E2 Estrogen (Estradiol)

Estradiol is a form of estrogen, a hormone that plays a crucial role in the development and regulation of the female reproductive system and secondary sexual characteristics. It is primarily produced in the ovaries, but also in smaller amounts by the adrenal glands and fat tissues. Estradiol is essential for various physiological processes in both women and men, although it is most commonly associated with female health.

Biological function

The emergence of secondary sex characteristics in women is influenced by estrogens, particularly estradiol. These changes begin at puberty, are most prominent during the reproductive years, and diminish with reduced estradiol levels after menopause. Estradiol leads to breast development, and alters body shape, affecting bones, joints, and fat distribution. In females, estradiol causes breast development, hip widening, a feminine fat distribution (with fat primarily in the breasts, hips, thighs, and buttocks), and the maturation of the vagina and vulva. It also influences the pubertal growth spurt (indirectly through increased growth hormone secretion) and epiphyseal closure (thereby affecting final height) in both sexes.

Reproduction

Female reproductive system

In females, estradiol functions as a growth hormone for reproductive organ tissues, maintaining the lining of the vagina, cervical glands, endometrium, and the fallopian tube lining. It promotes the growth of the myometrium. Estradiol is essential for sustaining oocytes in the ovary. Throughout the menstrual cycle, estradiol produced by developing follicles initiates, through a positive feedback loop, the hypothalamic-pituitary events that result in the luteinizing hormone surge, triggering ovulation. In the luteal phase, estradiol, along with progesterone, readies the endometrium for implantation. During pregnancy, estradiol levels rise due to placental production. The role of estradiol, together with estrone and estriol, in pregnancy is not entirely understood. They may enhance uterine blood flow, myometrial growth, stimulate breast development, and at term, aid in cervical softening and the expression of myometrial oxytocin receptors. In baboons, inhibiting estrogen production results in pregnancy loss, indicating estradiol's role in maintaining pregnancy. Research is exploring the role of estrogens in initiating labor. Estradiol's actions are necessary prior to progesterone exposure in the luteal phase.

Skeletal system

Estradiol significantly influences bone health. Those lacking it (or other estrogens) tend to grow tall and eunuchoid, as epiphyseal closure is delayed or may not occur. Bone density is also impacted, leading to early osteopenia and osteoporosis. Low estradiol levels might also indicate a higher risk of fractures, with post-menopausal women experiencing the most frequent bone fractures. Women after menopause face a rapid decrease in bone mass due to a relative lack of estrogen.

Skin health

Both the estrogen receptor and the progesterone receptor have been identified in the skin, including in keratinocytes and fibroblasts. During menopause and beyond, lower levels of female sex hormones lead to atrophy, thinning, and more pronounced wrinkling of the skin, along with a decrease in skin elasticity, firmness, and strength. These changes accelerate skin aging and are due to reduced collagen content, irregularities in the morphology of epidermal skin cells, decreased ground substance between skin fibers, and reduced capillaries and blood flow. Additionally, the skin becomes more dry during menopause due to diminished skin hydration and surface lipids (sebum production). Alongside chronological aging and photoaging, estrogen deficiency during menopause is one of the three primary factors influencing skin aging.

Hormone replacement therapy, involving systemic treatment with estrogen alone or combined with a progestogen, offers well-documented and significant benefits for the skin of postmenopausal women. These benefits include increased skin collagen content, thickness, elasticity, hydration, and surface lipids. Topical estrogen has shown similar positive effects on the skin. Furthermore, a study found that topical 2% progesterone cream significantly enhances skin elasticity and firmness and noticeably reduces wrinkles in peri- and postmenopausal women. However, skin hydration and surface lipids did not significantly change with topical progesterone. These findings imply that progesterone, like estrogen, also offers beneficial effects on the skin and may independently protect against skin aging.

Nervous system

Estrogens can be synthesized in the brain from steroid precursors. Acting as antioxidants, they have demonstrated neuroprotective properties.

The positive and negative feedback loops of the menstrual cycle involve ovarian estradiol, which connects to the hypothalamic-pituitary system to regulate gonadotropins.

Estrogen is believed to have a crucial impact on women's mental health, with suggested links between hormone levels, mood, and well-being. Sharp decreases, fluctuations, or prolonged low levels of estrogen may be associated with significant mood drops. Clinical recovery from depression postpartum, perimenopause, and postmenopause has been shown to be effective once estrogen levels are stabilized and/or restored.

Estrogen has been found to enhance the secretion of oxytocin and to increase the expression of its receptor, the oxytocin receptor, in the brain. In women, a single dose of estradiol has been found to be enough to raise circulating oxytocin levels.

