Advertisement

The effect of menopausal hormone therapy on the risk of melanoma and keratinocyte skin cancer: A systematic review and meta-analysis of observational studies

      Highlights

      • Menopausal hormone therapy (MHT) is associated with increased risk of both melanoma and keratinocyte cancer.
      • Specific factors such as the type of MHT, histologic tumor and the duration of MHT use may affect that risk.
      • Close dermatologic follow-up of women who are taking MHT should be considered.

      Abstract

      Background

      Whether menopausal hormone therapy (MHT) increases the risk of skin cancer is controversial.

      Aim

      To systematically review and meta-analyze evidence regarding the association of MHT with the risk of melanoma and keratinocyte cancer (KC).

      Material and methods

      A comprehensive literature search was conducted of the PubMed, Scopus and Cochrane databases, through to 30 October 2021. Skin neoplasms were divided into melanoma and KC. In the latter category, both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) were considered. The results are presented as hazard ratios (HR) with 95 % confidence intervals (CI). The I2 index was used to assess heterogeneity. Subgroup analysis and sensitivity analysis were also conducted in order to explore potential differences among studies.

      Results

      Twenty-seven studies were included in the qualitative and 23 in the quantitative analysis, with a total of 2,612,712 menopausal women (25,126 with skin cancer; 20,150 with melanoma). MHT was associated with an increased risk of melanoma (HR 1.11; 95 % CI 1.05–1.19; I2 45%). With regard to MHT type, both estrogen monotherapy (HR 1.22, 95 % CI 1.16–1.29; I2 0%) and estrogen in combination with progestogen (HR 1.11, 95 % CI 1.05–1.18, I2 26%) significantly increased that risk. Regarding melanoma subtype, superficial spreading melanoma (SSM) and lentigo maligna melanoma (LMM) were the only histologic subtypes associated with MHT use. MHT was also associated with an increased risk of KC (HR 1.17, 95 % CI 1.04–1.31, I2 83%), specifically BCC (HR 1.22, 95 % CI 1.12–1.32; I2 29%). Longer duration (>5 years) of MHT, current use and estrogen monotherapy were associated with an increased KC risk compared with no use.

      Conclusion

      The use of MHT by postmenopausal women was associated with an increased risk of melanoma and KC. This risk was higher for current MHT users and those treated for over 5 years.

      Abbreviations:

