Skip to main content
Log in

Oral Contraceptives and Skin Cancer

Is There a Link?

  • Current Opinion
  • Published:
American Journal of Clinical Dermatology Aims and scope Submit manuscript

Abstract

The skin expresses estrogen, progesterone, and androgen receptors. In the presence of steroid hormones, such as those contained in oral contraceptives, the skin likely responds to hormonal signals that control the cell cycle, apoptosis, DNA replication, and other cellular functions. Some estrogen-responsive pathways have the potential to promote tumor development, including the augmentation of epidermal growth factor signaling, the expression of proto-oncogenes, and inhibition of apoptosis. The question of whether oral contraceptives increase the risk for the development of skin cancer, particularly melanoma, is still an area of concern. This paper reviews the available evidence, the bulk of which suggests that while the skin responds to estrogens, progestins, and androgens, these responses do not significantly increase the risk of developing skin cancer when estrogen exposure is not excessive.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jensen EV, DeSombre ER. Estrogen-receptor interaction. Science. 1973; 182 (108): 126–34

    Article  PubMed  CAS  Google Scholar 

  2. Evans RM. The steroid and thyroid hormone receptor superfamily. Science. 1988; 240 (4854): 889–95

    Article  PubMed  CAS  Google Scholar 

  3. Onate SA, Tsai SY, Tsai MJ, et al. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995; 270 (5240): 1354–7

    Article  PubMed  CAS  Google Scholar 

  4. Carroll JS, Swarbrick A, Musgrove EA, et al. Mechanisms of growth arrest by c-myc antisense oligonucleotides in MCF-7 breast cancer cells: implications for the antiproliferative effects of antiestrogens. Cancer Res 2002; 62 (11): 3126–31

    PubMed  CAS  Google Scholar 

  5. Webb P, Nguyen P, Valentine C, et al. The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Mol Endocrinol. 1999; 13 (10): 1672–85

    Article  PubMed  CAS  Google Scholar 

  6. Kushner PJ, Agard DA, Greene GL, et al. Estrogen receptor pathways to AP-1. J Steroid Biochem Mot Biol. 2000; 74 (5): 311–7

    Article  CAS  Google Scholar 

  7. Kushner PJ, Agard D, Feng WJ, et al. Oestrogen receptor function at classical and alternative response elements. Novartis Found Symp. 2000; 230: 20–6

    Article  PubMed  CAS  Google Scholar 

  8. Horwitz KB, Alexander PS. In situ photolinked nuclear progesterone receptors of human breast cancer cells: subunit molecular weights after transformation and translocation. Endocrinology. 1983; 113 (6: 2195–201

    Article  PubMed  CAS  Google Scholar 

  9. Lessey BA, Alexander PS, Horwitz KB. The subunit structure of human breast cancer progesterone receptors: characterization by chromatography and photoaffinity labeling. Endocrinology. 1983; 112 (4): 1267–74

    Article  PubMed  CAS  Google Scholar 

  10. Arnett-Mansfield RL, deFazio A, Wain GV, et al. Relative expression of progesterone receptors A and B in endometrioid cancers of the endometrium. Cancer Res. 2001; 61 (11): 4576–82

    PubMed  CAS  Google Scholar 

  11. Hanekamp EE, Kuhne EC, Smid-Koopman E, et al. Loss of progesterone receptor may lead to an invasive phenotype in human endometrial cancer. Fur J Cancer. 2002; 38 Suppl. 6: S71–2

    CAS  Google Scholar 

  12. Gregory CW, He B, Wilson EM. The putative androgen receptor-A form results from in vitro proteolysis. J Mol Endocrinol. 2001; 27 (3): 309–19

    Article  PubMed  CAS  Google Scholar 

  13. Tilley WD, Marcelli M, Wilson JD, et al. Characterization and expression of a cDNA encoding the human androgen receptor. Proc Natl Acad Sci U S A. 1989; 86 (1): 327–31

    Article  PubMed  CAS  Google Scholar 

  14. Wilson CM, McPhaul MI. A and B forms of the androgen receptor are present in human genital skin fibroblasts. Proc Natl Acad Sci U S A. 1994; 91 (4): 1234–8

    Article  PubMed  CAS  Google Scholar 

  15. Catalano MG, Pfeffer U, Raineri M, et al. Altered expression of androgen-receptor isoforms in human colon-cancer tissues. Int J Cancer. 2000; 86 (3): 325–30

