01 Introduction
Estrogens are a class of sex hormones. There are 3 main endogenous estrogens with estrogenic activity: Estrone (E1), Estradiol (E2), and Estriol (E3). Estradiol(E2) is the most potent and prevalent type of estrogen. Estrone (E4) is produced only during pregnancy. Estrogens are synthesized in all vertebrates and some insects, and their presence in vertebrates and insects suggests that estrogen-like sex hormones have an ancient evolutionary history. Quantitatively, Estrogen circulates at lower levels than Androgens in both men and women. Although Estrogen levels are significantly lower in men than women, Estrogen still has an important physiological role in the male body. Like all steroid hormones, Estrogens diffuse easily across cell membranes. Once inside the cell, they bind to and activate estrogen receptors (ERs), which regulate the expression of many genes. In addition, estrogens bind to and activate fast-signaling membrane estrogen receptors (mERs), such as GPER (GPR30).
02 Chemical Structure & Classification
Estrogens are steroid hormones with the basic chemical structure of a steroid nucleus, consisting of three six-membered rings (A, B, and C) and a five-membered ring (D). They mainly consist of estradiol (E2), estrone (E1) and estriol (E3). Estradiol, the most active estrogen, is chemically known as 17β-estradiol and has a beta-hydroxyl group at the 17th position of the carbon atom, a structure that is essential for its binding to the estrogen receptor and its physiological function. Estrone has one less 17-beta hydroxyl group in its structure than estradiol and is relatively less active. Estriol, a metabolite of estradiol and estrone, is the least active.
03 Synthesis Pathway
Ovarian synthesis: In the granulosa cells of the ovary, cholesterol is the starting material for estrogen synthesis. Cholesterol is first converted to pregnenolone by cytochrome P450 side chain cleavage enzymes (P450scc). Pregnenolone undergoes a series of enzymatic reactions, including 17-hydroxylase and 17,20-cleaving enzyme, to produce dehydroepiandrosterone (DHEA), which is converted to androstenedione by 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase (17β-HSD). Finally, androstenedione is converted to estradiol by aromatase. This is the main pathway for ovarian synthesis of estradiol, a process that is regulated by gonadotropins (FSH and LH).
Synthesis in peripheral tissues: In addition to the ovary, estrogen can be synthesized in peripheral tissues such as adipose tissue, liver, and adrenal glands. For example, in adipose tissue, androstenedione can be converted to estrone by aromatase, and estrone can be converted to estradiol by 17β-HSD. This pathway becomes particularly important in postmenopausal women because estrogen synthesized in peripheral tissues maintains estrogen levels in the body to some extent after ovarian function declines.
04 Metabolic Process
Estrogens are metabolized in the body mainly by the liver. Estradiol and Estrone first undergo hydroxylation in the liver, introducing hydroxyl groups at different positions (e.g., 2-position, 4-position, 16-position, etc.) to form a variety of metabolites. These metabolites' water solubility is increased, facilitating their elimination from the urine. For example, Estradiol can be metabolized to Estriol, a more water-soluble Estrogen metabolite, and most Estriol is excreted in the urine. In addition, estrogen can be bound to glucuronic acid or sulfuric acid to form bound estrogens, and this form of binding further increases the water solubility of Estrogen and facilitates its excretion.
05 Functions & Roles
Estrogen acts mainly by binding to the estrogen receptor (ER). There are 2 subtypes of estrogen receptors, ERα and ERβ, which have different distributions and functions in different tissues. When estrogen binds to the receptor, it causes a conformational change in the receptor, causing the receptor to interact with other proteins to form a hormone-receptor complex. This complex can bind to estrogen response elements (EREs) in the promoter regions of target genes and regulate gene transcription. For example, in breast tissue, estrogen binds to the estrogen receptor and promotes the proliferation and differentiation of breast cells by regulating the transcription of relevant genes; in uterine tissue, it regulates the expression of genes related to the proliferation of endometrial cells, contributing to endometrial hyperplasia.
