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Fertility preservation for people with cancer

Testicular function

Clinical Question

Is the testicular function of men and boys who received cancer treatment reduced in comparison to men and boys in the general population?

Cancer treatment, in particular chemotherapy and radiation, damages spermatogenic function in patients with cancer as the stem cells are immediately affected. Accordingly, sperm output falls rapidly and to a varying degree and duration (including being permanent). In addition, cancer treatment can as also be damaging to testicular Leydig cells, resulting in decreased testosterone levels. Hypogonadism is typically primary (testicular) hypogonadism in these cases, however certain cancer treatments may cause secondary (pituitary) hypogonadotrophic hypogonadism. Certain cancer treatments are more gonadotoxic than others, including platinum-based chemotherapies and radiation therapy.[1][2][3][4]

Assessment of Sertoli cell function and sperm production utilises sperm count[5][1][6][7][8][9] or surrogate measures such as follicle stimulating hormone (FSH),[5][10][10][1][6][7][11][12][13][8][9][14] and inhibin B[5][1][13][8] although inhibin B is typically measured in a research setting rather than in routine clinical practice. Although these markers give an indication of sperm production not sperm function, findings are consistent with impaired spermatogenesis in men and boys treated for cancer, with a reduced sperm count, raised FSH and decreased inhibin B.

Effects on sperm count or markers of spermatogenesis in men and boys treated for cancer are greatest with higher doses of cyclophosphamide and testicular irradiation[1], and cranial irradiation and chemotherapy, compared to radiotherapy alone[13]. In a study of boys treated for cancer, those with Hodgkin and non-Hodgkin lymphomas, acute myeloid leukaemia, neuroblastoma and sarcoma had lower inhibin B levels and higher FSH levels than other cancer types,[12] though it is important to note that in this study sperm counts often improved 24 months after treatment. Sperm concentrations were also lower in men previously treated for childhood lymphoblastic leukaemia compared to controls.[6]

Assessment of Leydig cell function and testosterone production is measured by testosterone and luteinising hormone (LH). Testosterone was measured in all but one of the included studies,[4][5][10][15][1][16][6][7][2][11][12][3][13][8][9] and LH was measured in most studies. Decreased testosterone levels and/ or increased LH levels were seen in many studies, with some larger studies identifying risk factors for hypogonadism, including a higher risk with BEP (bleomycin, etoposide, cisplatin) chemotherapy for testicular cancer, especially if LH was >8 U/L,[4] more than four cycles of cisplatin, or cancers treated with radiation.[15][1]

A study of men treated for unilateral testicular cancer and followed up for ten years showed hypogonadism risk was increased in those treated with surgery alone compared to controls (odds ratio 2.0), but the highest risk was in those treated with high dose cisplatin (odds ratio 7.9).[2] Hypogonadism was present in 23% of men treated for childhood cancer compared to 4.3% of controls, especially in those with a history of testicular irradiation, brain tumours or chemotherapy treatment.[3]

The highest level of evidence for loss of testicular function in men after cancer treatment comes from prospective cohort studies. One of the largest prospective cohort studies comes from the CECOS centres in France. Studies from this population have shown that lymphoma treatment had damaging effects on spermatogenesis,[17] as did adjuvant treatments for testicular germ cell tumor[18]. Significant sperm aneuploidy was induced in lymphoma [19] and men with testicular cancer [20].

Other prospective cohorts have also demonstrated greater damage to sperm DNA in men with testicular cancer and lymphoma[21] as well as premature hormonal ageing in men previously treated for testicular cancer.[22].


Evidence Summary

Evidence summaryLevelReferences
Loss of testicular hormone function is more common in men treated for testicular cancer and men treated for cancer during childhood than the general population and may occur many years after the original treatment. Sperm quality is reduced in men previously treated for cancer compared with the general population. Azoospermia may occur after cancer treatment including chemotherapy and radiation.II[18], [17], [20], [22], [12], [19]

Recommendation

Evidence-based recommendationGrade
Health professionals should advise male patients with cancer about to receive cancer treatment of the risk of loss of testicular hormone function and a reduction in sperm count. Patients of any age with a risk of infertility (or their families in the case of children) should be given the opportunity to discuss fertility preservation before cancer treatment.A

Consensus-based recommendation

Consensus-based recommendation
Post-pubertal boys and men should have reproductive follow up from 12 months after completion of cancer treatment. Ongoing follow up should be dictated by pathology (which should include blood tests for testosterone, LH and FSH) and/or symptoms of hypogonadism.

