Steroid Hormones

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Steroid Hormones
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Objectives

• 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

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Steroid Hormones

• Types of steroid hormones
• 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

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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
• Adrenal cortex cortisol, aldosterone
  androgens (androstendione)
• Testis testosterone
• Ovaries estrogens progesterone
• Placenta progesterone
• Some peripheral tissues (as adipose tissue
  the brain)

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Steroid Hormones
Cholesterol is the precursor of steroid hormones
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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

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General Functions of Steroid Hormones

• Steroid hormones play important roles in
• 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
• Inflammatory responses
• Stress responses
• Bone metabolism
• Cardiovascular fitness
• Behavior, cognition mood

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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)
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Lipoproteins in Blood
Sources of Cholesterol for Steroid Synthesis
LH
Acetyl CoA
Cholesterolpool
ATP
cholesterol
cAMP
Protein Kinase
mitochondria
STAR
Desmolase
Pregnenolone
Pregnenolone
In Adrenal Cortex Testis Ovary
ALL STEROID HORMONES
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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

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Steroid hormone synthesis in the Adrenal Cortex
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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)

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Cholesterol
Steroid Hormone Synthesis In Adrenal Cortex
Desmolase
Pregnenolone
3-ß-Hydroxysteroid dehydrogenase
Progesterone
17-a-Hydroxylase
21-a-Hydroxylase
17-a-Hydroxyprogesterone
11-Deoxycorticosterone
androgen
21-a-Hydroxylase
Androstenedione
11-Deoxycortisol
11- ß -Hydroxylase
Testosterone
Corticosterone
Peripheral Tissues
NOT IN ADRENAL CORTEX
Aldosterone
Cortisol
Estradiol
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Regulation of Cortisol Secretion from the Adrenal
Cortex

• Negative feedback control
• ACTH release from the anterior pituitary is
  stimulated by hypothalamic secretion of
  corticotrophin releasing hormone (CRH).
• CRH ? ? ACTH ? ? ?Cortisol
• ? Cortisol (or synthetic steroids)
• Suppress CRH ACTH secretion

Hypothalamus
Pituitary
Adrenal
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Testosterone Production in the Testis
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Pathway of Testosterone Production in the Testis

• 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
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Pathway of Testosterone Production in the Testis

• The main steroid produced in the male is
  testosterone produced from the testis. .
• In the male, there is peripheral conversion of
  testosterone to
• Dihydrotestosterone in androgen target
  tissues, like muscles by 5 a reductase
• Or to
• Estradiol mostly in adipose tissue by enzyme
  cytochrome P450 aromatase

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Control of Testicular Function by the Pituitary
Gonadotrophins (LH FSH)
Hypothalamus
GnRH
LH testosterone synthesis in testis FSH
spermatogenesis in testis

-
Anterior Pituitary
LH
FSH


Testis
Testosterone Spermatogenesis Development
of secondary male sex characters
Anabolism
Testosterone

Spermatogenesis
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Synthesis of Steroid Hormones in the Ovary
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Synthesis of Steroid Hormones in the Ovary

• 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
• Androstendione
  Testosterone
  Estradiol
• 
  
  Aromatase

Stimulated by FSH
Stimulated by LH
Granulosa Cells of the Ovary
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Synthesis of steroid Hormones in the Ovary
FSH secretion of estrogen Regulates growth of
ovarian follicle
LH estrogen secretion ovulation
FSH receptors
LH FSH stimulates estrogen secretion FSH
regulates growth of ovarian follicles LH
stimulates ovulation
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Mechanism of Action of Steroid Hormones
Cytosolic Receptors
Hormone Receptor Complex
HRE of genes
Transcription of genes is increased
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Mechanism of Action of Steroid Hormones
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Congenital Adrenal Hyperplasia (CAH)

• It is the result of an inherited enzyme defect in
  steroid hormones biosynthesis in the adrenal
  cortex.
• 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
• The condition might be fatal unless diagnosed
  early

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21 ?-Hydroxylase Deficiency
17?-hydroxy-progesterone
Progesterone
Androstenedione
In Peripheral Tissues
21 ?-hydroxylase
11-deoxycorticosterone
11-deoxycortisol
Testosterone
Cortisol
Aldosterone
Precocious sexual development in ?
Virilisation of ?
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21 ?-Hydroxylase Deficiency

• Accounts for 95 of all cases of CAH
• Autosomal recessive condition
• Low or absent synthesis of Cortisol Aldosterone
• ? Cortisol ?? ACTH secretion ? Adrenal Gland
  hyperplasia
• Some of the accumulated precursors are diverted
  to the biosynthesis of sex hormones ? Signs of
  Androgen Excess
• ? stimulation of adrenal androgen production
  ? virilisation in baby girls
• precocious puberty in boys
• In severe cases, Aldosterone Deficiency is
  evident ? salt water loss ? hypovolaemia
  shock ? neonatal adrenal crisis

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21 ?-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
• 2- Neonatal Diagnosis (after birth)
• Serum sample taken at least 2 days after
  birth (earlier samples may contain
• maternally derived 17-hydroxyprogesterone)
• Classic 21-hydroxylase deficiency is
  characterized by markedly elevated serum levels
  of 17-hydroxyprogesterone
• 3- Late-onset (in adult life)
• 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)

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Disorders of Male Sexual Differentiation

• 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

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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