      MHT (menopausal hormone therapy,), KC (keratinocyte cancer), BCC (basal cell carcinoma), SCC (squamous cell carcinoma), ET (estrogen monotherapy), EPT (estrogen – progestogen therapy), HR (hazard ratio)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Maturitas
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Sood R.
        • Faubion S.S.
        • Kuhle C.L.
        • Thielen J.M.
        • Shuster L.T.
        Prescribing menopausal hormone therapy: an evidence-based approach.
        Int. J. Women's Health. 2014; 6: 47-57
        • Pinkerton J.V.
        Hormone therapy for postmenopausal women.
        N. Engl. J. Med. 2020; 382: 446-455
        • Chlebowski R.T.
        • Anderson G.L.
        • Aragaki A.K.
        • Manson J.E.
        • Stefanick M.L.
        • Pan K.
        • et al.
        Association of Menopausal Hormone Therapy with Breast Cancer Incidence and Mortality during Long-term Follow-up of the Women’s health initiative randomized clinical trials.
        JAMA. 2020; 324: 369-380
        • Zhang G.-Q.
        • Chen J.-L.
        • Luo Y.
        • Mathur M.B.
        • Anagnostis P.
        • Nurmatov U.
        • et al.
        Menopausal hormone therapy and women’s health: an umbrella review.
        PLoS Med. 2021; 18e1003731
        • Sung H.
        • Ferlay J.
        • Siegel R.L.
        • Laversanne M.
        • Soerjomataram I.
        • Jemal A.
        • et al.
        Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J. Clin. 2021; 71: 209-249
        • Aggarwal P.
        • Knabel P.
        • Fleischer Jr, A.B.
        United States burden of melanoma and non-melanoma skin cancer from 1990 to 2019.
        J. Am. Acad. Dermatol. 2021; 85: 388-395
        • Apalla Z.
        • Nashan D.
        • Weller R.B.
        • Castellsagué X.
        Skin cancer: epidemiology, disease burden, pathophysiology, diagnosis, and therapeutic approaches.
        Dermatol. Ther. 2017; 7: 5-19
        • Ramaraj P.
        Is melanoma a hormone-dependent cancer or a hormone-responsive cancer?.
        in: Lemamy G.-J. Cancer Prognosis. IntechOpen, London2018https://doi.org/10.5772/intechopen.76499
        • Brincat M.P.
        • Baron Y.M.
        • Galea R.
        Estrogens and the skin.
        Climacteric. 2005; 8: 110-123
        • Morgese F.
        • Sampaolesi C.
        • Torniai M.
        • Conti A.
        • Ranallo N.
        • Giacchetti A.
        • et al.
        Gender differences and outcomes in melanoma patients.
        Oncol. Ther. 2020; 8: 103-114
        • Bellenghi M.
        • Puglisi R.
        • Pontecorvi G.
        • De Feo A.
        • Care A.
        • Mattia G.
        Sex and gender disparities in melanoma.
        Cancers (Basel). 2020; 12
        • Schwartz M.R.
        • Luo L.
        • Berwick M.
        Sex differences in melanoma.
        Curr. Epidemiol. Rep. 2019; 6: 112-118
        • Dika E.
        • Patrizi A.
        • Lambertini M.
        • Manuelpillai N.
        • Fiorentino M.
        • Altimari A.
        • et al.
        Estrogen receptors and melanoma: a review.
        Cells. 2019; 8
        • Bieber A.K.
        • Martires K.J.
        • Driscoll M.S.
        • Grant-Kels J.M.
        • Pomeranz M.K.
        • Stein J.A.
        Nevi and pregnancy.
        J. Am. Acad. Dermatol. 2016; 75: 661-666
        • Chan M.P.
        • Chan M.M.
        • Tahan S.R.
        Melanocytic nevi in pregnancy: histologic features and Ki-67 proliferation index.
        J. Cutan. Pathol. 2010; 37: 843-851
        • Kyrgidis A.
        • Lallas A.
        • Moscarella E.
        • Longo C.
        • Alfano R.
        • Argenziano G.
        Does pregnancy influence melanoma prognosis? A meta-analysis.
        Melanoma Res. 2017; 27: 289-299
        • Donley G.M.
        • Liu W.T.
        • Pfeiffer R.M.
        • McDonald E.C.
        • Peters K.O.
        • Tucker M.A.
        • et al.
        Reproductive factors, exogenous hormone use and incidence of melanoma among women in the United States.
        Br. J. Cancer. 2019; 120: 754-760
        • Cervenka I.
        • Mahamat-Saleh Y.
        • Savoye I.
        • Dartois L.
        • Boutron-Ruault M.C.
        • Fournier A.
        • et al.
        Oral contraceptive use and cutaneous melanoma risk: a french prospective cohort study.
        Int. J. Cancer. 2018; 143: 2390-2399
        • Suresh R.
        • Twigg A.
        • Murase J.E.
        The relationship between menopausal hormone therapy and keratinocyte carcinoma: a review.
        Int. J. Womens Dermatol. 2019; 5: 8-13
        • Gandini S.
        • Iodice S.
