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Estrane

Estrane is a C₁₈H₃₀ steroid hydrocarbon that serves as the fundamental parent structure for the estrane series of steroids, featuring a gonane core composed of four fused cycloalkane rings—three six-membered (A, B, and C) and one five-membered (D)—with no methyl group at the C-10 position.^[1]^[2] This saturated tetracyclic framework, also known as 19-norandrostane, distinguishes estrane from other steroid classes like androstane (C₁₉) and pregnane (C₂₁), and it forms the basis for numerous biologically active compounds.^[3]^[4] In biochemistry, estrane is the core nucleus shared by all estrogens, such as estradiol and estrone, which are essential female sex hormones involved in reproductive development, menstrual cycle regulation, and secondary sexual characteristics.^[3] Derivatives of estrane also include synthetic progestins like norethindrone and dienogest, widely used in oral contraceptives, hormone replacement therapy, and treatments for conditions like endometriosis due to their progestogenic and antiestrogenic properties.^[5] Additionally, estrane-based compounds exhibit influences on vascular smooth muscle tone and have been explored for antiproliferative applications in steroid synthesis research.^[3] Estrane itself is not a naturally occurring metabolite in humans but is detected in the exposome as a result of exposure to its derivatives, and it plays a key role in steroid nomenclature and structural analysis, with over 200 related crystal structures documented since 1945.^[4]^[3] Its chemical properties, including a high logP value of approximately 5.5 indicating lipophilicity, make it suitable for modification into pharmaceuticals and research tools.^[4]^[2]

Chemistry

Structure

Estrane is the parent C₁₈ steroid hydrocarbon, featuring a characteristic tetracyclic nucleus composed of three fused six-membered cyclohexane rings designated as A, B, and C, along with a terminal five-membered cyclopentane ring D arranged in a linear perhydrocyclopentaphenanthrene configuration.^[6] The rings are fused at specific shared carbon atoms: ring A with ring B at positions 5 and 10, ring B with ring C at positions 8 and 9, and ring C with ring D at positions 13 and 14.^[7] The carbon skeleton of estrane contains 18 atoms, qualifying it as a gonane derivative distinguished by an angular methyl substituent at C13 (the C18 methyl group) but absent the C19 methyl at C10 found in related androstane structures.^[6] This configuration yields a molecular formula of C₁₈H₃₀ for the fully saturated form. Estrane relates to gonane, the fundamental C₁₇ steroid parent hydrocarbon, through the incorporation of the C18 methyl at position 13.^[6] Standard steroid numbering spans carbons 1 through 18 across the nucleus: ring A encompasses positions 1–5 and 10; ring B includes 5–10; ring C covers 8–9 and 11–14; and ring D comprises 13–17, with the C18 methyl attached to C13.^[7] The stereochemistry adheres to the natural steroid convention, with trans fusions at the B/C and C/D junctions and either trans (5α-series) or cis (5β-series) at A/B; principal chiral centers occur at C8 (β-hydrogen), C9 (α-hydrogen), C10 (β), C13 (β), and C14 (α).^[6] The systematic IUPAC name for a saturated estrane isomer is (8R,9R,10S,13S,14S)-13-methyl-1,2,3,4,5,6,7,8,9,10,11,12,14,15,16,17-hexadecahydrocyclopentaphenanthrene.^[1] In estrogen derivatives, the A ring often adopts an aromatic structure, introducing unsaturation and planarity distinct from the saturated parent.^[6]

