Download 3rd Lecture Endocrine Biochemistry

2nd Lecture Endocrine Biochemistry 2017
Objectives of 2nd lecture
• To shed light on the normal function of ADH as example of
hypothalamic hormones.
• Draw attention to the clinical disorders that results from abnormal
ADH levels.
• To evaluate the functions & clinically oriented disorders of two
important polypeptide pituitary hormones (GH & prolactin).
The pituitary composed of 2 lobes:
– anterior lobe “ adenohypophysis”
– posterior lobe “neurohypophysis”
Posterior Pituitary Hormones:
Hormones synthesized in the hypothalamus are transported down the
axons to the endings in the posterior pituitary. These hormones are stored
in vesicles in the posterior pituitary until release into the circulation. The
principal Hormones are Vasopressin & Oxytocin
Arginine-vasopressin (ADH)
• ADH is a polypeptide hormone has a short half life (15-20 min) and
metabolised in kidneys and liver
• In hyperosmolality e.g. during dehydration, this hormone is released
from posterior pituitary and acts on renal tubule through special
receptors enhancing water reabsorption from tubules to the blood
(without salts). It will dilute the blood and therefore corrects
osmolality, but concentrated urine is produced. The reverse is true,
when the subject drinks a lot of water/fluid, this will decrease blood
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2nd Lecture Endocrine Biochemistry 2017
osmolality and inhibits ADH secretion, with more loss of water in
urine (dilute urine is produced).
Posterior Pituitary: Regulation of Osmolality
Plasma Osmolality is monitored by osmoreceptor in the hypothalamus. An
increase in plasma osmolality stimulates secretion of vasopressin. Small
changes above the normal plasma osmotic pressure (285 mosm/kg)
stimulate release of vasopressin
Disorders of ADH:
Is of 2 types:
1) Def. of ADH
2) Excess ADH
Disease or trauma that causes damage of hypothalamus or posterior
pituitary causes deficiency of ADH resulting in a syndrome called Central
diabetes insipidus (CDI). Also, congenital absence of tubular receptors of
ADH (renal cause), results in a similar syndrome called nephrogenic
diabetes insipidus.
Q: Are there hormones involved in control of body water? Yes, examples
are: Atrial natriuretric peptide (ANP), aldosterone, prostoglandins ,
angiotensin II and kidney urodilin (ANP-like hormone) but ADH is the most
imp one.
Causes of central DI
 Secretion of vasopressin is regulated at the paraventricular &
supraoptic nuclei, which sense changes in osmolarity. Destruction of
the paraventricular or supraoptic nuclei or of the posterior pituitary
by any of the below conditions results in decreased vasopressin
secretion
– Brain tumor
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2nd Lecture Endocrine Biochemistry 2017
–
pituitary / cranial surgery
–
closed head trauma
–
granulomatous disease
– Histiocytosis X
–
CNS infections
• DI may be idiopathic or inherited either as an autosomal dominant or
as an autosomal recessive trait (locus 20p13)
Nephrogenic DI (NDI)
• NDI arises from defective or absent receptor sites at the cortical
collecting duct segment of the nephron (X-linked, vasopressin V2
receptor deficiency, locus Xq28) or defective or absent aquaporin,
the protein that transports water at the collecting duct (autosomal
recessive, locus 12q13)
• The X-linked variety of NDI accounts for about 90% of all cases
• Aquaporin enhances water entry into the cell from the lumen
• Absence of the vasopressin receptor does not allow this process to
take place, causing inhibition of water uptake and polyuria
• Alternatively, defective or absent aquaporin impairs the process in
the presence of normal V2 receptors
Signs and symptoms
The most common symptom of diabetes insipidus are:
– Polydepsia
– Polyuria
– Nocturia & bed-wetting
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2nd Lecture Endocrine Biochemistry 2017
Diabetes insipidus can cause dehydration which can cause:
• Dry mouth
• Muscle weakness
• Hypotension (low blood pressure)
• Sunken appearance of the eyes
• Weight loss
Diabetes insipidus can also cause an electrolyte imbalance (Hypernatremia
& hyperchloremia). Electrolyte imbalance can cause symptoms such as
headache, fatigue, irritability and muscle pains. Seizure secondary to
Hypernatremia can happen
Diagnostic Studies
• Diagnosis should be suspected in any patient with sudden increased
thirst & urination
• Laboratory examination will reveal very diluted urine, made up
mostly of water with no solute
• Examination of the blood will reveal very concentrated blood, high in
solute and low in fluid volume
– The serum sodium may be as high as 170 mEq/L
– Specific gravity of < 1.005 (low)
– Urine osmolality of < 100 mOsm/kg (low)
– Serum osmolality > 290 mOsm/kg (High)
The water deprivation test is useful in patients with polyuria. The
differential diagnosis of polyuria are:
• Diabetes insipidus (either central or nephrogenic),
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2nd Lecture Endocrine Biochemistry 2017
• psychogenic polydipsia, or
• An osmotic diuresis (e.g., hyperglycemia ) .
