Steroid Horm

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Steroid Hormones

Chemical Classification of
Hormones
Hormones are chemical messengers that transport
signals from one cell to another
There are 4 major chemical classes of hormones

steroid hormones - i.e. progesterone


peptide hormones - i.e. insulin
amino acid derivatives - epinephrine
prostaglandins and related compounds
Mechanism of Hormone
Action
All hormone action is receptor mediated

1. Peptide hormones and catecholamines bind to cell


surface receptors

2. Steroid and thyroid hormones act via intracellular


receptors
Structure of Steroid
Hormones
Steroids are lipophilic molecules.
All steroids, except calcitriol, have
cyclopentanoperhydrophenanthrene
structure (sterane).

The parental precursor of


steroids - cholesterol
Steroid Hormone Classes

Progestins
Glucocorticoids
Mineralocorticoids
Androgens
Estrogens
Vitamin D
Steroid Hormones
Are not packaged, but synthesized and immediately
released.
Are all derived from the same parent compound:
cholesterol.
Enzymes which produce steroid hormones from
cholesterol are located in mitochondria and smooth
ER.
Steroids are lipid soluble and thus are freely
permeable to membranes so are not stored in cells.
Steroid Hormones
Are not water soluble so have to be carried in the
blood complexed to specific binding globulins.
Corticosteroid binding globulin carries cortisol.
Sex steroid binding globulin carries testosterone and
estradiol.
In some cases a steroid is secreted by one cell and
is converted to the active steroid by the target cell:
(androgen is secreted by the gonad and converted
into estrogen in the brain).
Steroid hormones
Steroid hormones play important roles in:
- carbohydrate regulation (glucocorticoids)
- mineral balance (mineralocorticoids)
- reproductive functions (gonadal steroids)

Steroids also play roles in inflammatory responses,


stress responses, bone metabolism, cardiovascular
fitness, behavior, cognition, and mood.
Steroid Hormones
Adrenal cortex
Composed of 3 layers (zones):
outer zone (zona glomerulosa) produces aldosterone
(mineralocorticoid)
middle zone (zona fasciculata) produces cortisol
(glucocorticoid)
inner zone (zona reticularis) produces androgens

Corpus luteum and ovary


produce progesteron and estradiol

Testes
produces testosterone and dihydrotestosterone (DHT)
DHT
Progestins Are the Biosynthetic
Precursors of the All Other Steroid
Hormones

Cholesterol

Progestins

Glucocorticoids Androgens

Mineralocorticoids Estrogens
Pregnenolone (C-21)

produced directly from cholesterol, the


precursor molecule for all C18, C19 and C21
steroids
Progesterone (C-21)
A progestin, produced directly from
pregnenolone.
Secreted from the corpus luteum.
Maintains (with estradiol) the uterine
endometrium for implantation.
Differentiation factor for mammalian
glands.

Estradiol (C-18) Female: regulates gonadotrope secretion


in ovarian cycle.
Maintains (with progesterone) uterine
endometrium.
Differentiation of mammalian gland.
Responsible for secondary female sex
characteristics.
Male: negative feedback inhibitor of Leydig
cell synthesis of testosterone.
Testosterone (C-19)

After conversion to dihydrotestosterone,


production of sperm proteins in Sertoli cells.
Responsible for secondary male sex
characteristics.
Produced from progesterone.

Dehydroepiandrosterone

Week androgen, which can be


converted to estrogen.
Various protective effects. It may play a
role in the aging process.
Regulates NAD+ coenzymes.
Aldosterone (C-21)
The principal mineralocorticoid.
Produced from progesterone in the
zona glomerulosa of adrenal cortex.
Causes sodium ion uptake via
conductance channel.
Occures in high levels during stress.
Rises blood pressure and fluid volume.

Dominant glucocorticoid in humans,


Cortisol synthesized from progesterone in the zona
fasciculata of the adrenal cortex.
(C-21) Stress adaptation through various cellular
phenotypic expression, stress adaptation.
Slight elevation of liver glycogen. Numerous
effects on the immune system, killing effect on
certain T cells in high doses.
Na+ uptake in epithelia lumen.
1, 25-Dihydroxyvitamin D3 (Calcitriol)

Causes synthesis of Ca2+ transport protein.