References

  1. Jahnukainen K, Heikkinen R, Henriksson M, Cooper TG, Puukko-Viertomies LR, Mäkitie O. Semen quality and fertility in adult long-term survivors of childhood acute lymphoblastic leukemia. Fertil Steril 2011 Oct;96(4):837-42 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21868007.
  2. Nord C, Bjøro T, Ellingsen D, Mykletun A, Dahl O, Klepp O, et al. Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer. Eur Urol 2003 Sep;44(3):322-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12932930.
  3. Romerius P, Ståhl O, Moëll C, Relander T, Cavallin-Ståhl E, Wiebe T, et al. Hypogonadism risk in men treated for childhood cancer. J Clin Endocrinol Metab 2009 Nov;94(11):4180-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19789207.
  4. Bandak M, Lauritsen J, Johansen C, Kreiberg M, Skøtt JW, Agerbaek M, et al. Sexual function in a nationwide cohort of 2260 testicular cancer survivors after 17 years follow-up. J Urol 2018 May 3 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29730199.
  5. Bordallo MA, Guimarães MM, Pessoa CH, Carriço MK, Dimetz T, Gazolla HM, et al. Decreased serum inhibin B/FSH ratio as a marker of Sertoli cell function in male survivors after chemotherapy in childhood and adolescence. J Pediatr Endocrinol Metab 2004 Jun;17(6):879-87 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15270406.
  6. Marquis A, Kuehni CE, Strippoli MP, Kühne T, Brazzola P, Swiss Pediatric Oncology Group.. Sperm analysis of patients after successful treatment of childhood acute lymphoblastic leukemia with chemotherapy. Pediatr Blood Cancer 2010 Jul 15;55(1):208-10 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20310003.
  7. Mustieles C, Muñoz A, Alonso M, Ros P, Yturriaga R, Maldonado S, et al. Male gonadal function after chemotherapy in survivors of childhood malignancy. Med Pediatr Oncol 1995 Jun;24(6):347-51 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7715540.
  8. Thomson AB, Campbell AJ, Irvine DC, Anderson RA, Kelnar CJ, Wallace WH. Semen quality and spermatozoal DNA integrity in survivors of childhood cancer: a case-control study. Lancet 2002 Aug 3;360(9330):361-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12241775.
  9. van Casteren NJ, van der Linden GH, Hakvoort-Cammel FG, Hählen K, Dohle GR, van den Heuvel-Eibrink MM. Effect of childhood cancer treatment on fertility markers in adult male long-term survivors. Pediatr Blood Cancer 2009 Jan;52(1):108-12 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18819129.
  10. Greenfield DM, Walters SJ, Coleman RE, Hancock BW, Eastell R, Davies HA, et al. Prevalence and consequences of androgen deficiency in young male cancer survivors in a controlled cross-sectional study. J Clin Endocrinol Metab 2007 Sep;92(9):3476-82 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17579201.
  11. Nuver J, Smit AJ, Wolffenbuttel BH, Sluiter WJ, Hoekstra HJ, Sleijfer DT, et al. The metabolic syndrome and disturbances in hormone levels in long-term survivors of disseminated testicular cancer. J Clin Oncol 2005 Jun 1;23(16):3718-25 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15738540.
