Steroid

The steroid nucleus (core structure) is called gonane (cyclopentanoperhydrophenanthrene). It is typically composed of seventeen carbon atoms, bonded in four fused rings: three six-member cyclohexane rings (rings A, B and C in the first illustration) and one five-member cyclopentane ring (the D ring). Steroids vary by the functional groups attached to this four-ring core and by the oxidation state of the rings. Sterols are forms of steroids with a hydroxy group at position three and a skeleton derived from cholestane. Steroids can also be more radically modified, such as by changes to the ring structure, for example, cutting one of the rings. Cutting Ring B produces secosteroids one of which is vitamin D3. == Nomenclature ==

Rings and functional groups which was first described in gall stones from Ancient Greek chole- 'bile' and stereos 'solid'. Gonane, also known as steran or cyclopentanoperhydrophenanthrene, the nucleus of all steroids and sterols, is composed of seventeen carbon atoms in carbon-carbon bonds forming four fused rings in a three-dimensional shape. The three cyclohexane rings (A, B, and C in the first illustration) form the skeleton of a perhydro derivative of phenanthrene. The D ring has a cyclopentane structure. When the two methyl groups and eight carbon side chains (at C-17, as shown for cholesterol) are present, the steroid is said to have a cholestane framework. The two common 5α and 5β stereoisomeric forms of steroids exist because of differences in the side of the largely planar ring system where the hydrogen (H) atom at carbon-5 is attached, which results in a change in steroid A-ring conformation. Isomerisation at the C-21 side chain produces a parallel series of compounds, referred to as isosteroids. Examples of steroid structures are: File:Testosteron.svg|alt=Chemical diagram|Testosterone, the principal male sex hormone and an anabolic steroid File:Cholsäure.svg|alt=Chemical diagram|Cholic acid, a bile acid File:Dexamethasone structure.svg|alt=Chemical diagram|Dexamethasone, a synthetic corticosteroid drug File:Lanosterin.svg|alt=Chemical diagram|Lanosterol, the biosynthetic precursor to animal steroids. The number of carbons (30) indicates its triterpenoid classification. File:Progesteron.svg|alt=Chemical diagram|Progesterone, a steroid hormone involved in the female menstrual cycle, pregnancy, and embryogenesis File:Medrogestone.png|alt=Chemical diagram|Medrogestone, a synthetic drug with effects similar to progesterone File:Sitosterol structure.svg|alt=Chemical diagram|β-Sitosterol, a plant or phytosterol, with a fully branched hydrocarbon side chain at C-17 and an hydroxyl group at C-3 In addition to the ring scissions (cleavages), expansions and contractions (cleavage and reclosing to a larger or smaller rings)—all variations in the carbon-carbon bond framework—steroids can also vary: • in the bond orders within the rings, • in the number of methyl groups attached to the ring (and, when present, on the prominent side chain at C17), • in the functional groups attached to the rings and side chain, and • in the configuration of groups attached to the rings and chain. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers, indicating their position in the steroid nucleus. These trivial names can also be used as a base to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β denote absolute stereochemistry at chiral centers—a specific nomenclature distinct from the R/S convention of organic chemistry to denote absolute configuration of functional groups, known as Cahn–Ingold–Prelog priority rules. The R/S convention assigns priorities to substituents on a chiral center based on their atomic number. The highest priority group is assigned to the atom with the highest atomic number, and the lowest priority group is assigned to the atom with the lowest atomic number. The molecule is then oriented so that the lowest priority group points away from the viewer, and the remaining three groups are arranged in order of decreasing priority around the chiral center. If this arrangement is clockwise, it is assigned an R configuration; if it is counterclockwise, it is assigned an S configuration. In contrast, steroid nomenclature uses α and β to denote stereochemistry at chiral centers. The α and β designations are based on the orientation of substituents relative to each other in a specific ring system. In general, α refers to a substituent that is oriented towards the plane of the ring system, while β refers to a substituent that is oriented away from the plane of the ring system. In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as solid wedges. The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids that is used regardless of whether an atom is present in the steroid in question. This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta) which designates unsaturation, for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ4-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ4-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ4-" or "4-ene" means the double bond between positions 4 and 5. The saturation of carbons of a parent steroid can be done by adding "dihydro-" prefix, i.e., a saturation of carbons 4 and 5 of testosterone with two hydrogen atoms is 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. The Δ5-steroids are those with a double bond between carbons 5 and 6 and the Δ4 steroids are those with a double bond between carbons 4 and 5. [sic] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision). This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa. The term "11-oxygenated" refers to the presence of an oxygen atom as an oxo (=O) or hydroxy (-OH) substituent at carbon 11. "Oxygenated" is consistently used within the chemistry of the steroids since the 1950s. Some studies use the term "11-oxyandrogens" as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11. However, in chemical nomenclature, the prefix "oxy" is associated with ether functional groups, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (R-O-R), therefore, using "oxy" within the name of a steroid class may be misleading. One can find clear examples of "oxygenated" to refer to a broad class of organic molecules containing a variety of oxygen containing functional groups in other domains of organic chemistry, and it is appropriate to use this convention. == Species distribution ==