    Article  PubMed  CAS  Google Scholar 

  16. Ho KJ, Liao JK. Nonnuclear actions of estrogen. Arterioscler Thromb Vase Biol. 2002; 22 (12): 1952–61

    Article  CAS  Google Scholar 

  17. McCann JP, Mayes JS, Hendricks GR, et al. Subcellular distribution and glycosylation pattern of androgen receptor from sheep omental adipose tissue. J Endocrinol; 2001; 169 (3): 587–93

    Article  PubMed  CAS  Google Scholar 

  18. Harvey BJ, Doolan CM, Condliffe SB, et al. Non-genomic convergent and divergent signaling of rapid responses to aldosterone and estradiol in mammalian colon. Steroids. 2002; 67 (6): 483–91

    Article  PubMed  CAS  Google Scholar 

  19. Singleton DW, Feng Y, Burd CJ, et al. Nongenomic activity and subsequent c-fos induction by estrogen receptor ligands are not sufficient to promote deoxyribonucleic acid synthesis in human endometrial adenocarcinoma cells. Endocrinology. 2003; 144 (1): 121–8

    Article  PubMed  CAS  Google Scholar 

  20. Filardo EJ. Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer. J Steroid Biochem Mol Biol. 2002; 80 (2): 231–8

    Article  PubMed  CAS  Google Scholar 

  21. Filardo EJ, Quinn JA, Frackelton AR, et al. Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and CAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis. Mol Endocrinol. 2002; 16 (1): 70–84

    Article  PubMed  CAS  Google Scholar 

  22. Ahola TM, Alkio N, Manninen T, et al. Progestin and G protein-coupled receptor 30 inhibit mitogen-activated protein kinase activity in MCF-7 breast cancer cells. Endocrinology. 2002; 143 (12): 4620–6

    Article  PubMed  CAS  Google Scholar 

  23. Ahola TM, Manninen T, Alkio N, et al. G protein-coupled receptor 30 is critical for a progestin-induced growth inhibition in MCF-7 breast cancer cells. Endocrinology. 2002; 143 (9): 3376–84

    Article  PubMed  CAS  Google Scholar 

  24. Ahola TM, Purmonen S, Pennanen P, et al. Progestin upregulates G-protein-coupled receptor 30 in breast cancer cells. Eur J Biochem. 2002; 269 (10): 2485–90

    Article  PubMed  CAS  Google Scholar 

  25. Fraser D, Padwick ML, Whitehead M, et al. Presence of an oestradiol receptor-related protein in the skin: changes during the normal menstrual cycle. Br J Obstet Gynaecol. 1991; 98 (12): 1277–82

    Article  PubMed  CAS  Google Scholar 

  26. Pelletier G, El-Alfy M. Immunocytochemical localization of estrogen receptors alpha and beta in the human reproductive organs. J Clin Endocrinol Metab. 2000; 85 (12): 4835–40

    Article  PubMed  CAS  Google Scholar 

  27. Sun J, Baudry J, Katzenellenbogen JA, et al. Molecular basis for the subtype discrimination of the estrogen receptor-beta-selective ligand, diarylpropionitrile. Mol Endocrinol. 2003; 17 (2): 247–58

    Article  PubMed  CAS  Google Scholar 

  28. Sun J, Huang YR, Harrington WR, et al. Antagonists selective for estrogen receptor alpha. Endocrinology. 2002; 143 (3): 941–7

    Article  PubMed  CAS  Google Scholar 

  29. Shiau AK, Barstad D, Radek IT, et al. Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism. Nat Struct Biol. 2002; 9 (5): 359–64

    PubMed  CAS  Google Scholar 

  30. Harris HA, Katzenellenbogen JA, Katzenellenbogen BS. Characterization of the biological roles of the estrogen receptors, ERα and ERβ, in estrogen target tissues in vivo through the use of an ERa-selective ligand. Endocrinology. 2002; 143 (11): 4172–7

    Article  PubMed  CAS  Google Scholar 

  31. Rickard DJ, Waters KM, Ruesink TJ, et al. Estrogen receptor isoform-specific induction of progesterone receptors in human osteoblasts. J Bone Miner Res. 2002; 17 (4): 580–92

