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2000
Volume 20, Issue 3
  • ISSN: 1574-8871
  • E-ISSN: 1876-1038

Abstract

Immune checkpoint inhibitor therapy has become the established method of treatment for various types of cancers, consequently introducing a spectrum of side effects referred to as immune-mediated adverse events, affecting almost every organ, including the reproductive system. Moreover, very little clinical data is available that suggests the detrimental effect of immune checkpoint inhibitor therapy on fertility, sexual health, or potential pregnancies. In this manuscript, we reviewed the impact of immunotherapy on male and female fertility and its effect on sexual health. Patients undergoing systemic treatment with immunotherapy often experience sexual dysfunction, decreased sexual drive, erectile dysfunction, and a decline in vaginal lubrication. Fertility-desiring patients who do not receive adequate counseling may ultimately face a higher likelihood of developing anxiety, depression, and a decreased quality of life post-treatment. Therefore, it is crucial to address the reproductive consequences of planned treatment, disseminate knowledge about novel treatments and preventive measures for reproductive side effects, and provide guidance on fertility preservation. Individuals experiencing secondary reproductive dysfunction due to the tumor or its treatment should receive proactive treatment for the underlying condition and be offered hormone replacement therapy.

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2025-02-04
2025-12-29

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References

  1. RobertC. A decade of immune-checkpoint inhibitors in cancer therapy.Nat. Commun.2020111380110.1038/s41467‑020‑17670‑y32732879
     [Google Scholar]
  2. KyiC. PostowM.A. Checkpoint blocking antibodies in cancer immunotherapy.FEBS Lett.2014588236837610.1016/j.febslet.2013.10.01524161671
     [Google Scholar]
  3. NguyenL.T. OhashiP.S. Clinical blockade of PD1 and LAG3 — Potential mechanisms of action.Nat. Rev. Immunol.2015151455610.1038/nri379025534622
     [Google Scholar]
  4. RobertC. SchachterJ. LongG.V. AranceA. GrobJ.J. MortierL. DaudA. CarlinoM.S. McNeilC. LotemM. LarkinJ. LoriganP. NeynsB. BlankC.U. HamidO. MateusC. Shapira-FrommerR. KoshM. ZhouH. IbrahimN. EbbinghausS. RibasA. KEYNOTE-006 investigators Pembrolizumab versus Ipilimumab in advanced melanoma.N. Engl. J. Med.2015372262521253210.1056/NEJMoa150309325891173
     [Google Scholar]
  5. FreemanG.J. LongA.J. IwaiY. BourqueK. ChernovaT. NishimuraH. FitzL.J. MalenkovichN. OkazakiT. ByrneM.C. HortonH.F. FouserL. CarterL. LingV. BowmanM.R. CarrenoB.M. CollinsM. WoodC.R. HonjoT. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.J. Exp. Med.200019271027103410.1084/jem.192.7.102711015443
     [Google Scholar]
  6. KeirM.E. ButteM.J. FreemanG.J. SharpeA.H. PD-1 and its ligands in tolerance and immunity.Annu. Rev. Immunol.200826167770410.1146/annurev.immunol.26.021607.09033118173375
     [Google Scholar]
  7. TermeM. UllrichE. AymericL. MeinhardtK. DesboisM. DelahayeN. ViaudS. RyffelB. YagitaH. KaplanskiG. Prévost-BlondelA. KatoM. SchultzeJ.L. TartourE. KroemerG. ChaputN. ZitvogelL. IL-18 induces PD-1-dependent immunosuppression in cancer.Cancer Res.201171165393539910.1158/0008‑5472.CAN‑11‑099321724589
     [Google Scholar]
  8. FanoniD. TavecchioS. RecalcatiS. BaliceY. VenegoniL. FioraniR. CrostiC. BertiE. New monoclonal antibodies against B-cell antigens: Possible new strategies for diagnosis of primary cutaneous B-cell lymphomas.Immunol. Lett.2011134215716010.1016/j.imlet.2010.09.02220951741
     [Google Scholar]
  9. OkazakiT. HonjoT. PD-1 and PD-1 ligands: From discovery to clinical application.Int. Immunol.200719781382410.1093/intimm/dxm05717606980
     [Google Scholar]
