RESUMO
The mammary gland undergoes morphologic changes during the menstrual cycle. Proliferation of normal breast epithelium is most extensive during the natural luteal phase. To determine the impact of one cycle of a combined oral contraceptive (COC) on breast homeostasis, we evaluated the proliferation index (PI), determined by KI-67 expression, in normal human mammary epithelial cells and correlated it with cellular proliferation in spontaneous menstrual cycles during the same period. Normal breast tissue samples were obtained from 82 patients randomized in two groups. Forty-two women in group A received one cycle of a COC (30 mug ethinyl estradiol and 150 mug levonorgestrel) administrated daily for 21 days, beginning on the first day of the menstrual cycle. Group B patients (n = 40) experienced a natural menstrual cycle. Menstrual cycle phase characterization was based on the date of the last period and subsequent menses and on progesterone serum levels obtained at the time of biopsy. The PI (number of Ki-67-positive nuclei per 1,000 epithelial cells), was significantly larger in group A (5.47 +/- 3.87), than in group B (3.27 +/- 3.24), p < 0.01. A cyclical variation of PI was observed in COC cycles. The rise in PI in the first week of the COC cycles was significantly higher than in the natural cycle (COC = 7.02 +/- 4.94; non-COC = 1.10 +/- 0.67; p < 0.0011). There was no significant difference between the two groups during the other weeks. Additionally, there was an inverse correlation between proliferation and chronological age, irrespective of the stage of the cycle. The PI of COC (p = 0.175) and natural cycles (p = 0.466) were not statistically different in younger patients. COC users have increased proliferative activity at the beginning of the menstrual cycle. This alteration in the pattern of proliferative activity may relate to the increased risk of breast cancer that has been associated with COCs.
Assuntos
Mama/patologia , Proliferação de Células/efeitos dos fármacos , Anticoncepcionais Orais Combinados/administração & dosagem , Ciclo Menstrual/efeitos dos fármacos , Adolescente , Adulto , Fatores Etários , Biópsia por Agulha , Mama/efeitos dos fármacos , Relação Dose-Resposta a Droga , Esquema de Medicação , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica , Modelos Lineares , Fase Luteal/efeitos dos fármacos , Fase Luteal/fisiologia , Ciclo Menstrual/fisiologia , Probabilidade , Progesterona/metabolismo , Radioimunoensaio , Valores de Referência , Sensibilidade e EspecificidadeRESUMO
INTRODUCTION: During the menstrual cycle, the mammary gland goes through sequential waves of proliferation and apoptosis. In mammary epithelial cells, hormonal and non-hormonal factors regulate apoptosis. To determine the cyclical effects of gonadal steroids on breast homeostasis, we evaluated the apoptotic index (AI) determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining in human mammary epithelial cells during the spontaneous menstrual cycle and correlated it with cellular proliferation as determined by the expression of Ki-67 during the same period. METHODS: Normal breast tissue samples were obtained from 42 randomly selected patients in the proliferative (n = 21) and luteal (n = 21) phases. Menstrual cycle phase characterization was based on the date of the last and subsequent menses, and on progesterone serum levels obtained at the time of biopsy. RESULTS: The proliferation index (PI), defined as the number of Ki-67-positive nuclei per 1,000 epithelial cells, was significantly larger in the luteal phase (30.46) than in the follicular phase (13.45; P = 0.0033). The AI was defined as the number of TUNEL-positive cells per 1,000 epithelial cells. The average AI values in both phases of the menstrual cycle were not statistically significant (P = 0.21). However, the cell renewal index (CRI = PI/AI) was significantly higher in the luteal phase (P = 0.033). A significant cyclical variation of PI, AI and CRI was observed. PI and AI peaks occurred on about the 24th day of the menstrual cycle, whereas the CRI reached higher values on the 28th day. CONCLUSIONS: We conclude that proliferative activity is dependent mainly on hormonal fluctuations, whereas apoptotic activity is probably regulated by hormonal and non-hormonal factors.