The Endocrine System
Hormone Function and Breast Development
The endocrine system is comprised of glands that secrete hormones, chemical substances that travel in the bloodstream to target tissues, where they help to regulate body growth and direct the development and functioning of primary and secondary sexual structures including breasts.
The endocrine system sends messages throughout the body via hormones, chemical messengers produced by glands within the body. The endocrine system is responsible for physical growth, energy balance and the development of sex organs, including the breasts.
Many hormones work in concert to influence initial breast development and to prepare the breast for lactation during and just after pregnancy. In this complex endocrine system, tiny, targeted amounts of hormone can exert big changes in the body.
This section describes normal endocrine system functioning. Endocrine disrupting compounds may contribute to breast cancer risk by skewing normal endocrine function.
The Incredible Hormone System
Synthetic Steroid Hormones
Insulin-like Growth Factor-1 (IGF-1)
Estrogen-Related Receptors (ERR)
The Aryl Hydrocarbon Receptor (AhR)
The Incredible Hormone System
The endocrine system is comprised of glands that secrete hormones, chemical substances that travel in the bloodstream to target tissues, where they help to regulate body growth, maintain metabolic homeostasis, and direct the development and functioning of primary and secondary sexual structures.
Hormones are secreted directly into the bloodstream and therefore travel throughout the body. However, hormones only affect particular target tissues. Cells of these target organs have specific protein receptors that bind to the particular hormone (for example, estradiol, an estrogen, binds to the estrogen receptors). Once the hormone has bound to its receptor, changes in cell activity occur.
Usually, when a hormone bind to a receptor this creates a hormone-receptor complex which interacts with DNA in the nucleus of the cell. This leads to changes in protein synthesis. Many of these proteins are involved in growth and proliferation of the cells and can control whether or not cell division is regulated normally (as in healthy tissues) or grows out of control (as in tumor cells).
In addition to this main receptor mechanism by which hormones work, they can also alter cell activity through paths that do not involve direct binding of hormone-receptor complexes to DNA. These so-called non-genomic pathways often have important effects on metabolic systems within cells and in signaling between cells (Falkenstein, 2001; Hall 2000).
Figure 1: The endocrine system is made up of organs, called glands, which send chemical messages throughout the body. These glands produce and release hormones, which maintain physical growth and energy balance and support the development of sex organs, including the breasts. By U.S. National Library of Medicine [Public domain], via Wikimedia Commons.
Major endocrine glands are shown in figure 1. Most of the glands of the neck and abdominal region are regulated through feedback systems mediated by hormones of the hypothalamus (a brain structure that sits above the pituitary) and the pituitary gland.
Because hormones have such important roles in maintaining metabolic and reproductive systems, it is critical that the concentrations of these compounds be carefully regulated. Feedback systems between the hypothalamus and pituitary help to maintain appropriate levels of circulating hormones. Both the synthesis and the breakdown (metabolism) of hormones are further regulated by a series of pathways, especially in the glands in which they are produced and the target organs in which they exert their effects. Endocrine disrupting compounds exert many of their effects by altering the activity of the natural hormones.
There are two major chemical subclasses of hormones. The steroid hormones—including the estrogens, progesterone, androgens and glucocorticoids—all are derived from the cholesterol molecule, while amine and peptide hormones are derived from amino acids. Amine hormones are secreted by the thyroid and adrenal glands; they are derived from tyrosine. Peptide hormones are comprised of short chains of amino acids, and are secreted by the hypothalamus and pituitary, as well as the parathyroids and organs of the digestive system.
Steroid hormones include the female reproductive hormones (estrogens and progesterone) secreted primarily by the ovaries, the male reproductive hormones (androgens) secreted primarily by the testes, and the adrenal metabolic hormones (glucocorticoids and aldosterone). The adrenal glands of both males and females also secrete small but important amounts of androgens, which, in turn, can be metabolized to estrogens by the enzyme aromatase.
Estrogens are a class of steroid hormones that have served as chemical cell pathway regulators for up to 500 million years (Callard et al., 2012). Among the oldest and evolutionarily best-conserved signals, estrogens are found in plants as well as in both vertebrate and invertebrate animals. In mammals, including humans, estrogens are important in the development of the female reproductive system (including the mammary glands and breast tissue), as well as in the regulation of metabolic, nervous and cardiovascular systems.
This video, produced by Vassar College's Environmental Risks and Breast Cancer project, explains how estrogens work.
The most prominent estrogen secreted by the mammalian ovary is estradiol (sometimes abbreviated E2). During the time from early puberty through the onset of menopause, estradiol levels fluctuate regularly over the course of the menstrual cycle, reaching a peak just prior to ovulation. After ovulation, estradiol, in conjunction with progesterone, alters the uterine endometrium in anticipation of implantation of a fertilized egg. During pregnancy, ovarian estradiol is supplement by estradiol secreted by the placenta.
