Steroid Hormones
Introduction
Important Note: Be Sure To See Why Show-Tech Is The Best Choice For Alternative Steroid Supplements Around! With the exception of retinoic acid,
the steroid hormones are all derived from cholesterol. Moreover, with the
exception of vitamin D, they
all contain the same cyclopentanophenanthrene ring and atomic numbering system
as cholesterol. The conversion of C27 cholesterol to the 18-, 19-,
and 21-carbon steroid hormones (designated by the nomenclature C with a
subscript number indicating the number of carbon atoms, e.g. C19 for
androstanes) involves the rate-limiting, irreversible cleavage of a 6-carbon
residue from cholesterol, producing pregnenolone
(C21) plus isocaproaldehyde. Common names of the steroid
hormones are widely recognized, but systematic nomenclature is gaining
acceptance and familiarity with both nomenclatures is increasingly important.
Steroids with 21 carbon atoms are known systematically as pregnanes, whereas those containing 19 and 18 carbon atoms
are known as androstanes and estranes, respectively. The important mammalian steroid
hormones are shown below along with the structure of the precursor, pregneolone.
Retinoic acid and vitamin D are not derived from pregnenolone, but from vitamin
A and cholesterol respectively.
 |
Pregnenolone: produced directly from cholesterol, the
precusor molecule for all C18, C19 and
C21 steroids |
 |
Progesterone: a progestin, produced directly from
pregnenolone and secreted from the corpus luteum, responsible for
changes associated with luteral phase of the menstrual cycle,
differentiation factor for mammary glands |
 |
Aldosterone:
the principal mineralocorticoid, produced from progesterone in the zona
glomerulosa of adrenal cortex, raises blood pressure and fluid volume,
increases Na+ uptake |
 |
Testosterone: an androgen, male sex hormone
synthesized in the testes, responsible for secondary male sex
characteristics, produced from progesterone |
 |
Estradiol:
an estrogen, principal female sex hormone, produced in the ovary,
responsible for secondary female sex characteristics |
 |
Cortisol:
dominant glucocorticoid in humans, synthesized from progesterone in the
zona fasciculata of the adrenal cortex, involved in stress
adaptation, elevates blood pressure and Na+ uptake, numerous
effects on the immune system |
All the steroid hormones exert their action by passing through the plasma
membrane and binding to intracellular receptors. The mechanism of action of the
thyroid hormones is similar; they interact with intracellular receptors. Both
the steroid and thyroid hormone-receptor complexes exert their action by binding
to specific nucleotide squences in the DNA of responsive genes. These DNA
sequences are identified as hormone response elements,
HREs. The interaction of steroid-receptor complexes with DNA leads to
altered rates of transcription of the associated genes.
Steroid Hormone Biosynthesis Reactions
The particular steroid hormone class synthesized by a given cell type
depends upon its complement of peptide hormone receptors, its response to
peptide hormone stimulation and its genetically expressed complement of enzymes.
The following indicates which peptide hormone is responsible for stimulating the
synthesis of which steroid hormone:
- Luteinizing Hormone (LH):
- progesterone and testosterone
- Adrenocorticotropic hormone (ACTH):
- Follicle Stimulating Hormone (FSH):
- Angiotensin II/III:
The first reaction in converting cholesterol to C18,
C19 and C21 steroids involves the cleavage of a 6-carbon
group from cholesterol and is the principal committing, regulated, and
rate-limiting step in steroid biosynthesis. The enzyme system that catalyzes the
cleavage reaction is known as P450-linked side chain cleaving enzyme
(P450ssc), or desmolase, and is found in the mitochondria of
steroid-producing cells, but not in significant quantities in other cells.
Mitochondrial desmolase is a complex enzyme system consisting of cytochrome
P450, and adrenadoxin (a P450 reductant). The activity of each of these
components is increased by 2 principal cAMP- and PKA-dependent processes. First,
cAMP stimulates PKA, leading to the phosphorylation of a cholesteryl-ester
esterase and generating increased concentrations of cholesterol, the substrate
for desmolase. Second, long-term regulation is effected at the level the gene
for desmolase. This gene contains a cAMP regulatory element (CRE) that binds
cAMP and increases the level of desmolase RNA transcription, thereby leading to
increased levels of the enzyme. Finally, cholesterol is a negative feedback
regulator of HMG CoA reductase activity (see regulation
of cholesterol synthesis). Thus, when cytosolic cholesterol is depleted,
de novo cholesterol synthesis is stimulated by freeing HMG CoA reductase
of its feedback constraints. Subsequent to desmolase activity, pregnenolone
moves to the cytosol, where further processing depends on the cell (tissue)
under consideration.