Steroids are present across all domains of life, including bacteria, archaea, and eukaryotes. In eukaryotes, steroids are particularly abundant in fungi, plants, and animals. Eukaryotic Eukaryotic cells, encompassing animals, plants, fungi, and protists, are characterized by their complex cellular structures, including a true nucleus and membrane-bound organelles. Sterols, a subgroup of steroids, play crucial roles in maintaining membrane fluidity, supporting cell signaling, and enhancing stress tolerance. These compounds are integral to eukaryotic membranes, where they contribute to membrane integrity and functionality. During eukaryogenesis—the evolutionary process that gave rise to modern eukaryotic cells—steroids likely facilitated the endosymbiotic acquisition of mitochondria. Prokaryotic Although sterol biosynthesis is rare in prokaryotes, certain bacteria, including Methylococcus capsulatus, specific methanotrophs, myxobacteria, and the planctomycete Gemmata obscuriglobus, are capable of producing sterols. In G. obscuriglobus, sterols are essential for cell viability, but their roles in other bacteria remain poorly understood. Prokaryotic sterol synthesis involves the tetracyclic steroid framework, as found in myxobacteria, as well as hopanoids, pentacyclic lipids that regulate bacterial membrane functions. These sterol biosynthetic pathways may have originated in bacteria or been transferred from eukaryotes. Sterol synthesis depends on two key enzymes: squalene monooxygenase and oxidosqualene cyclase. Phylogenetic analyses of oxidosqualene cyclase (Osc) suggest that some bacterial Osc genes may have been acquired via horizontal gene transfer from eukaryotes, as certain bacterial Osc proteins closely resemble their eukaryotic homologs. Fungi can alter their ergosterol content (e.g. through loss of function mutations in the enzymes ERG3 or ERG6, inducing depletion of ergosterol, or mutations that decrease the ergosterol content) to develop resistance to drugs that target ergosterol. All mushrooms contain large quantities of ergosterol, in the range of tens to hundreds of milligrams per 100 grams of dry weight. and Melanthiaceae (specially the genus Veratrum), cardiac glycosides, the phytosterols and the brassinosteroids (which include several plant hormones). Animal Animal steroids include compounds of vertebrate and insect origin, the latter including ecdysteroids such as ecdysterone (controlling molting in some species). Vertebrate examples include the steroid hormones and cholesterol; the latter is a structural component of cell membranes that helps determine the fluidity of cell membranes and is a principal constituent of plaque (implicated in atherosclerosis ). Steroid hormones include: • Sex hormones, which influence sex differences and support puberty and reproduction. These include androgens, estrogens, and progestogens. • Corticosteroids, including most synthetic steroid drugs, with natural product classes the glucocorticoids (which regulate many aspects of metabolism and immune function) and the mineralocorticoids (which help maintain blood volume and control renal excretion of electrolytes) • Anabolic steroids, natural and synthetic, which interact with androgen receptors to increase muscle and bone synthesis. In popular use, the term "steroids" often refers to anabolic steroids. == Types ==