    Article  PubMed  CAS  Google Scholar 

  32. Lindberg MK, Moverare S, Skrtic S, et al. Estrogen receptor (ER)-β reduces ERα-regulated gene transcription, supporting a ‘ying yang’ relationship between ERα and ERβ in mice. Mol Endocrinol. 2003; 17 (2): 203–8

    Article  PubMed  CAS  Google Scholar 

  33. Moverare S, Lindberg MK, Faergemann J, et al. Estrogen receptor-α, but not estrogen receptor-β, is involved in the regulation of the hair follicle cycling as well as the thickness of epidermis in male mice. J Invest Dermatol. 2002; 119 (5): 1053–8

    Article  PubMed  CAS  Google Scholar 

  34. Avila DM, Wilson CM, Nandi N, et al. Immunoreactive AR and genetic alterations in subjects with androgen resistance and undetectable AR levels in genital skin fibroblast ligand-binding assays. J Clin Endocrinol Metab. 2002; 87 (1): 182–8

    Article  PubMed  CAS  Google Scholar 

  35. Alesci S, Bornstein SR. Neuroimmunoregulation of androgens in the adrenal gland and the skin. Horm Res. 2000; 54 (5-6): 281–6

    Article  PubMed  CAS  Google Scholar 

  36. Labrie F, Luu-The V, Labrie C, et al. Intracrinology and the skin. Horm Res. 2000; 54 (5-6): 218–29

    Article  PubMed  CAS  Google Scholar 

  37. Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermatol. 2001; 45 (3 Suppl.): S116–24

    Article  PubMed  CAS  Google Scholar 

  38. Izu K, Yamamoto O, Yamaguchi J, et al. A case of autoimmune progesterone dermatitis [in German]. J Uoeh. 2001; 23 (4): 431–6

    PubMed  CAS  Google Scholar 

  39. Uotinen N, Puustinen R, Pasanen S, et al. Distribution of progesterone receptor in female mouse tissues. Gen Comp Endocrinol. 1999; 115 (3): 429–41

    Article  PubMed  CAS  Google Scholar 

  40. Kommoss F, Kiechle-Schwarz M, Dubois A, et al. Co-cultivation of ovarian carcinoma cells with dermal fibroblasts induces fibroblast expression of sex steroid receptor transcripts and protein. Int J Gynecol Cancer. 1995; 5 (2): 101–6

    Article  PubMed  Google Scholar 

  41. Im S, Lee ES, Kim W, et al. Expression of progesterone receptor in human keratinocytes. J Korean Med Sci. 2000; 15 (6: 647–54

    PubMed  CAS  Google Scholar 

  42. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002; 288 (3): 321–33

    Article  PubMed  CAS  Google Scholar 

  43. Brekelmans CT. Risk factors and risk reduction of breast and ovarian cancer. Curr Opin Obstet Gynecol. 2003; 15 (1): 63–8

    Article  PubMed  Google Scholar 

  44. Matsumum Y, Ananthaswamy HN. Molecular mechanisms of photocarcinogenesis. Front Biosci. 2002; 7: d765–83

    Article  Google Scholar 

  45. Nataraj AJ, Trent JC, Ananthaswamy HN. p53 gene mutations and photocarcinogenesis. Photochem Photobiol. 1995; 62 (2): 218–30

    Article  PubMed  CAS  Google Scholar 

  46. Nishigori C, Yarosh DB, Donawho C, et al. The immune system in ultraviolet carcinogenesis. J Investig Dermatol Symp Proc. 1996; 1 (2): 143–6

    PubMed  CAS  Google Scholar 

  47. van Steeg H, Kraemer KH. Xeroderma pigmentosum and the role of UV-induced DNA damage in skin cancer. Mol Med Today. 1999; 5 (2): 86–94

    Article  PubMed  Google Scholar 

  48. McGregor JM, Yu CC, Dublin EA, et al. Aberrant expression of p53 tumour-suppressor protein in non-melanoma skin cancer. Br J Dermatol. 1992; 127 (5): 463–9

    Article  PubMed  CAS  Google Scholar 

  49. Shea CR, McNutt NS, Volkenandt M, et al. Overexpression of p53 protein in basal cell carcinomas of human skin. Am J Pathol. 1992; 141 (1): 25–9

