[tribal]

Gynecomastia Development

INTRODUCTION
This chapter will review: the ontogeny and physiology of breast development; factors that influence breast enlargement in the male; the differential diagnosis of gynecomastia; the process of diagnostic investigation; and treatment of gynecomastia.

BREAST DEVELOPMENT

Male breast development occurs in an analogous fashion to female breast development. At puberty in the female breast, complex hormonal interplay occurs resulting in growth and maturation of the adult female breast.

In early fetal life, epithelial cells, derived from the epidermis of the area programmed to later become the areola, proliferate into ducts, which connect to the nipple at the skin's surface. The blind ends of these ducts bud to form alveolar structures in later gestation. With the decline in fetal prolactin, placental estrogen and progesterone at birth, the infantile breast regresses until puberty (15).

During thelarche, the initial clinical appearance of the breast bud, growth and division of the ducts occur, eventually giving rise to club-shaped terminal end buds, which then form alveolar buds. Approximately a dozen alveolar buds will cluster around a terminal duct, forming the type 1 lobule. Eventually, the type 1 lobule will mature into types 2 and 3 lobules, called ductules, by increasing its number of alveolar buds to as many as 50 in type 2 and 80 in type 3 lobules. The entire differentiation process takes years after the onset of puberty and, if pregnancy is not achieved, may never be completed (42).

HORMONAL REGULATION OF BREAST DEVELOPMENT

The initiation and progression of breast development involves a coordinated effort of pituitary and ovarian hormones, as well as local mediators (see Figure 1).

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 (15). This is demonstrated by experiments in ER a knockout mice which display grossly impaired ductal development, whereas the PR knockout mice possess significant ductal development, but lack alveolar differentiation (28,6).

Although estrogens and progestogens are vital to mammary growth, they are ineffective in the absence of anterior pituitary hormones (13). Thus, neither estrogen alone nor estrogen plus progesterone can sustain breast development without other mediators, such as GH and IGF-1, as 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. (23, 40). 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 (49). Furthermore, other data indicates that estrogen promotes GH secretion and increased 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 (33). 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 (42). 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 (42). 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 (41). 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 (28, 18).

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. (44, 25). Prolactin stimulates epithelial cell proliferation only in the presence of estrogen and enhances lobulo-alveolar differentiation only with concomitant progesterone.

ANDROGEN AND AROMATASE

Estrogen effects on the breast may be the result of either circulating estradiol levels or locally produced estrogens. Aromatase P450 catalyzes the conversion of the C19 steroids, androstenedione, testosterone, and 16-a-hydroxyandrostenedione to estrone, estradiol-17b and estriol. As such, an overabundance of substrate or an increase in enzyme activity can increase estrogen concentrations and thus initiate the cascade to breast development in females and males. For example, in the more complete forms of androgen insensitivity syndromes in genetically male (XY) patients, excess androgen aromatizes into estrogen resulting in not only gynecomastia, but also a phenotypic female appearance. Furthermore, the biologic effects of over expression of the aromatase enzyme in female and male mice transgenic for the aromatase gene result in increased breast proliferation. In female transgenetics, over expression of aromatase promotes the induction of hyperplastic and dysplastic changes in breast tissue. Over expression of aromatase in male transgenics caused increased mammary growth and histological changes similar to gynecomastia, an increase in estrogen and progesterone receptors and an increase in downstream growth factors such as TGF-beta and bFGF (17). Interestingly, treatment with an aromatase inhibitor leads to involution of the mammalian gland phenotype (27). Thus, although androgens do not stimulate breast development directly, they may do so if they aromatize to estrogen. This occurs in cases of androgen excess or in patients with increased aromatase activity.

PHYSIOLOGIC GYNECOMASTIA

Gynecomastia, breast development in males, can occur normally during three phases of life. The first occurs shortly after birth in both males and females. This is caused by the high levels of estradiol and progesterone produced by the mother during pregnancy, which stimulates newborn breast tissue. It can persist for several weeks after birth and can cause mild breast discharge called "witch's milk" (42).Puberty marks the second situation in which gynecomastia can occur physiologically. In fact, up to 60% of boys have detectable gynecomastia by age 14. Although it is mostly bilateral, it can occur unilaterally, and usually resolves within 3 years of onset (42).

Interestingly, in early puberty, the pituitary gland releases gonadotropins in order to stimulate testicular production of testosterone mostly at nighttime. Estrogens, however, rise throughout the entire day. Some studies have shown that a decreased androgen to estrogen ratio exists in boys with pubertal gynecomastia when compared with boys who do not develop gynecomastia (34). Furthermore, another study showed increased aromatase activity in the skin fibroblasts of boys with gynecomastia. Thus, the mechanism by which pubertal gynecomastia occurs may be due to either decreased production of androgens or increased aromatization of circulating androgens, thus increasing the estrogen to androgen ratio (29).

The third age range in which gynecomastia is frequently seen is during older age (>60 years). Although the exact mechanisms by which this can occur have not been fully elucidated, evidence suggests that it may result from increased peripheral aromatase activity secondary to the increase in total body fat, coupled with mild hypogonadism associated with aging. For instance, investigators have shown increased urinary estrogen levels in obese individuals, and have demonstrated aromatase expression in adipose tissue (36). Thus, like the gynecomastia of obesity, the gynecomastia of aging may partly result from increased aromatase activity, causing increased circulating estrogen levels (7). Moreover, not only does total body fat increase with age, but there may be an increase in aromatase activity in the adipose tissue already present, increasing circulating estrogens even further. Lastly, SHBG increases with age in men. Since SHBG binds estrogen with less affinity than testosterone, the bioavailable estradiol to bioavailable testosterone ratio may increase in the obese older male.