Steroids

Steroids form a group of structurally related compounds, which are widely distributed in animals and plants included in the steroids are the sterols (from which the name steroid is derived e.g. Vitamin D, the bile acids, number of sex hormones, the adrenal cortex hormone, some carcinogenic hydrocarbons, certain sapogenins. The structures of steroids are based on the 1, 2-cyclopentenophenanthrene skeleton. Sterols occur in animal and Plant oils and fats, They are crystalline compound and contain an alcoholic group; they occur free or as esters of the higher fatty acids, and are isolated from the unsaponifiable portion of oils and fats

Cholesterol, 5α-cholestan-3β-ol (cholestanol) and 5β-cholestan-3β-ol (coprostanol) are the animal sterols; ergosterol and stigmasterol are the plant sterols. The steroids that are obtained from animal sources are often referred to as Zoosterols and those obtained from plant sources as the phytosterols. A third group of sterols obtained from yeast and fungi are referred to as the mycosterols

Cholesterol

3β)-cholest-5-en-3-ol

5α-cholestanol-3b-ol (cholestanol)

5β-cholestan-3β-ol (coprostanol)

ergosterol stigmasterol

Nomenclature of steroids Steroids are numbered as shown in the figure followed.

When some of the carbon atoms in the figure are missing, the numbering of the remainder remains unchanged. Solid lines (preferably thickened) denote groups above the plane of the nucleus (β- configuration), and dotted or broken lines denote groups below the plane (α-configuration), if the configuration of the substituent is unknown, its bond to the nucleus is drawn as a wavy line and this is indicated by ε in the name. Wherever possible, the name of the steroid should specify stereochemical configuration.

Steroid important parent hydrocarbons

5(α or β-)gonane 5(α or β)oestrane

When a methylene group is missing from the side-chain, this is indicated by the prefix 'nor' preceded by the number of the carbon atom, which has disappeared. When a ring has been contracted or enlarged, this is indicated by prefixes 'nor' and 'homo' respectively, preceded by a small capital letter indicating the ring affected. The prefix 'nor' is also used to indicate the loss of an angular methyl group, and in this case is preceded by the number designating that methyl group: 18-nor and 19-nor. When ring-fission has occurred with addition of a hydrogen atom to each new terminal group, this is indicated by the numbers showing the position of the bond broken, followed by the prefix 'seco'. The prefix cyclo', preceded by the numbers of the positions concerned, is used to indicate a three-membered ring.

5β-Cholane

Cholesterol This is the sterol of' the higher animals, occurring free or as fatty esters in all animals in the brain and spinal cord. Cholesterol was first isolated from human gallstone. The main sources of cholesterol are the fish-liver oils. Cholesterol is a white crystalline solid, which is optically active. It is an essential structural component of animal cell membrane that is required to establish proper membrane permeability and fluidity. Cholesterol is thus considered within the class of lipid molecules. In addition to its importance within cells, cholesterol also serves as a precursor for the biosynthesis of steroid hormones, bile acids, and vitamin D. Cholesterol is the principal sterol synthesized by animals, all cells; in vertebrates the liver typically produces greater amounts than other cells. It is almost completely absent among prokaryotes (i.e., bacteria), although there are some exceptions such as Mycoplasma, which require cholesterol for growth. The structure of cholesterol was elucidated only after a tremendous amount of work was done particularly by Wieland, Windaus and their coworkers (1903-1932)

Colour Reactions of Cholesterol (i)The Salkowaski reaction (1908): When concentrated sulphuric acid is added to cholesterol in chloroform, a red colour is produced in the chloroform layer. (ii)The Liebermann- Burchard reaction (1885, 1890): A greenish colour is developed when the solution of cholesterol in chloroform is treated with concentrated sulphuric acid and acetic anhydride. When an ethanolic solution of cholesterol is treated with an ethanolic solution of digitonin, a large white precipitate of cholesterol digitonide is formed, a complex containing one molecule of cholesterol and one of digitonin, from which component may be recovered by dissolving the complex in pyridine.