  12. O'Flaherty C, Hales BF, Chan P, Robaire B. Impact of chemotherapeutics and advanced testicular cancer or Hodgkin lymphoma on sperm deoxyribonucleic acid integrity. Fertil Steril 2010 Sep;94(4):1374-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19591994.
  13. Schmiegelow M, Lassen S, Poulsen HS, Schmiegelow K, Hertz H, Andersson AM, et al. Gonadal status in male survivors following childhood brain tumors. J Clin Endocrinol Metab 2001 Jun;86(6):2446-52 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11397837.
  14. van Waas M, Neggers SJ, Te Winkel ML, Beishuizen A, Pieters R, van den Heuvel-Eibrink MM. Endocrine late sequelae in long-term survivors of childhood non-Hodgkin lymphoma. Ann Oncol 2012 Jun;23(6):1626-32 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22048153.
  15. Isaksson S, Bogefors K, Ståhl O, Eberhard J, Giwercman YL, Leijonhufvud I, et al. High risk of hypogonadism in young male cancer survivors. Clin Endocrinol (Oxf) 2018 Mar;88(3):432-441 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29245176.
  16. Kurobe M, Kawai K, Suetomi T, Iwamoto T, Waku N, Kawahara T, et al. High prevalence of hypogonadism determined by serum free testosterone level in Japanese testicular cancer survivors. Int J Urol 2018 May;25(5):457-462 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29478250.
  17. Bujan L, Walschaerts M, Brugnon F, Daudin M, Berthaut I, Auger J, et al. Impact of lymphoma treatments on spermatogenesis and sperm deoxyribonucleic acid: a multicenter prospective study from the CECOS network. Fertil Steril 2014 Sep;102(3):667-674.e3 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25044088.
  18. Bujan L, Walschaerts M, Moinard N, Hennebicq S, Saias J, Brugnon F, et al. Impact of chemotherapy and radiotherapy for testicular germ cell tumors on spermatogenesis and sperm DNA: a multicenter prospective study from the CECOS network. Fertil Steril 2013 Sep;100(3):673-80 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23755953.
  19. Martinez G, Walschaerts M, Le Mitouard M, Borye R, Thomas C, Auger J, et al. Impact of Hodgkin or non-Hodgkin lymphoma and their treatments on sperm aneuploidy: a prospective study by the French CECOS network. Fertil Steril 2017 Feb;107(2):341-350.e5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27810161.
  20. Rives N, Walschaerts M, Setif V, Hennebicq S, Saias J, Brugnon F, et al. Sperm aneuploidy after testicular cancer treatment: data from a prospective multicenter study performed within the French Centre d'Étude et de Conservation des Oeufs et du Sperme network. Fertil Steril 2017 Mar;107(3):580-588.e1 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28069184.
  21. O'Flaherty C, Vaisheva F, Hales BF, Chan P, Robaire B. Characterization of sperm chromatin quality in testicular cancer and Hodgkin's lymphoma patients prior to chemotherapy. Hum Reprod 2008 May;23(5):1044-52 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18346994.
  22. Sprauten M, Brydøy M, Haugnes HS, Cvancarova M, Bjøro T, Bjerner J, et al. Longitudinal serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in a population-based sample of long-term testicular cancer survivors. J Clin Oncol 2014 Feb 20;32(6):571-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24419125.