The various hydroxylases involved in the synthesis of the steroid hormones
have a nomenclature that indicates the site of hydroxylation (e.g. 17a-hydroxylase introduces a hydroxyl group to carbon 17).
These hydroxylase enzymes are members of the cytochrome P450 class of enzymes
and as such also have a nomenclature indicative of the site of hydroxylation in
addition to being identified as P450 class enzymes (e.g. the 17a-hydroxylase is also identified as P450c17).
Steroids of the Adrenal Cortex
The adrenal cortex is responsible for production of 3 major classes of
steroid hormones: glucocorticoids, which regulate
carbohydrate metabolism; mineralocorticoids, which
regulate the body levels of sodium and potassium; and androgens, whose actions are similar to that of steroids
produced by the male gonads. Adrenal insufficiency is known as Addison
disease, and in the absence of steroid hormone replacement therapy can
rapidly cause death (in 1--2 weeks).
The adrenal cortex is composed of 3 main tissue regions: zona glomerulosa, zona
fasciculata, and zona reticularis.
Although the pathway to pregnenolone synthesis is the same in all zones of the
cortex, the zones are histologically and enzymatically distinct, with the exact
steroid hormone product dependent on the enzymes present in the cells of each
zone.
 |
| Synthesis of the various adrenal steroid
hormones from cholesterol. Only the terminal hormone structures are
included. 3b-DH is 3b-dehydrogenase, P450c11 is 11b-hydroxylase, P450c17 is 17a-hydroxylase, P450c21 is 21b-hydroxylase. |
Zona glomerulosa cells lack the P450c17 that converts pregnenolone and
progesterone to their C17 hydroxylated analogs. Thus, the pathways to
the glucocorticoids (deoxycortisol and cortisol) and the androgens
[dehydroepiandosterone (DHEA) and androstenedione] are blocked in these cells.
Zona glomerulosa cells are unique in the adrenal cortex in containing the enzyme
responsible for converting corticosterone to aldosterone, the principal and most
potent mineralocorticoid. This enzyme is P450c18 (or 18a-hydroxylase), also called aldosterone synthase. The result
is that the zona glomerulosa is mainly responsible for the conversion of
cholesterol to the weak mineralocorticoid, corticosterone and the principal
mineralocorticoid, aldosterone.
Cells of the zona fasciculata and zona reticularis lack aldosterone synthase
(P450c18) that converts corticosterone to aldosterone, and thus these tissues
produce only the weak mineralocorticoid corticosterone. However, both these
zones do contain the P450c17 missing in zona glomerulosa and thus produce the
major glucocorticoid, cortisol. Zona fasciculata and zona reticularis cells also
contain the C17,20 lyase, whose activity is responsible for producing the
androgens, dehydroepiandosterone (DHEA) and androstenedione. Thus, fasciculata
and reticularis cells can make corticosteroids and the adrenal androgens, but
not aldosterone.
As noted earlier, P450ssc is a mitochondrial activity. Its product,
pregnenolone, moves to the cytosol, where it is converted either to androgens or
to 11-deoxycortisol and 11-deoxycorticosterone by enzymes of the endoplasmic
reticulum. The latter 2 compounds then re-enter the mitochondrion, where the
enzymes are located for tissue-specific conversion to glucocorticoids or
mineralocorticoids, respectively.
Regulation of Adrenal Steroid Synthesis
Adrenocorticotropic hormone (ACTH) of the hypothalamus regulates the hormone
production of the zona fasciculata and zona reticularis. ACTH receptors in the
plasma membrane activate adenylate cyclase with production of the second
messenger, cAMP. The effect of ACTH on the production of cortisol is
particularly important, with the result that a classic feedback loop is
prominent in regulating the circulating levels of corticotropin releasing
hormone, (CRH), ACTH, and cortisol.
Mineralocorticoid secretion from the zona glomerulosa is stimulated by an
entirely different mechanism. Angiotensins II and III, derived from the action
of the kidney protease renin on liver-derived angiotensinogen, stimulate zona glomerulosa cells by
binding a plasma membrane receptor coupled to phospholipase C. Thus, angiotensin
II and III binding to their receptor leads to the activation of PKC and elevated
intracellular Ca2+ levels. These events lead to increased P450ssc
activity and increased production of aldosterone. In the kidney, aldosterone
regulates sodium retention by stimulating gene expression of mRNA for the
Na+/K+-ATPase responsible for the reaccumulation of sodium
from the urine.