Stigmasterol This is best obtained from soya bean oil. Since stigmasterol forms acetate, a hydroxyl group is therefore present. Stigmasterol also forms a tetra bromide; thus it contains two double bonds. Hydrogenation of stigmasterol produces stigmastanol, and since the acetate of this gives the acetate of 3β-hydroxynor-5α-cholanic acid on oxidation with chromium trioxide, it follows that stigmastanol differs from 5α-cholastan-3β-ol only in the nature of the side-chain. Ozonolysis of stigmasterol gives, among other products, ethyl isopropyl acetaldehyde. This suggests that the side-chain is as shown in the figure, with a double bond at 22, 23 as well as the presence of a C24 ethyl group. Stigmasterol is used as a precursor in the manufacture of semi synthetic progesterone, a valuable human hormone that plays an important physiological role in the regulatory and tissue rebuilding mechanisms related to estrogen effects, as well as acting as an intermediate in the biosynthesis of androgens , estrogens, and corticoids. It is also used as the precursor of vitamin D3vitamin . The Upjohn company used stigmasterol as the starting raw material for the synthesis of cortisone.

β-Sitotsterol (22, 23-dihydrostigmasterol)Sitosterols are white, waxy powders with a characteristic odor. They are hydrophobic

and soluble in alcohols. β-Sitotsterol lowers plasma concentration of Low Density Lipoprotein (LDL), has no effect on Very Low Density Lipoprotein (VLDL). The sterol is believed to lower plasma levels of cholesterol by interfering with its absorption. Dose: 6 gm (with coffee, tea or milk) taken 30 minutes before meals and at bed time. The unwanted effects include laxative nausea and vomiting. It has a double bond at 5(6)-position, but no double bond at 22 (23)-positions. Thus it is a 22(23)- dihydrostigmasterol. It is found in pecans, avocados, pumpkin seeds), cashew fruit, rice bran, wheat germ, corn oils, soybeans and dandelion coffee. In Europe, β-sitosterol is used in herbal therapy, especially for benign prostatic hyperplasia .

Bile AcidsThe bile acids are produced from metabolism of cholesterol in liver. Structurally

they correspond to cholane. The principal primary bile acids are cholic acids (3α, 7α, 12α-trihydroxy-5β-cholan-24-oic acid) and chenodeoxycholic acid (3α, 7α, dihydroxy-5β-cholan-24-oic acid). In the liver they are conjugated with glycine (H2NCH2COOH) or taurine (H2NCH2CH2SO3H) to give the glycolic acid , taurocholic acid , glycochenodeoxycholic and taurochenodeoxycholic acid, before secreted in the bile. Cholic acid downregulates cholesterol-7-α-hydroxylase (rate-limiting step in bile acid synthesis), and cholesterol does the opposite. This is why chenodeoxycholic acid is used to treat gallstone.

Chenodeoxycholic acidCholic acid

Taurocholic acid

ErgosterolErgosterol (ergosta-5,7,22-trien-3β-ol) is a sterol found in fungi, and named for ergo,

a common name for the members of the fungal genus Claviceps from which ergosterol was first isolated. Ergosterol does not occur in plant or animal cells. It is a component of yeast and fungal cell membranes, serving the same function cholestreol serves in animal cells. Ergosterol is occasionally reported analytically to occur in grasses such as rye), and in plant flowers such as hops. However, such detection is usually assumed to be detection of fungal growth upon (and sometimes contamination of) the plant, as fungi form an integral part of the grass decay system. This ergosterol assay technique may thus be used to assay grass, grain, and feed systems for fungal content. Since ergosterol is the provitamin of vitamin D2, the ultaviolet (UV) radiation of fungus-bearing grass materials can result in vitamin D2 production, but this is production of a form of vitamin D from fungus ergosterol (much as in UV radiation of yeasts and mushrooms) and is not true vitamin D production by the plant itself from UV light, a process that cannot happen