Nomenclature

Estrane is a C₁₈ steroid hydrocarbon defined as the parent structure for the estrane series, derived from gonane—a hypothetical C₁₇ tetracyclic hydrocarbon—by the addition of a methyl group at carbon 13, and distinguished from the C₁₉ androstane by the absence of a methyl group at carbon 10.^[8]^[9] The fully saturated form is named estrane, with stereochemistry at the C5 bridgehead specified by prefixes such as 5α- or 5&beta-.^[8] The nomenclature of estrane originates from its structural relation to estrogens, a class of hormones associated with the estrous cycle in female mammals, with the prefix "estra-" derived from the Greek oistros (meaning gadfly or frenzy) via the term "estrus," reflecting the hormones' role in inducing sexual receptivity.^[10]^[11] This distinguishes estrane from other steroid series, such as pregnane (C₂₁, with an additional two-carbon side chain at C17) and cholestane (C₂₇, with an eight-carbon side chain at C17).^[8] Steroid nomenclature rules established by the International Union of Pure and Applied Chemistry (IUPAC) and the International Union of Biochemistry (IUB) designate "estra-" as the prefix for the C₁₈ series, with the suffix "-ane" indicating full saturation of the ring system.^[8] Unsaturation is denoted by replacing "-ane" with "-ene" for a single double bond, "-adiene" for two, or "-triene" for three (e.g., estrene for one double bond, estranetriene for three), with locants specifying bond positions such as in estra-1,3,5(10)-triene.^[8]^[10] Estrane serves as a synonym for 19-norandrostane, emphasizing the conceptual removal of the C19 methyl from androstane to yield the C₁₈ skeleton.^[12] A common point of confusion is the distinction from estrone, which refers to a specific derivative (estra-1,3,5(10)-trien-17-one) rather than the parent hydrocarbon estrane.^[13]

Biosynthesis and metabolism

Biosynthetic pathway

The biosynthesis of the estrane skeleton, the C18 core structure of estrogens, occurs through steroidogenesis, a multi-step enzymatic process beginning with cholesterol as the universal precursor. The pathway initiates in the mitochondria of steroidogenic cells, where cholesterol is transported from low-density lipoprotein particles and converted to pregnenolone by the cytochrome P450 enzyme CYP11A1 (also known as cholesterol side-chain cleavage enzyme). This rate-limiting reaction involves three sequential monooxygenations—hydroxylations at C22 and C20 followed by cleavage of the C17-C20 side chain—requiring molecular oxygen (O₂) and NADPH as cofactors, yielding pregnenolone and isocaproic acid.^[14]^[15] From pregnenolone, the pathway branches toward androgen intermediates via the Δ⁴ or Δ⁵ routes, ultimately producing the C19 steroid androstenedione. In the Δ⁴ route, pregnenolone is isomerized to progesterone by 3β-hydroxysteroid dehydrogenase (3β-HSD), followed by 17α-hydroxylation of progesterone to 17α-hydroxyprogesterone catalyzed by the hydroxylase activity of CYP17A1. Subsequent 17,20-lyase activity of CYP17A1 cleaves the side chain to form androstenedione. The alternative Δ⁵ route proceeds via 17α-hydroxypregnenolone (from CYP17A1 hydroxylase) to dehydroepiandrosterone (DHEA) (via lyase), then to androstenedione through 3β-HSD. These steps, also dependent on O₂ and NADPH, occur primarily in the endoplasmic reticulum and establish the androgen precursor essential for estrane formation.^[15]^[14] The formation of the estrane skeleton proper involves the aromatization of androstenedione to estrone, mediated by the cytochrome P450 enzyme aromatase (CYP19A1). This complex reaction comprises three sequential oxidations at C19: initial hydroxylation to 19-hydroxyandrostenedione, oxidation to the 19-aldehyde (19-oxandrostenedione), and final oxidative elimination of the C19 methyl group as formic acid, accompanied by aromatization of ring A through dehydrogenation and loss of the 2β-hydrogen. Each oxidation step requires NADPH, O₂, and the P450 reductase electron transfer system, resulting in the conversion of the C19 androgen to the C18 phenolic estrone, which features the characteristic aromatic A ring of the estrane nucleus. This process represents the irreversible commitment to estrogen production.^[16]^[14] Estrone biosynthesis is tissue-specific, occurring prominently in the ovaries, placenta, and adipose tissue. In the ovaries, estrogen production follows the two-cell, two-gonadotropin model: theca interna cells, stimulated by luteinizing hormone (LH), express CYP17A1 to generate androstenedione from pregnenolone precursors, which diffuses to adjacent granulosa cells. There, follicle-stimulating hormone (FSH) induces expression of CYP19A1 via cyclic AMP signaling, enabling aromatization to estrone; granulosa cells also possess androgen receptors to facilitate this paracrine interaction, with inhibin from granulosa cells further enhancing thecal androgen output in preovulatory follicles. Placental syncytiotrophoblasts perform similar CYP19A1-mediated aromatization using maternal and fetal adrenal androgens, while adipose tissue contributes postmenopausally through local CYP19A1 activity on circulating androstenedione. Estrone can be further reduced to estradiol by 17β-hydroxysteroid dehydrogenase in target tissues.^[17]^[14] The estrane biosynthetic pathway exhibits strong evolutionary conservation across vertebrates, with core enzymes like CYP11A1, CYP17A1, and CYP19A1 present in fish, amphibians, reptiles, birds, and mammals, reflecting an ancient origin in early chordates. CYP19 orthologs, including the conserved nine-exon gene structure and substrate-binding sites for androstenedione, appear in cephalochordates such as amphioxus, indicating that aromatization predates vertebrate divergence; minor variations occur in non-mammalian species, such as duplicated CYP19 genes in teleost fish for tissue-specific regulation.^[18]