During puberty, estradiol promotes the growth and development of the mammary gland and surrounding breast tissue. During adolescence and adulthood, estradiol enhances normal mammary (breast) cell proliferation and also increases the rate of cell division of mammary tumor cells when they are present (Dosineaux-Sixou et al., 2003; Fox et al., 2009; Russo and Russo, 2008). Early exposure to estradiol or estradiol-mimicking hormones influences the development of the primitive fetal mammary structures in ways that may predispose the breast tissue to later development of cancer.
Like other estrogens, estradiol exerts its effects on cellular activity mainly by binding to nuclear estrogen receptors (called ERα and ERβ), leading to changes in the expression of many genes involved in cell proliferation, cell-signal transduction, and inhibition of programmed cell death (apoptosis). In addition, recent studies indicate that estradiol can exert more rapid, non-genomic effects on cellular signaling pathways by interacting with membrane-associated receptors on the cell and mitochondrial membranes (Yager et al., 2006). These multiple mechanisms and sites of action for various hormones, like estradiol, and their disruptors may help explain the complex biological consequences of exposures to these compounds (Tilghman et al., 2010).
Estriol (E3) is an estrogen that is mainly found in substantial amounts during pregnancy, when it is secreted by the placenta. Higher estriol levels during fetal development are associated with higher birth weight, which in turn is associated with a later increased risk for development of breast cancer (Mucci et al., 2003).
Estrone(E1) is an estrogen that is present in breast tissue (and many other tissues) and urine in significant concentrations in post-menopausal women, with higher circulating levels of estrone (as well as estradiol) in the bloodstream being associated with increased risk for post-menopausal breast cancer (EHBCCG, 2002). Post-menopausal estrone production comes primarily from the metabolism of androgens.
Estradiol and estrone can be broken down in breast and other tissues to various metabolites, one of which may be correlated with a decreased risk for breast cancer (2-hydroxyestrone) and another that has been associated with an increased risk for cancer (16?-hydroxyestrone). What may be more important than absolute levels of these two metabolites is their ratio, with higher 2-hydroxyestrone to 16α-hydroxyestrone levels being more protective (Eliassen et al., 2012; Fuhrman et al., 2012; Taioli et al., 2010; Kaba et al., 2006). Many factors, including diet, may affect the relative ratios of these two metabolites (McCann, 2008).
Progesterone is the major naturally secreted hormone in the class of steroids called “progestins” or “progestogens.” Progesterone is secreted by the ovary during the phase of the menstrual cycle following ovulation (the luteal phase) if the egg is not fertilized. If the egg is fertilized and successful pregnancy ensues, progesterone is secreted for the first several weeks by the ovary, and subsequently, for the duration of the pregnancy, by the placenta.
Progesterone is critical in several aspects of breast development. Although it is estradiol that initiates development of the mammary ductal system during puberty and adolescence, progesterone is critical for the subsequent branching of the ductal system. During pregnancy, progesterone (along with prolactin) is important in the maturation of the mammary aveoli, structures that are critical for the production and secretion of milk during lactation. The rapid decrease in progesterone secretion following childbirth is one of the key signals allowing for production and release of milk in response to suckling (Lee and Ormandy, 2012; Obr and Edwards, 2012).
Androgens are a class of steroid hormones of which the most prominent is testosterone, the main hormone secreted by the male testes. But androgens—including testosterone, dihydroepiandrosterone (DHEA) and androstenedione—are also secreted by the adrenal glands of both males and females. Testosterone and other androgens inhibit the development of breast tissue, and the balance between the proliferative effects of estrogens and the inhibitory effects of androgens may contribute to the regulation of mammary cell proliferation in both normal development and in cancerous tissues (Dimitrakakis and Bondy, 2009). Androgen receptors are found in the majority of invasive breast cancers and, when activated, can alter a number of pathways involved in the development and metastasis of cancers (Gucalp and Traina, 2012). To complicate matters further, testosterone and DHEA can be converted to estradiol by a pathway controlled by the enzyme aromatase, increasing risk for developing breast cancer (Buluan et al., 2012). Testosterone can also be converted to dihydrotestosterone (DHT) via the 5α-reductase enzymatic pathway. DHT is a more specific and potent androgen than the parent testosterone molecule.
Via their conversion to estradiol, androgens can therefore enhance mammary-cell proliferation, although androgens themselves, especially DHT, inhibit mammary cell proliferation and breast development (Aka et al., 2010; Dimitrakakis and Bondy, 2009).
Synthetic Steroid Hormones
Synthetic estrogens and progestins have been important pharmaceutical products since the early 1940s, when diethylstilbestrol (DES) was first prescribed to pregnant women to prevent miscarriages. Prescriptions to pregnant women ended following a report in 1971 demonstrating that daughters who had been exposed in utero had an increased risk for a rare vaginal cancer (clear cell adenocarcinoma). Later studies demonstrated an increased risk for breast cancer in women taking DES during pregnancy, as well as for their daughters and now, possibly, their granddaughters.
