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 adenohypophysisposterior 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 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:
Def. of ADH
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
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
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),
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:
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
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
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 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;
-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.
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
Giving the dwarf child HGH which has been extracted from cadavers.
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:
Basal serum GH level: if within high normal range exclude hGH deficiency. But low levels not confirm hGH defSo 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 withGalactorrhea (abnormal breast milk production),
Headaches,
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.
Increased prolactin levels (through its effect on FSH) can interfere with clomiphenes 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?????