Cutaneous Melanoma and Hormones: Focus on Sex Differences and the Testis

Cutaneous melanoma, the most aggressive type of skin cancer, remains one the most represented forms of cancer in the United States and European countries, representing, in Australia, the primary cause of cancer-related deaths. Recently, many studies have shown that sex disparities previously observed in most cancers are particularly accentuated in melanoma, where male sex is consistently associated with an increased risk of disease progression and a higher mortality rate. The causes of these sex differences rely on biological mechanisms related to sex hormones, immune homeostasis and oxidative processes. The development of newer therapies, such as immune checkpoint inhibitors (ICIs) (i.e., anti–PD-1 and anti–CTLA-4 monoclonal antibodies) has dramatically changed the treatment landscape of metastatic melanoma patients, though ICIs can interfere with the immune response and lead to inflammatory immune-related adverse events (irAEs). Recently, some studies have shown a potential adverse influence of this immunotherapy treatment also on male fertility and testicular function. However, while many anticancer drugs are known to cause defects in spermatogenesis, the effects of ICIs therapy remain largely unknown. Notwithstanding the scarce and conflicting information available on this topic, the American Society of Clinical Oncology guidelines recommend sperm cryopreservation in males undergoing ICIs. As investigations regarding the long-term outcomes of anticancer immunotherapy on the male reproductive system are still in their infancy, this review aims to support and spur future research in order to understand a potential gonadotoxic effect of ICIs on testicular function, spermatogenesis and male fertility.

[1]  R. Flyckt,et al.  Minding the Bathwater: Fertility and Reproductive Toxicity in the Age of Immuno-Oncology. , 2022, JCO oncology practice.

[2]  F. Mancini,et al.  The Role of Testosterone in Spermatogenesis: Lessons From Proteome Profiling of Human Spermatozoa in Testosterone Deficiency , 2022, Frontiers in Endocrinology.

[3]  D. Schadendorf,et al.  Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma , 2021, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  E. Broniatowska,et al.  Molecular Proof of a Clinical Concept: Expression of Estrogen Alpha-, Beta-Receptors and G Protein-Coupled Estrogen Receptor 1 (GPER) in Histologically Assessed Common Nevi, Dysplastic Nevi and Melanomas , 2021, Medicina.

[5]  T. Falcone,et al.  Targeted cancer treatment and fertility: effect of immunotherapy and small molecule inhibitors on female reproduction. , 2021, Reproductive biomedicine online.

[6]  O. Dekkers,et al.  Sex-Based Differences in Treatment with Immune Checkpoint Inhibition and Targeted Therapy for Advanced Melanoma: A Nationwide Cohort Study , 2021, Cancers.

[7]  Z. Apalla,et al.  Effect of estrogen in malignant melanoma , 2021, Journal of cosmetic dermatology.

[8]  A. Enk,et al.  Male fertility during and after immune checkpoint inhibitor therapy: A cross-sectional pilot study. , 2021, European journal of cancer.

[9]  T. Key,et al.  Prospective analyses of testosterone and sex hormone‐binding globulin with the risk of 19 types of cancer in men and postmenopausal women in UK Biobank , 2021, International journal of cancer.

[10]  S. Mott,et al.  Testosterone deficiency in men receiving immunotherapy for malignant melanoma , 2021, Oncotarget.

[11]  B. Özdemir Immune checkpoint inhibitor-related hypogonadism and infertility: a neglected issue in immuno-oncology , 2021, Journal for ImmunoTherapy of Cancer.

[12]  A. Geller,et al.  Epidemiology of Melanoma. , 2021, Hematology/oncology clinics of North America.

[13]  D. Fisher,et al.  Biology of Melanoma. , 2021, Hematology/oncology clinics of North America.

[14]  Ran Mo,et al.  Sex-specific survival benefit in early skin melanoma based on 8th AJCC edition: an analysis of data from the Surveillance, Epidemiology, and End Results (SEER) database , 2020, Annals of translational medicine.

[15]  M. Rabinowitz,et al.  Onset of azoospermia in man treated with ipilimumab/nivolumab for BRAF negative metastatic melanoma , 2020, Urology case reports.

[16]  J. Foskett,et al.  ZIP9 Is a Druggable Determinant of Sex Differences in Melanoma , 2020, Cancer Research.

[17]  P. Lambert,et al.  Understanding the impact of sex and stage differences on melanoma cancer patient survival: a SEER-based study , 2020, British journal of cancer.

[18]  M. Szczyrek,et al.  Endocrine Adverse Events of Nivolumab in Non-Small Cell Lung Cancer Patients—Literature Review , 2020, Cancers.

[19]  S. Loges,et al.  Influence of Androgens on Immunity to Self and Foreign: Effects on Immunity and Cancer , 2020, Frontiers in Immunology.

[20]  L. Ginaldi,et al.  Sex and Gender Influences on Cancer Immunotherapy Response , 2020, Biomedicines.

[21]  L. C. Spolidorio,et al.  Testosterone Increases Fibroblast Proliferation in vitro Through Androgen and Estrogen Receptor Activation. , 2020, Journal of the International Academy of Periodontology.

