The Effects of Postmenopausal Hormone Replacement Therapy and Oral Contraceptives on the Endogenous Estradiol Metabolism

The estradiol metabolism may be of clinical relevance in the pathophysiology of various diseases; the increase in D-ring metabolites over A-ring metabolites in breast cancer patients is of special interest. Since estrogen therapy has been blamed for increasing the risk of breast cancer, the effects of hormonal replacement therapy (HRT) and oral contraception were investigated on the ratio of the main D-ring metabolite, 16α-hydroxyestrone (16-OHE1), to the main A-ring metabolite, 2-hydroxyestrone (2-OHE1). In our study, hormone replacement therapy (HRT) in postmenopausal women consisted of administration of estradiol valerate either with or without addition of the progestin dienogest. In the second part of the study, women of reproductive age received ethinylestradiol plus dienogest or ethinylestradiol plus norethisterone acetate as oral contraceptives (OC). 2-OHE1 and 16-OHE1 were measured by enzyme immunoassay in 8 h night-urine collected before and after 3 months of hormone administration. With HRT, that is, estradiol valerate or estradiol valerate plus dienogest, the ratios before treatment were 0.47 and 0.60; after 3 months, they were 0.54 and 0.52, respectively. There were no significant differences. With oral contraception, that is, ethinylestradiol plus dienogest or norethisterone acetate, the ratios before administration were 0.62 and 0.68, vs. 0.31 and 0.54 after 3 months, respectively. The ratio after ethinylestradiol and dienogest was significantly lower after treatment. HRT and OC in the estrogen-progestin combinations tested did not impose any negative effects on estradiol metabolism - they did not elicit a higher D-ring metabolism, which is considered to increase breast cancer risk.

Estradiol Metabolism - Hormone Replacement Therapy - Oral Contraception

References

• 1 Thorneycroft I CH. Breast cancer and estrogen replacement therapy. In: Eskin BA (ed.) The Menopause, comprehensive management.  New York:; The Parthenon Publishing Group, 2000: 287-297
• 2 Hankinson S E, Stampfer M. Influence of therapeutic steroids on the incidence and severity of breast cancer. In: Fraser JS, Jansen RPS, Lobo RA, Whitehead MI (eds). Estrogens and progestogens in clinical practice.  London:; Churchill Livingstone, 1998: 865-878
• 3 Zhu B T, Conney A H. Functional role of estrogen metabolism in target cells: review and perspectives.  Carcinogenesis. 1998;  19 1-27
• 4 Lippert T H, Seeger H, Mueck A O. Metabolism of endogenous estrogens.  In: Oettel M, Schillinger E (eds). Estrogens and antiestrogens - handbook of experimental pharmacology.  Berlin:; Springer Verlag, 1999: 243-271
• 5 Lippert T H, Seeger H, Mueck A O. The impact of endogenous estradiol metabolites on carcinogenesis.  Steroids. 2000;  65 357-369
• 6 Telang N T, Suto A, Wong G Y, Osborne M P, Bradlow H L. Induction of 16α-hydroxylase of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells.  J Natl Cancer Inst. 1992;  84 634-638
• 7 Bradlow H L, Telang N T, Sepkovic D W, Osborne M P. 2-Hydroxyestrone: the “good” estrogen.  Journal of Endocrinology. 1996;  150 S259-S265
• 8 Osborne M P, Bradlow H L, Wong G Y, Telang N T. Upregulation of estradiol 16α-hydroxylation in human breast tissue: Potential biomarker of breast cancer risk.  J Natl Cancer Inst. 1993;  85 1917-1920
• 9 Kabat G C, Chang C J, Sparano J A, Sepkovic D W, Hu X P, Khalil A, Rosenblatt R, Bradlow H L. Urinary estrogen metabolites and breast cancer: A case-control study.  Cancer Epidemiol Biomarkers Prev. 1997;  6 505-509
• 10 Meilahn E N, De Stavol B, Allen D S, Fentiman I, Bradlow H L, Stepkovic D W, Kuller L H. Do urinary oestrogen metabolites predict breast cancer? Guernsey III cohort follow-up.  Br J Cancer. 1998;  78 1250-1255
• 11 Muti P, Bradlow H L, Micheli A, Krogh V, Freudenheim J L, Schunemann H J, Stanulla M, Yang J, Sepkovic D W, Trevisan M, Berrino F. Estrogen metabolism and risk of breast cancer: a prospective study of 2 : 16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women.  Epidemiology. 2000;  11 635-640
• 12 Michnovicz J J, Adlercreutz H, Bradlow H L. Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans.  J Natl Cancer Inst. 1997;  89 718-723
• 13 Lippert T H, Seeger H, Mueck A O. Estradiol metabolism during oral and transdermal estradiol replacement therapy in the postmenopause.  Hormone Metab Res. 1998;  30 598-600
• 14 Niwa T, Bradlow H L, Fishman J, Swaneck G E. Induction and inhibition of estradiol hydroxylase activities in MCF-7 human breast cancer cells in culture.  Steroids. 1990;  55 297-302
• 15 Telang N T, Bradlow H L, Kurihara H, Osborne M P. In vitro biotransformation of estradiol by explant cultures of murine mammary tissues.  Breast Cancer Res Treat. 1989;  13 173-181
• 16 Seeger H, Mueck A O, Lippert T H. Effect of norethisterone acetate on estradiol metabolism in postmenopausal women.  Horm Metab Res. 2000;  32 436-439