 Available from:http://www.ncbi.nlm.nih.gov/pubmed/22690948IVLow561
Ginsberg JP, Carlson CA, Lin K, Hobbie WL, Wigo E, Wu X, et al. An experimental protocol for fertility preservation in prepubertal boys recently diagnosed with cancer: a report of acceptability and safety. Hum Reprod 2010 Jan;25(1):37-41 Available from:http://www.ncbi.nlm.nih.gov/pubmed/19861330IVLow5145
Ginsberg JP, Li Y, Carlson CA, Gracia CR, Hobbie WL, Miller VA, et al. Testicular tissue cryopreservation in prepubertal male children: an analysis of parental decision-making. Pediatr Blood Cancer 2014 Sep;61(9):1673-8 Available from:http://www.ncbi.nlm.nih.gov/pubmed/24777742IVLow5421
Ho WLC, Bourne H, Gook D, Clarke G, Kemertzis M, Stern K, et al. A short report on current fertility preservation strategies for boys. Clin Endocrinol (Oxf) 2017 Sep;87(3):279-285 Available from:http://www.ncbi.nlm.nih.gov/pubmed/28504866IVLow5301
Hsiao W, Stahl PJ, Osterberg EC, Nejat E, Palermo GD, Rosenwaks Z, et al. Successful treatment of postchemotherapy azoospermia with microsurgical testicular sperm extraction: the Weill Cornell experience. J Clin Oncol 2011 Apr 20;29(12):1607-11 Available from:http://www.ncbi.nlm.nih.gov/pubmed/21402606IVLowN/A84N/A
Küpker W, Schlegel PN, Al-Hasani S, Fornara P, Johannisson R, Sandmann J, et al. Use of frozen-thawed testicular sperm for intracytoplasmic sperm injection. Fertil Steril 2000 Mar;73(3):453-8 Available from:http://www.ncbi.nlm.nih.gov/pubmed/10688995IVLow51751
Meseguer M, Garrido N, Remohí J, Pellicer A, Simón C, Martínez-Jabaloyas JM, et al. Testicular sperm extraction (TESE) and ICSI in patients with permanent azoospermia after chemotherapy. Hum Reprod 2003 Jun;18(6):1281-5 Available from:http://www.ncbi.nlm.nih.gov/pubmed/12773459IVLow5121
Ming JM, Chua ME, Lopes RI, Maloney AM, Gupta AA, Lorenzo AJ. Cryopreservation of testicular tissue in pre-pubertal and adolescent boys at risk for infertility: A low risk procedure. J Pediatr Urol 2018 Jun;14(3):274.e1-274.e5 Available from:http://www.ncbi.nlm.nih.gov/pubmed/29571658IVLow5271
Res U, Res P, Kastelic D, Stanovnik M, Kmetec A, Merlo A. Birth after treatment of a male with seminoma and azoospermia with cryopreserved-thawed testicular tissue. Hum Reprod 2000 Apr;15(4):861-4 Available from:http://www.ncbi.nlm.nih.gov/pubmed/10739833IVLow511
Shin T, Kobayashi T, Shimomura Y, Iwahata T, Suzuki K, Tanaka T, et al. Microdissection testicular sperm extraction in Japanese patients with persistent azoospermia after chemotherapy. Int J Clin Oncol 2016 Dec;21(6):1167-1171 Available from:http://www.ncbi.nlm.nih.gov/pubmed/27306218IVLow5661
Shiraishi K, Matsuyama H. Microdissection testicular sperm extraction and salvage hormonal treatment in patients with postchemotherapy azoospermia. Urology 2014 Jan;83(1):100-6 Available from:http://www.ncbi.nlm.nih.gov/pubmed/24269225IVLow5261
Uijldert M, Meißner A, de Melker AA, van Pelt AMM, van de Wetering MD, van Rijn RR, et al. Development of the testis in pre-pubertal boys with cancer after biopsy for fertility preservation. Hum Reprod 2017 Dec 1;32(12):2366-2372 Available from:http://www.ncbi.nlm.nih.gov/pubmed/29040511IVLow2641
Zorn B, Virant-Klun I, Stanovnik M, Drobnic S, Meden-Vrtovec H. Intracytoplasmic sperm injection by testicular sperm in patients with aspermia or azoospermia after cancer treatment. Int J Androl 2006 Oct;29(5):521-7 Available from:http://www.ncbi.nlm.nih.gov/pubmed/16524365IVLow4301
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