Regulates calcium and phosphorus homeostasis.
Biosynthesis of Steroid
Hormones
Peptide hormones are encoded by specific genes;
steroid hormones are synthesized from the
enzymaticaly modified cholesterol.
Thus, there is no gene which encodes individual
hormone.
The regulation of steroidogenesis involves control of
the enzymes which modify cholesterol into the
steroid hormone of interest.
Sources of Cholesterol for Steroid
Synthesis
Cholesterol can be made within the cell from acetyl CoA
(de novo synthesis).
This is a multistep process, involving many enzymatic
reactions.
A key rate-limiting enzyme is HMG-CoA reductase.
There is negative feedback regulation of HMG-CoA
reductase activity by cholesterol, so that high intracellular
cholesterol inhibits de novo synthesis.

HMG-CoA reductase
acetyl CoA HMG-CoA mevalonate cholesterol
Sources of Cholesterol for Steroid
Synthesis
Cholesterol is also taken up by the cell in the form of
low density lipoprotein (LDL).
- LDL is a complex composed of cholesterol,
phospholipids, triglycerides, and proteins (proteins
and phospholipids make LDL soluble in blood).
- LDL is taken into cells via LDL receptors, and
broken down into esterified cholesterol, and then free
cholesterol:
20
22
Mitochondrial side chain cleavage enzyme
cholesteroldesmolase initiates the synthesis of
the progestins.
Isocaproic aldehyde

It hydroxylates C 20 and 22 and involves the


cleavage of a 6-carbon group from cholesterol
(isocaproic aldehyde).

This reaction require cytochrom P- 450 as an


intermediate electron carrier (integral part of the
inner mitochondrial membrane, a flavoprotein
containing both FAD and FMN).

Electron pass from the reduced NADPH to FAD,


then to FMN and finally to an O2
Hormonal Stimulation Of Steroid Hormone
Biosynthesis
Hormone stimulation depends
on the cell type and receptor
(ACTH for cortisol synthesis,
FSH for estradiol synthesis, LH
for testosterone synthesis etc.)

Hormone binds to cell


membrane receptor and activates
adenylate cyclase mediated by a
stimulatory G protein.

Receptor, activated by
hormone, may directly stimulate a
calcium channel or indirectly
stimulate it by activating the
phosphatidylinositol (PI) cycle.
Hormonal Stimulation Of Steroid Hormone
Biosynthesis
The increase in cAMP
activates protein kinase whose
phosphorylations cause
increased hydrolysis of
cholesteryl esters from droplet
to free cholesterol and increase
cholesterol transport into the
mitochodrion.

Elevated Ca 2+ levels and


protein phophorylation bring
about induced levels of the
side chain cleavage reaction.

Steroid is produced, secreted


into the extracellular space and
circulated to the target tissue in
the bloodstream
Biosynthesis of Steroid
Hormones

Critical step is the cell activity in mobilizing


cholesterol stored in a droplets, transport of
cholesterol to mitochondrion.
The rate-limiting step is the rate of cholesterol side
chain cleavage in mitochondrion by enzymes
known as the cytochrome P450 side chain
cleavage enzyme complex.
Steroidogenic Enzymes
Common name Old name Current name

Cholesteroldesmolase P450SCC CYP11A1


(Side-chain cleavage enzyme)
3-hydroxysteroid dehydroge- 3 -DH 3 -DH
nase
17-hydroxylase/17,20 lyase P450C17 CYP17

21-hydroxylase P450C21 CYP21A2

11-hydroxylase P450C11 CYP11B1

Aldosterone synthase P450C11AS CYP11B2

Aromatase P450aro CYP19


Steroids of the
Adrenal Cortex

Mitochondria

Zona glomerulosa cells lack the P450c17 that converts pregnenolone and progesterone to their
C17 hydroxylated analogs. Thus, the pathways to the glucocorticoids and the androgens are
blocked.
http://themedicalbiochemistrypage.org/steroid-hormones.html
Steroid Hormones of the
Gonades

Hormones that affect the development


of the reproductive organs and sexual
characteristics.
Testes
Leydig cells produce:
Testosterone
Sertoli cells produce:
dihydrotestosterone (DHT) but most of conversion of testosterone to DHT occurs outside the testes.
17--estradiol a small amount of testosterone is also converted into estradiol by aromatization (inhibits testosterone synthesis)
inhibin polypeptide hormone, which inhibits FSH releasing
FSH binds to the Sertoli cells and stimulates the synthesis of androgen-binding protein (ABP). ABP binds testosterone (produced by Leydig cells) and
transports it to the site of spermatogenesis.
Gonadal Steroid Hormones

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.

http://themedicalbiochemistrypage.org/steroid-hormones.html
Synthesis of Estrogens

Estrogens are formed by aromatization of androgens.


