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Estrone

Estrone is a naturally occurring and one of the three primary in humans, characterized by its aromatized C18 structure featuring a 3-hydroxyl group and a 17-ketone , with the molecular formula C₁₈H₂₂O₂. It serves as a key female , playing essential roles in reproductive , particularly during when it becomes the predominant circulating . Estrone is biosynthesized primarily through the of in peripheral tissues such as , ovaries, and the during . In premenopausal women, it is produced in smaller amounts compared to , but its levels increase post-menopause due to enhanced extragonadal conversion from adrenal androgens. The hormone can be reversibly converted to by the 17β-hydroxysteroid dehydrogenase, allowing interconversion between these estrogens . Physiologically, estrone binds to estrogen receptors (ERα and ERβ) to regulate the development and maintenance of female secondary sexual characteristics, modulate secretion via on the hypothalamic-pituitary axis, and support conservation. It also influences cardiovascular function, , and neuroendocrine processes, though its weaker estrogenic potency compared to means it often acts as a reservoir for more active forms. In men, trace amounts contribute to overall balance. Medically, estrone is utilized in hormone replacement therapy (HRT) to alleviate menopausal symptoms such as hot flashes and vaginal atrophy, and to prevent postmenopausal . However, its use is associated with risks including increased chances of , , , and deep vein , necessitating careful monitoring and risk-benefit assessment. Elevated circulating levels of estrone have been linked to and certain hormone-dependent cancers, highlighting its role as a in endocrine disorders.

Chemistry

Structure and nomenclature

Estrone is an with the molecular formula C18H22O2 and a molecular weight of 270.366 g/mol. Its systematic IUPAC name is 3-hydroxyestra-1,3,5(10)-trien-17-one, reflecting the specific positioning of functional groups on the backbone. The core structure of estrone consists of a steroidal , characterized by four fused rings labeled A, B, C, and D. Ring A is and aromatic, featuring a hydroxyl group at position 3 and conjugated s that contribute to its ic properties; ring B includes a between C5 and C10; rings C and D form the saturated backbone with a at C13. At position 17 on ring D, estrone bears a (oxo) group, distinguishing its chemical identity within the family. Estrone is classified as an steroid, belonging to the subclass of estrogens and derivatives, which are C18 steroids with a 3-hydroxylated nucleus. It is one of the three primary endogenous estrogens in mammals, alongside and , playing a key role in hormonal . Regarding isomers and , estrone features a specific chiral configuration at key asymmetric centers, including (8R,9S,13S,14S), which is typical of naturally occurring hormones. The 17-keto configuration sets estrone apart from its close analog , which instead has a 17β-hydroxyl group, resulting in distinct biological activities despite their structural similarity. While estrone lacks stereoisomerism at C17 due to the planar keto moiety, variations in ring fusions or substituents can yield synthetic isomers, though the natural form adheres to the standard gonane-derived .

Physical and chemical properties

Estrone is a white to off-white crystalline powder. Its ranges from 258 to 261 °C, reflecting its thermal stability as a solid under standard conditions. Estrone demonstrates poor aqueous , with a reported value of 1.30 mg/L in pure at 25 °C, which limits its dissolution in biological fluids without solubilizing agents. In contrast, it is readily soluble in organic solvents, including (approximately 4 mg/mL at 15 °C), acetone (20 mg/mL), and dioxane (50 mg/mL), facilitating its use in and pharmaceutical preparations. Estrone is generally stable in air at but exhibits sensitivity to , undergoing with half-lives of 2–3 hours under UV in aqueous environments, and to aerial oxidation, necessitating storage under inert conditions to maintain integrity. The hydroxyl group at the 3-position imparts acidic character to estrone, with a of approximately 10.4, enabling in basic media and influencing its polarity and profile. This group is reactive toward conjugation, forming or esters at the 3-position through esterification, a process that enhances water for .

