title: Effects of estradiol, progestogens, and of tibolone on breast proliferation and apoptosis.
abstract: OBJECTIVE
  To study the effects of estrogen therapy, alone or combined with progestogens, and of tibolone on the expression of proliferation and apoptosis markers in normal breast tissue.
  
  
  METHODS
  Thirty 250-day-old Wistar rats were castrated and 3 weeks later received one of the following treatments by gavage for 5 weeks: (1) estradiol benzoate; (2) estradiol benzoate + medroxyprogesterone acetate; (3) estradiol benzoate + norethisterone acetate; (4) estradiol benzoate + dydrogesterone; (5) tibolone; (6) placebo. Following treatment, the expression of proliferating cell nuclear antigen (PCNA) and caspase-3 was analyzed by quantitative immunohistochemistry in the breast tissue, and proliferation and apoptosis were analyzed semiquantitatively by microscopic imaging.
  
  
  RESULTS
  There was a statistically significant difference among the groups for PCNA, caspase-3 and the caspase-3 : PCNA ratio. Tibolone was associated with the lowest proliferative activity, followed by estradiol benzoate + dydrogesterone; however, estradiol benzoate + dydrogesterone showed the greatest rate of apoptosis.
  
  
  CONCLUSIONS
  The various progestogens can have more or less proliferative and pro-apoptotic effects than estradiol alone. Among the treatment schemes analyzed, the estradiol + dydrogesterone combination resulted in a higher apoptosis rate in relation to the proliferation rate and tibolone was associated with the lowest proliferation.
authors.affiliation: Discipline of Gynecology of the Faculdade de Medicina do ABC.
authors.forename: L M
authors.initials: LM
authors.lastname: Pompei
authors.forename: E P
authors.initials: EP
authors.lastname: Cunha
authors.forename: M L
authors.initials: ML
authors.lastname: Steiner
authors.forename: T R
authors.initials: TR
authors.lastname: Theodoro
authors.forename: A M A A
authors.initials: AM
authors.lastname: Mader
authors.forename: G
authors.initials: G
authors.lastname: Petri
authors.forename: M A S
authors.initials: MA
authors.lastname: Pinhal
authors.forename: C E
authors.initials: CE
authors.lastname: Fernandes
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001940:Breast / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D004338:Drug Combinations; D004394:Dydrogesterone / Q000008:administration & dosage / Q000494:pharmacology; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage / Q000494:pharmacology; D009640:Norethindrone / Q000008:administration & dosage / Q000494:pharmacology; D009652:Norpregnenes / Q000008:administration & dosage / Q000494:pharmacology*; D011372:Progestins / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004338:Drug Combinations; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D009652:Norpregnenes; D011372:Progestins; C418365:estradiol, norethindrone drug combination; C074283:estradiol 3-benzoate; D004958:Estradiol; D004394:Dydrogesterone; D017258:Medroxyprogesterone Acetate; C027385:tibolone; D009640:Norethindrone
keywords: APOPTOSIS; BREAST CANCER; ESTROGEN; PROGESTOGENS; PROLIFERATION