Sex steroid effects on normal breast tissue

Abstract

In Sweden, it is estimated that about one million women are treated with estrogen/progestogen for contraception and hormone replacement therapy (HRT). The possibility of an increased cancer risk in target organs has been vividly discussed for many years. There is a great need for biological knowledge about the regulation of the normal breast during physiologic conditions and during treatment with exogenous hormones.

Eighty-nine healthy volunteers were recruited for fine needle aspiration biopsy, 42 women for determination of sex steroid receptors and 47 women for assessment of proliferation, in normal breast epithelial cells. They had no history or symptoms of any breast disease. Estrogen and progesterone receptors and the proliferation marker Ki-67 MIB-1 were determined by immunocytochemistry. Estrogen receptors were down regulated during the luteal phase. Progesterone receptors remained constant throughout the cycle and proliferation increased from the follicular to the luteal phase, in most women. These data indicate a striking difference from the epithelial cells of the endometrium where both progesterone receptors and the proliferation rate are known to decline during the luteal phase.

The estrogen converting enzymes sulfatase and 17 beta- hydroxy steroid dehydrogenase were studied in normal breast tissue from 52 women undergoing reduction mammoplasty. Oral contraceptive users had a significantly lower rate of total hydrolysis and of estrone formation than non-users. Positive correlations were found between the rates of estrone formation and serum progesterone values. 17 beta- hydroxy steroid dehydrogenase type 1 protein was detected throughout the menstrual cycle and in higher amounts in women on hormonal contraception. There was a negative correlation between expression of the enzyme and serum estradiol levels, which suggests it to be a regulatory mechanism of intratissue estradiol concentration in normal breast tissue. Enhanced 17HSD type 1 protein expression might increase tissue concentrations of estradiol in normal breast tissue during hormonal contraception. Surgically postmenopausal adult female cynomolgus macaques were given either no treatment, or long-term treatment with conjugated equine estrogens or conjugated equine estrogens plus medroxyprogesterone acetate.

The mammary glands of these monkeys have many similarities to humans in anatomic features, hormonal regulation and cytokeratin immunophenotype, that is not shared by the commonly used laboratory rodents. Immunostaining of mammary sections was done for estrogen receptor, progesterone receptor, and the proliferation marker Ki-67 MIB-1. Estrogen receptors declined in the combined treatment group. Progesterone receptors were increased by treatment with conjugated equine estrogens alone. Proliferation and sex steroid receptor expression in ten different locations of the macaque breast were investigated and revealed no differences by quadrants or by distance from the nipple. Combined therapy with conjugated equine estrogens and medroxyprogesterone acetate induced a greater proliferative response than conjugated equine estrogens alone.