Biochemistry

Biosynthesis

Estrone is primarily synthesized in the body through the peripheral of , a key precursor, catalyzed by the (encoded by the CYP19A1 gene). This rate-limiting step occurs predominantly in , where converts directly into estrone, as well as in the ovaries and . In , particularly in postmenopausal women, this extraglandular pathway becomes the dominant source of estrone production due to the abundance of the and the availability of circulating . An alternative biosynthetic route for estrone involves the oxidation of , the more potent , mediated by 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2). This reversible interconversion between estrone and allows for dynamic regulation of activity, with 17β-HSD2 favoring the inactivation of to estrone in certain tissues. In premenopausal women, ovarian production of estrone is tightly regulated by gonadotropins: (FSH) induces expression in granulosa cells, while (LH) promotes synthesis in cells, providing substrates for . Postmenopause, with ovarian function declining, estrone synthesis shifts to , where it accounts for the majority of residual production and becomes the principal circulating . Quantitatively, estrone represents approximately 20–40% of total circulating estrogens (primarily estrone and ) in premenopausal cycling women, where predominates, but its contribution rises dramatically to nearly 100% in postmenopausal women due to the reliance on peripheral . During , placental biosynthesis of estrone intensifies, drawing on (DHEAS) precursors from both maternal and fetal adrenal sources to support elevated levels essential for . This fetal-placental unit ensures high estrone output, primarily through activity in the .

Metabolism

Estrone undergoes extensive in the body, primarily through phase I oxidation and phase II conjugation reactions, leading to its inactivation and preparation for elimination. The primary metabolic pathways involve conjugation to form more water-soluble derivatives and oxidative modifications in the liver. These processes occur mainly in the liver and target tissues, regulating estrone's and activity. The main primary metabolites of estrone are estrone sulfate and estrone glucuronide, formed via sulfation and , respectively. Sulfation is catalyzed by estrogen sulfotransferase SULT1E1, particularly at low physiological concentrations of estrone, producing estrone-3-sulfate, a major circulating form that serves as a for active s. Glucuronidation occurs primarily through UDP-glucuronosyltransferase UGT1A8, yielding estrone-3-glucuronide, which enhances for further processing. Additionally, estrone can be metabolized to through 16α-hydroxylation followed by reduction at the 17-position. In the liver, estrone is subject to P450-mediated , generating key hydroxylated metabolites such as 2-hydroxyestrone and 16α-hydroxyestrone. 2-Hydroxyestrone formation is primarily catalyzed by , , and CYP1B1 enzymes, while 16α-hydroxyestrone is mainly formed by and related enzymes; 2-hydroxyestrone is considered protective and 16α-hydroxyestrone potentially more genotoxic due to its reactivity. These metabolites often undergo subsequent conjugation to facilitate their removal. Estrone is reversibly interconverted with the more potent in target tissues, such as the breast and , via reduction by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). This catalyzes the NADPH-dependent reduction of estrone to , amplifying local estrogenic effects, while the reverse oxidation is mediated by other 17β-HSD isoforms. The half-life of unconjugated estrone is short, ranging from 10 to 70 minutes, reflecting rapid metabolism and clearance. However, conjugation to sulfate or significantly prolongs its , allowing estrone sulfate to persist for hours as a stable reservoir. Genetic variations in CYP1B1, such as the Val432Leu polymorphism (rs1056836), influence the ratio of 4-hydroxyestrone to 2-hydroxyestrone. The cited study found no significant association with risk but noted modestly higher levels in Leu carriers. These polymorphisms affect enzymatic activity and profiles, highlighting interindividual differences in .

Distribution and levels

Estrone circulates in the primarily bound to proteins, with greater than 95% bound to proteins, primarily , and a smaller fraction to (SHBG), leaving about 2% in the free, biologically active form. In , estrone concentrations vary by and physiological ; in premenopausal women, levels typically from 17 to 200 pg/mL during the and can rise to 37 to 200 pg/mL in the . In men, levels are lower, generally ranging from 10 to 60 pg/mL. Postmenopause, estrone becomes the predominant circulating , with levels ranging from 7 to 40 pg/mL, though some assays report broader ranges up to 125 pg/mL depending on individual factors. Tissue distribution of estrone is notable for high concentrations in , where local of contributes significantly to its production, particularly in postmenopausal women. Levels are low in children, remaining undetectable to 29 pg/mL prepubertally, and increase during to peak in the reproductive years before declining slightly postmenopause, when estrone dominates over . In males, estrone is present at minimal levels systemically but is produced in the testes via . Clinical assessment of estrone levels employs methods such as () or liquid chromatography-tandem (LC-MS/MS), with the latter offering higher specificity and sensitivity for low concentrations. Factors influencing estrone levels include , which elevates concentrations through increased adipose activity, and , which can disrupt SHBG production and alter protein binding.