Gynecological cancers

Estradiol has been linked to the development and progression of cancers such as breast cancer, ovarian cancer, and endometrial cancer. It influences target tissues primarily by interacting with two nuclear receptors known as estrogen receptor α (ERα) and estrogen receptor β (ERβ). These estrogen receptors play a role in modulating gene expression. When estradiol binds to the ERs, the receptor complexes attach to specific DNA sequences, potentially causing DNA damage and increasing cell division and DNA replication. Eukaryotic cells respond to DNA damage by either stimulating or inhibiting the G1, S, or G2 phases of the cell cycle to initiate DNA repair. Consequently, this leads to cellular transformation and cancer cell proliferation.

Cardiovascular system

Estrogen has an impact on specific blood vessels. Enhanced arterial blood flow has been observed in coronary arteries. 17-beta-estradiol (E2) is regarded as the most potent estrogen present in humans. E2 affects vascular function, apoptosis, and damage during cardiac ischemia and reperfusion. E2 can shield the heart and individual cardiac myocytes from ischemia-related injuries. Following a heart attack or prolonged hypertension, E2 prevents the harmful effects of pathological heart remodeling

During pregnancy, elevated levels of estrogens, particularly estradiol, increase coagulation and the risk of venous thromboembolism.

Other functions

Estradiol has intricate effects on the liver. It influences the production of various proteins, such as lipoproteins, binding proteins, and proteins involved in blood clotting. In elevated levels, estradiol can cause cholestasis, such as cholestasis of pregnancy.

Certain gynecological conditions rely on estrogen, including endometriosis, leiomyomata uteri, and uterine bleeding.

Biological activity

Estradiol primarily functions as an agonist of the estrogen receptor (ER), which is a nuclear steroid hormone receptor. The ER has two subtypes, ERα and ERβ, and estradiol effectively binds to and activates both. Activation of the ER leads to changes in gene transcription and expression in cells that express ER, which is the main way estradiol exerts its biological effects in the body. Estradiol also acts as an agonist of membrane estrogen receptors (mERs), like GPER (GPR30), a newly identified non-nuclear receptor for estradiol, through which it can produce various rapid, non-genomic effects. Unlike ER, GPER seems to be selective for estradiol and has very low affinities for other natural estrogens like estrone and estriol. Other mERs besides GPER include ER-X, ERx, and Gq-mER.

ERα/ERβ are initially inactive, trapped in multimolecular chaperone complexes centered around heat shock protein 90 (HSP90), containing p23 protein and immunophilin, and are mostly located in the cytoplasm and partially in the nucleus. In the E2 classical pathway, or estrogen classical pathway, estradiol enters the cytoplasm, where it binds to ERs. Once estradiol is bound, ERs detach from the chaperone complexes, allowing them to dimerize, move to the nucleus, and bind to specific DNA sequences (estrogen response element, ERE), facilitating gene transcription that can occur over hours and days.

When administered by subcutaneous injection in mice, estradiol is approximately 10 times more potent than estrone and about 100 times more potent than estriol. Therefore, estradiol is the primary estrogen in the body, although the roles of estrone and estriol as estrogens are considered significant.

Biosynthesis

Estradiol, similar to other steroid hormones, originates from cholesterol. Following side chain cleavage and utilizing either the Δ5 or Δ4- pathway, androstenedione serves as the primary intermediary. Some of the androstenedione is transformed into testosterone, which is then converted to estradiol by aromatase. Alternatively, androstenedione can be aromatized into estrone, which is subsequently converted to estradiol via 17β-hydroxysteroid dehydrogenase (17β-HSD).

During the reproductive years, the majority of estradiol in women is synthesized by the granulosa cells of the ovaries through the aromatization of androstenedione (produced in the theca folliculi cells) to estrone, which is then converted to estradiol by 17β-HSD. Smaller quantities of estradiol are also produced by the adrenal cortex, and in men, by the testes.

Estradiol is not exclusively produced in the gonads; notably, fat cells generate active precursors to estradiol, continuing even after menopause. Estradiol is also synthesized in the brain and within arterial walls.

Distribution

In plasma, estradiol is primarily bound to SHBG and albumin. Only about 2.21% (± 0.04%) of estradiol is free and biologically active, with this percentage remaining stable throughout the menstrual cycle.

The inactivation of estradiol involves its conversion to less-active estrogens, such as estrone and estriol. Estriol is the main urinary metabolite. Estradiol is conjugated in the liver to form estrogen conjugates like estradiol sulfate and estradiol glucuronide, which are excreted via the kidneys. Some water-soluble conjugates are excreted through the bile duct and partially reabsorbed after hydrolysis from the intestinal tract. This enterohepatic circulation helps maintain estradiol levels.