Metabolic transformations

Metabolic transformations of estrane derivatives, such as estradiol and estrone, primarily involve phase I oxidative and reductive reactions followed by phase II conjugations to facilitate inactivation and excretion. These processes occur mainly in the liver, with contributions from extrahepatic tissues, and serve to maintain hormonal homeostasis by converting active estrogens into less potent or inactive metabolites.^[19] In phase I metabolism, cytochrome P450 (CYP) enzymes catalyze hydroxylation at key positions on the estrane nucleus. For instance, CYP1A1, CYP1A2, and CYP3A4 mediate 2-hydroxylation of estradiol to form 2-hydroxyestradiol, a major pathway accounting for approximately 50% of estradiol metabolism, while CYP1B1 primarily drives 4-hydroxylation to 4-hydroxyestradiol. These hydroxy metabolites, known as catechol estrogens, can undergo further oxidation to quinones, such as 4-hydroxyestrone-3,4-quinone, via enzymatic or non-enzymatic mechanisms, potentially leading to reactive species that form DNA adducts. Additionally, 16α-hydroxylation by CYP1A1, CYP2C8, and CYP3A4 produces 16α-hydroxyestrone, which retains significant estrogenic activity. 17β-Hydroxysteroid dehydrogenase (17β-HSD) enzymes, particularly isoforms 1 and 2, facilitate interconversion between estrone and estradiol; while 17β-HSD1 promotes the reductive activation of estrone to estradiol, 17β-HSD2 catalyzes the oxidative inactivation of estradiol to estrone, contributing to the catabolic direction in target tissues.^[19]^[20]^[19]^[21] Phase II metabolism involves conjugation to enhance water solubility for elimination. Glucuronidation, mediated by UDP-glucuronosyltransferase (UGT) enzymes such as UGT1A1, UGT1A3, UGT2B7, and UGT2B4, occurs predominantly at the 17β-hydroxyl group of estradiol and the 3-hydroxyl position, forming estrone-3-glucuronide and estradiol-17β-glucuronide. Sulfation, catalyzed by sulfotransferase (SULT) enzymes including SULT1A1, SULT1E1, and SULT2A1, targets the 3-phenolic hydroxyl group, yielding estrone-3-sulfate and estradiol-3-sulfate, which are stable conjugates that serve as circulating reservoirs. These conjugations occur rapidly post-hydroxylation, with both pathways competing for substrates to promote excretion.^[22]^[22]^[23] Excreted metabolites are primarily eliminated via the kidneys in urine (about 54% as conjugates), with a smaller portion (around 6%) via feces following enterohepatic recirculation, where gut bacteria hydrolyze conjugates for potential reabsorption. The plasma half-life of estradiol varies by administration route but is typically 1-2 hours for endogenous forms, influenced by factors such as age, liver function, and pregnancy, which can prolong clearance due to increased binding or reduced hepatic metabolism. Clearance rates average 1.3 mL/min/kg intravenously, reflecting efficient hepatic processing.^[24]^[25]^[24] Genetic variations further modulate these transformations. Polymorphisms in the CYP19A1 gene, such as rs4441215 and rs936306, alter aromatase activity and thereby influence downstream estrogen metabolite levels, while variants in HSD17B1 and HSD17B2 (e.g., rs4888202) affect the estrone-estradiol equilibrium and overall clearance rates, potentially increasing estrogen exposure in postmenopausal women.^[26]^[26]