Excretion

Estrone and its metabolites are primarily eliminated from the body through renal and biliary routes, with conjugated forms (glucuronides and sulfates) being the main excreted species. The liver conjugates estrone via sulfation and to form water-soluble derivatives, which facilitates their elimination. The major portion of these conjugates undergoes biliary secretion into the intestine, where they contribute to fecal elimination, representing approximately 5-10% of total output after accounting for . However, due to , a significant proportion—up to 80%—of biliary conjugates is deconjugated by intestinal and reabsorbed into the circulation, thereby prolonging the of estrone in the body. In the gut, bacterial and sulfatase enzymes hydrolyze the conjugates, releasing unconjugated estrone for potential or fecal loss. Renal excretion accounts for the bulk of net elimination, with about 80-90% of metabolites appearing in as conjugates. is the predominant urinary form, alongside conjugates and other hydroxylated metabolites. Total urinary excretion in women typically ranges from 5 to 20 μg per day, varying with phase and physiological state. Fecal elimination primarily involves unconjugated estrone resulting from intestinal deconjugation of biliary conjugates, with minimal direct unconjugated from other sources. Impaired hepatic or renal disrupts these pathways, reducing conjugation efficiency in the liver or clearance via the kidneys, which leads to elevated circulating levels of estrone and its metabolites.

Mechanism of action

Estrone functions primarily as a for the estrogen receptors ERα (encoded by ESR1) and ERβ (encoded by ESR2), acting as an at both subtypes to initiate estrogenic signaling. Its is substantially lower than that of 17β-, with relative ligand affinities of approximately 4.5% for ERα and 4.0% for ERβ, corresponding to values for coactivator recruitment in the range of 30–75 nM depending on the receptor and assay conditions. This reduced potency arises from the 17-keto group in estrone, which diminishes the stability of receptor-ligand interactions compared to the 17β-hydroxyl group in , leading to weaker overall estrogenic activity—typically 1/10th to 1/20th that of across various assays. In the classical genomic pathway, estrone-bound estrogen receptors undergo conformational changes that promote dimerization, either as homodimers (ERα-ERα or ERβ-ERβ) or heterodimers (ERα-ERβ), followed by translocation. The dimer then binds to specific DNA sequences known as estrogen response elements (ERE) in the promoter regions of target genes, recruiting coactivators such as SRC-3 to modulate transcription. For instance, this mechanism upregulates the expression of genes like the (PGR), which is critical for coordinated hormonal responses in target tissues. Additionally, estrone influences hepatic production of proteins such as (SHBG) and thyroid-binding globulin (TBG), altering circulating hormone levels. Estrone also elicits rapid non-genomic effects through membrane-associated forms of ERα and ERβ, as well as potentially G protein-coupled estrogen receptor 1 (GPER1), bypassing nuclear transcription. These actions occur within seconds to minutes and involve activation of intracellular signaling cascades, including the (MAPK)/extracellular signal-regulated kinase (ERK) pathway and the 3-kinase (PI3K)/Akt pathway, leading to outcomes such as calcium mobilization and modulation. In pituitary tumor cells expressing high levels of membrane ERα, estrone activates ERK oscillations with potency comparable to at concentrations as low as 10^{-12} M, though it exhibits a longer delay in compared to . The tissue selectivity of estrone's actions is influenced by the differential distribution and affinity preferences of ER subtypes, with ERα predominating in reproductive tissues like the and , where estrone exerts effects despite its lower potency. Furthermore, estrone is metabolized to 2-methoxyestrone, which exhibits properties by acting as an electron donor and inhibiting , potentially contributing to protective effects independent of classical ER signaling.

Physiological roles

Estrone, an endogenous with lower potency than but higher than , plays a supportive role in reproductive , primarily by contributing to endometrial during the menstrual 's proliferative , though its effects are less pronounced than those of . It also aids in production, facilitating transport, as part of the broader estrogen-mediated changes in secretions. Compared to , estrone serves as a minor contributor to pubertal development and menstrual regulation, acting mainly as a precursor and reservoir for more potent estrogens. In postmenopausal women, where estrone becomes the predominant circulating due to peripheral in , it helps maintain by inhibiting activity and promoting function, thereby mitigating age-related bone loss. Estrone also supports vascular health through effects on endothelial cells, including enhanced and tube formation, with minimal effects on , which contribute to cardiovascular protection. Additionally, its involvement in may underlie disruptions leading to hot flashes, a common menopausal symptom. Beyond reproduction, estrone exerts non-reproductive effects, including primarily via activation of β (ERβ) in the , where it modulates neuronal survival and reduces . In the cardiovascular system, estrone, as an , contributes to and improved endothelial function, potentially reducing the risk of , though with lower potency than . Endogenous estrone levels have been associated with lower (HDL) cholesterol and higher levels in postmenopausal women. In males, where estrone levels are low but present through of androgens, it supports by regulating germ cell development and fluid reabsorption in the of the testis. It also contributes to health by balancing epithelial and stromal cell proliferation via receptors, preventing excessive growth. Pathophysiologically, elevated estrone levels are associated with , where local increases in endometriotic tissues promote lesion growth and inflammation through enhanced signaling. Conversely, estrone deficiency, often occurring in , exacerbates symptoms such as reduced and metabolic disturbances due to impaired estrogen-mediated .