Estradiol is also metabolized by hydroxylation into catechol estrogens. In the liver, it undergoes non-specific metabolism by CYP1A2, CYP3A4, and CYP2C9 through 2-hydroxylation into 2-hydroxyestradiol, and by CYP2C9, CYP2C19, and CYP2C8 through 17β-hydroxy dehydrogenation into estrone, with other cytochrome P450 (CYP) enzymes and metabolic transformations also playing a role.

Estradiol is further conjugated with an ester into lipoidal estradiol forms such as estradiol palmitate and estradiol stearate to some degree; these esters are stored in adipose tissue and may serve as a long-term reservoir of estradiol.

Excretion

Estradiol is excreted as glucuronide and sulfate estrogen conjugates in urine. After an intravenous injection of labeled estradiol in women, nearly 90% is excreted in urine and feces within 4 to 5 days. Enterohepatic recirculation delays the excretion of estradiol.

Level

Estradiol levels in premenopausal women vary significantly throughout the menstrual cycle, with reference ranges differing across sources. During the early to mid follicular phase (or the first week of the menstrual cycle, known as menses), estradiol levels are minimal, usually ranging from 20 to 80 pg/mL according to most laboratories. These levels gradually rise during the mid to late follicular phase (or the second week of the menstrual cycle) until the pre-ovulatory phase.

During pre-ovulation (approximately 24 to 48 hours), estradiol levels peak, reaching their highest concentrations of the menstrual cycle. Typically, circulating levels range from 130 to 200 pg/mL, but in some women, they may reach 300 to 400 pg/mL, with some laboratories setting the upper limit of the reference range even higher (e.g., 750 pg/mL). After ovulation (mid-cycle) and during the luteal phase (the latter half of the menstrual cycle), estradiol levels stabilize, fluctuating between about 100 and 150 pg/mL during the early and mid luteal phase, and dropping to around 40 pg/mL in the late luteal phase, or a few days before menstruation.

The mean integrated levels of estradiol over a full menstrual cycle have been reported by various sources as 80, 120, and 150 pg/mL. Although there are conflicting reports, one study found mean integrated estradiol levels of 150 pg/mL in younger women, whereas in older women, levels ranged from 50 to 120 pg/mL.

During the reproductive years, estradiol levels in women are generally higher than those of estrone, except during the early follicular phase of the menstrual cycle. Thus, estradiol is considered the predominant estrogen in terms of absolute serum levels and estrogenic activity during these years.

During pregnancy, estriol becomes the predominant circulating estrogen, and this is the only time estetrol is present in the body. In contrast, estrone predominates during menopause, based on serum levels. In men, estradiol, derived from testosterone, is present at serum levels comparable to those in postmenopausal women (14–55 versus <35 pg/mL, respectively). It has also been noted that in a comparison between 70-year-old men and women, estradiol levels are approximately 2- to 4-fold higher in men.

Measurement

In women, serum estradiol is measured in a clinical laboratory and primarily reflects ovarian activity. The Estradiol blood test quantifies estradiol in the blood, assessing the function of the ovaries, placenta, and adrenal glands. This test can identify baseline estrogen levels in women with amenorrhea or menstrual dysfunction, and detect hypoestrogenicity and menopause. Additionally, monitoring estrogen during fertility therapy helps assess follicular growth and treatment progress. Estrogen-producing tumors show persistently high levels of estradiol and other estrogens. In precocious puberty, estradiol levels are inappropriately elevated.

Ranges

Laboratory results should always be interpreted using the specific ranges provided by the laboratory conducting the test.

Chemistry

Estradiol is an estrane steroid.[82] It is also referred to as 17β-estradiol to differentiate it from 17α-estradiol, or as estra-1,3,5(10)-triene-3,17β-diol. It has two hydroxyl groups, one at the C3 position and another at the 17β position, along with three double bonds in the A ring. Due to these two hydroxyl groups, estradiol is often abbreviated as E2. Structurally related estrogens, estrone (E1), estriol (E3), and estetrol (E4), have one, three, and four hydroxyl groups, respectively.

Neuropsychopharmacology

Product insert information for commercial prescription estradiol indicates it may cause depression. In a randomized, double-blind, placebo-controlled study, estradiol demonstrated gender-specific effects on fairness sensitivity. Overall, when the division of a given amount of money was framed as either fair or unfair in a modified version of the ultimatum game, estradiol increased the acceptance rate of fair-framed proposals among men and decreased it among women. However, among the placebo group, "the mere belief of receiving estradiol treatment significantly increased the acceptance of unfair-framed offers in both sexes," suggesting that "environmental" factors influenced responses to these presentations of the ultimatum game.

Availability of Estradiol Medication

Forms of Estradiol

• Tablets

• Transdermal patches

• Topical gels and creams

• Injectable forms

• Pellets

• Vaginal rings and tablets

Considerations

• Consult with a healthcare professional before starting estradiol.

• Discuss potential side effects and contraindications.

• Regular monitoring may be necessary during treatment.