        • Koomen E.
        • Di Pietro A.
        • Sera F.
        • Caini S.
        Hormonal and reproductive factors in relation to melanoma in women: current review and meta-analysis.
        Eur. J. Cancer. 2011; 47: 2607-2617
        • Cervenka I.
        • Al Rahmoun M.
        • Mahamat-Saleh Y.
        • Fournier A.
        • Boutron-Ruault M.-C.
        • Severi G.
        • et al.
        Exogenous hormone use and cutaneous melanoma risk in women: the european prospective investigation into cancer and nutrition.
        Int. J. Cancer. 2020; 146: 3267-3280
        • Botteri E.
        • Stoer N.C.
        • Weiderpass E.
        • Pukkala E.
        • Ylikorkala O.
        • Lyytinen H.
        Menopausal hormone therapy and risk of melanoma: a Nationwide register-based study in Finland.
        Cancer Epidemiol. Biomark. Prev. 2019; 28: 1857-1860
        • Botteri E.
        • Stoer N.C.
        • Sakshaug S.
        • Graff-Iversen S.
        • Vangen S.
        • Hofvind S.
        • et al.
        Menopausal hormone therapy and risk of melanoma: do estrogens and progestins have a different role?.
        Int. J. Cancer. 2017; 141: 1763-1770
        • Hicks B.M.
        • Kristensen K.B.
        • Pedersen S.A.
        • Holmich L.R.
        • Pottegard A.
        Hormone replacement therapy and the risk of melanoma in post-menopausal women.
        Hum. Reprod. 2019; 34: 2418-2429
        • Tang J.Y.
        • Spaunhurst K.M.
        • Chlebowski R.T.
        • Wactawski-Wende J.
        • Keiser E.
        • Thomas F.
        • et al.
        Menopausal hormone therapy and risks of melanoma and nonmelanoma skin cancers: women's health initiative randomized trials.
        J. Natl. Cancer Inst. 2011; 103: 1469-1475
        • Birch-Johansen F.
        • Jensen A.
        • Olesen A.B.
        • Christensen J.
        • Tjonneland A.
        • Kjaer S.K.
        Does hormone replacement therapy and use of oral contraceptives increase the risk of non-melanoma skin cancer?.
        Cancer Causes Control. 2012; 23: 379-388
        • Cahoon E.K.
        • Kitahara C.M.
        • Ntowe E.
        • Bowen E.M.
        • Doody M.M.
        • Alexander B.H.
        • et al.
        Female estrogen-related factors and incidence of basal cell carcinoma in a Nationwide US cohort.
        J. Clin. Oncol. 2015; 33: 4058-4065
        • Brooke B.S.
        • Schwartz T.A.
        • Pawlik T.M.
        MOOSE reporting guidelines for meta-analyses of observational studies.
        JAMA Surg. 2021; 156: 787-788
        • Tierney J.F.
        • Stewart L.A.
        • Ghersi D.
        • Burdett S.
        • Sydes M.R.
        Practical methods for incorporating summary time-to-event data into meta-analysis.
        Trials. 2007; 8: 16
        • Persson I.
        • Yuen J.
        • Bergkvist L.
        • Schairer C.
        Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy–long-term follow-up of a swedish cohort.
        Int. J. Cancer. 1996; 67: 327-332
        • Adami H.-O.
        • Persson I.
        • Hoover R.
        • Schairer C.
        • Bergkvist L.
        Risk of Cancer in Women Receiving Hormone Replacement Therapy. 44(5). 1989: 833-839
        • Koomen E.R.
        • Joosse A.
        • Herings R.M.
        • Casparie M.K.
        • Guchelaar H.J.
        • Nijsten T.
        Does use of estrogens decrease the breslow thickness of melanoma of the skin? Oral contraceptives and hormonal replacement therapy.
        Melanoma Res. 2009; 19: 327-332
        • Lea C.S.
        • Holly E.A.
        • Hartge P.
        • Lee J.S.
        • Dt Guerry
        • Elder D.E.
        • et al.
        Reproductive risk factors for cutaneous melanoma in women: a case-control study.
        Am. J. Epidemiol. 2007; 165: 505-513
        • Holly E.A.
        • Cress R.D.
        • Ahn D.K.
        Cutaneous melanoma in women: ovulatory life, menopause, and use of exogenous estrogens.
        Cancer Epidemiol. Biomark. Prev. 1994; 3: 661-668
        • Holly E.A.
        • Weiss N.S.
        • Liff J.M.
        Cutaneous melanoma in relation to exogenous hormones and reproductive factors.
        J. Natl. Cancer Inst. 1983; 70: 827-831
        • Beral V.
        • Evans S.
        • Shaw H.
        • Milton G.
        Oral contraceptive use and malignant melanoma in Australia.
        Br. J. Cancer. 1984; 50: 681-685
      1. J Westerdahl A Olsson H Fau - Måsbäck , C Måsbäck A Fau - Ingvar , N Ingvar C Fau - Jonsson , N Jonsson . Risk of Malignant Melanoma in Relation to Drug Intake, Alcohol, Smoking and Hormonal Factors. (0007-0920 (Print)).