Natural and synthetic derivatives

Natural derivatives

Natural derivatives of estrane primarily encompass the endogenous estrogens found in mammals, which share a core structure featuring an aromatic A ring and a phenolic hydroxyl group at the C3 position. The main compounds include estradiol (17β-hydroxyestra-1,3,5(10)-trien-3-ol), the most potent estrogen; estrone (estra-1,3,5(10)-triene-3,17-dione), its oxidized form with a ketone at C17; and estriol (16α-hydroxyestra-1,3,5(10)-triene-3,17β-diol), which bears an additional hydroxyl group at C16α.^[13] These variations at C17—either a hydroxyl or ketone group—distinguish their relative potencies and metabolic roles while maintaining the estrane skeleton.^[27] These estrogens are biosynthesized mainly in the ovaries from cholesterol via androstenedione and testosterone through aromatase activity, with the adrenal glands contributing precursor androgens that undergo peripheral conversion.^[28] Estrone predominates postmenopause due to its formation from adrenal androstenedione in adipose tissue via aromatase, while estradiol is the primary circulating form during reproductive years.^[29] Estriol is uniquely produced in high amounts by the placenta during pregnancy, utilizing dehydroepiandrosterone sulfate from the fetal adrenal glands as a precursor, highlighting the fetoplacental unit's role.^[30] Circulating levels of estradiol in premenopausal women typically range from 30 to 400 pg/mL, varying with menstrual cycle phase.^[31] Other natural estranes include equine-specific estrogens such as equilin (3-hydroxyestra-1,3,5(10),7-tetraen-17-one) and equilenin (estra-1,3,5(10),6,8-pentaene-3,17-dione), isolated from the urine of pregnant mares; these feature additional double bonds in rings B and/or C, conferring distinct estrogenic properties compared to human variants.^[32]^[33]^[34] Estrane-based estrogens occur predominantly in mammals, supporting reproductive physiology, though phytoestrogens in plants like soy isoflavones mimic estrogenic effects via receptor binding but lack the true estrane structure.^[35] The estrane-derived estrogen signaling pathway is evolutionarily conserved across vertebrates, originating from ancient steroid receptor systems that regulated reproduction before the divergence of progesterone and androgen pathways, underscoring its fundamental role in gonadal development and function.^[18]^[36]

Synthetic derivatives

Synthetic derivatives of estrane encompass a class of artificially synthesized steroids, primarily 19-nor compounds, engineered for enhanced pharmaceutical properties such as improved oral bioavailability and targeted hormonal activity. These modifications typically involve alterations to the estrane nucleus, including the addition of ethynyl groups, alkyl substitutions, or double bonds, to optimize interactions with steroid receptors while minimizing unwanted effects like androgenicity. The estrane progestins, derived from norethindrone, form the core of this group and are widely used in formulations for reproductive health.^[37] The pioneering synthesis of norethindrone (17α-ethynyl-19-nortestosterone) occurred in 1951 at Syntex Laboratories by Luis Miramontes under the direction of Carl Djerassi, marking a key advancement in oral progestin development during the 1950s. This compound was created through semi-synthetic routes starting from steroid precursors like diosgenin or androstenedione, involving steps such as 19-demethylation and ethynylation at the 17α position to confer oral activity suitable for contraception. Total synthesis approaches from non-steroidal precursors, though more complex, have also been explored, often building the estrane skeleton via multi-step carbon-carbon bond formations from simpler hydrocarbons or cholesterol-derived intermediates.^[38]^[39] Representative synthetic estrane progestins include ethynodiol diacetate, which features acetate groups at the 3β and 17β positions alongside the 17α-ethynyl substitution on the 19-nor backbone, enhancing metabolic stability. Dienogest introduces a 17α-cyanomethyl group with Δ^4 and Δ^9(10) double bonds, altering the structure to reduce progestogenic side activities while maintaining potency.^[40] Tibolone, a tissue-selective agent, incorporates a 7α-methyl group on a norethynodrel-like framework, allowing it to metabolize into estrogenic, progestogenic, and androgenic metabolites for balanced effects. These compounds are commonly paired with synthetic estrogens like ethinylestradiol in combined oral contraceptives or used in hormone replacement therapy regimens.^[41]^[42] Structure-activity relationships among estrane progestins highlight how the 17α-ethynyl substitution dramatically increases progestogenic potency and hepatic first-pass resistance, enabling low-dose oral administration, while the 19-nor modification diminishes androgenic binding to the androgen receptor. Further tweaks, such as introducing halogens (e.g., fluorine at C6 or C9) or additional alkyl groups, fine-tune receptor selectivity and duration of action; for instance, double bonds in the structure of dienogest confer anti-androgenic properties by altering conformational flexibility. These modifications stem from systematic studies linking steric and electronic changes to receptor affinity, prioritizing reduced androgenicity for safer profiles in long-term use.^[39]^[37]

