Transcript Synthesis of Steroid Hormones

Steroid Hormones
Objectives
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Recall the overall role of steroids in human body.
Understand the physiological roles of cholesterol especially in synthesis
of steroid hormones.
Recall the biochemical and clinical aspects of all types of adrenal steroids.
Explain with appropriate details the biochemical and physiological
aspects of steroids from the testis and ovaries
Recognize the biochemical and clinical relations of congenital adrenal
hyperplasia and testicular feminization syndrome
Steroid Hormones
Types of steroid hormones:
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Glucocorticoids: cortisol is the major representative in most mammals
Mineralocorticoids: aldosterone being most prominent
Sex hormones:
Androgens: such as testosterone
Estrogens: including estradiol & estrone
Progestogens: also known a progestins such as progesterone
Steroid Hormones
All steroid hormones are:
 Derived from cholesterol
& differ only in the ring structure & side chains attached to it.
 Lipid soluble & thus are freely permeable to membranes so are not stored
in cells
Steroid hormones are synthesized in:
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Adrenal cortex: cortisol, aldosterone & androgens (androstendione)
Testis: testosterone
Ovaries: estrogens & progesterone
Placenta: progesterone
Some peripheral tissues (as adipose tissue & the brain)
Steroid Hormones
Cholesterol
is the precursor of
steroid hormones
Transport of Steroid Hormones in Blood
Steroid hormones have to be carried in the blood complexed to specific binding
plasma proteins (globulins).
 Cortisol: by corticosteroid binding globulin (transcortin)
 Sex steroids (testosterone & estradiol): by sex hormone-binding protein (SHBG)
 Aldosterone: by the plasma protein albumin
General Functions of Steroid Hormones
Steroid hormones play important roles in:
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Metabolic regulation (glucocorticoids i.e. cortisol)
Electrolyte balance (mineralocorticoids i.e. aldosterone)
Reproductive functions (gonadal steroids i.e. testosterone & estrogens)
Steroids also play roles in:
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Inflammatory responses
Stress responses
Bone metabolism
Cardiovascular fitness
Behavior, cognition & mood
Steroid Hormone Synthesis
A series of enzymatic steps in the mitochondria & ER of steroidogenic tissues
convert cholesterol into all of the other steroid hormones & intermediates.
An important control point this process is the transport of free cholesterol
from the cytoplasm into mitochondria.
This step is carried out by the Steroidogenic Acute Regulatory Protein (STAR)
Sources of
Cholesterol for
Steroid Synthesis
Lipoproteins
in Blood
LH
Cholesterol
pool
Acetyl CoA
ATP
cholesterol
Protein
Kinase
mitochondria
Desmolase
cAMP
STAR
Pregnenolone
Pregnenolone
In:
Adrenal Cortex
Testis
Ovary
ALL STEROID
HORMONES
Steroid Hormone Synthesis
The first enzymatic step is
the conversion of cholesterol to pregnenolone
which occurs in the mitochondria.
This reaction is carried out by the enzyme desmolase
This is a rate limiting, nonreversible step
in the initiation of steroid biosynthesis.
This step occurs in
Adrenal Cortex, Ovary & Testis
Steroid hormone synthesis
in the Adrenal Cortex
Organization of the Adrenal Gland
The adrenal gland is composed of the adrenal cortex & adrenal medulla
1- The
adrenal cortex:
The zona glomerulosa: secretes aldosterone
The zona fasciculata: secretes cortisol
The zona reticularis: secretes the adrenal androgens
2- The
adrenal medulla:
Secretes adrenaline (epinephrine)
Cholesterol
Steroid Hormone
Desmolase
Synthesis
Pregnenolone
In Adrenal Cortex
3-β-Hydroxysteroid dehydrogenase
Progesterone
17-α-Hydroxylase
21-α-Hydroxylase
17-α-Hydroxyprogesterone
11-Deoxycorticosterone
11- β -Hydroxylase
21-α-Hydroxylase
11-Deoxycortisol
Corticosterone
Aldosterone
Cortisol
androgen
Androstenedione
Testosterone
NOT
IN
ADRENAL
CORTEX
Peripheral
Tissues
Estradiol
Regulation of Cortisol Secretion from the
Adrenal Cortex
Negative feedback control:
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ACTH release from the anterior pituitary is
stimulated by hypothalamic secretion of
corticotrophin releasing hormone (CRH).
CRH   ACTH  Cortisol
Hypothalamus
Pituitary
 Cortisol (or synthetic steroids)
Adrenal
Suppress CRH & ACTH secretion
Testosterone Production
in the Testis
Pathway of Testosterone Production
in the Testis
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The production of androgens from cholesterol is identical to that in the
adrenal, except that it continues from androstenedione to testosterone.
Cholesterol
In the Testis
Androstenedione
Testosterone
17b-hydroxysteroid
Oxidoreductase
N.B. In the adrenal cortex, androstendione (adrenal androgen) is formed.