[22]  J. Hooper,et al.  Association of Impaired Spermatogenesis With the Use of Immune Checkpoint Inhibitors in Patients With Metastatic Melanoma. , 2020, JAMA oncology.

[23]  X. Bai,et al.  Mapping endocrine toxicity spectrum of immune checkpoint inhibitors: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase , 2020, Endocrine.

[24]  G. Ciriello,et al.  Sustained androgen receptor signaling is a determinant of melanoma cell growth potential and tumorigenesis , 2020, bioRxiv.

[25]  J. Welborn,et al.  Germline mutations predisposing to melanoma , 2020, Journal of cutaneous pathology.

[26]  J. Wernberg,et al.  Epidemiology and Risk Factors of Melanoma. , 2020, The Surgical clinics of North America.

[27]  Franck Rouby,et al.  Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database , 2019, Scientific Reports.

[28]  J. D'haese,et al.  Advances in cancer immunotherapy 2019 – latest trends , 2019, Journal of Experimental & Clinical Cancer Research.

[29]  Matthew R. Schwartz,et al.  Sex Differences in Melanoma , 2019, Current Epidemiology Reports.

[30]  K. Goldberg,et al.  Analysis of the Association Between Adverse Events and Outcome in Patients Receiving a Programmed Death Protein 1 or Programmed Death Ligand 1 Antibody. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  Matthew J. Frigault,et al.  Management of Immunotherapy-Related Toxicities, Version 1.2019. , 2019, Journal of the National Comprehensive Cancer Network : JNCCN.

[32]  I. Camacho-Arroyo,et al.  Testosterone Promotes Glioblastoma Cell Proliferation, Migration, and Invasion Through Androgen Receptor Activation , 2019, Front. Endocrinol..

[33]  F. Cools,et al.  A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors , 2018, Hormone and Metabolic Research.

[34]  K. Hargadon,et al.  Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. , 2018, International immunopharmacology.

[35]  A. Goldhirsch,et al.  Different effectiveness of anticancer immunotherapy in men and women relies on sex-dimorphism of the immune system , 2018, Oncotarget.

[36]  J. Wolchok,et al.  5-year survival outcomes in patients (pts) with advanced melanoma treated with pembrolizumab (pembro) in KEYNOTE-001. , 2018 .

[37]  R. Gelber,et al.  Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis. , 2018, The Lancet. Oncology.

[38]  D. Bedognetti,et al.  NY-ESO-1 Based Immunotherapy of Cancer: Current Perspectives , 2018, Front. Immunol..

[39]  Demetrios A. Spandidos,et al.  Cutaneous melanoma: From pathogenesis to therapy (Review) , 2018, International journal of oncology.

[40]  Matthew D. Hellmann,et al.  Immune‐Related Adverse Events Associated with Immune Checkpoint Blockade , 2018, The New England journal of medicine.

[41]  P. Dickman,et al.  Sex differences in cancer risk and survival: A Swedish cohort study. , 2017, European journal of cancer.

[42]  S. Ghafouri-Fard,et al.  Melanoma: a prototype of cancer-testis antigen-expressing malignancies. , 2017, Immunotherapy.

[43]  D. Schadendorf,et al.  Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma , 2017, The New England journal of medicine.

[44]  Huirong Shi,et al.  Novel strategies to prevent the development of multidrug resistance (MDR) in cancer. , 2017, Oncotarget.

[45]  R. Sullivan,et al.  Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[46]  S. Klein,et al.  Sex differences in immune responses , 2016, Nature Reviews Immunology.

[47]  Y. Shentu,et al.  Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial , 2016, The Lancet.

[48]  C. Rudin,et al.  Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[49]  I. Melero,et al.  Agonists of Co-stimulation in Cancer Immunotherapy Directed Against CD137, OX40, GITR, CD27, CD28, and ICOS. , 2015, Seminars in oncology.

[50]  L. Crinò,et al.  Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[51]  T. Jones,et al.  Testosterone and obesity , 2015, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[52]  P. Baade,et al.  Melanoma survival is superior in females across all tumour stages but is influenced by age , 2015, Archives of Dermatological Research.

[53]  F. Cappuzzo,et al.  Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. , 2015, The Lancet. Oncology.

[54]  D. Schadendorf,et al.  Nivolumab in previously untreated melanoma without BRAF mutation. , 2015, The New England journal of medicine.

[55]  M. Sznol Blockade of the B7-H1/PD-1 Pathway as a Basis for Combination Anticancer Therapy , 2014, Cancer journal.

[56]  Shutao Zhao,et al.  Testicular defense systems: immune privilege and innate immunity , 2014, Cellular and Molecular Immunology.

[57]  J. Wolchok,et al.  Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. , 2014, Endocrine-related cancer.

[58]  P. Fox,et al.  Immunohistochemical Expression of Hormone Receptors in Melanoma of Pregnant Women, Nonpregnant Women, and Men , 2014, The American Journal of dermatopathology.

[59]  C. Zouboulis,et al.  Steroidogenesis in the skin: Implications for local immune functions , 2013, The Journal of Steroid Biochemistry and Molecular Biology.

