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 5βcholestan-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
5β-cholestan-3β-ol (coprostanol)
5α-cholestanol-3b-ol
(cholestanol)
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 (βconfiguration), 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 Acids
The 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 (ratelimiting step in bile acid synthesis), and cholesterol does the
opposite. This is why chenodeoxycholic acid is used to treat gallstone.
Chenodeoxycholic acid
Cholic acid
Taurocholic acid
Ergosterol
Ergosterol (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 lifethreatening 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 22carbon 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
Dioscorea ‫نبات اليام‬
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, 19nortestosterone derivatives (estranges), and norgestrel and related
compounds in the gonane series
progesterone
norgestrel
17-acetoxyprogesterone
levonorgestrel
19-nortestosterone
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.
Estrogen
The 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.
estradiol (E2),
estriol
(E3).
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 ( ‫ (المنشطات‬and
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
Testosterone
Testosterone 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.
Dihydrotestosterone
In 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