Body of Evidence

Is the testicular function of male cancer survivors who had cancer treatment, more adversely affected than males in the general population, as measured by markers of their testicular function after treatment?

CitationLevel of EvidenceQuality of EvidenceSize of EffectNumber of PatientsRelevance of Evidence
Bandak M, Jørgensen N, Juul A, Lauritsen J, Kier MGG, Mortensen MS, et al. Longitudinal Changes in Serum Levels of Testosterone and Luteinizing Hormone in Testicular Cancer Patients after Orchiectomy Alone or Bleomycin, Etoposide, and Cisplatin. Eur Urol Focus 2016 Dec 15 Available from:http://www.ncbi.nlm.nih.gov/pubmed/28753832III-3LowN/A156N/A
Bordallo MA, Guimarães MM, Pessoa CH, Carriço MK, Dimetz T, Gazolla HM, et al. Decreased serum inhibin B/FSH ratio as a marker of Sertoli cell function in male survivors after chemotherapy in childhood and adolescence. J Pediatr Endocrinol Metab 2004 Jun;17(6):879-87 Available from:http://www.ncbi.nlm.nih.gov/pubmed/15270406III-3LowN/A212
Bujan L, Walschaerts M, Brugnon F, Daudin M, Berthaut I, Auger J, et al. Impact of lymphoma treatments on spermatogenesis and sperm deoxyribonucleic acid: a multicenter prospective study from the CECOS network. Fertil Steril 2014 Sep;102(3):667-674.e3 Available from:http://www.ncbi.nlm.nih.gov/pubmed/25044088IIMediumN/AN/AN/A
Bujan L, Walschaerts M, Moinard N, Hennebicq S, Saias J, Brugnon F, et al. Impact of chemotherapy and radiotherapy for testicular germ cell tumors on spermatogenesis and sperm DNA: a multicenter prospective study from the CECOS network. Fertil Steril 2013 Sep;100(3):673-80 Available from:http://www.ncbi.nlm.nih.gov/pubmed/23755953IIMediumN/AN/AN/A
Greenfield DM, Walters SJ, Coleman RE, Hancock BW, Eastell R, Davies HA, et al. Prevalence and consequences of androgen deficiency in young male cancer survivors in a controlled cross-sectional study. J Clin Endocrinol Metab 2007 Sep;92(9):3476-82 Available from:http://www.ncbi.nlm.nih.gov/pubmed/17579201III-3Low11761
Isaksson S, Bogefors K, Ståhl O, Eberhard J, Giwercman YL, Leijonhufvud I, et al. High risk of hypogonadism in young male cancer survivors. Clin Endocrinol (Oxf) 2018 Mar;88(3):432-441 Available from:http://www.ncbi.nlm.nih.gov/pubmed/29245176III-3LowN/A217N/A
Jahnukainen K, Heikkinen R, Henriksson M, Cooper TG, Puukko-Viertomies LR, Mäkitie O. Semen quality and fertility in adult long-term survivors of childhood acute lymphoblastic leukemia. Fertil Steril 2011 Oct;96(4):837-42 Available from:http://www.ncbi.nlm.nih.gov/pubmed/21868007III-3LowN/A51N/A
Kurobe M, Kawai K, Suetomi T, Iwamoto T, Waku N, Kawahara T, et al. High prevalence of hypogonadism determined by serum free testosterone level in Japanese testicular cancer survivors. Int J Urol 2018 May;25(5):457-462 Available from:http://www.ncbi.nlm.nih.gov/pubmed/29478250III-3LowN/A52N/A
La Vignera S, Cannarella R, Duca Y, Barbagallo F, Burgio G, Compagnone M, et al. Hypogonadism and Sexual Dysfunction in Testicular Tumor Survivors: A Systematic Review. Front Endocrinol (Lausanne) 2019;10:264 Available from:http://www.ncbi.nlm.nih.gov/pubmed/31133982III-3LowN/AN/AN/A
Marquis A, Kuehni CE, Strippoli MP, Kühne T, Brazzola P, Swiss Pediatric Oncology Group.. Sperm analysis of patients after successful treatment of childhood acute lymphoblastic leukemia with chemotherapy. Pediatr Blood Cancer 2010 Jul 15;55(1):208-10 Available from:http://www.ncbi.nlm.nih.gov/pubmed/20310003III-3LowN/A11N/A
Martinez G, Walschaerts M, Le Mitouard M, Borye R, Thomas C, Auger J, et al. Impact of Hodgkin or non-Hodgkin lymphoma and their treatments on sperm aneuploidy: a prospective study by the French CECOS network. Fertil Steril 2017 Feb;107(2):341-350.e5 Available from:http://www.ncbi.nlm.nih.gov/pubmed/27810161IILowN/AN/AN/A