Medical use

Hormone replacement therapy

Estrone has historically been employed in (HRT) to address deficiency in menopausal and hypogonadal women, primarily through intramuscular injections of aqueous suspensions. Under the brand name Theelin, it was administered in doses ranging from 0.1 to 5 mg to alleviate symptoms of . These injectable formulations, introduced in the early , are now rarely utilized due to their inconvenience and have been supplanted by more patient-friendly oral and options that provide steadier delivery. In , estrone is indicated for the management of vasomotor symptoms such as hot flashes, treatment of vulvovaginal , and prevention of postmenopausal in women at high risk for fractures. Historical dosing regimens typically involved 0.1 to 2 mg administered intramuscularly every 1 to 3 weeks. When used in women with an intact , estrone is combined with progestins to counteract the risk of . Estrone effectively relieves vasomotor and genitourinary symptoms of menopause. Recent 2024-2025 clinical guidelines and studies highlight the role of low-dose conjugated equine estrogens—predominantly estrone sulfate—in supporting long-term bone health, with evidence showing sustained increases in bone mineral density and reduced fracture incidence in postmenopausal women.

Other indications

In the mid-20th century, estrone and its sulfate conjugate were utilized in estrogen replacement therapies to address conditions associated with estrogen deficiency, including amenorrhea and dysmenorrhea. For instance, soluble estrone sulfate was administered to alleviate symptoms of estrogen deficiency, helping to restore menstrual regularity in affected women during the 1950s. Investigational uses of estrone include its potential role in , where it serves as a weaker compared to , with relative binding affinities of 4-10% to α and 2-3.5% to β, making it less commonly prescribed due to reduced potency in feminizing effects. Recent studies as of 2025 have examined estrone conjugates, such as GLP-1-estrogen hybrids, for symptom management, demonstrating neuroprotective benefits through enhanced mitochondrial function and reduced in preclinical models. Diagnostically, measurement of urinary estrone-3-glucuronide (E1G) levels provides a non-invasive marker for assessing ovarian function, reflecting follicular development and production throughout the . Elevated E1G concentrations indicate active ovarian steroidogenesis, aiding in the evaluation of and ovulatory status in clinical settings.

Safety profile

Contraindications

Estrone is absolutely contraindicated in individuals with a known or suspected history of estrogen-sensitive cancers, including , endometrial, and ovarian cancers, due to the potential for hormone stimulation of tumor growth via estrogen receptors. It is also prohibited in cases of undiagnosed abnormal , as this may indicate underlying endometrial pathology that could be exacerbated by exposure. Active or recent thromboembolic disorders, such as or , represent another absolute , given the prothrombotic effects of estrogens. Relative contraindications include liver dysfunction, such as active or , where estrogen metabolism may be impaired, leading to elevated levels and heightened toxicity risk. with aura is considered a relative owing to the increased risk associated with use in this population. Uncontrolled similarly warrants caution, as it amplifies cardiovascular risks during therapy. is relatively contraindicated, as estrone can transfer into and potentially suppress or affect the . In patients with a history of , estrone increases the risk of recurrence through stimulation, making it unsuitable for those with prior estrogen-sensitive disease. Venous risk is elevated 2- to 3-fold with oral , particularly in the first year of use, due to changes in coagulation factors. Estrone is classified as X by the FDA, indicating it is contraindicated during pregnancy because of potential teratogenic effects on fetal development. As of November 2025, the FDA has removed warnings for cardiovascular risks associated with therapies, recommending individualized risk-benefit assessment rather than broad avoidance in women over 60 for primary prevention, though caution is advised based on patient-specific factors.