By function Steroids function in a wide variety of physiological processes, including metabolism, inflammation regulation, immune response, reproduction, and cellular signaling. Their effects are mediated primarily through binding to specific intracellular receptors, which then influence gene transcription and protein synthesis. Steroids can be broadly classified by their primary biological roles, with the major classes of steroid hormones illustrated below, along with prominent members and examples of their functions. • Corticosteroids: Produced by the adrenal cortex, these hormones regulate stress responses, electrolyte balance, and immune function. • Glucocorticoids: Involved in carbohydrate metabolism, anti-inflammatory actions, and immunosuppression. • Cortisol, which increases blood glucose levels during stress and suppresses immune activity to prevent excessive inflammation. • Mineralocorticoids: Control salt and water balance to maintain blood pressure. • Aldosterone, which promotes sodium reabsorption in the kidneys, thereby regulating extracellular fluid volume. • Sex steroids: Derived mainly from the gonads and adrenal glands, these influence sexual development, reproduction, and secondary sexual characteristics. • Progestogens: Essential for preparing the reproductive system for pregnancy. • Progesterone, which supports implantation and sustains early pregnancy by maintaining the uterine lining. • Androgens: Promote male reproductive development and maintenance. • Testosterone, which drives spermatogenesis and the growth of male secondary sex characteristics such as muscle mass and facial hair. • Estrogens: Key to female reproductive cycles and skeletal health. • Estradiol, which stimulates endometrial proliferation during the menstrual cycle and contributes to bone density. Other steroids extend beyond hormonal roles and include compounds involved in neuroprotection, digestion, and neuromuscular activity: • Neurosteroids such as dehydroepiandrosterone (DHEA) and allopregnanolone, which modulate neurotransmitter receptors in the brain. • Bile acids such as taurocholic acid, which aid in lipid digestion and absorption in the intestine. • Aminosteroid neuromuscular blocking agents (synthetic), such as pancuronium bromide, used in anesthesia to induce muscle relaxation. • Steroidal antiandrogens (synthetic), such as cyproterone acetate, which block androgen receptors in hormone therapy. • Steroidogenesis inhibitors (exogenous), such as alfatradiol, which suppress steroid synthesis for therapeutic purposes. • Membrane sterols such as cholesterol (essential for cell membrane fluidity), ergosterol (a fungal membrane component), and various phytosterols (plant-derived sterols with cholesterol-lowering effects). • Toxins such as steroidal saponins (plant defense compounds) and cardenolides/cardiac glycosides (which affect heart function). Steroids with an open-ring structure, known as secosteroids, include: • Vitamin D forms such as ergocalciferol (from plant sources), cholecalciferol (from animal sources and sunlight), and calcitriol (the active form that regulates calcium homeostasis). By structure Intact ring system Steroids can be classified based on their chemical composition. One example of how MeSH performs this classification is available at the Wikipedia MeSH catalog. Examples of this classification include: (vitamin D), an example of a 9,10-secosteroid , an example of a complex C-nor-D-homosteroid In biology, it is common to name the above steroid classes by the number of carbon atoms present when referring to hormones: C18-steroids for the estranes (mostly estrogens), C19-steroids for the androstanes (mostly androgens), and C21-steroids for the pregnanes (mostly corticosteroids). The classification "17-ketosteroid" is also important in medicine. The gonane (steroid nucleus) is the parent 17-carbon tetracyclic hydrocarbon molecule with no alkyl sidechains. Cleaved, contracted, and expanded rings Secosteroids (Latin seco, "to cut") are a subclass of steroidal compounds resulting, biosynthetically or conceptually, from scission (cleavage) of parent steroid rings (generally one of the four). Major secosteroid subclasses are defined by the steroid carbon atoms where this scission has taken place. For instance, the prototypical secosteroid cholecalciferol, vitamin D3 (shown), is in the 9,10-secosteroid subclass and derives from the cleavage of carbon atoms C-9 and C-10 of the steroid B-ring; 5,6-secosteroids and 13,14-steroids are similar. Norsteroids (nor-, L. norma; "normal" in chemistry, indicating carbon removal) and homosteroids (homo-, Greek homos; "same", indicating carbon addition) are structural subclasses of steroids formed from biosynthetic steps. The former involves enzymic ring expansion-contraction reactions, and the latter is accomplished (biomimetically) or (more frequently) through ring closures of acyclic precursors with more (or fewer) ring atoms than the parent steroid framework. Combinations of these ring alterations are known in nature. For instance, ewes who graze on corn lily ingest cyclopamine (shown) and veratramine, two of a sub-family of steroids where the C- and D-rings are contracted and expanded respectively via a biosynthetic migration of the original C-13 atom. Ingestion of these C-nor-D-homosteroids results in birth defects in lambs: cyclopia from cyclopamine and leg deformity from veratramine. A further C-nor-D-homosteroid (nakiterpiosin) is excreted by Okinawan cyanobacteriosponges. e.g., Terpios hoshinota, leading to coral mortality from black coral disease. Nakiterpiosin-type steroids are active against the signaling pathway involving the smoothened and hedgehog proteins, a pathway which is hyperactive in a number of cancers. == Biological significance ==

