Hormones and application

1. Jimma University
institute Of Health Sciences
Department Of Biochemistry
Course Title: Hormone $ Bio Signaling
Seminal Presentation on- Hypothalamus $ Pituitary H
By: Abdlhafiz kasim ID RM0879/15-0
Submitted to:Instructor Tesfaye( MSC )
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2. Objectives
• At the end of this chapter the students will able to:
– Identify some of the major Adrenal hormone
– List and explain the hormones of adrenal hormones along
with their abnormalities
– Understanding the mechanism action of adrenal steroid
hormones
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3. Adrenal glands
 Adrenal glands: two small, triangular-shaped glands located at the
upper portion of each kidney
 It is composed of an outer cortex and an inner medulla
 Outer cortex
 Outermost zona glomerulosa: Synthesis site of
mineralocorticoids
 Central zona fasciculata: Synthesis site of glucocorticoids
 Inner zona reticularis: Synthesis site of adrenal sex steroid
hormones
 Inner medulla: Synthesis site of catecholamines.
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5. Adrenal cortical steroid synthesis
 The adrenal cortical steroid hormones are derived from the
cholesterol via a branched metabolic pathway
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6. 1.Glucocorticoid (Cortisol)
 Cortisol is the principal glucocorticoids.
 Target organ - every cell of the body
 Effects
Regulation of carbohydrate, protein and lipid
metabolism; maintenance of blood pressure and
suppression of the immune response
 General characteristics
Steroids, lipid-soluble, protein bound, slow effects
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7. Regulation of cortisol secretion
 Hypothalamic regulation: it produces cortico-tropin releasing
factor(CRF).
 Pituitary regulation: it produces ACTH in response to CRF
 Negative feed-back: cortisol has direct –ve feed back effect on
hypothalamus to decrease CRF & on pituitary to decrease secretion
of ACTH.
 Effect of physiological stress on ACTH secretion: Physical & mental
stress can lead to increase cortisol secretion within minutes via
increase ACTH.
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9. Mechanism Of Action
 All of the steroids act primarily at the level of cell nucleus (‘nuclear’
action) to increase m-RNA synthesis and increased protein
synthesis.
 The first step occurs within minutes, which involves the binding of
the steroids to a corresponding specific receptor protein present in
cytosol.
 Glucocorticoids pass into target cells through plasma membrane and
binds to specific glucocorticoid.
 receptor protein present in cytosol. The receptors occur in a wide
variety of target tissues, viz. liver,
 muscles, adipose tissue,
 lymphoid tissue,
 skin,
 bone,
 fibroblasts, etc.
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10.  In humans, there are two types of receptor proteins:
1 α form: Containing approx 777 amino acids
2 β form: Having 742 amino acids.
 Both differ in amino acid sequence in the C- terminal
end. The receptor molecule has three distinct domains:
I. A steroid binding domain near c-terminus
II. A DNA binding domain near the middle of the molecule
in c-terminal half, and
III. A transcription-activating domain near the N terminal
side. A heat-shock protein, hap 90, binds to the receptor
in the absence of hormone and prevents folding into the
active conformation of the receptor protein.
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11.  Glucocorticoids binds to the specific receptor in cytosol
to steroid-binding site.
 This binding causes dissociation of the “hsp 90” stabiliser
and permits conversion to the active configuration.
 The steroid-receptor complex enters the nucleus, and
bind by DNA-binding site to the Hormone responsive
 element (HRE) of specific nuclear genes. This
modulates the transcription rate of those genes, leading
to increased synthesis of many proteins and enzymes
and also to decreased synthesis of some proteins like
corticotrophin.
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12. Glucocorticoid transport
 The lipid-soluble glucocorticoids are transported in circulation
bound to carrier proteins
Cortisol is 90-97% protein-bound
Cortisol-binding globulin (CBG) – major transport
protein
Albumin
Sex-hormone binding globulin (SHBG)
Conditions that change the level of binding protein affect the
level of total hormone, but not of the biologically active free
hormone
Causes of increased CBG
Estrogen, hyperthyroidism, etc.
Causes of decreased CBG
Malnutrition, chronic liver disease, etc.
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13. Hypersecretion of cortisol
 Cushing’s syndrome
Clinical disorder that result from supraphysiological level of
cortisol in the circulation (hypercorticortisolism)
The cause can be primary to the adrenal cortex (adrenal
adenoma in carcinoma) secondary to overproduction of
ACTH (pituitary adenoma) or an ectopic carcinoma that
produce ACTH, eg carcinoma of the lung.
The diagnosis is confirmed by dexamethasone suppression
test.
Plasma ACTH levels are low in primary adrenal disease and
high when there is uncontrolled production of ACTH by a
neoplasm.