        • Smith M.A.
        • Fine J.A.
        • Barnhill R.L.
        • Berwick M.
        Hormonal and reproductive influences and risk of melanoma in women.
        Int. J. Epidemiol. 1998; 27: 751-757
        • Naldi L.
        • Altieri A.
        • Imberti G.L.
        • Giordano L.
        • Gallus S.
        • La Vecchia C.
        • et al.
        Cutaneous malignant melanoma in women. Phenotypic characteristics, sun exposure, and hormonal factors: a case-control study from Italy.
        Ann. Epidemiol. 2005; 15: 545-550
        • De Giorgi V.
        • Gori A.
        • Savarese I.
        • D'Errico A.
        • Scarfi F.
        • Papi F.
        • et al.
        Role of BMI and hormone therapy in melanoma risk: a case-control study.
        J. Cancer Res. Clin. Oncol. 2017; 143: 1191-1197
        • Koomen E.R.
        • Joosse A.
        • Herings R.M.
        • Casparie M.K.
        • Guchelaar H.J.
        • Nijsten T.
        Estrogens, oral contraceptives and hormonal replacement therapy increase the incidence of cutaneous melanoma: a population-based case-control study.
        Ann. Oncol. 2009; 20: 358-364
        • Østerlind A.
        • Tucker M.A.
        • Stone B.J.
        • Jensen O.M.
        The Danish Case-control Study of Cutaneous Malignant Melanoma. III. Hormonal and Reproductive Factors in Women. 42(6). 1988: 821-824
        • Cervenka I.
        • Al Rahmoun M.
        • Mahamat-Saleh Y.
        • Savoye I.
        • Boutron-Ruault M.C.
        • Fournier A.
        • et al.
        Postmenopausal hormone use and cutaneous melanoma risk: a french prospective cohort study.
        Int. J. Cancer. 2019; 145: 1754-1767
        • Støer N.C.
        • Botteri E.
        • Busund M.
        • Ghiasvand R.
        • Vangen S.
        • Lund E.
        • Weiderpass E.
        • Veierød M.B.
        Menopausal hormone therapy and risk of melanoma: a population-based cohort study.
        Br. J. Dermatol. 2021; 185: 1266-1267
        • Olsen C.M.
        • Pandeya N.
        • Dusingize J.C.
        • Thompson B.S.
        • Green A.C.
        • Neale R.E.
        • Webb P.M.
        • Whiteman D.C.
        Reproductive factors, hormone use and melanoma risk: an Australian prospective cohort study.
        Br. J. Dermatol. 2021; 184: 361-363https://doi.org/10.1111/bjd.19498
        • Simin J.
        • Tamimi R.
        • Lagergren J.
        • Adami H.O.
        • Brusselaers N.
        Menopausal hormone therapy and cancer risk: an overestimated risk?.
        Eur. J. Cancer. 2017; 84: 60-68
        • Kuklinski L.F.
        • Zens M.S.
        • Perry A.E.
        • Gossai A.
        • Nelson H.H.
        • Karagas M.R.
        Sex hormones and the risk of keratinocyte cancers among women in the United States: a population-based case-control study.
        Int. J. Cancer. 2016; 139: 300-309
        • Olsen C.M.
        • Pandeya N.
        • Thompson B.S.
        • Dusingize J.C.
        • Subramaniam P.
        • Nagle C.M.
        • et al.
        Hormonal and reproductive factors and incidence of basal cell carcinoma and squamous cell carcinoma in a large, prospective cohort.
        J. Am. Acad. Dermatol. 2018; 78: 615-8 e2
        • Sun Q.
        • Sun H.
        • Cong L.
        • Zheng Y.
