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 mevalonate pathway main article: 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 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 human steroidogenesis, with the major classes of steroid hormones, individual steroids and enzymatic 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. human steroidogenesis of these classes occurs in a number of locations: progestogens are the precursors of all other human steroids, and all human tissues which produce steroids must first convert cholesterol to pregnenolone. this conversion is the rate-limiting step of steroid synthesis, which occurs inside the mitochondrion of the respective tissue. cortisol, corticosterone, aldosterone, and testosterone are produced in the adrenal cortex. estradiol, estrone and progesterone are made primarily in the ovary, estriol in placenta during pregnancy, and testosterone primarily in the testes (some testosterone is also 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). stromal cells have been shown to produce steroids in response to signaling produced by androgen-starved prostate cancer cells. some neurons and glia in the central nervous system (cns) express the enzymes required for the local synthesis of pregnenolone, progesterone, dhea and dheas, de novo or from peripheral sources. production rates, secretion rates, clearance rates, and blood levels of major sex hormones sex sex hormone reproductivephase bloodproduction rate gonadalsecretion rate metabolicclearance rate reference range (serum levels) si units non-si units men androstenedione – 2.8 mg/day 1.6 mg/day 2200 l/day 2.8–7.3 nmol/l 80–210 ng/dl testosterone – 6.5 mg/day 6.2 mg/day 950 l/day 6.9–34.7 nmol/l 200–1000 ng/dl estrone – 150 μg/day 110 μg/day 2050 l/day 37–250 pmol/l 10–70 pg/ml estradiol – 60 μg/day 50 μg/day 1600 l/day <37–210 pmol/l 10–57 pg/ml estrone sulfate – 80 μg/day insignificant 167 l/day 600–2500 pmol/l 200–900 pg/ml women androstenedione – 3.2 mg/day 2.8 mg/day 2000 l/day 3.1–12.2 nmol/l 89–350 ng/dl testosterone – 190 μg/day 60 μg/day 500 l/day 0.7–2.8 nmol/l 20–81 ng/dl estrone follicular phase 110 μg/day 80 μg/day 2200 l/day 110–400 pmol/l 30–110 pg/ml luteal phase 260 μg/day 150 μg/day 2200 l/day 310–660 pmol/l 80–180 pg/ml postmenopause 40 μg/day insignificant 1610 l/day 22–230 pmol/l 6–60 pg/ml estradiol follicular phase 90 μg/day 80 μg/day 1200 l/day <37–360 pmol/l 10–98 pg/ml luteal phase 250 μg/day 240 μg/day 1200 l/day 699–1250 pmol/l 190–341 pg/ml postmenopause 6 μg/day insignificant 910 l/day <37–140 pmol/l 10–38 pg/ml estrone sulfate follicular phase 100 μg/day insignificant 146 l/day 700–3600 pmol/l 250–1300 pg/ml luteal phase 180 μg/day insignificant 146 l/day 1100–7300 pmol/l 400–2600 pg/ml progesterone follicular phase 2 mg/day 1.7 mg/day 2100 l/day 0.3–3 nmol/l 0.1–0.9 ng/ml luteal phase 25 mg/day 24 mg/day 2100 l/day 19–45 nmol/l 6–14 ng/ml notes and sources notes: "the concentration of a steroid in the circulation is determined by the rate at which it is secreted from glands, the rate of metabolism of precursor or prehormones into the steroid, and the rate at which it is extracted by tissues and metabolized. the secretion rate of a steroid refers to the total secretion of the compound from a gland per unit time. secretion rates have been assessed by sampling the venous effluent from a gland over time and subtracting out the arterial and peripheral venous hormone concentration. the metabolic clearance rate of a steroid is defined as the volume of blood that has been completely cleared of the hormone per unit time. the production rate of a steroid hormone refers to entry into the blood of the compound from all possible sources, including secretion from glands and conversion of prohormones into the steroid of interest. at steady state, the amount of hormone entering the blood from all sources will be equal to the rate at which it is being cleared (metabolic clearance rate) multiplied by blood concentration (production rate = metabolic clearance rate × concentration). if there is little contribution of prohormone metabolism to the circulating pool of steroid, then the production rate will approximate the secretion rate." sources: see template. alternative pathways in plants and bacteria, the non-mevalonate pathway (mep pathway) uses pyruvate and glyceraldehyde 3-phosphate as substrates to produce ipp and dmapp. 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 or the isolation of "analytical quantities" of the substance of interest (where the focus is on identifying and quantifying the substance (for example, in biological tissue or fluid). the amount isolated depends on the analytical method, but is generally less than one microgram. 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.: 10–19 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. semisynthesis the semisynthesis of steroids often begins from precursors such as cholesterol, phytosterols, or sapogenins. 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