  10. DongH. StromeS.E. SalomaoD.R. TamuraH. HiranoF. FliesD.B. RocheP.C. LuJ. ZhuG. TamadaK. LennonV.A. CelisE. ChenL. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion.Nat. Med.20028879380010.1038/nm73012091876
     [Google Scholar]
  11. ParsaA.T. WaldronJ.S. PannerA. CraneC.A. ParneyI.F. BarryJ.J. CacholaK.E. MurrayJ.C. TihanT. JensenM.C. MischelP.S. StokoeD. PieperR.O. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma.Nat. Med.2007131848810.1038/nm151717159987
     [Google Scholar]
  12. ChenL. HanX. Anti–PD-1/PD-L1 therapy of human cancer: Past, present, and future.J. Clin. Invest.201512593384339110.1172/JCI8001126325035
     [Google Scholar]
  13. MerelliB. MassiD. CattaneoL. MandalàM. Targeting the PD1/PD-L1 axis in melanoma: Biological rationale, clinical challenges and opportunities.Crit. Rev. Oncol. Hematol.201489114016510.1016/j.critrevonc.2013.08.00224029602
     [Google Scholar]
  14. GongJ. Chehrazi-RaffleA. ReddiS. SalgiaR. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: A comprehensive review of registration trials and future considerations.J. Immunother. Cancer201861810.1186/s40425‑018‑0316‑z29357948
     [Google Scholar]
  15. Le TourneauC. HoimesC. ZarwanC. WongD.J. BauerS. ClausR. WermkeM. HariharanS. von HeydebreckA. KasturiV. ChandV. GulleyJ.L. Avelumab in patients with previously treated metastatic adrenocortical carcinoma: Phase 1b results from the JAVELIN solid tumor trial.J. Immunother. Cancer20186111110.1186/s40425‑018‑0424‑930348224
     [Google Scholar]
  16. DisisM.L. Disis. Mechanism of action of immunotherapy.Semin. Oncol.201441Suppl. 5S3S1310.1053/j.seminoncol.2014.09.004
     [Google Scholar]
  17. VaddepallyR.K. KharelP. PandeyR. GarjeR. ChandraA.B. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence.Cancers202012373810.3390/cancers1203073832245016
     [Google Scholar]
  18. ZhuS. ZhangT. ZhengL. LiuH. SongW. LiuD. LiZ. PanC. Combination strategies to maximize the benefits of cancer immunotherapy.J. Hematol. Oncol.202114115610.1186/s13045‑021‑01164‑534579759
     [Google Scholar]
  19. MartinsF. SofiyaL. SykiotisG.P. LamineF. MaillardM. FragaM. ShabafrouzK. RibiC. CairoliA. Guex-CrosierY. KuntzerT. MichielinO. PetersS. CoukosG. SpertiniF. ThompsonJ.A. ObeidM. Adverse effects of immune-checkpoint inhibitors: Epidemiology, management and surveillance.Nat. Rev. Clin. Oncol.201916956358010.1038/s41571‑019‑0218‑031092901
     [Google Scholar]
  20. PedicordV.A. MontalvoW. LeinerI.M. AllisonJ.P. Single dose of anti–CTLA-4 enhances CD8 + T-cell memory formation, function, and maintenance.Proc. Natl. Acad. Sci. USA2011108126627110.1073/pnas.101679110821173239
     [Google Scholar]
  21. WalterJ.R. XuS. PallerA.S. ChoiJ.N. WoodruffT.K. Oncofertility considerations in adolescents and young adults given a diagnosis of melanoma: Fertility risk of Food and Drug Administration–approved systemic therapies.J. Am. Acad. Dermatol.201675352853410.1016/j.jaad.2016.04.03127543212
     [Google Scholar]
  22. HerbstR.S. SoriaJ.C. KowanetzM. FineG.D. HamidO. GordonM.S. SosmanJ.A. McDermottD.F. PowderlyJ.D. GettingerS.N. KohrtH.E.K. HornL. LawrenceD.P. RostS. LeabmanM. XiaoY. MokatrinA. KoeppenH. HegdeP.S. MellmanI. ChenD.S. HodiF.S. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.Nature2014515752856356710.1038/nature1401125428504
     [Google Scholar]
  23. PowlesT. EderJ.P. FineG.D. BraitehF.S. LoriotY. CruzC. BellmuntJ. BurrisH.A. PetrylakD.P. TengS. ShenX. BoydZ. HegdeP.S. ChenD.S. VogelzangN.J. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.Nature2014515752855856210.1038/nature1390425428503
     [Google Scholar]
  24. Brunet-PossentiF. OpsomerM.A. GomezL. OuzaidI. DescampsV. Immune checkpoint inhibitors-related orchitis.Ann. Oncol.201728490690710.1093/annonc/mdw69628039179
     [Google Scholar]
  25. QuachH.T. RobbinsC.J. BalkoJ.M. ChiuC.Y. MillerS. WilsonM.R. NelsonG.E. JohnsonD.B. Severe epididymo-orchitis and encephalitis complicating anti-PD-1 therapy.Oncologist201924787287610.1634/theoncologist.2018‑072230936376