In the late 1950s the first oral contraceptive pill, comprised of a synthetic estrogen (mestranol) and progestin (norethynodrel), was approved by the FDA for sale first as a hormone replacement therapy and then, within a couple of years, as a form of contraception. Current formulations of oral contraceptives contain estrogen (either mestranol or ethinyl estradiol) and progestin (norgesterol, levonorgestrel or norethniodrone), or are made only with synthetic progestins. Both oral contraceptives and hormone replacement therapy (HRT; often derived from pregnant mare’s serum) have been linked with increased risk for development of breast cancer, especially within five to 10 years of taking the hormonal supplements.
The thyroid hormones thyroxin (T4) and triiodothyronine (T3) are hormones derived from the amino acid tyrosine. T3 and T4 are critical for the regulation of metabolic functioning across the tissues of the body, and, like the steroid hormones, they exert their major effects by binding to specific nuclear hormone receptors that regulate the expression of genes involved in cell differentiation, growth and metabolism. Additionally, and again like the steroids, thyroid hormones can exert a rapid effect on cell activity by binding to membrane receptors (Davis et al., 2009).
Thyroid hormones are necessary for normal development and growth of mammary tissues across the life span. Additionally, recent data indicate that thyroid hormones, especially T3, as well as abnormalities in thyroid hormone receptors, may have a role in the development of post-menopausal breast cancers (Davis et al., 2009; Conde et al., 2006).
Peptide hormones exert their effects by binding to specific receptor proteins in the cell membrane. They then alter cellular activity through changes in a variety of pathways regulating cell-signal transduction.
Insulin is a peptide hormone that is secreted by the pancreas and is critical in the regulation of carbohydrate and fat metabolism through its actions on cells of the liver, fat (adipose) tissue, and muscles. Like all tissues, mammary tissue is dependent on insulin for normal development and cellular proliferation. Many breast cancers have increased numbers of insulin receptors that can influence the proliferation rate of cells in the mammary tumor (Chappell et al., 2001). The development of insulin resistance is thought to contribute to the association between obesity and an increased risk for development of breast cancer in post-menopausal women (Kaaks, 1996; Gunter et al., 2009).
b. Insulin-like Growth Factor-1
Insulin-like growth factor-1 (IGF-1), as its name suggests, is a hormone that is very similar in structure to insulin and mediates the effects of growth hormone (GH) on the development and growth of cells and organs of the body, including the mammary gland. During development of the branching structure of the maturing mammary system, IGF-1 increases cell proliferation and ductal formation (Kleinberg and Ryan, 2008). An increased risk for pre-menopausal breast cancer has been found in women with higher blood levels of IGF-1 (Hankinson et al., 1998).
Prolactin is a peptide hormone secreted by the pituitary, an important endocrine gland located at the base of the brain. Prolactin levels increase over the course of pregnancy, enhancing the growth and final maturation of the complex internal structures of the mammary system. Following birth, continued high secretion of prolactin stimulates the alveoli of the mammary system to produce milk.
Lower levels of prolactin are secreted outside of the pregnancy and lactation cycle and are involved in the regulation of the reproductive hormones and also development and health of neurons and associated cells. Higher blood levels in non-pregnant, non-lactating women have been associated with an increased risk for developing both premenopausal and postmenopausal breast cancer (Harvey, 2011).
Melatonin is a hormone secreted by the pineal gland, a small endocrine structure in the brain, but outside the blood-brain barrier. Stimulation of the retina of the eye by light decreases the secretion of melatonin by the pineal gland. Melatonin levels increase naturally in the dark, such as during the night with absence of strong artificial light. In addition to its functions in regulating the daily rhythms of sleep and the secretion of reproductive hormones, melatonin is a potent antioxidant. Many studies in both people and lab animals indicate that melatonin may serve to inhibit cancer development, especially hormone-dependent tumors by decreasing cell proliferation and increasing apoptosis (programmed cell death) in tumors (Proiotti et al., 2013).
Other Important Receptor Proteins
The Estrogen-Related Receptor gamma (ERRγ) is a protein receptor that has many similar properties to the estrogen receptor, but it does not form a complex with estradiol, the natural estrogen. Several endocrine disrupting compounds, including bisphenol A, parabens and DDT, all exert some of their effects by binding to this protein (DeCoster and van Larabeke, 2012; Zhang et al., 2013).
Another protein receptor belonging to the same chemical category as hormone receptors, is the aryl hydrocarbon receptor (AhR). Although it is currently unclear what the naturally occurring ligand (substance that binds) is for the AhR, evidence suggests that the AhR system is important in regulating responses to cellular stress that can lead to disruption of normal cell functioning (Kund, 2009). At least some of the effects of some endocrine disrupting compounds, including phthalates, are mediated through complex interactions between the AhR pathway and estrogen-receptor-mediated pathways.