Biological and pharmacological roles

Biological functions

Estrane derivatives, particularly estradiol, serve as the primary endogenous ligands for the estrogen receptors ERα and ERβ, which are nuclear receptors that mediate both genomic and non-genomic signaling pathways. Upon binding estradiol, ERα and ERβ undergo conformational changes that facilitate their dimerization, nuclear translocation, and interaction with estrogen response elements (EREs) on DNA, thereby regulating the transcription of target genes involved in cell proliferation, differentiation, and survival. This genomic action typically occurs over hours to days and influences a wide array of physiological processes. In parallel, non-genomic actions are initiated rapidly (within minutes) through membrane-associated forms of ERα and ERβ, activating signaling cascades such as MAPK/ERK and PI3K/Akt pathways, which modulate ion channel activity, cytoskeletal dynamics, and immediate cellular responses without direct gene transcription.^[43]^[44]^[45] In reproductive physiology, estradiol plays a central role in regulating the menstrual cycle by stimulating the proliferation of the endometrial lining during the follicular phase and providing negative and positive feedback on the hypothalamic-pituitary-gonadal axis to control gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) secretion. The mid-cycle surge in estradiol triggers the LH surge, which induces ovulation by promoting follicular rupture and subsequent luteinization. Post-ovulation, estradiol collaborates with progesterone to facilitate endometrial receptivity for implantation, ensuring the preparation of the uterus for potential pregnancy. These actions are essential for cyclic fertility and maintaining reproductive tract integrity.^[46]^[47]^[48] Beyond reproduction, estradiol exerts protective effects on bone density by inhibiting osteoclast activity and promoting osteoblast function, thereby reducing bone resorption and preventing postmenopausal osteoporosis. In the cardiovascular system, it enhances endothelial nitric oxide production, reduces vascular inflammation, and improves lipid profiles, contributing to lower risks of atherosclerosis and ischemic events in premenopausal women. In the brain, estradiol supports neuroprotection by mitigating oxidative stress, promoting neuronal survival, and modulating mood through interactions with serotonin and dopamine systems, with implications for cognitive function and affective disorders.^[49]^[50]^[51]^[52]^[53] During development, estradiol drives the emergence of secondary sex characteristics at puberty, including breast development, widening of the hips, and fat redistribution, through ER-mediated gene expression in target tissues. In fetal development, it contributes to the differentiation and maintenance of female reproductive structures, such as the Müllerian ducts, which form the oviducts, uterus, and upper vagina, although initial patterning occurs independently of estrogen signaling. These developmental roles establish sexual dimorphism and ensure reproductive competence in adulthood.^[54]^[55]^[56] Estradiol levels exhibit circadian rhythms during the follicular phase, and seasonal variations in some species that align reproductive cycles with environmental cues, influencing overall hormonal homeostasis. It interacts synergistically with progesterone to regulate endometrial cycling and antagonistically with testosterone to maintain androgen-estrogen balance, preventing excessive masculinization or unopposed estrogenic effects. These dynamics ensure coordinated endocrine signaling across physiological states.^[57]^[58] Pathologically, estrogen imbalance, such as hyperestrogenism in polycystic ovary syndrome (PCOS), disrupts ovarian function and contributes to anovulation and endometrial hyperplasia, increasing risks for endometrial cancer. In endometriosis, local estrogen production exacerbates lesion growth and inflammation via ER signaling. Elevated estradiol also promotes proliferation in estrogen receptor-positive breast cancers by stimulating cell cycle progression and inhibiting apoptosis.^[59]^[60]^[61]^[62]

