Biological role of estrogen and estrogen receptors

Introduction: Nuclear receptors such as the estrogen receptor (ER) are ligand-dependent transcription factors. There are two different ER subtypes, ERα and ERβ, that mediate the biological effects of estrogens and antiestrogens. ERβ exists in multiple isoforms. Different ligands induce different ER conformations, and there is a dramatic difference in the topology of the ER surface between agonist- and antagonist-bound receptor. Coactivators and corepressors interact with ligand-bound ERα and -β and play, together with the receptor, an important role in the regulation of ER target-gene expression. Different modes or mechanisms of target gene regulation affect the agonist/antagonist profile of a ligand. Selective Estrogen Receptor Modulators (SERMs) have a tissue- and gene-specific mixed agonist/antagonist effect. Alternative indirect activation pathways, other than binding of natural or synthetic small organic hormones or drugs, can also modulate the ER activity. Estrogens have also very rapid effects, so-called nongenomic effects. Nonreceptor-dependent antioxidant effects by estrogens have been reported, protecting from neurodegenerative disorders or atherogenesis. Breast Tissue: There is no pubertal breast development in aromatase-deficient women due to lack of or too-low levels of circulating estrogens. Estrogen therapy of aromatase deficient female patients led to normal pre- and postpubertal breast development. ERα has been shown to be necessary for mouse mammary gland development. ERβ is abundantly expressed in rat breast. Both ERα and ERβ are present in human breast cancer. Measurement of both ERα and ERβ is suggested for the selection of appropriate breast cancer therapy. Urogenital Tract: ERβ is widely expressed in bladder, urethra, testis, prostate, and ovary in the mouse. The absence of ERα results in infertility in both male and female mice. The absence of ERβ results in partial infertility in female mice but no impaired fertility in male mice. ERβ-deficient mice display hyperplasia, dysplasia, and PIN-lesions of the prostate. Deficiency of aromatase in human females led to ambiguous genitalia and polycystic ovaries. Estrogen replacement therapy of aromatase-deficient female patients led to the resolution of the ovarian cysts and menarche. Male patients with estrogen deficiency or estrogen insensitivity are reported with macroorchidism or oligozoospermia. ERβ-selective agonists may protect from abnormal prostate growth and may be the therapy of choice for urge incontinence. Bone: Estrogens have an important role in maintaining a balanced bone metabolism. Estrogens protect postmenopausal women from bone loss and the development of osteoporosis. Estrogens may play an important role for the maintenance of bone mass also in aging men. Estrogens are important for the pubertal growth spurt and epiphyseal closure in girls as well as in boys. There are likely both direct and indirect (systemic) effects of estrogens on bone metabolism and homeostasis. Both ERα and ERβ are expressed in the bone-forming osteoblasts. Estrogen insensitivity in a male patient caused by ERα deficiency led to osteopenia and continuous longitudinal growth due to unfused epiphyses. Male and female patients with aromatase deficiency have increased bone turnover, delayed bone maturation, low BMD, and tall stature due to unfused epiphyses. Estrogen replacement therapy of both female and male aromatase-deficient patients resulted in growth spurt, closure of the epiphyses, and increased bone mineral density. Lack of ERβ expression in the female ERβ -/- mice led to a masculinized bone phenotype of the long bones but no effect on the bone phenotype in male mice. Available data suggest that ERα plays an important role in bone in both men and women, but that ERβ perhaps has a role in bone physiology only in women. The Cardiovascular System: A number of gender-related cardiovascular differences have been reported, (1) lower risk for young women than for young men to develop atherosclerosis and cardiovascular disease, (2) higher prevalence of left ventricular hypertrophy in men than in women, (3) significantly greater intimal thickening after vascular injury in men than in women, and (4) the rapid vascular response to estrogen in women but not in men. The estrogen receptors α and β are expressed in vascular endothelial cells, smooth muscle cells, and in myocardial cells. Both ERα and ERβ can mediate the vascular injury response to estrogens, suppressing smooth muscle cell proliferation and intimal thickening. Estrogens have both genomic and nongenomic effects on vascular tissue. Part of the beneficial effects of estrogen on cardiovascular function and reactivity comes from liver-specific effects of estrogens on the serum lipid/cholesterol profile. ERα most likely mediates the liver-specific effects of estrogens. Also, monocytes/macrophages are potential targets for the beneficial effects of estrogens on the cardiovascular system and the development of atherosclerosis. Central Nervous System and the Hypothalamo-Pituitary Axis: Estrogens are reported to influence a variety of functions in the central nervous system (CNS) such as learning, memory, awareness, fine motor skills, temperature regulation, mood, and reproductive functions. Estrogens are also linked to symptoms of depression and treatment of depressive illness. Different brain structures and neurotransmitter systems are involved in the different effects of estrogens. The predominant expression and localization of ERβ in rat neocortex, hippocampus, and nuclei of the basal forebrain suggests an important role for ERβ in learning and memory. Estrogen, through effects on the hypothalamo-pituitary axis (HPA), modulates the expression and secretion of hormones such as LH, FSH, growth hormone (GH), and prolactin (PRL), from the anterior pituitary gland. Female and male patients with aromatase deficiency have elevated levels of LH and FSH, and elevated circulating levels of androgens. Substitution with conjugated estrogens in both male and female aromatase-deficient patients resulted in normalization of gonadotropin and testosterone levels. Clinical data on an ERα -/- male patient also showed increased circulating LH and FSH levels despite high estrogen levels. In ERα -/- mice the serum LH but not the FSH levels were elevated despite 10-fold higher circulating levels of estrogen. Available data indicate that estrogens rather than testosterone (both men and women) together with inhibins are the major regulators of serum gondotropin levels, and that ERα seems to be more involved in this process than ERβ. Hormone Replacement: Traditional, Alternatives, and Future Perspectives: The most common regimens in use to treat symptoms of the menopause and postmenopausal health risks are 17β-estradiol, esterified estrogens or conjugated equine estrogens in combination with a progestin, for example, medroxyprogesterone acetate (MPA). The awareness of undesired effects and serious health risks (breast cancer, endometrial cancer, and venous thromboembolism) with existing hormone replacement therapy (HRT) (first generation HRT) calls for alternatives with improved safety profile. Alternative regimens for women who do not wish to take today's first generation HRT exist. Non-ER-subtype-selective SERMs (second generation HRT) display tissue-selective estrogen agonism. Although the most frequent and serious health risk of first generation HRT are set aside by these SERMs, they still suffer from low efficacy compared with first generation HRT, and they aggravate hot flushes. The existence of two ER subtypes, ERα and ERβ, gives the opportunity to develop ER subtype-selective ligands that will most likely better provide the benefits of estrogen replacement therapy, with an improved therapeutic profile (third generation HRT).