Steroids and their metabolites often function as signalling molecules (the most notable examples are steroid hormones), and steroids and phospholipids are components of cell membranes. Steroids such as cholesterol decrease membrane fluidity. Similar to lipids, steroids are highly concentrated energy stores. However, they are not typically sources of energy; in mammals, they are normally metabolized and excreted. Steroids play critical roles in a number of disorders, including malignancies like prostate cancer, where steroid production inside and outside the tumour promotes cancer cell aggressiveness. == Biosynthesis and metabolism ==

(PP or IPP) and dimethylallyl pyrophosphate (DMAPP) form geranyl pyrophosphate (GPP), squalene and lanosterol (which can be converted into other steroids). The hundreds of steroids found in animals, fungi, and plants are made from lanosterol (in animals and fungi; see examples above) or cycloartenol (in other eukaryotes). Both lanosterol and cycloartenol derive from cyclization of the triterpenoid squalene. In subsequent steps DMAPP and IPP conjugate to form farnesyl diphosphate (FPP), which further conjugates with each other to form the linear triterpenoid squalene. Squalene biosynthesis is catalyzed by squalene synthase, which belongs to the squalene/phytoene synthase family. Subsequent epoxidation and cyclization of squalene generate lanosterol, which is the starting point for additional modifications into other steroids (steroidogenesis). In other eukaryotes, the cyclization product of epoxidized squalene (oxidosqualene) is cycloartenol. Mevalonate pathway The mevalonate pathway (also called HMG-CoA reductase pathway) begins with acetyl-CoA and ends with dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate (IPP). DMAPP and IPP donate isoprene units, which are assembled and modified to form terpenes and isoprenoids (a large class of lipids, which include the carotenoids and form the largest class of plant natural products). Here, the activated isoprene units are joined to make squalene and folded into a set of rings to make lanosterol. Lanosterol can then be converted into other steroids, such as cholesterol and ergosterol. Two classes of drugs target the mevalonate pathway: statins (like rosuvastatin), which are used to reduce elevated cholesterol levels, and bisphosphonates (like zoledronate), which are used to treat a number of bone-degenerative diseases. Steroidogenesis pathways. Changes in molecular structure from a precursor are highlighted in white. Steroidogenesis is the biological process by which steroids are generated from cholesterol and changed into other steroids. The pathways of steroidogenesis differ among species. The major classes of steroid hormones, as noted above (with their prominent members and functions), are the progestogens, corticosteroids (corticoids), androgens, and estrogens. • Cortisol, corticosterone, aldosterone are produced in the adrenal cortex. (some testosterone may also be produced in the adrenal cortex). • Estradiol is converted from testosterone directly (in males), or via the primary pathway DHEA – androstenedione – estrone and secondarily via testosterone (in females). During diseases pathways otherwise not significant in healthy humans can become utilized. For example, in one form of congenital adrenal hyperplasia a deficiency in the 21-hydroxylase enzymatic pathway leads to an excess of 17α-Hydroxyprogesterone (17-OHP) – this pathological excess of 17-OHP in turn may be converted to dihydrotestosterone (DHT, a potent androgen) through among others 17,20 Lyase (a member of the cytochrome P450 family of enzymes), 5α-Reductase and 3α-Hydroxysteroid dehydrogenase. == Catabolism and excretion ==

