ESTROGEN, GH AND IGF-1, PROGESTERONE, & PROLACTIN
Estrogen and progesterone act in an integrative fashion to stimulate normal adult female breast development. Estrogen, acting through its ER a receptor, promotes duct growth, while progesterone, also acting through its receptor (PR), supports alveolar development (18). This is demonstrated by experiments in ER knockout mice, which display grossly impaired ductal development, whereas PR knockout mice possess significant ductal development, but lack alveolar differentiation (31, 7).
Although estrogens and progestogens are vital to mammary growth, they are ineffective in the absence of anterior pituitary hormones (15). Thus, neither estrogen alone nor estrogen plus progesterone can sustain breast development without other mediators, such as GH and IGF-1. This was confirmed by studies involving the administration of estrogen and GH to hypophysectomized and oophorectomized female rats, which resulted in breast ductal development. The GH effects on ductal growth are mediated through stimulation of IGF-1. This is demonstrated by studies of estrogen and GH administration to IGF-1 knockout rats that showed significantly decreased mammary development when compared to age-matched IGF-1- intact controls. Combined estrogen and IGF-1 treatment in these IGF-1 knockout rats restored mammary growth (26, 45). In addition, Walden et al. demonstrated that GH-stimulated production of IGF-1 mRNA in the mammary gland itself, suggesting that IGF-1 production in the stromal compartment of the mammary gland acts locally to promote breast development (55). Furthermore, other data indicates that estrogen promotes GH secretion and increases GH levels, stimulating the production of IGF-1, which synergizes with estrogen to induce ductal development.
Like estrogen, progesterone has minimal effects in breast development without concomitant anterior pituitary hormones; again indicating that progesterone interacts closely with pituitary hormones. For example, prolonged treatment of dogs with progestogens such as depot medroxyprogesterone acetate or with proligestone caused increased GH and IGF-1 levels, suggesting that progesterone may also have an effect on GH secretion (36). In addition, clinical studies have correlated maximal cell proliferation to specific phases in the female menstrual cycle. For example, maximal proliferation occurs not during the follicular phase when estrogens reach peak levels and progesterone is low (less than 1 ng/mL [3.1nmol]), but rather, it occurs during the luteal phase when progesterone reaches levels of 10-20 ng/mL (31- 62nmol) and estrogen levels are two to three times lower than in the follicular phase (47). Furthermore, immunohistochemical studies of ER and PR showed that the highest percentage of proliferating cells, found almost exclusively in the type 1 lobules, contained the highest percentage of ER and PR positive cells (47). Similarly, there is immunocytological presence of ER, PR, and androgen receptors (AR) in gynecomastia and male breast carcinoma. ER, PR and AR expression was observed in 100% (30/30) of gynecomastia cases (48). Given these data and the fact that PR knockout mice lack alveolar development in breast tissue, it appears as if progesterone, analogous to estrogen, may increase GH secretion and act through its receptor on mammary tissue to enhance breast development, specifically alveolar differentiation (31, 21).
Prolactin is another anterior pituitary hormone integral to breast development. Prolactin is not only secreted by the pituitary gland but may be produced in normal mammary tissue epithelial cells and breast tumors. (50, 28). Prolactin stimulates epithelial cell proliferation only in the presence of estrogen and enhances lobulo-alveolar differentiation only with concomitant progesterone. Recently, receptors for luteinizing hormone/ human chorionic gonadotropin have been found in both male and female breast tissues, though its function remains to be determined (11)