Because ergosterol is present in cell membranes of fungi, yet absent in those of animals, it is a useful target for antifungal drug. Ergosterol is also present in the cell membranes of some protists, such as trypanosomes. This is the basis for the use of some antifungals against West African sleeping sickness. Amphotericin B, an antifungal drug, targets ergosterol. It binds physically to ergosterol within the membrane, thus creating a polar pore in fungal membranes. This causes ions (predominantly K and Na) and other molecules to leak out, which will kill the cell. Amphotericin B has been replaced by safer agents in most circumstances, but is still used, despite its side effects, for life-threatening fungal or protozoan infections. Miconazole, itraconazole, and clotrimazole work in a different way, inhibiting synthesis of ergosterol from lanosterol. Ergosterol is a smaller molecule than lanosterol; it is synthesized by combining two molecules of farnesyl pyrophosphate, a 15-carbon-long terpenoid, into lanosterol, which has 30 carbons. Then, two methyl groups are removed, making ergosterol. The "azole" class of antifungal agents inhibit the enzyme that performs these demethylation steps in the biosynthetic pathway between lanosterol and ergosterol.

Diosgenin

Sapogenins are aglycones of glycosidic saponins; the latter are so called because they have the property of forming soapy lather in water. The steroidal sapogenin have 27 carbons and are internal ketals of 16, 26-dihydroxy-22-keto-steroids, illustrated as Sapogenin shown next slide.

saponin

Sapogenins have two additional rings, which are heterocyclic; ring E is five-membered and corresponds to tetrahydro furan and ring F is six membered and relates to tetrahydro pyran. The rings are joined at 22-carbon in spiroketal fashion, and the parent structure is therefore called spirostan. The stereochemical problems connected with the spiroketal system and rings E and F are complex.

Diosgenin, chemically named as (25R)-spirost-5-en-3β-ol, is prominent among the sapogenins used in steroid industry. The sources are yams of different species of Dioscorea Diosgenin is submitted to Marker degradation to obtain pregnenolone acetate. When diosgenin, as the acetate, is heated with acetic anhydride at 200°C, there occurs rupture of ring F with the introduction of 20, 22-double bond to give pseudosapogenin diacetate. In a modified procedure, diosgenin acetate is refluxed with acetic anhydride-pyridine in the presence of catalyst like methylamine hydrochloride. The pseudodiosgenin diacetate on chromic acid oxidation forms the keto ester diacetate, which on boiling with acetic acid gives 16-dehydropregnenolone acetate. The latter can be selectively reduced catalytically to afford pregnenolone acetate (20-oxo-5-pregnen3β-yl- acetate. Pregnenolone derived from the ester is directly convertible to progesterone

اليام Dioscoreaنبات

Sex Steroids

Sex steroids: steroid hormones that affect sexual development and reproductive functioning. There are three types of sex steroids in humans: progestins, androgens, and estrogens.

Progestins include the naturally occurring hormone progesterone, 17-acetoxyprogesterone derivatives in the pregnane series, 19-nortestosterone derivatives (estranges), and norgestrel and related compounds in the gonane series

progesterone 17-acetoxyprogesterone 19-nortestosterone

norgestrellevonorgestrel

Progesterone

Progesterone is produced in the ovaries (by the corpus luteum ), the adrenal glands (near the kidney), and during pregnancy, in the

placenta . Progesterone is also stored in adipose (fat) tissue . In humans, increasing amounts of progesterone are produced during pregnancy. An additional source of progesterone is milk products. After consumption of milk products the level of bioavailable progesterone goes up. Progesterone is used as a part of hormone replacement therapy in women who have passed menopause (the change of life) and have not had a hysterectomy (surgery to remove the uterus). Hormone replacement therapy usually includes estrogen, which is used to treat symptoms of menopause and reduce the risk of developing certain diseases. However, estrogen can also cause abnormal thickening of the lining of the uterus and increase the risk of developing uterine cancer. Progesterone helps to prevent this thickening and decreases the risk of developing uterine cancer.