Steroids are primarily oxidized by cytochrome P450 oxidase enzymes, such as CYP3A4. These reactions introduce oxygen into the steroid ring, allowing the cholesterol to be broken up by other enzymes into bile acids. These acids can then be eliminated by secretion from the liver in bile. The expression of the oxidase gene can be upregulated by the steroid sensor PXR when there is a high blood concentration of steroids. Steroid hormones, lacking the side chain of cholesterol and bile acids, are typically hydroxylated at various ring positions or oxidized at the 17 position, conjugated with sulfate or glucuronic acid and excreted in the urine. == Isolation, structure determination, and methods of analysis ==

Steroid isolation, depending on context, is the isolation of chemical matter required for chemical structure elucidation, derivitzation or degradation chemistry, biological testing, and other research needs (generally milligrams to grams, but often more The methods of isolation to achieve the two scales of product are distinct, but include extraction, precipitation, adsorption, chromatography, and crystallization. In both cases, the isolated substance is purified to chemical homogeneity; combined separation and analytical methods, such as LC-MS, are chosen to be "orthogonal"—achieving their separations based on distinct modes of interaction between substance and isolating matrix—to detect a single species in the pure sample. Structure determination refers to the methods to determine the chemical structure of an isolated pure steroid, using an evolving array of chemical and physical methods which have included NMR and small-molecule crystallography. Methods of analysis overlap both of the above areas, emphasizing analytical methods to determining if a steroid is present in a mixture and determining its quantity. == Chemical synthesis ==

Microbial catabolism of phytosterol side chains yields C-19 steroids, C-22 steroids, and 17-ketosteroids (i.e. precursors to adrenocortical hormones and contraceptives). The addition and modification of functional groups is key when producing the wide variety of medications available within this chemical classification. These modifications are performed using conventional organic synthesis and/or biotransformation techniques. Precursors Semisynthesis The semisynthesis of steroids often begins from precursors such as cholesterol, The efforts of Syntex, a company involved in the Mexican barbasco trade, used Dioscorea mexicana to produce the sapogenin diosgenin in the early days of the synthetic steroid pharmaceutical industry. Total synthesis Some steroidal hormones are economically obtained only by total synthesis from petrochemicals (e.g. 13-alkyl steroids). For example, the pharmaceutical Norgestrel begins from methoxy-1-tetralone, a petrochemical derived from phenol. == Research awards ==

A number of Nobel Prizes have been awarded for steroid research, including: • 1927 (Chemistry) Heinrich Otto Wieland — Constitution of bile acids and sterols and their connection to vitamins • 1928 (Chemistry) Adolf Otto Reinhold Windaus — Constitution of sterols and their connection to vitamins • 1939 (Chemistry) Adolf Butenandt and Leopold Ružička — Isolation and structural studies of steroid sex hormones, and related studies on higher terpenes • 1950 (Physiology or Medicine) Edward Calvin Kendall, Tadeus Reichstein, and Philip Hench — Structure and biological effects of adrenal hormones • 1965 (Chemistry) Robert Burns Woodward — In part, for the synthesis of cholesterol, cortisone, and lanosterol • 1969 (Chemistry) Derek Barton and Odd Hassel — Development of the concept of conformation in chemistry, emphasizing the steroid nucleus • 1975 (Chemistry) Vladimir Prelog — In part, for developing methods to determine the stereochemical course of cholesterol biosynthesis from mevalonic acid via squalene == See also ==