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.
Ovaries
17--estradiol is the main hormone produced during the follicular phase of the menstrual cycle.

After ovulation progesterone is made by follicular cells, which now constitute the corpus luteum.

Regulation of Sex Hormones Synthesis


Steroid Steroid producing Signal Second Signal system
hormone cells messenger

Testosterone Leydig cells LH cAMP Hypothalamic-pituitary


17-- Granulosa cells FSH cAMP Hypothalamic-pituitary
Estradiol
Progesterone Corpus luteum LH cAMP Hypothalamic-pituitary
Calcitriol - 1,25 (OH)2-D3
Calcitriol - 1,25 (OH)2-D3
1-hydroxylation is the rate-limiting step in calcitriol
synthesis

Regulation of 1-hydroxylase
Activation Inhibition
Hypocalcemia Calcitriol
Parathroid hormone
Hypophosphatemia
Calcitriol
- increases uptake of Ca2+ and phosphate from the intestine
- stimulates calcium binding protein synthesis
Schematic model to describe the action of 1,25-
(OH2)D3 in the intestine in stimulating intestinal
calcium transport.

Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations


Transport of Hormones
in the Bloodstream
Steroids are lipophilic molecules they are bound to
protein carriers in the blood
Carrier-
Albumin bound
hormone
Corticosteroid binding globulin
(CBG) or transcortin
Sex hormone binding globulin Endocrine
cell
Free hormone Hormone
Receptor
(SHBG)
Androgen binding protein (ABP) Hormone
degradation Biological
effects

Only the free fraction is biologically active usually less than 10%
Hormone half life
Steroids and thyroid hormone, which are
bound to plasma proteins, have a long half life (~
hours)

Peptides and catecholamines are water-


soluble, they are transported dissolved in plasma
generally have a very short half life (~ seconds
to minutes)
Transport of Adrenal
Steorid Hormones in the
Bloodstream
CORTISOL ALDOSTERONE
70% is bound to corticosteroid 60% of aldosterone is bound to
binding globulin (transcortin) albumin
22% of cortisol is bound to albumin 10 % is bound to transcortin
8% free cortisol A small amount of aldosterone is
bound to other plasma
proteins

Transcortin is produced in the liver and its synthesis is increased by


estrogens.
Hormone bound to transport proteins are protect from metabolism and
inactivation.
Transport proteins assist in maintaining a level of hormones in circulation.
Transport of Sex Hormones in
the Bloodstream
Testosterone & estradiol bind to sex hormone binding globulin
(SHBG).
Progesterone binds to transcortin.
Affinity of SHBG for testosterone is higher than for estradiol.

Before puberty - the level of SHBG is about the same in males and
females .
At the puberty - there is a small decrease in the level of circulating
SHBG in females and larger decrease in males, insuring relatively
greater amount of the unbound, biologically active sex hormones.

In adults, males have half of the amount of SHBG than females.

Testosterone lowers SHBG levels in blood, whereas estradiol raises


SHBG levels.
Mechanism of Steroid
Hormone Action

Steroid hormones are soluble


in the plasma membrane and
readily enter the cytosol.

Steroids bind to intracellular


receptor either in the cytosol
or in the nucleus.

The hormone-receptor
complex acts as a
transcription factor which
turns on / turns off the genes.

Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations


Mechanism of Steroid
Hormone Action
Messenger RNA is transcribed,
leaves the nucleus, and is
translated into a specific
protein by ribosome.

The specific proteins then carry


out function in the target cell.

Because steroid hormones


initiate protein synthesis their
effects are produced more
slowly, but are more long-
lasting than those produced by
other hormones.
Intracellular receptors
Model of typical steroid hormone receptor

H2N- 1 2 3 4 - COOH

1. Variable domain interacts with other transcription factors


2. DNA-binding domain zinc finger
3. Domain for dimerization a site of dimerization of two
receptor-hormone complexes
4. Hormone- binding domain

zinc finger structure


Hormone Catabolism and
Excretion

Inactivation of steroids involves reductions and


conjugation to glucuronides or sulfate to increase their
water solubility.

Most are catabolized by the liver and kidneys.


70% of the conjugated steroids are excreted in the
urine, 20 % leave in feces and rest exit through the
skin.

estron-3sulfate

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