The interplay between renin from the kidney and plasma angiotensinogen is
important in regulating plasma aldosterone levels, sodium and potassium levels,
and ultimately blood pressure. Among the drugs most widely employed used to
lower blood pressure are the angiotensin converting enzyme
(ACE) inhibitors. These compounds are potent competitive inhibitors
of the enzyme that converts angiotensin I to the physiologically active
angiotensins II and III. This feedback loop is closed by potassium, which is a
potent stimulator of aldosterone secretion. Changes in plasma potassium of as
little as 0.1 millimolar can cause wide fluctuations (+/- 50%) in plasma levels
of aldosterone. Potassium increases aldosterone secretion by depolarizing the
plasma membrane of zona glomerulosa cells and opening a voltage-gated calcium
channel, with a resultant increase in cytoplasmic calcium and the stimulation of
calcium-dependent processes.
Although fasciculata and reticularis cells each have the capability of
synthesizing androgens and glucocorticoids, the main pathway normally followed
is that leading to glucocorticoid production. However, when genetic defects
occur in the 3 enzyme complexes leading to glucocorticoid production, large
amounts of the most important androgen, dehydroepiandrosterone (DHEA), are
produced. These lead to hirsutism and other
masculinizing changes in secondary sex characteristics.
Gonadal Steroid Hormones
Although many steroids are produced by the testes and the ovaries, the two
most important are testosterone and estradiol. These compounds are under tight
biosynthetic control, with short and long negative feedback loops that regulate
the secretion of follicle stimulating hormone
(FSH) and luteinizing hormone (LH) by
the pituitary and gonadotropin releasing hormone
(GnRH) by the hypothalamus. Low levels of circulating sex hormone
reduce feedback inhibition on GnRH synthesis (the long loop), leading to
elevated FSH and LH. The latter peptide hormones bind to gonadal tissue and
stimulate P450ssc activity, resulting in sex hormone production via cAMP and PKA
mediated pathways. The roles of cAMP and PKA in gonadal tissue are the same as
that described for glucocorticoid production in the adrenals, but in this case
adenylate cyclase activation is coupled to the binding of LH to plasma membrane
receptors.
The biosynthetic pathway to sex hormones in male and female gonadal tissue
includes the production of the androgens---androstenedione and
dehydroepiandrosterone. Testes and ovaries contain an additional enzyme, a
17b-hydroxysteroid dehydrogenase, that enables
androgens to be converted to testosterone
In males, LH binds to Leydig cells, stimulating production of the principal
Leydig cell hormone, testosterone. Testosterone is secreted to the plasma and
also carried to Sertoli cells by androgen binding protein
(ABP). In Sertoli cells the D-4 double bond
of testosterone is reduced, producing dihydrotestosterone. Testosterone and
dihydrotestosterone are carried in the plasma, and delivered to target tissue,
by a specific gonadal-steroid binding globulin
(GBG). In a number of target tissues, testosterone can be converted
to dihydrotestosterone (DHT). DHT is the most potent of the male steroid
hormones, with an activity that is 10 times that of testosterone. Because of its
relatively lower potency, testosterone is sometimes considered to be a
prohormone.
 |
| Synthesis of the male sex hormones in
Leydig cells of the testis. P450SSC, 3b-DH, and
P450c17 are the same enzymes as those needed for adrenal steroid hormone
synthesis. 17,20-desmolase is the same as 17,20-lyase of adrenal hormone
synthesis.. |
Testosterone is also produced by Sertoli cells but in these cells it is
regulated by FSH, again acting through a cAMP- and PKA-regulatory pathway. In
addition, FSH stimulates Sertoli cells to secrete androgen-binding protein (ABP), which transports
testosterone and DHT from Leydig cells to sites of spermatogenesis. There,
testosterone acts to stimulate protein synthesis and sperm development.
In females, LH binds to thecal cells of the ovary, where it stimulates the
synthesis of androstenedione and testosterone by the usual cAMP- and
PKA-regulated pathway. An additional enzyme complex known as aromatase is
responsible for the final conversion of the latter 2 molecules into the
estrogens. Aromatase is a complex endoplasmic reticulum enzyme found in the
ovary and in numerous other tissues in both males and females. Its action
involves hydroxylations and dehydrations that culminate in aromatization of the
A ring of the androgens.
 |
| Synthesis of the major female sex hormones
in the ovary. Synthesis of testosterone and androstenedione from
cholesterol occurs by the same pathways as indicated for synthesis of the
male sex hormones. |
Aromatase activity is also found in granulosa cells, but in these cells the
activity is stimulated by FSH. Normally, thecal cell androgens produced in
response to LH diffuse to granulosa cells, where granulosa cell aromatase
converts these androgens to estrogens. As granulosa cells mature they develop
competent large numbers of LH receptors in the plasma membrane and become
increasingly responsive to LH, increasing the quantity of estrogen produced from
these cells. Granulosa cell estrogens are largely, if not all, secreted into
follicular fluid. Thecal cell estrogens are secreted largely into the
circulation, where they are delivered to target tissue by the same globulin
(GBG) used to transport testosterone.