06 Interaction with Other Biochemicals
Estrogen and progesterone work together to play an important role in the female reproductive cycle and pregnancy. During the menstrual cycle, estrogen encourages the endometrium to proliferate, while progesterone causes the endometrium to enter a secretory phase in preparation for the implantation of a fertilized egg. During pregnancy, the two work synergistically to maintain the pregnancy, with estrogen promoting uterine and mammary gland development and progesterone primarily maintaining endometrial decidualization and inhibiting uterine contractions.
Estrogen also interacts with growth hormone (GH) and insulin-like growth factor-1 (IGF-1). During bone growth and development, estrogen and IGF-1 synergistically promote the proliferation and differentiation of osteoblasts and increase bone density. At the same time, estrogen can regulate insulin sensitivity and influence glucose metabolism and lipid metabolism.
07 Functions & Roles of ERs
Estrogen receptors (ERs) are important members of the nuclear receptor superfamily and act mainly by regulating gene expression. ERs are classified into 2 main subtypes: ERα and ERβ, encoded by the ESR1 and ESR2 genes, respectively. ERα and ERβ share structural similarities, but they differ significantly in function and tissue distribution.
The main function of ERs is to act as transcription factors that regulate the transcription of target genes by inducing conformational changes upon binding to estrogen, which in turn dimerizes and binds to estrogen response elements (EREs) on DNA. This classical mechanism enables ERs to regulate key cellular processes such as cell proliferation, differentiation, and apoptosis. In addition, ERs can act through non-genomic pathways, i.e., they can regulate gene expression by interacting with other proteins or signaling pathways without directly binding to DNA.
ERs are widely distributed in a variety of tissues, including breast, uterus, ovary, bone, heart, brain, and adipose tissue, etc. ERα is predominantly expressed in the breast, uterus, ovary, and bone, whereas ERβ predominates in the nervous system, cardiovascular system, and the male reproductive system. The expression and function of ERs in these tissues are critical for maintaining normal physiological functions, for example, in the female reproductive system, ERs regulate the menstrual cycle, endometrial growth, and preparation for pregnancy; in bone health, ERs control bone density homeostasis; and in the cardiovascular system, ERs enhance arterial flexibility and reduce plaque formation.
However, dysfunction of ERs has been associated with a variety of diseases, including breast, endometrial, and ovarian cancers, osteoporosis, cardiovascular diseases, and neurodegenerative diseases. For example, in breast cancer, ERα usually promotes cell proliferation, whereas ERβ has antiproliferative effects. In addition, aberrant expression or dysfunction of ERs may also affect other types of cancer, such as colorectal and lung cancer.
Estrogen receptors play a wide range of important roles in the human body through their complex signaling mechanisms, not only influencing normal physiological processes but also playing key roles in the pathogenesis of a variety of diseases. Therefore, an in-depth understanding of the functions and roles of ERs is important for the development of targeted therapeutic strategies.
Jonlnbio | Estrogen(E) Cited Product Literature (partial)
IF 10.3
Article: Bisphenol B and bisphenol AF exposure enhances uterinediseases risks in mouse.
Journal: Environment International
Cited products:
JL11232 Mouse Estrogen (E) ELISA Kit
JL20678 Mouse Progesterone (PROG) ELISA Kit
JL20674 Mouse Free triiodothyronine (FT3) ELISA Kit
IF 9.5
Article: Estrogen promotes the onset and development of idiopathic scoliosis via disproportionate endochondral ossification of the anterior and posterlor column in a blpedal rat model.
Journal: Experimental & Molecular Medicine
Cited products:
JL12534 Rat Estrogen(E) ELISA Kit
IF 8.1
Article: Effects of nonylphenol administration on serum, liver and testis estrogen metabolism.
Journal: Chemosphere
Cited products:
JL12534 Rat Estrogen(E) ELISA Kit