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14. Hyposecretion of cortisol
 Adreno cortical insufficiency, evident by a low plasma cortisol
concentration
 The causes may be:
Primary to the adrenal cortex because of destruction of
cortical tissue by autoimmundisease or infection (addison’s
disease) or
Secondary to ACTH deficiency
 The diagnosis is confirmed by finding a subnormal cortisol
response to the administration of exogenous ACTH (rapid
ACTH stimulation test)
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15. 2.Mineralocorticoids (aldosterone)
 Aldosterone: the principal mineralocorticoid hormone .
 Target organs - kidneys, sweat and salivary glands and GI tract.
 Effects: Aldosterone regulates electrolyte balance and extracellular
fluid balance .
It regulates blood volume and blood pressure.
In the kidney, aldosterone causes active sodium reabsorption,
potassium and hydrogen excretion and passive water
reabsorption.
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16. Mechanism of Action
 Mineralocorticoids enter the target cells through the plasma
membranes and binds to a specific protein present in cytosol,
and nucleoplasm, called ‘Mineralocorticoid receptors’.
 Both high-affinity and low-affinity mineralocorticoid receptors
have been described.
 They are present in epithelial cells of renal distal tubular cells
and collecting ducts and also in gastrointestinal mucosa,
salivary gland ducts and sweat ducts.
 The steroid-receptor complex then enters the nucleus and
binds to hormone responsive element (HRE) of specific
nuclear genes and increases the transcription rates of genes.
 Thus, aldosterone initiates an increase in m-RNA synthesis ↑,
at the level of transcription of DNA.
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17. Aldosterone release
 Three release stimulators
Renin-angiotensin system (RAS) – primary stimulation
Extracellular potassium and sodium
ACTH
Aldosterone
 Its production is primarily controlled by the renin-
angiotensin system.
 ACTH has a slight stimulatory effect on aldosterone synthesis,
but this is usually of no significance.
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18. (Aldosterone ) Con..
• Renin
 Protein produced by the juxtaglomerular apparatus of the
kidney in response to decreased renal pressure and/or
decreased serum sodium levels.
 Acts on angiotensinogen to produce angiotensin I which is
converted to angiotensin II by angiotensin converting
enzyme.
 Angiotensin II is a potent vasoconstrictor and also
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19. Aldosterone control
 Atrial natriuretic peptide
 Plasma k+ level
 Role of ACTH
 Plasma Na+ level
 Renin- angiotensin system
 Aldosterone has negative feedback on the juxtaglomerular
apparatus of the kidney.
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21. Hyperaldosteronism
 Primary hyperaldosteronism (conn’s syndrome)
 It is overproduction of aldosterone due to the presence of an
aldosterone secreting adrenal adenoma.
 These patients usually have elevated serum Na+ concentration,
lowered K+ and hypertension.
 Secondary hyperaldosteronism
 It result from abnormalliteis in the renin-angiotensin system
 It result from
Excess production of renin→associated with increased
plasma renin
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22. Hypoaldosteronism
 Aldosterone deficiency is most often due to destruction of the
adrenal glands.
 If sodium intake is not adequate, the patient will develop
severe water and electrolyte abnormalities and may die from
vascular collapse and/or hyperkalemia.
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23. Laboratory diagnosis
 Determination of aldosterone by RIA and FPIA
 Determination of sodium and potasium in serum and urine
 Two blood samples are often drawn for aldosterone evaluation,
one in the early morning and one mid-afternoon.
 Because a 24-hour urine specimen reflects hormone
production over an entire day, it will usually provide a more
reliable aldosterone measurement.
 Elevated blood levels should ideally be confirmed with a 24-
hour urine test.
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24. Cont…
 Results will also vary between patients depending upon
average sodium intake, time of day, source of specimen, age,
sex, and posture.
 Reference ranges for blood plasma levels: radioimmunoassay
Supine: 3-10 ng/dL.
Upright: Female: 5-30 ng/dL; Male: 6-22 ng/dL
Urine: 2-80 micrograms/24 hr.
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25. 3.Catecholamines
 Catecholamines – epinephrine, norepinephrine and dopamine.
 Epinephrine is the major adrenal catecholamine (80-90%)
Affects metabolism (mobilizes energy stores) and increases heart
rate and blood pressure in times of stress
Functions as a neurotransmitter
 Norepinephrine (10-20%) and dopamine function solely as
neurotransmitters
 Catecholamine adrenal release is stimulated by stressors such as fear and
pain.
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26. Adrenal catecholamine synthesis
• The adrenal medullary catecholamines are derived from the amino acid
tyrosine.