     [Google Scholar]
  26. TürkmenN.B. ÇiftçiO. TaşlıdereA. AydınM. EkeB.C. The effect of aromatase inhibitors against possible testis toxicity in pembrolizumab treated rats.Andrologia20225410e1455710.1111/and.1455736177829
     [Google Scholar]
  27. PetersM. PearlmanA. TerryW. MottS.L. MongaV. Testosterone deficiency in men receiving immunotherapy for malignant melanoma.Oncotarget202112319920810.18632/oncotarget.2787633613847
     [Google Scholar]
  28. RyderM. CallahanM. PostowM.A. WolchokJ. FaginJ.A. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: A comprehensive retrospective review from a single institution.Endocr. Relat. Cancer201421237138110.1530/ERC‑13‑049924610577
     [Google Scholar]
  29. ScovellJ.M. BenzK. SamarskaI. KohnT.P. HooperJ.E. MatosoA. HeratiA.S. Association of impaired spermatogenesis with the use of immune checkpoint inhibitors in patients with metastatic melanoma.JAMA Oncol.2020681297129910.1001/jamaoncol.2020.164132556068
     [Google Scholar]
  30. SalzmannM. TosevG. HeckM. SchadendorfD. MaatoukI. EnkA.H. HartmannM. HasselJ.C. Male fertility during and after immune checkpoint inhibitor therapy: A cross-sectional pilot study.Eur. J. Cancer2021152414810.1016/j.ejca.2021.04.03134062486
     [Google Scholar]
  31. RabinowitzM.J. KohnT.P. PeñaV.N. SamarskaI.V. MatosoA. HeratiA.S. Onset of azoospermia in man treated with ipilimumab/nivolumab for BRAF negative metastatic melanoma.Urol. Case Rep.20213410148810.1016/j.eucr.2020.10148833299797
     [Google Scholar]
  32. HimpeJ. LammerantS. Van den BerghL. LapeireL. De RooC. The impact of systemic oncological treatments on the fertility of adolescents and young adults-A systematic review.Life2023135120910.3390/life1305120937240854
     [Google Scholar]
  33. ChenA.P. SharonE. O’Sullivan-CoyneG. MooreN. FosterJ.C. HuJ.S. Van TineB.A. ConleyA.P. ReadW.L. RiedelR.F. BurgessM.A. GlodJ. DavisE.J. MerriamP. NaqashA.R. FinoK.K. MillerB.L. WilskerD.F. BegumA. Ferry-GalowK.V. DeshpandeH.A. SchwartzG.K. LadleB.H. OkunoS.H. BeckJ.C. ChenJ.L. TakebeN. FogliL.K. RosenbergerC.L. ParchmentR.E. DoroshowJ.H. Atezolizumab for advanced alveolar soft part sarcoma.N. Engl. J. Med.20233891091192110.1056/NEJMoa230338337672694
     [Google Scholar]
  34. XuP.C. LuanY. YuS.Y. XuJ. CoulterD.W. KimS.Y. Effects of PD-1 blockade on ovarian follicles in a prepubertal female mouse.J. Endocrinol.20222521153010.1530/JOE‑21‑020934647523
     [Google Scholar]
  35. DumaN. LambertiniM. It is time to talk about fertility and immunotherapy.Oncologist202025427727810.1634/theoncologist.2019‑083732091651
     [Google Scholar]
  36. AlesiL.R. WinshipA.L. HuttK.J. Evaluating the impacts of emerging cancer therapies on ovarian function.Curr. Opin. Endocr. Metab. Res.202118152810.1016/j.coemr.2020.12.004
     [Google Scholar]
  37. EnglandC.G. EhlerdingE.B. HernandezR. RekoskeB.T. GravesS.A. SunH. LiuG. McNeelD.G. BarnhartT.E. CaiW. Preclinical pharmacokinetics and biodistribution studies of 89 Zr-labeled pembrolizumab.J. Nucl. Med.201758116216810.2967/jnumed.116.17785727493273
     [Google Scholar]
  38. TrailaA. DimaD. Achimas-CadariuP. MicuR. Fertility preservation in Hodgkin’s lymphoma patients that undergo targeted molecular therapies: An important step forward from the chemotherapy era.Cancer Manag. Res.2018101517152610.2147/CMAR.S15481929942153
     [Google Scholar]
  39. QuandtZ. KimS. Villanueva-MeyerJ. CoupeC. YoungA. KangJ.H. YazdanyJ. SchmajukG. RushS. ZivE. PerdigotoA.L. HeroldK. LechnerM.G. SuM.A. TyrrellJ.B. BluestoneJ. AndersonM. MasharaniU. Spectrum of Clinical Presentations, Imaging Findings, and HLA Types in Immune Checkpoint Inhibitor–Induced Hypophysitis Spectrum of clinical presentations, imaging findings, and HLA types in immune checkpoint inhibitor–induced hypophysitis.J. Endocr. Soc.202374bvad01210.1210/jendso/bvad012
     [Google Scholar]