Patients who undergo the water deprivation test should have:
• the urine volume and urine osmolality every hour and
• plasma sodium concentration every two hours once water
deprivation begins.
The test is stopped when:
– patient has lost > 5% of original body weight
– patient has reached certain limits of low blood pressure &
increased heart rate
– urine is no longer changing significantly from one sample to
the next in terms of solute concentration
The next step of the test involves injecting a synthetic form of ADH, with
one last urine sample examined 60 minutes later
Comparing plasma and urine osmolarity allows to diagnose either
– central DI, Nephrogenic DI, partial DI, or
– psychogenic polydepsia
• But these two conditions (DI or polydipsia) are characterized by
polyuria with a dilute urine osmolarity, So how to distinguish
between them?
If the serum sodium is high (D.I.) but if it is low (polydipsia)
The problem is when serum sodium is within the normal range!!!
This can be solved by the next step (i.e. response to Exogenous ADH) of
WDT as follow:
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2nd Lecture Endocrine Biochemistry 2017
• In central D.I., exogenous ADH leads to a rapid rise in urine
osmolality:
• In complete D.I., the urine osm will more than double,
• while in partial central D.I. (which is more common) there will be an
increase of at least 15% in the urine osm.
• Generally individuals with central D.I. are able to concentrate their
urine osm > 300 mosm/kg.
How we can differentiate between DM & DI?
• Low urine specific gravity of DI distinguish it from DM (High SG) due
to presence of urine glucose in the latter case.
Syndrome of Inappropriate antidiuretic Hormone (SIADH)
The syndrome of inappropriate secretion of ADH (SIADH) is characterized
by the non-physiologic release of ADH, resulting in impaired water
excretion with normal sodium excretion
• SIADH is associated with disease that affect osmoreceptor in the
hypothalamus
• SIADH is characterized by:
– fluid retention
– serum hypo-osmolarity
– dilutional hyponatraemia
– hypchloremia
– concentrated urine in the presence of normal or increased
intravascular volume
– normal renal function
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2nd Lecture Endocrine Biochemistry 2017
Diagnosis of SIADH
• Diagnosis of SIADH is made by simultaneous measurement of urine &
serum osmolarity
• A serum osmolarity lower than the urine osmolarity indicates the
inappropriate excretion of concentrated urine in the presence of very
dilute serum
• Dilutional hyponatraemia is indicated by serum sodium < 134mEq/l,
serum osmolarity less than 280mOsm/kg & specific gravity > 1.005
• other Labs include decreased BUN, creatinine
Treatment
• If symptoms are mild & serum sodium >125 meq:
– treatment may be fluid restriction of 800-1000ml/day
This restriction should result in
– a gradual daily reduction in weight,
–
progressive rise in serum sodium concentration and
osmolality, and
–
symptomatic improvement
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2nd Lecture Endocrine Biochemistry 2017
Human Growth Hormone:HGH is a glycoprotein H. its half life is only 20 hours. The level of
HGH in the body decreases with age. It is thought that the
features of aging such as smaller muscle mass and wrinkles is due
to the small amount of this hormone. This hormone regulates
growth and development of the body. It is also called
somatotropin.
The highest blood level of this hormone
occurs after
 Severe exercise,
 Deep sleep,
 Some drugs and
 Hypoglycaemia.
These four factors have been used in
laboratories to estimate growth hormone
level after stimulation, to diagnose
growth hormone deficiency.
GH has 2 important functions
 Growth function occurs through specific factors called
somatomedins (also called insulin-like growth factors {IGF I
and IGF II} and sulphation factors) — they are produced from
liver cells in response to GH. They promote their growth
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2nd Lecture Endocrine Biochemistry 2017
effect on target tissues (bone and cartilage) through specific
cell membrane receptors. In addition, normal growth
required also good nutrition, emotional stability, and normal
thyroid function (T3 stimulates GH gene expression and
general metabolic function).
 Metabolic function: it stimulates protein synthesis and
lipolysis (results in increased FFA in blood), but it inhibits
glucose uptake by peripheral cells causing hyperglycaemia,
(i.e. insulin antagonist), as it prevents insulin binding to its
receptors.