EstrogenThe three major naturally occurring estrogens in women are estrone

(E1), estradiol (E2), and estriol (E3). Estradiol is the predominant estrogen during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity. During menopause, estrone is the predominant circulating estrogen and during pregnancy estriol is the predominant circulating estrogen in terms of serum levels. Though estriol is the most plentiful of the three estrogens it is also the weakest, whereas estradiol is the strongest with a potency of approximately 80 times that of estriol. Thus, estradiol is the most important estrogen in non-pregnant females who are between the menarche and menopause stages of life. However, during pregnancy this role shifts to estriol, and in postmenopausal women estrone becomes the primary form of estrogen in the body. All of the different forms of estrogen are synthesized from androgens, specifically testosterone and androstenedione, by the enzyme aromatase.

estriol (E3) . estradiol (E2) ,

estrone (E1) ,

Androgens

Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes the activity of the accessory male sex organs and development of male secondary sex characteristics. Androgens were first discovered in 1936. Androgens are also the original anabolic steroids ( (المنشطات and the precursor of all estrogens. The primary and most well-known androgen is testosterone. Dihydrotestosterone (DHT) and androstenedione are less known generally, but are of equal importance in male development. Later in life DHT contributes to male balding, prostate growth and sebaceous gland activity

testosterone Dihydrotestosterone

androstenedione

TestosteroneTestosterone is a steroid hormone from the androgen group and is found in mammals,

reptiles, birds, and other vertebrates. In mammals, testosterone is secreted primarily in the testicles of males and the ovaries of females, although small amounts are also secreted by the adrenal glands. It is the principal male sex hormone and an anabolic steroid.

In men, testosterone plays a key role in the development of male reproductive tissues such as the prostate as well as promoting secondary sexual characteristics such as increased muscle, bone mass, and the growth of body hair . In addition, testosterone is essential for health and well-being as well as the prevention of osteoporosis.

On average, in adult human males, the plasma concentration of testosterone is about 7–8 times as great as the concentration in adult human females plasma, but, as the metabolic consumption of testosterone in males is greater, the daily production is about 20 times greater in men. Females are also more sensitive to the hormone. Testosterone is observed in most vertebrates. Fish make a slightly different form called 11-ketotestosterone. Its counterpart in insects is ecdysone. These ubiquitous steroids suggest that sex hormones have an ancient evolutionary history.

DihydrotestosteroneIn men, approximately 5% of testosterone undergoes 5α-reduction to form the more potent

androgen, dihydrotestosterone. DHT has two to three times greater androgen receptor affinity than testosterone and has 15-30 times greater affinity than adrenal androgens. The dissociation rate of testosterone from the receptor is five-fold faster than DHT. During embryogenesis DHT has an essential role in the formation of the male external genitalia, while in the adult DHT acts as the primary androgen in the prostate and in hair follicles.

An example illustrating the significance of DHT for the development of secondary sex characteristics is congenital 5-α-reductase (5-AR) deficiency. This gene lesion can result in pseudohermaphroditism. This condition typically presents with underdeveloped male genitalia and prostate. These individuals are often raised as girls due to their lack of conspicuous male genitalia. In the onset of puberty, although their DHT levels remain very low, their testosterone levels elevate normally. Their musculature develops like that of other male adults. After puberty, men with this condition have a large deficiency of pubic and body hair, and no incidence of male pattern baldness.

Unlike other androgens such as testosterone, DHT cannot be converted by the enzyme aromatase to estradiol. Therefore, it is frequently used in research settings to distinguish between the effects of testosterone caused by binding to the androgen receptor and those caused by testosterone's conversion to estradiol and subsequent binding to estrogen receptors.

Androstenedione

Androstenedione is the common precursor of male and female sex hormones. Some androstenedione is also secreted into the plasma, and may be converted in peripheral tissues to testosterone and estrogens. In premenopausal women, the adrenal glands and ovaries each produce about half of the total androstenedione (about 3 mg/day). After menopause, androstenedione production is about halved, due primarily to the reduction of the steroid secreted by the ovary. Nevertheless, androstenedione is the principal steroid produced by the postmenopausal ovary. In females, androstenedione is released into the blood by theca cells. The function of this is to provide androstenedione substrate for estrogen production in granulosa cells, since these cells lack 17,20 lyase required for androstenedione. Likewise, theca cells lack the enzyme aromatase required to make estrogens themselves. Thus, theca cells and granulosa cells work together to form estrogen