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27. Mechanism of Action
 Role of Cyclic AMP: Catecholamines on binding to β-receptors (β1
and β2) activate adenyl cyclase which increases cyclic AMP level in
the cells.
 Increased cyclicAMP activates c-AMP-dependent protein kinases
which phosphorylates specific protein/or enzymes and
activate/inactivate them.
 β-receptor action is mediated through increased intracellular c-AMP level.
 Catecholamines on binding to α-receptors, inhibit adenyl cyclase,
thus decreasing the intracellular c-AMP level.
 α-receptor action is mediated through decreasing intracellular c-AMP level.
 Role of Ca++ and Phospho-inositides: Catecholamines on binding
with α1 receptors, effect the formation of “inositol-1,4,5-tri-PO4”
and diacylglycerol, and/or intracellular Ca++, these may act as
‘second messengers’ to produce tissue responses during α-effects.
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30. 4.Gonadal hormones(Sex steroids)
 Predominately produced by the adult male testes and female
ovaries
 Adrenal cortex also produces small amounts of sex steroids
 Responsible for
 manifestation of primary and secondary sex characteristics
 Human reproduction
 Characteristics – steroid, lipid-soluble, slow effects, bound to carrier
proteins (SHBG, albumin)
 Their secretion is under hypothalamus-pituitary-gonadal axis control
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31. Classes of female sex steroids
 Androgens
 Dehydroepiandrosterone (DHEA), DHEAS, testosterone,
dihydrotestosterone (DHT), androstenedione
The predominate adrenal androgens are DHEA and
DHEAS
 Estrogens
 Estradiol, estrone
 Progestin's
 Progesterone
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32. Mechanism of Action:
 Free testosterone enters the target cells by simple diffusion or facilitated diffusion.
In the cytoplasm of target cells, the testosterone is converted to ‘active’ form
dihydrotestosterone.
 Dihydrotestosterone has greater affinity than testosterone for the specific receptor.
 The hormone is tightly bound to the receptor and “hormone-receptor complex” then
binds to the ‘hormone-responsive element’ (HRE) present with specific nuclear
genes. This induces the transcription of those genes leading to increased synthesis
of respective proteins which produce cellular effects.
– 17-Ketosteroids
– (17-oxo-steroids)
 The androgens excreted in urine are classed as 17- ketosteroids (17-oxo-steroids).
In the case of females, it gives an idea about the condition of the adrenal cortex and
its functions.
– In males: 17-ketosteroids arise from testes (1/3 of the total), while the major amount arises
from the adrenal cortex (2/3 of total).
– In females: The 17-ketosteroids are almost entirely from adrenal cortical origin.
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33. Female sex hormones
 Two different chemical types of steroid hormones are produced and
secreted by the ovary in non pregnant women.
– Estrogen and progesterone
 During pregnancy, the same hormones are produced by the ovary,
but in different proportion.
 The placenta also makes the hormones that are necessary for the
maintenance of pregnancy.
– Estrogen, progesterone, HCG, lactogen
 This production is under control of
– hypothalamus(GnRH)→Pituitary(FSH,LH)→ovary/placenta
(female sex steroids)
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34. Estrogen
 Originate in the ovarian follicles and in the placenta during
pregnancy
 Function
– Participate in the menstrual cycle
– development and maintenance of the reproductive organs and
secondary sex characteristics.
 Three clinically important estrogens: C18 steroid
– Estradiol(E2): major hormone in non-pregnant
– Estrone(E1)
– Estriol(E3): major hormone in pregnant
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35. Mechanism of Action
• (Similar to Androgens): After entering the
target cells, it binds to a specific ‘receptor’
present in cytosol, “receptor-steroid complex”
then binds to hormone-responsive element
(HRE) associated with specific nuclear genes,
which translates for synthesis of specific
proteins and enzymes.
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36. Estradiol
 The principal and most potent estrogen
 It exists in a reversible state with estrone (with weaker biologic
action), but it must be converted into E1 before it is degraded.
– Estradiol (E2) ↔ Estrone (E1) → Estriol(E3) → degradation
 Plasma E2 levels
– Useful for the investigation of women with menstrual difficulties
 To ascertain weather a problem is of pituitary or ovarian origin.
– Measurement of pituitary tropic hormones, FSH and LH
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37. Estriol(E3)
• It has no hormonal activity
• Produced in relatively large quantity during the last trimester of
pregnancy by the placental conversion of fetal adrenal steroids.
• Its concentration in urine or plasma of pregnant women
provides indication of fetal well being (fetoplacental viability)
– Sudden drop in estriol concentration or output is a danger
signal of fetoplacental dysfunction.
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38. Progesterone
 It is a C21 compound and chemically more closely related to the
adrenal steroids.