Pharmacological applications

Synthetic estrane derivatives, particularly progestins such as norethindrone and estrogens like estradiol and its esters, play a central role in various pharmacological applications. In contraception, combined oral contraceptives containing ethinylestradiol (an estrane-derived estrogen) and estrane progestins like norethindrone are widely used to prevent pregnancy. These formulations suppress ovulation by inhibiting gonadotropin release from the pituitary gland, thicken cervical mucus to impede sperm migration, and alter the endometrium to reduce implantation likelihood.^[63]^[64] For hormone replacement therapy (HRT), estradiol valerate, an esterified estrane estrogen, is employed to alleviate menopausal symptoms including hot flashes and vaginal atrophy. It replenishes estrogen levels to mitigate vasomotor instability and urogenital tissue thinning. Transdermal administration of estradiol derivatives bypasses hepatic first-pass metabolism, potentially reducing thromboembolic risks compared to oral routes, while providing steady systemic delivery.^[65]^[66] Additional indications for estrane derivatives include treatment of hypogonadism, where estradiol replacement restores estrogen deficiency to support secondary sexual characteristics and bone health, and osteoporosis prevention by maintaining bone mineral density through estrogen-mediated inhibition of osteoclast activity.^[66]^[65] Estrane progestins exhibit mixed receptor activities, displaying strong progestogenic effects at the progesterone receptor while showing antiestrogenic properties by downregulating estrogen receptors in target tissues like the breast. This selectivity contributes to their efficacy in contraception and HRT without excessive estrogenic stimulation.^[5] Typical dosages for estrane progestins range from 0.35 to 5 mg daily, depending on the indication, with lower doses for progestin-only contraception and higher for HRT endometrial protection. Esterification, as in estradiol valerate, enhances bioavailability and prolongs duration of action, allowing for less frequent dosing in injectable or oral forms.^[67]^[65] A historical milestone was the 1960 FDA approval of Enovid, the first oral contraceptive containing the estrane progestin norethynodrel and mestranol, revolutionizing reproductive health. Ongoing research focuses on developing estrane-based formulations with improved safety profiles, such as those incorporating natural estrogens to minimize venous thromboembolism risk. Recent advancements include prolonged-release formulations of combined oral contraceptives containing dienogest (2 mg) and ethinylestradiol (0.02 mg), designed to provide steady hormone levels and reduce side effects.^[68]^[69]^[70]