Mustieles C, Muñoz A, Alonso M, Ros P, Yturriaga R, Maldonado S, et al. Male gonadal function after chemotherapy in survivors of childhood malignancy. Med Pediatr Oncol 1995 Jun;24(6):347-51 Available from:http://www.ncbi.nlm.nih.gov/pubmed/7715540III-3Low115N/A
Nord C, Bjøro T, Ellingsen D, Mykletun A, Dahl O, Klepp O, et al. Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer. Eur Urol 2003 Sep;44(3):322-8 Available from:http://www.ncbi.nlm.nih.gov/pubmed/12932930III-3LowN/A1,2351
Nuver J, Smit AJ, Wolffenbuttel BH, Sluiter WJ, Hoekstra HJ, Sleijfer DT, et al. The metabolic syndrome and disturbances in hormone levels in long-term survivors of disseminated testicular cancer. J Clin Oncol 2005 Jun 1;23(16):3718-25 Available from:http://www.ncbi.nlm.nih.gov/pubmed/15738540III-3LowN/A130N/A
O'Flaherty C, Hales BF, Chan P, Robaire B. Impact of chemotherapeutics and advanced testicular cancer or Hodgkin lymphoma on sperm deoxyribonucleic acid integrity. Fertil Steril 2010 Sep;94(4):1374-9 Available from:http://www.ncbi.nlm.nih.gov/pubmed/19591994IILow1162
Rives N, Walschaerts M, Setif V, Hennebicq S, Saias J, Brugnon F, et al. Sperm aneuploidy after testicular cancer treatment: data from a prospective multicenter study performed within the French Centre d'Étude et de Conservation des Oeufs et du Sperme network. Fertil Steril 2017 Mar;107(3):580-588.e1 Available from:http://www.ncbi.nlm.nih.gov/pubmed/28069184IILowN/AN/AN/A
Romerius P, Ståhl O, Moëll C, Relander T, Cavallin-Ståhl E, Wiebe T, et al. Hypogonadism risk in men treated for childhood cancer. J Clin Endocrinol Metab 2009 Nov;94(11):4180-6 Available from:http://www.ncbi.nlm.nih.gov/pubmed/19789207III-3Low11441
Schmiegelow M, Lassen S, Poulsen HS, Schmiegelow K, Hertz H, Andersson AM, et al. Gonadal status in male survivors following childhood brain tumors. J Clin Endocrinol Metab 2001 Jun;86(6):2446-52 Available from:http://www.ncbi.nlm.nih.gov/pubmed/11397837III-3LowN/A30N/A
Schmiegelow M, Lassen S, Poulsen HS, Schmiegelow K, Hertz H, Andersson AM, et al. Gonadal status in male survivors following childhood brain tumors. J Clin Endocrinol Metab 2001 Jun;86(6):2446-52 Available from:http://www.ncbi.nlm.nih.gov/pubmed/11397837III-3LowN/A377N/A
Sprauten M, Brydøy M, Haugnes HS, Cvancarova M, Bjøro T, Bjerner J, et al. Longitudinal serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels in a population-based sample of long-term testicular cancer survivors. J Clin Oncol 2014 Feb 20;32(6):571-8 Available from:http://www.ncbi.nlm.nih.gov/pubmed/24419125IILowN/AN/AN/A
Thomson AB, Campbell AJ, Irvine DC, Anderson RA, Kelnar CJ, Wallace WH. Semen quality and spermatozoal DNA integrity in survivors of childhood cancer: a case-control study. Lancet 2002 Aug 3;360(9330):361-7 Available from:http://www.ncbi.nlm.nih.gov/pubmed/12241775III-3LowN/A33N/A
van Casteren NJ, van der Linden GH, Hakvoort-Cammel FG, Hählen K, Dohle GR, van den Heuvel-Eibrink MM. Effect of childhood cancer treatment on fertility markers in adult male long-term survivors. Pediatr Blood Cancer 2009 Jan;52(1):108-12 Available from:http://www.ncbi.nlm.nih.gov/pubmed/18819129III-3Low12481
van Waas M, Neggers SJ, Te Winkel ML, Beishuizen A, Pieters R, van den Heuvel-Eibrink MM. Endocrine late sequelae in long-term survivors of childhood non-Hodgkin lymphoma. Ann Oncol 2012 Jun;23(6):1626-32 Available from:http://www.ncbi.nlm.nih.gov/pubmed/22048153III-3LowN/A62N/A
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