Steroid Hormone Receptors
The receptors to which steroid hormones bind are ligand-activated proteins
that regulate transcription of selected genes. Unlike peptide
hormone receptors, that span the plasma membrane and bind ligand outside the
cell, steroid hormone receptors are found in the cytosol and the nucleus. The
steroid hormone receptors belong to the steroid and thyroid hormone receptor
super-family of proteins, that includes receptors for steroid hormones, thyroid
hormones, vitamin D and vitamin A (retinoic acid).
When these receptors bind ligand they undergo a conformational change that
renders them activated to recognize and bind to specific nucleotide sequences.
These specific nucleotide sequences in the DNA are referred to as hormone-response elements (HREs). When ligand-receptor
complexes interact with DNA they alter the transcriptional level (responses can
be either activating or repressing) of the associated gene. Thus, the
steroid-thyroid family of receptors all have three distinct domains: a
ligand-binding domain, a DNA-binding domain and a transcriptional regulatory
domain. Although there is the commonly observed effect of altered
transcriptional activity in response to hormone-receptor interaction, there are
family member-specific effects with ligand-receptor interaction. Binding of
thyroid hormone to its receptor results in release of the receptor from DNA.
Several receptors are induced to interact with other transcriptional mediators
in response to ligand binding.
Binding of glucocorticoid leads to translocation
of the ligand-receptor complex from the cytosol to the nucleus.
The receptors for the retinoids (vitamin A and its
derivatives) are identified as RARs (for
retinoic acid, RA receptors) and exist in at least three subtypes, RARa, RARb and RARg. In addition, there is another family of nuclear receptors
termed the retinoid X receptors (RXRs) that
represents a second class of retinoid-responsive transcription factors. The RXRs
have been shown to enhance the DNA-binding activity of RARs and the thyroid
hormone receptors (TRs). There are also three distinct RXRs (a, b and g). The major difference between the RARs and RXRs is that
the former exhibit highest affinity for all-trans-retinoic acid
(all-trans-RA) and the latter for 9-cis-RA.
Additional super-family members are the peroxisome
proliferator-activated receptors (PPARs). These receptors were
originally discovered as proteins activated by agents that stimulate
proliferation of peroxisomes in rat liver. An intracellular lipid-binding
protein identified as aP2 is expressed exclusively in differentiated adipocytes.
An adipocyte-specific enhancer of the aP2 gene is a target for peroxisome
proliferators, fatty acids and 9-cis-RA. Subsequent to these observations
it was found that there is an adipocyte-specific PPAR family identified as
PPARg. The PPARg proteins form
heterodimers with RXRs to activate adipocyte-specific enhancers such as the one
in the aP2 gene.
Recent evidence has demonstrated a role for PPARg
proteins in the etiology of type 2
diabetes. A relatively new class of drugs used to increase the sensitivity
of the body to insulin are the thiazolidinedione
drugs. These compounds bind to and alter the function of PPARg. Mutations in the gene for PPARg
have been correlated with insulin resistance. It is still not completely clear
how impaired PPARg signaling can affect the sensitivity
of the body to insulin or indeed if the observed mutations are a direct or
indirect cause of the symptoms of insulin resistance.
TO SEE THE LATEST IN NEXT GENERATION BODYBUILDING SUPPLEMENTS AND SAFE ALTERNATIVES TO STEROIDS CLICK BELOW!
SHOW-TECH™ IS ONE OF THE MOST EXCITING AND HOTTEST CELL VOLUMIZATION PRODUCTS AVAIALABLE
AND HAS SHOWN NOTHING SHORT OF AMAZING RESULTS FOR LEAN MASS GAINS, DEFINITION, AND A TRUE CUT AND BULK
BALANCE FOR EXPLOSIVE GAINS WITHOUT THE HARMFUL EFFECTS OF ILLEGAL STEROID INJECTIONS! FAST MUSCLE
GAINS FOR ALL LEVELS OF BODYBUILDING FROM THE BEGINNER TO THE SHOWMAN!
Web Author: Sharp Labs Inc.™
SEE WHAT SHOW-TECH™ CAN DO FOR YOU!
Hardcore Bodybuilding At Its Best!
Copyright2006 And Up - Sharp Labs Inc.
"ALL RIGHTS RESERVED"
|