        • Wu N.
        • Cong X.
        Effects of exogenous hormones and reproductive factors on female melanoma: a meta-analysis.
        Clin Epidemiol. 2020; 12: 1183-1203
        • Tang X.
        • Zhang H.
        • Cui Y.
        • Wang L.
        • Wang Z.
        • Zhang Y.
        • et al.
        Postmenopausal exogenous hormone therapy and melanoma risk in women: a systematic review and time-response meta-analysis.
        Pharmacol. Res. 2020; 160105182
        • Wiedemann C.
        • Nagele U.
        • Schramm G.
        • Berking C.
        Inhibitory effects of progestogens on the estrogen stimulation of melanocytes in vitro.
        Contraception. 2009; 80: 292-298
        • Becher R.
        • Kloke O.
        • Höffken K.
        • Scheulen M.E.
        • Wandl U.B.
        • Bojar H.
        • et al.
        Phase II study of high-dose medroxyprogesterone acetate in advanced malignant melanoma.
        Br. J. Cancer. 1989; 59: 948
        • Moroni G.
        • Gaziano R.
        • BuË C.
        • Agostini M.
        • Perno C.F.
        • Sinibaldi-Vallebona P.
        • et al.
        Progesterone and melanoma cells: an old story suspended between life and death.
        J. Steroids Hormonal Sci. 2015; 6: 1-5
        • Ramaraj P.
        • Cox J.L.
        In vitro effect of progesterone on human melanoma (BLM) cell growth.
        Int. J. Clin. Exp. Med. 2014; 7: 3941-3953
        • Linos E.
        • Li W.Q.
        • Han J.
        • Li T.
        • Cho E.
        • Qureshi A.A.
        Lifetime ultraviolet radiation exposure and lentigo maligna melanoma.
        Br. J. Dermatol. 2017; 176: 1666-1668
        • Higgins II, H.
        • Cho E.
        • Weinstock M.
        • Li T.
        • Qureshi A.
        • Li W.
        Gender differences, UV exposure and risk of lentigo maligna in a nationwide healthcare population cohort study.
        J. Eur. Acad. Dermatol. Venereol. 2019; 33: 1268-1271https://doi.org/10.1111/jdv.15348
        • Caini S.
        • De Angelis S.P.
        • Corso F.
        • Fantini C.
        • Raimondi S.
        • Pala L.
        • et al.
        Exogenous sex hormones, menstrual and reproductive history, and risk of non-melanoma skin cancer among women: a systematic literature review and meta-analysis.
        Sci. Rep. 2021; 11: 8524
        • Natale C.A.
        • Li J.
        • Zhang J.
        • Dahal A.
        • Dentchev T.
        • Stanger B.Z.
        • et al.
        Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade.
        elife. 2018; : 7
        • Bhari N.
        • Schwaertz R.A.
        • Apalla Z.
        • et al.
        Effect of estrogen in malignant melanoma.
        J. Cosmet. Dermatol. 2022; 21: 1905-1912
        • Marzagalli M.
        • Montagnani Marelli M.
        • Casati L.
        • Fontana F.
        • Moretti R.M.
        • Limonta P.
        Estrogen receptor beta in melanoma: from molecular insights to potential clinical utility.
        Front. Endocrinol. 2016; 7: 140
        • Cives M.
        • Mannavola F.
        • Lospalluti L.
        • Sergi M.C.
        • Cazzato G.
        • Filoni E.
        • et al.
        Non-melanoma skin cancers: biological and clinical features.
        Int. J. Mol. Sci. 2020; 21