Progestogen addition with low-dose levonorgestrel intrauterine system in menopausal hormone treatment gives less normal breast tissue proliferation than oral norethisterone acetate or medroxyprogesterone acetate

Abstract

Background: The impact of hormones on the development of breast cancer is despite extensive studies, incompletely understood. Combined estrogen-progestogen treatment augments the risk for breast cancer beyond that of estrogen alone, according to numerous studies. The role of breast cell proliferation as a promoter in the development and growth of breast cancer is well recognized. Materials and methods: Seventy-nine patients from three randomised trials were subject to a re-analysis of breast cell proliferation: (1) 22 women received continuous combined treatment with oral estradiol (E2) 2 mg/norethisterone acetate (NETA) 1 mg once daily for 3 months. (2) Thirty-seven women received 2 months of sequential treatment with oral conjugated equine estrogens (CEE) 0.625 mg daily combined with medroxyprogesterone acetate (MPA) 5 mg for 14/28 days of each cycle. (3) Twenty women received oral estradiol-valerate (E2V) 2 mg daily combined with levonorgestrel (LNG) intrauterine system (IUS), 20 μg/24 h for 2 months. Fine needle aspiration (FNA) (studies 1 and 3) and core needle biopsy (CNB) (study 2) were used for the assessment of breast cell proliferation. Results: There were no baseline proliferation differences, but at the end of treatment there was a highly significant between-group difference for E2V/LNG IUS versus the other two groups (p = 0.0025). E2/NETA and CEE treatments gave a 4-7-old increase in proliferation during treatment (p = 0.04) and (p = 0.007), respectively, which was absent in the E2V/LNG group, showing a significant correlation with insulin-like growth factor binding protein-3 (IGFBP 3) serum levels. Conclusion: E2V in combination with very low serum concentrations of LNG in the IUS gives no increase in proliferation in the normal breast.