Side effects

Estrone administration, like other therapies, is associated with a range of adverse reactions that vary in frequency and severity. Common side effects, occurring in more than 10% of users, include , breast tenderness, , weight gain due to fluid retention, and mood changes such as or . Serious adverse effects, reported in less than 1% of cases, encompass when estrone is used without opposing progestin, gallbladder disease requiring surgical intervention, and that may precipitate . Long-term use of estrone in combined elevates risk, with a of 1.2 to 1.5 after five or more years of exposure. Recent evidence as of 2025, including studies showing potential protective effects when initiated early post-menopause, has led the FDA to remove the for probable ; however, risks may persist with late initiation in women aged 65 and older. On November 10, 2025, the FDA initiated removal of warnings from menopausal products, including those containing estrone, regarding risks of , , and probable , based on an updated scientific review emphasizing benefits for symptom relief when used appropriately. Dose-dependent effects include injection site reactions such as pain and, rarely, formation following intramuscular administration of estrone aqueous suspension, as well as withdrawal bleeding upon discontinuation. To mitigate risks, regular monitoring with annual mammograms for and assessments for cardiovascular evaluation is recommended during estrone therapy. Mechanisms underlying risks with estrone overlap with those in contraindications for high-risk patients.

History

Discovery and isolation

Estrone, the first estrogen to be isolated in pure form, was discovered through collaborative efforts in reproductive during the early 20th century. In , American physiologist Edgar Allen and biochemist Edward Adelbert Doisy identified estrogenic activity in extracts from sow ovaries by demonstrating their ability to induce vaginal cornification—characterized by the appearance of cornified epithelial cells in vaginal smears—in ovariectomized rats; this observation established the foundational for detecting estrogenic substances. Building on this, Doisy's team achieved a major breakthrough in 1929 by extracting, purifying, and crystallizing from the follicular fluid of ovaries, marking the first of a pure ; they initially named the compound "theelin" due to its role in inducing estrus. Independently in the same year, German biochemist isolated and crystallized from human pregnancy urine, confirming its identity through bioassays and that yielded the molecular formula C₁₈H₂₂O₂. The structural elucidation of estrone occurred throughout , primarily through Butenandt's degradation studies that reduced the group and identified characteristics, corroborated by UV revealing absorption bands indicative of an aromatic A-ring in the framework. These efforts established estrone as a derivative, distinguishing it from other known hormones. Butenandt's pioneering contributions to the isolation and characterization of sex hormones, including estrone, earned him the , shared with Leopold Ruzicka for related work on polymethylenes and higher .

Therapeutic development

In the , estrone was rapidly commercialized as a therapeutic agent, with introducing it under the brand name Theelin as an injectable preparation derived from pregnant mare urine for alleviating menopausal symptoms. This marked one of the earliest widespread clinical applications of a purified , building on its isolation from human sources and enabling scalable production for hormone replacement. By the late , multiple pharmaceutical companies had followed suit, offering estrone injections as a standard treatment for estrogen deficiency states, which spurred further research into its and dosing regimens. Estrone became commercially available in the late 1930s following the enactment of the Federal Food, Drug, and Cosmetic Act, which regulated drug approvals. Advancements in synthesis significantly enhanced estrone's availability and purity for therapeutic use. In 1948, Swiss chemists Georg Anner and Karl Miescher achieved the first total synthesis of estrone, providing a non-biological route that confirmed its structure and facilitated production independent of animal sources. Complementing this, semi-synthetic methods emerged in the mid-20th century, converting plant sterols such as diosgenin from yams via microbial fermentation and chemical degradation; these processes, building on steroid synthesis techniques pioneered in the industry, lowered costs and supported industrial-scale manufacturing for clinical formulations. Estrone reached peak clinical utilization from the through the , when it dominated replacement regimens due to its oral and injectable , with sales of products broadly tripling during this period amid growing awareness of menopausal health needs. However, its prominence waned as -based formulations, such as and micronized introduced in the 1960s and , gained favor for their closer mimicry of endogenous profiles and improved tolerability. Post-1975, estrone's use declined sharply following reports linking unopposed to elevated risk, prompting a 50% drop in overall prescriptions and a shift toward combined estrogen-progestin therapies as safer alternatives. By the 2000s, pure estrone formulations were largely discontinued in many markets, including the U.S. and , due to these safety concerns and the availability of more potent options; nonetheless, estrone conjugates like estropipate ( estrone ) have persisted in niche applications for symptoms and prevention, remaining FDA-approved and commercially available. As of , estrone has seen a limited revival within bioidentical protocols, where it is semi-synthesized from plant sterols to match human estrone structure, appealing to patients seeking "natural" alternatives for menopausal symptom relief despite lacking superior efficacy evidence over conventional . In November , the FDA removed the on cardiovascular risks for certain menopausal hormone therapies, which may further support the use of estrone formulations. Concurrently, preclinical research explores estrone-conjugated nanoparticles for targeted drug delivery, such as estrone-targeted PEGylated liposomes to enhance uptake in estrogen receptor-positive cervical cancers, aiming to improve specificity and reduce systemic toxicity in applications.