They are released to blood & converted in the testis (& peripheral tissues)
to testosterone
Pathway of Testosterone Production
in the Testis
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The main steroid produced in the male is testosterone produced from the
testis. .
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In the male, there is peripheral conversion of testosterone to:
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Dihydrotestosterone: in androgen target tissues, like muscles by 5 a reductase
Or to
Estradiol : mostly in adipose tissue by enzyme cytochrome P450 aromatase
Control of Testicular Function by
the Pituitary Gonadotrophins (LH & FSH)
Hypothalamus
LH
++ testosterone synthesis in testis
FSH
++ spermatogenesis in testis
GnRH
+
Anterior
Pituitary
-
LH
FSH
+Testis +
Testosterone
Spermatogenesis
+
Testosterone
++ Spermatogenesis
++ Development of secondary
male sex characters
++ Anabolism
Synthesis of Steroid Hormones
in the Ovary
Synthesis of Steroid Hormones
in the Ovary
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In the ovary:
Estradiol is formed from the conversion of androgens (testosterone) into
estradiol by the enzyme cytochrome P450 aromatase (in granulosa cells).
The androgens required for conversion come from the neighboring theca
cells.
Cholesterol
Theca Cells
Stimulated by FSH
Stimulated
by LH
Granulosa Cells of the Ovary
Androstendione
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Testosterone
Estradiol
Aromatase
Synthesis of steroid Hormones in the Ovary
LH
++ estrogen secretion
++ ovulation
LH
FSH
FSH
++ secretion of estrogen
Regulates growth of ovarian follicle
FSH receptors
LH receptor
cholesterol
Estradiol
Theca
cells
Androstendione
Granulosa
cells
Androstendione
aromatase
Testosterone
LH & FSH stimulates estrogen secretion
FSH regulates growth of ovarian follicles
LH stimulates ovulation
Mechanism of Action of Steroid Hormones
Cytosolic
Receptors
Hormone Receptor
Complex
HRE
of genes
Transcription
of genes
is increased
Mechanism of Action of Steroid Hormones
Congenital Adrenal Hyperplasia (CAH)
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It is the result of an inherited enzyme defect in steroid hormones biosynthesis
in the adrenal cortex.
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The Adrenal Cortex :
 Cannot secrete cortisol  absent negative feedback to the pituitary) 
ACTH continues to drive steroid biosynthesis  adrenal hyperplasia &
accumulation of cortisol precursors (depending on which enzyme is lacking)
 Cannot secrete aldosterone  electrolyte disturbances
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The condition might be fatal unless diagnosed early
21 a-Hydroxylase Deficiency
Progesterone
17a-hydroxyprogesterone
Androstenedione
21 a-hydroxylase
In
Peripheral
Tissues
11-deoxycorticosterone
11-deoxycortisol
Aldosterone
Cortisol
Testosterone
Virilisation
of ♀
Precocious
sexual development
in ♂
21 a-Hydroxylase Deficiency
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Accounts for ~ 95% of all cases of CAH
Autosomal recessive condition
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Low or absent synthesis of Cortisol & Aldosterone
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 Cortisol  ACTH secretion  Adrenal Gland hyperplasia
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Some of the accumulated precursors are diverted to the biosynthesis of sex
hormones  Signs of Androgen Excess:
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 stimulation of adrenal androgen production  virilisation in baby girls &
precocious puberty in boys
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In severe cases, Aldosterone Deficiency is evident  salt & water loss 
hypovolaemia & shock  neonatal adrenal crisis
21 a-Hydroxylase Deficiency
Diagnosis:
1- Prenatal Diagnosis (Intrauterine, before birth)
DNA testing and detection of mutations in the CYP21 gene can be helpful for prenatal diagnosis &
confirmation of diagnosis
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2- Neonatal Diagnosis (after birth)
 Serum sample taken at least 2 days after birth (earlier samples may contain
maternally derived 17-hydroxyprogesterone)
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Classic 21-hydroxylase deficiency is characterized by markedly elevated serum levels of 17hydroxyprogesterone
3- Late-onset (in adult life)
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May require corticotropin stimulation test:
Injecting a 0.125-mg or 0.25-mg bolus of corticotropin
Measuring base-line and stimulated levels of 17-hydroxyprogesterone.
High level after stimulation is diagnostic ( 2x upper reference range)
Disorders of Male Sexual Differentiation
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They are rare group of disorders
The defect may be in:
 Impaired Testosterone production
 Inactive androgen receptors  target tissues cannot respond to
stimulation by circulating testosterone
e.g. Testicular Feminization Syndrome
Testicular Feminization Syndrome
 46, XY karyotype
 X-linked recessive disorder
 Androgen receptor resistance
high testosterone blood level
 In peripheral tissue, testosterone will be converted by aromatase
into estradiol
feminization