    PubMed  CAS  Google Scholar 

  50. Stephenson TJ, Royds J, Silcocks PB, et al. Mutant p53 oncogene expression in keratoacanthoma and squamous cell carcinoma. Br J Dermatol. 1992; 127 (6): 566–70

    Article  PubMed  CAS  Google Scholar 

  51. Kimonis VE, Goldstein AM, Pastakia B, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet. 1997; 69 (3): 299–308

    Article  PubMed  CAS  Google Scholar 

  52. Pierceall WE, Goldberg LH, Tainsky MA, et al. Ras gene mutation and amplification in human nonmelanoma skin cancers. Mol Carcinog. 1991; 4 (3): 196–202

    Article  PubMed  CAS  Google Scholar 

  53. Pierceall WE, Mukhopadhyay T, Goldberg LH, et al. Mutations in the p53 tumor suppressor gene in human cutaneous squamous cell carcinomas. Mol Carcinog. 1991; 4 (6): 445–9

    Article  PubMed  CAS  Google Scholar 

  54. Dai D, Litman ES, Schonteich E, et al. Progesterone regulation of activating protein-1 transcriptional activity: a possible mechanism of progesterone inhibition of endometrial cancer cell growth. J Steroid Biochem Mol Biol. 2003; 87 (2-3): 123–31

    Article  PubMed  CAS  Google Scholar 

  55. Dai D, Wolf DM, Litman ES, et al. Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors. Cancer Res. 2002; 62 (3): 881–6

    PubMed  CAS  Google Scholar 

  56. Rogers GS, Flowers JL, Pollack SV, et al. Determination of sex steroid receptor in human basal cell carcinoma. J Am Acad Dermatol. 1988; 18 (5 Pt 1): 1039–43

    Article  PubMed  CAS  Google Scholar 

  57. Gefeller O, Hassan K, Wille L. Cutaneous malignant melanoma in women and the role of oral contraceptives. Br J Dermatol. 1998; 138 (1): 122–4

    Article  PubMed  CAS  Google Scholar 

  58. Miller JG, Gee J, Price A, et al. Investigation of oestrogen receptors, sex steroids and soluble adhesion molecules in the progression of malignant melanoma. Melanoma Res. 1997; 7 (3): 197–208

    Article  PubMed  CAS  Google Scholar 

  59. Ladanyi A, Timar J, Bocsi J, et al. Sex-dependent liver metastasis of human melanoma lines in SCID mice. Melanoma Res. 1995; 5 (2): 83–6

    Article  PubMed  CAS  Google Scholar 

  60. Kanda N, Watanabe S. 17beta-estradiol, progesterone, and dihydrotestosterone suppress the growth of human melanoma by inhibiting interleukin-8 production. J Invest Dermatol. 2001; 117 (2): 274–83

    Article  PubMed  CAS  Google Scholar 

  61. Richardson B, Price A, Wagner M, et al. Investigation of female survival benefit in metastatic melanoma. Br J Cancer. 1999; 80 (12): 2025–33

    Article  PubMed  CAS  Google Scholar 

  62. Beral V, Ramcharan S, Faris R. Malignant melanoma and oral contraceptive use among women in California. Br J Cancer. 1977; 36 (6): 804–9

    Article  PubMed  CAS  Google Scholar 

  63. Pfahlberg A, Hassan K, Wille L, et al. Systematic review of case-control studies: oral contraceptives show no effect on melanoma risk. Public Health Rev. 1997; 25 (3-4): 309–15

    PubMed  CAS  Google Scholar 

  64. Karagas MR, Stukel TA, Dykes J, et al. A pooled analysis of 10 case-control studies of melanoma and oral contraceptive use. Br J Cancer. 2002; 86 (7): 1085–92

    Article  PubMed  CAS  Google Scholar 

  65. Feskanich D, Hunter DJ, Willett WC, et al. Oral contraceptive use and risk of melanoma in premenopausal women. Br J Cancer. 1999; 81 (5): 918–23

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

Preparation of this article was funded by the Cory Beach Family Fund (KL) and the US National Institutes of Health 1R01CA99908-01 (KL). The authors have no conflicts of interest relevant to this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kimberly K. Leslie.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leslie, K.K., Espey, E. Oral Contraceptives and Skin Cancer. Am J Clin Dermatol 6, 349–355 (2005). https://doi.org/10.2165/00128071-200506060-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00128071-200506060-00002

Keywords

Navigation