 It is an intermediate in the production of adrenal steroids.
 Formed in the corpus luteum, the body that develops from the
ruptured ovarian follicle.
 Function
– Stimulates the uterus to undergo changes that prepare it for
implantation of the fertilized ovum,
– Suppresses ovulation and secretion of pituitary LH.
– If pregnancy occurs, the secretion of progesterone by the corpus
luteum and by the placenta suppresses menstruation for the
duration of the pregnancy.
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39. Placental hormones
 Function of placenta: providing nutrients to the developing embryo and
removing its waste products
 Additionally in the pregnant women it serves as an endocrine organ
– Produce
• Estrogen
• Progesterone
• chorionic gonadotropin (hCG)
• lactogen.
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40. Mechanism of Action:
 The hormone binds to “specific receptor” on the cell
membrane of target tissues like ovaries and testes, activates
adenyl cyclase, which in turn increases cyclic AMP level ↑ .
 Cyclic AMP acts as “second messenger” to produce the
biological effects.
 Metabolic role; Luteotrophic effect: The hormone
produces enlargement of corpus luteum and stimulates its
secretion. It maintains a secretory corpus luteum in first
three months of pregnancy.
 Testosterone secretion: Like LH, the hormone stimulates the
growth of interstitial cells (Leydig cells) of embryonic
testes and produces testosterone. This helps in virilisation of
the reproductive system of male embryo.
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41. Human chorionic gonadotropin (hCG)
 It is a glycoprotein composed of 2 chains, alpha and beta.
 Alpha polypeptide chain is identical to the alpha chain on many
other hormones including TSH, LH and FSH.
 The beta chain is unique in hCG so is the specificity for
immunoassay techniques.
 The action of hCG is similar to that of LH
– It stimulate the corpus luteum to produce progesterone.
• Progesterone helps to maintain the pregnancy by preventing
menstruation.
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42. Clinical significance of hCG
 For diagnosis of pregnancy
– The detection of hCG in urine or serum is the basis of
current tests for pregnancy.
– The most sensitive can detect pregnancy with in 5 to 7 days
after conception.
– The antibody used for quantitation of serum hCG should be
specific to β-hCG in order to avoid cross reactions,
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43. Human placental lactogen
 It is a protein hormone that is structurally, immunologically and
functionally very similar to growth hormone and prolactin
 HPL appears to act in concert with HCG to stimulate estrogen and
progesterone synthesis by the corpus luteum.
 It stimulates development of the mammary gland (similar to prolactin)
 Has somatotropin actions similar to those of growth hormone.
 it increases maternal plasma glucose levels and mobilization of free
fatty acids and promotes positive nitrogen balance.
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44. Male sex hormones
 The male gonads are the testes.
 They have a double function:
– To produce and secrete the male hormone, testosterone
– To produce the spermatozoa
• Essential for fertilization of the ovum in the reproductive process.
 The testes are part of a hypothalamic-pituitary-gonadal axis.
– FSH stimulate spermatogenesis,
– LH stimulate the production of testosterone by interstitial (Leydig’s)
cells.
– Both LH and FSH suppressed by high levels of testosterone
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45. Testosterone
 The most potent naturally occurring androgen.
 Function
– Promote growth of secondary sex organs
• It causes growth and development of the male reproductive
system, prostate, and external genitalia.
– Promotes muscular and skeletal growth and is protein anabolic.
 Transport
• 80% by plasma globulin
• 17% by albumin
• < 3% unbound, active hormone.
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46. Testosterone cont’d
 All of the testosterone in males is derived from the testes; the
contribution of the adrenal cortex is negligible.
 Plasma testosterone levels are much lower in women, usually only
5% of those found in men.
 Testosterone in women arise from the tissue conversion of
androgens.
 Plasma testosterone concentration is a good way of studying
hypogonadism and hypergonadism.
 The role of the pituitary has to be assessed to determine whether an
abnormality is primary to testes or secondary to an LH deficiency or
excess.
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47. Testosterone cont’d
 Increased concentration of testosterone
– Testicular carcinomas
– Abnormalities of pituitary gonadotropin of males
– In female
• Virilism: development of male physical characteristics(depending
of voice, breast atrophy, increased hair growth)
• Hirsutism: growth of body hair in male like pattern
 Decreased plasma testosterone can be due to:
– Defects associated with testis
– Defects associated in pituitary
– Chromosomal abnormalities of sex hormones.
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48. Methods of Sex Steroid Analysis
 Estrogens and testosterol
RIA
Reference Ranges vary with method and timing of female
cycle
 More useful if tested along with FSH and LH
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49. THANKS!!!!!
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