Growth hormone disorders:
Gigantism
 If too much HGH is produced during childhood than a condition
called gigantism occurs.
 Individuals with this disorder have abnormally long skeleton
bones.
 Treatment for this disorder include;
- Surgical removal of a tumor from the pituitary gland
- Irradiation of the gland tissue.
Acromegaly
 Acromegaly is a condition caused when an adult body
produces too much HGH. The cause of the increased
production of HGH is a tumor in the pituitary gland.
Symptoms of this condition may include;
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2nd Lecture Endocrine Biochemistry 2017
-thickening of bone tissue.
-abnormal growth of the head, hands and feet.
-spinal deformities
 Treatment of acromegaly includes:
- surgical removal of the tumor
- radiation therapy
- injection of a growth hormone blocking drug
Q: Why we measured serum GH in laboratory?
We do this to investigate one of the following are two
abnormalities.
 Increased GH due to pituitary tumors,
Biochemical Dx: basal S. GH level
is higher than normal but it could
be within normal level so we
should do Glucose suppression
test. Acromegaly diagnose if there
is fall of s. GH. Plasma IGF-1 has long half life and it
correlates with severity of disease. With GH, IGF can be
used in monitoring of Rx of acromegaly.
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2nd Lecture Endocrine Biochemistry 2017
 Decreased GH (short stature), is due to either pituitary
deficiency of GH. People with this disorder have a short
stature with normal length arms and legs.
 Some treatment involved for these individuals are
o Giving the dwarf child HGH which has been extracted
from cadavers.
o Inserting sections of DNA, which are responsible for
HGH production, into bacteria. These bacteria then
produce
HGH as a
waste
product, this
HGH is then
used to treat
dwarfism.
or GH
insensitivity (absence of hepatic receptors)—called
Laron-Pygmies dwarf. The laboratory pictures are
completely different as in 1st type both GH & IGFs
(insulin like growth factors) levels in blood are low
while in 2nd type only IGFs levels are low while GH
level is normal or even high.
Lab Diagnostic Tests for short stature:
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2nd Lecture Endocrine Biochemistry 2017
• Basal serum GH level: if within high normal range exclude
hGH deficiency. But low levels not confirm hGH def
• So we sd do GH provocation (Stimulation)Test after
exercise or administration of drugs ex: clondine or insulin.
If there is no response (No increase in HGH level) after 2
tests indicates GH deficiency
Prolactin Hormone:
 This polypeptide hormone, which is also produced by the
anterior pituitary gland, stimulates the development of
mammary gland tissue and milk production (lactogenesis).
 The hypothalamus regulates the production of prolactin. The
hypothalamus secretes a hormone called dopamine which
inhibits the production of prolactin.
 In late pregnancy, an increase in the hormone estrogen will
stimulate prolactin production. Also, after a child is born
breast feeding stimulates nerve endings in the nipples which
stimulates the hypothalamus to release prolactin secreting
hormones.
Q: Why we measured serum prolactin in laboratory?
To investigate patients with
 Galactorrhea (abnormal breast milk production),
 Headaches,
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2nd Lecture Endocrine Biochemistry 2017
 Visual problems,
 Irregular bleeding and
 Infertility.
Q: Is any elevation in serum prolactin level is
pathological?
No/ sometimes it is temporarily elevated after:
 Eating,
 Stress,
 Sexual excitement and
 Certain drugs.
If an elevation of prolactin is discovered, it should be repeated to
confirm or exclude the diagnosis. Elevated prolactin levels may
cause: irregular periods, and infertility.
How elevated prolactin causes infertility?
Elevated prolactin causes anovulation (failure to release an egg in
each menstrual cycle) by interfering with the normal release of
FSH and LH from the pituitary. (i.e. high levels of prolactin usually
associated with low LH and FSH levels in blood.
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2nd Lecture Endocrine Biochemistry 2017
Increased prolactin levels (through its effect on FSH) can interfere
with clomiphene’s effectiveness so it can decreases the chance of
pregnancy in infertility treatments that is, if it is elevated in an
intrauterine insemination (IUI) or in vitro fertilization (IVF) cycle, it
should be treated.
Elevated prolactin causing anovulatory cycles not only carry out
risk of infertility, but the patient may predispose to:
 Thickening of the endometrium (endometrial hyperplasia or
carcinoma) because of unopposed estrogen.
 Osteoporosis and an increased incidence of heart disease
because of the generally lower estrogen levels.
Q: Does PRL level affected by menstrual cycle? Home work?????
Good Luck
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