  40. Barroso-SousaR. BarryW.T. Garrido-CastroA.C. HodiF.S. MinL. KropI.E. TolaneyS.M. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens.JAMA Oncol.20184217318210.1001/jamaoncol.2017.306428973656
     [Google Scholar]
  41. FajeA. ReynoldsK. ZubiriL. LawrenceD. CohenJ.V. SullivanR.J. NachtigallL. TritosN. Hypophysitis secondary to nivolumab and pembrolizumab is a clinical entity distinct from ipilimumab-associated hypophysitis.Eur. J. Endocrinol.2019181321121910.1530/EJE‑19‑023831176301
     [Google Scholar]
  42. BrietC. AlbarelF. KuhnE. MerlenE. ChansonP. CortetC. Expert opinion on pituitary complications in immunotherapy.Ann. Endocrinol.201879556256810.1016/j.ando.2018.07.00830126625
     [Google Scholar]
  43. HusebyeE.S. CastinettiF. CrisenoS. CuriglianoG. DecallonneB. FleseriuM. HighamC.E. LupiI. PaschouS.A. TothM. van der KooijM. DekkersO.M. Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: An ESE clinical practice guideline.Eur. J. Endocrinol.20221876G1G2110.1530/EJE‑22‑068936149449
     [Google Scholar]
  44. TulchinerG. PichlerR. UlmerH. StaudacherN. LindnerA.K. BrunnerA. ZelgerB. SteinkohlF. AignerF. HorningerW. ThurnherM. Sex-specific hormone changes during immunotherapy and its influence on survival in metastatic renal cell carcinoma.Cancer Immunol. Immunother.202170102805281710.1007/s00262‑021‑02882‑y33646368
     [Google Scholar]
  45. Di DalmaziG. IppolitoS. LupiI. CaturegliP. Hypophysitis induced by immune checkpoint inhibitors: A 10-year assessment.Expert Rev. Endocrinol. Metab.201914638139810.1080/17446651.2019.170143431842671
     [Google Scholar]
  46. Garon-CzmilJ. PetitpainN. RoubyF. SassierM. BabaiS. Yéléhé-OkoumaM. WeryhaG. KleinM. GilletP. Immune check point inhibitors-induced hypophysitis: A retrospective analysis of the French Pharmacovigilance database.Sci. Rep.2019911941910.1038/s41598‑019‑56026‑531857638
     [Google Scholar]
  47. FajeA.T. SullivanR. LawrenceD. TritosN.A. FaddenR. KlibanskiA. NachtigallL. Ipilimumab-induced hypophysitis: A detailed longitudinal analysis in a large cohort of patients with metastatic melanoma.J. Clin. Endocrinol. Metab.201499114078408510.1210/jc.2014‑230625078147
     [Google Scholar]
  48. PrivieroF. WebbC. Biology of iatrogenic sexual dysfunction in men and women survivors of cancer.Urol. Oncol.202240836637110.1016/j.urolonc.2021.01.01733563538
     [Google Scholar]
  49. SoodA. ColeD. AbdollahF. EilenderB. RoumayahZ. DeebajahM. DabajaA. AlaneeS. Endocrine, sexual function, and infertility side effects of immune checkpoint inhibitor therapy for genitourinary cancers.Curr. Urol. Rep.20181996810.1007/s11934‑018‑0819‑729971696
     [Google Scholar]
  50. YumuraY. TakeshimaT. KomeyaM. KurodaS. SaitoT. KaribeJ. Fertility and sexual dysfunction in young male cancer survivors.Reprod. Med. Biol.2022211e1248110.1002/rmb2.1248135949642
     [Google Scholar]
  51. BaettigF. VlajnicT. VetterM. GlatzK. HenchJ. FrankS. BihlM. LopezR. DobbieM. Heinzelmann-SchwarzV. MontavonC. Nivolumab in chemotherapy-resistant cervical cancer: Report of a vulvitis as a novel immune-related adverse event and molecular analysis of a persistent complete response.J. Immunother. Cancer20197128110.1186/s40425‑019‑0742‑631672171
     [Google Scholar]
  52. LoganS. PerzJ. UssherJ.M. PeateM. AnazodoA. Systematic review of fertility-related psychological distress in cancer patients: Informing on an improved model of care.Psychooncology2019281223010.1002/pon.492730460732
     [Google Scholar]
  53. KowalkowskiM.A. ChandrashekarA. AmielG.E. LernerS.P. WittmannD.A. LatiniD.M. GoltzH.H. Examining sexual dysfunction in non-muscle-invasive bladder cancer: Results of cross-sectional mixed-methods research.Sex. Med.20142314115110.1002/sm2.2425356311
     [Google Scholar]
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  • Article Type:     Review Article
Keyword(s): clinical trials; gonads; Immune checkpoint inhibitors; infertility; ipilimumab; nivolumab

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