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Progestogens Used in Postmenopausal Hormone Therapy
Tibolone is identical in structure to norethynodrel except it has a methyl group at carbon 7. It is metabolized rapidly and extensively into three metabolites.
[41]
Integration of the Non-genomic and Genomic Actions of Estrogen
Estrogen has rapid, non-genomic actions via membrane receptors, and gene transcription via nuclear receptors. Membrane signaling can also initiate gene ...
[42]
Non-Genomic Actions of Estrogens on the DNA Repair Pathways ...
Mar 19, 2021 · This review discusses scientific evidence supporting this non-genomic mechanism where estrogen modifies the DNA repair pathways, and its relationship to ...
[43]
Review Non-genomic actions of estrogens and their interaction with ...
Estrogens have genomic actions, regulating gene transcription, and non-genomic actions, initiated at the cell membrane, which can also impact transcription.
[44]
The Normal Menstrual Cycle and the Control of Ovulation - NCBI - NIH
Aug 5, 2018 · Estrogen levels rise and fall twice during the menstrual cycle. Estrogen levels rise during the mid-follicular phase and then drop ...
[45]
Estradiol Signaling in the Regulation of Reproduction and Energy ...
This rise in estradiol levels is essential for the induction of the luteinizing hormone surge that induces ovulation and luteinization of the follicular cells ...
[46]
Physiology, Menstrual Cycle - StatPearls - NCBI Bookshelf
Sep 27, 2024 · Hormones secreted from the hypothalamus and pituitary gland promote the maturation of ovarian follicles and trigger ovulation.
[47]
Estrogen and the Skeleton - PMC - PubMed Central - NIH
May 16, 2012 · Direct estrogen effects on osteocytes, osteoclasts, and osteoblasts lead to inhibition of bone remodeling, decreased bone resorption, and maintenance of bone ...
[48]
Estrogen and bone metabolism - PubMed
Estrogen plays an important role in the growth and maturation of bone as well as in the regulation of bone turnover in adult bone.
[49]
Estrogen and Mechanisms of Vascular Protection - PMC - NIH
Here we review cellular/molecular mechanisms by which estrogen modulates injury-induced inflammation, growth factor expression and oxidative stress in arteries ...
[50]
Estrogen and neuroprotection: from clinical observations to ...
We now appreciate that estrogen is a pleiotropic gonadal steroid that exerts profound effects on the plasticity and cell survival of the adult brain.
[51]
Effects of Estrogens on Central Nervous System Neurotransmission
Sep 11, 2019 · Growing evidence have indicated that local neural origin estrogens influence many brain regions to modulate brain development and behavior.
[52]
Female Development - StatPearls - NCBI Bookshelf - NIH
May 1, 2023 · Puberty begins in females from the ages of 8 to 10 years old. It is characterized by pubic hair development, breast enlargement, and menarche.
[53]
Molecular Mechanisms of Estrogen Action in Female Genital Tract ...
Feb 24, 2021 · While estrogen signaling has no impact on early Mullerian duct differentiation and gross patterning for the oviducts, uterus, cervix, and upper ...Missing: puberty | Show results with:puberty
[54]
Estradiol and the Developing Brain - PMC - PubMed Central - NIH
The actions of estradiol on developing brain are generally permanent and range from establishment of sex differences to pervasive trophic and neuroprotective ...
[55]
Sleep, Hormones, and Circadian Rhythms throughout the Menstrual ...
This review will address the variation of sleep at different menstrual phases in healthy and PMDD women, as well as changes in circadian rhythms.
[56]
Molecular pathways affecting reproductive efficiency in seasonal ...
Oct 15, 2025 · ... testosterone and females produce estrogen and progesterone (14). Seasonal regulation of the HPG axis. Seasonal breeders closely link their ...
[57]
Estrogen Receptors in Polycystic Ovary Syndrome - PubMed Central
Feb 21, 2021 · This article focuses on the recent progress in PCOS caused by the abnormal expression of estrogen and ERs in the ovaries and uterus.
[58]
Endocrine Risk Factors of Endometrial Cancer: Polycystic Ovary ...
Jul 2, 2020 · The aim of this review is to investigate the relationship between infertility, polycystic ovary syndrome (PCOS), OCs, and tamoxifen (TAM) and the risk of ...
[59]
Estrogen Signaling in Endometrial Cancer: a Key Oncogenic ...
Feb 2, 2019 · In this review, we discuss both the evidence that estrogen signaling plays a central role in endometrial cancer as well as the uncovered and yet ...
[60]
Unveiling the Role of Hormonal Imbalance in Breast Cancer ... - NIH
Jul 11, 2023 · This comprehensive review aims to unveil the role of hormonal imbalance in breast cancer by exploring the involvement of key hormones, including estrogen and ...Missing: PCOS | Show results with:PCOS
[61]
Oral Contraceptive Pills - StatPearls - NCBI Bookshelf - NIH
Currently, 3 types of oral contraceptive pills are broadly prescribed: combined estrogen-progesterone, progesterone-only, and continuous or extended-use pills.Continuing Education Activity · Indications · Mechanism of Action · Administration
[62]
Norethisterone: Uses, Interactions, Mechanism of Action - DrugBank
Norethisterone is extensively metabolized, primarily in the liver, to a number of metabolites via partial and total reduction of its A-ring.
[63]
Estradiol valerate: Uses, Interactions, Mechanism of Action - DrugBank
A medication used for birth control, unusual growth of the lining of the uterus, some effects of menopause, low estrogen, and some types of prostate cancer.Identification · Pharmacology · Interactions · References
[64]
Estrogen Therapy - StatPearls - NCBI Bookshelf - NIH
Feb 18, 2025 · Estrogen therapy is a form of hormone replacement therapy used to manage symptoms associated with menopause, including vasomotor symptoms such as hot flashes ...Continuing Education Activity · Indications · Administration · Adverse Effects
[65]
Norethindrone (oral route) - Side effects & dosage - Mayo Clinic
Oct 31, 2025 · Norethindrone is used to prevent pregnancy. It works by stopping a woman's egg from fully developing each month.
[66]
[PDF] FDA's Approval of the First Oral Contraceptive, Enovid
It was not until 1960 that the same drug was submitted to FDA for approval specifically as an oral contraceptive. At this point, concerns about the safety of ...
[67]
Are natural estrogens used in contraception at lower risk of venous ...
Aug 15, 2024 · This meta-analysis substantiates the lower VTE risk associated with natural estrogen-based COCs compared to synthetic alternatives.