[60]  D. Fisher,et al.  Disproportionate burden of melanoma mortality in young U.S. men: the possible role of biology and behavior. , 2013, JAMA dermatology.

[61]  S. Swetter,et al.  Melanoma survival disadvantage in young, non-Hispanic white males compared with females. , 2013, JAMA dermatology.

[62]  R. Simó,et al.  Testosterone induces cell proliferation and cell cycle gene overexpression in human visceral preadipocytes. , 2013, American journal of physiology. Cell physiology.

[63]  V. de Giorgi,et al.  Oestrogen receptor beta and melanoma: a comparative study , 2013, The British journal of dermatology.

[64]  Daishu Han,et al.  Structural, cellular and molecular aspects of immune privilege in the testis , 2012, Front. Immun..

[65]  S. Oertelt-Prigione The influence of sex and gender on the immune response. , 2012, Autoimmunity reviews.

[66]  R. Schreiber,et al.  Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion , 2011, Science.

[67]  J. Coebergh,et al.  Gender differences in melanoma survival: female patients have a decreased risk of metastasis. , 2011, The Journal of investigative dermatology.

[68]  J. M. Kumar,et al.  17β-estradiol-linked nitro-L-arginine as simultaneous inducer of apoptosis in melanoma and tumor-angiogenic vascular endothelial cells. , 2011, Molecular pharmaceutics.

[69]  Suzanne R. Thibodeaux,et al.  B7-H1–Dependent Sex-Related Differences in Tumor Immunity and Immunotherapy Responses , 2010, The Journal of Immunology.

[70]  A. Vandenbark,et al.  Membrane Estrogen Receptor Regulates Experimental Autoimmune Encephalomyelitis through Up-regulation of Programmed Death 11 , 2009, The Journal of Immunology.

[71]  A. Bokov,et al.  The Effect Of Gonadectomy And Estradiol On Sensitivity To Oxidative Stress , 2009, Endocrine Research.

[72]  J. Grant-Kels,et al.  Estrogen receptor expression in cutaneous melanoma. , 2009, Archives of dermatology.

[73]  G. Freeman,et al.  PD-1 and its ligands in tolerance and immunity. , 2008, Annual review of immunology.

[74]  P. Matarrese,et al.  Redox state and gender differences in vascular smooth muscle cells , 2008, FEBS letters.

[75]  A. Castrucci,et al.  Photoperiod and testosterone modulate growth and melanogenesis of s91 murine melanoma. , 2008, Medicinal chemistry (Shariqah (United Arab Emirates)).

[76]  A. Vandenbark,et al.  Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). , 2007, International immunology.

[77]  Johan Hartman,et al.  Estrogen Receptor β Inhibits Angiogenesis and Growth of T47D Breast Cancer Xenografts , 2006 .

[78]  A. Bleyer,et al.  Cancer epidemiology in older adolescents and young adults 15 to 29 years of age, including SEER incidence and survival: 1975-2000. , 2006 .

[79]  J. Gustafsson,et al.  Estrogen receptors alfa (ERα) and beta (ERβ) differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11 , 2005, Oncogene.

[80]  J. Tímár,et al.  In vitro and in vivo antitumor effect of 2‐methoxyestradiol on human melanoma , 2004, International journal of cancer.

[81]  T. Slaga,et al.  Cell cycle block and apoptosis induction in a human melanoma cell line following treatment with 2‐methoxyoestradiol: therapeutic implications? , 2003, Melanoma research.

[82]  J. Sastre,et al.  Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. , 2003, Free radical biology & medicine.

[83]  M. Capurro,et al.  Androgen receptors in human melanoma cell lines IIB-MEL-LES and IIB-MEL-IAN and in human melanoma metastases , 2002, Melanoma research.

[84]  S. Watanabe,et al.  17beta-estradiol, progesterone, and dihydrotestosterone suppress the growth of human melanoma by inhibiting interleukin-8 production. , 2001, The Journal of investigative dermatology.

[85]  J. Gustafsson,et al.  Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary tumors. , 2001, Cancer research.

[86]  J. Gustafsson,et al.  Estrogen receptor β in the breast: role in estrogen responsiveness and development of breast cancer , 2000, The Journal of Steroid Biochemistry and Molecular Biology.

[87]  P. Lorigan,et al.  Investigation of female survival benefit in metastatic melanoma , 1999, British Journal of Cancer.

[88]  M. Capurro,et al.  Atypical androgen receptor in the human melanoma cell line IIB-MEL-J. , 1995, Pigment cell research.

[89]  Michael S. Pepper,et al.  The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth , 1994, Nature.

[90]  F. Rampen Sex Differences in Survival from Cutaneous Melanoma , 1984, International journal of dermatology.

[91]  J. Mulder,et al.  MALIGNANT MELANOMA: AN ANDROGEN-DEPENDENT TUMOUR? , 1980, The Lancet.

[92]  W. McCarthy,et al.  Endocrine influences on survival from malignant melanoma , 1978, Cancer.

[93]  L. White Studies on Melanoma , 1959 .