Reproductive

Endocrine and Reproductive Physiology

Objectives:
1-What do the body activities controlled by?
2-Define hormones? Describe their chemical structure?
3- Explain the mechanisms of hormone secretion and action?
4-Discuss the control of hormone secretion?

Coordination of body functions:

The activities of the cells, tissues, and organs of the body are coordinated by the interplay of several types of chemical messenger systems, but specifically the control is by either the nervous system or the hormonal or endocrine system:
1. Neurotransmitters
2. Endocrine hormones
3. Neuroendocrine hormones
Paracrine effect
Autocrines.
Cytokines

The target for the action of the hormone

1- Many different types of cells of the body; for example, growth hormone.
2- Only specific target tissues, because only these tissues have receptors for the hormone. For example, adrenocorticotropic hormone (ACTH)

After the secretion of the hormones, small fraction will circulate freely and the major part will bind to plasma proteins which act as:
1- Storage site, release the hormones on need.
2- Buffer mechanism: to minimize the effect of particular hormones.

Chemical Structure of Hormones;

There are three general classes of hormones:
• Proteins and polypeptides, including hormones secreted by the anterior and posterior pituitary gland, the pancreas (insulin and glucagon), the parathyroid hormone, and others.
2. Steroids secreted by the adrenal cortex (cortisol and aldosterone), the ovaries (estrogen and progesterone), the testes (testosterone).

3. Derivatives of the amino acid tyrosine, secreted by the thyroid (thyroxine and triiodothyronine) and the adrenal medullae (epinephrine and norepinephrine).



Onset of Hormone Secretion
Some hormones, such as norepinephrine and epinephrine, are secreted within seconds after the gland is stimulated,
The actions of other hormones, such as thyroxin or growth hormone, may require months for full effect.

Control of hormonal secretion:

A- Feedback mechanism:
1-NEGATIVE FEEDBACK MECHANISM:
a- Direct negative feedback:
It relates the rate of release of the hormone to the blood concentration of that substance. e.g:
ACTH (adrenocorticotrophic hormone)
CORTISOL
ACTH
pitutary
CRH

b- Indirect negative feedback:

This type will act when the nervous system is involved in the process:

CRH
ACTH
CORTISOL


c- Short negative feedback:

2- POSITIOVE FEEDBACK MECHANISM:

Means increase in the release of particular hormone from a concerned gland in response to the increase in the increase chemical substance.
e.g. FSH (follicular stimulating hormone) secreted by the pituitary gland ,circulates in the blood to affect the ovary in the female

B- Influence of the nervous system;

Means the activity of the supplying nerve to the endocrine glands.
The glands that are primarily controlled by the nervous system are:
1- Adrenal medulla. 2- Posterior lobe of the pituitary gland.


There is what is called Cyclical Variations occur in hormone release, which are periodic variations in hormone release that are influenced by seasonal changes, various stages of development and aging, the diurnal (daily) cycle, and sleep.

Mechanism of action of the hormones:

The first step of a hormone’s action is to bind to specific receptors at the target cell, after dissociation of the binding protein.
Shape is important e.g feminizing testis, although the male has normal testes can secret enough testosterone, but there are no receptors for it so there is absence of secondary sex characteristics and organs.
e,g Nephrogenic diabetes insipidis.


So how does the hormone act?
When the hormone combines with its receptor, this usually initiates a cascade of reactions in the cell.
Binding of the hormone will cause activation of Adenyl cyclase which causes immediate conversion of small amounts of ATP to cyclic AMP (3,5, adenosine monophosphate)-cAMP, which is sometimes called intracellular hormonal mediator and is called the second messenger, because the hormone mediation is the first messenger ,this will activates cAMP dependent proteins and bring about various actions ,these are :
1- Increase in the permeability of the cellular membrane.
2- Influencing the formation of special enzymes in the cells.
3- Production of other hormones.

The locations for the different types of hormone receptors are generally the following:

1. In or on the surface of the cell membrane. The membrane receptors are specific mostly for the protein, peptide, and catecholamine hormones.
2. In the cell cytoplasm. The primary receptors for the different steroid hormones are found mainly in the cytoplasm.
3. In the cell nucleus. The receptors for the thyroid hormones are found in the nucleus and are believed to be located in direct association with one or more of the chromosomes.

The regulation of the number and sensitivity of hormone receptors

The number of receptors in a target cell usually does not remain constant from day to day, or even from minute to minute.

Objectives:

1-Describe the relation between the hypothalamus and pituitary gland?
2-Enumerate the hormones and factors released from the hypothalamus and pituitary?
3-Discuss the control of ADH secretion?
4-How does Oxytocin act on its receptors?


Pituitary Hormones and Their Control by the Hypothalamus

The hypothalamus is composed of nervous tissue situated below the thalamus and it is surrounded by part of the third ventricle with afferent and efferent fibers connecting it to the rest of CNS,
The synthesis of and storage of chemical substances takes place within a specific nerve cells ,the secretion of these substances takes place in close association with the blood vessels ,so we can apply the term neurosecretion and the term hormone on them .




Most of the hypothalamic nuclei end on the median eminence with the exception of supraoptic and paraventricular nuclei ,their axon terminate in the posterior lobe of the pituitary gland while the neurosecretion in the median eminence are released to the portal system to the adenohypophysis. Each neurosecretion acts on particular adenohypophysial cell to influence the release of a specific adenohypophysial hormone

. So the adenohypophysial hormones are influenced by releasing or inhibiting factors and hormones and these are:
1- Thyrtrophin releasing hormone(TRH).
2-Corticotrophin releasing hormone (CRH).
3-Somatostatin or growth hormone inhibiting hormone (GHIH).
4-Somatrophin releasing hormone or growth hormone releasing hormone(GHRH)
5-Melanocyte stimulating hormone releasing hormone.
6-Gonadotrophin releasing hormone (GnRH) (stimulate the release of FSH and LH).
7-Prolactin inhibiting factor (PIH) (no milk secretion in normal conditions because of this factor).

The pituitary gland:

It lies in the sella turcica, a bony cavity at the base of the brain (depression in the sphenoid bone) when there is enlargement of the gland as a result of a tumor there is widening of the sella turcica, in the X ray.
It is located beneath the hypothalamus and connected to it by the pituitary (or hypophysial) stalk.


It weighs about 0.5 gm this weight increases during pregnancy (because increase in gonadotropin hormones)
Physiologically, the pituitary gland is divisible into two distinct portions:
the anterior pituitary, (adenohypophysis),

and the posterior pituitary, (neurohypophysis)

Embryologically,

1-the anterior pituitary from Rathke’s pouch, which is an embryonic invagination of the pharyngeal epithelium (or the ectoderm of the roof of the primitive mouth), So it has a glandular structure it is called adenohypophysis.
2- the posterior pituitary from a neural tissue outgrowth from the hypothalamus(or from the base of the brain), So there are large numbers of glial-type cells in this gland.

The hormones of the anterior pituitary:

• Growth hormone-GH
• Adrenocorticotropin -ACTH(corticotrophin).
• Thyroid-stimulating hormone-TSH (thyrotropin).
• Prolactin promotes mammary gland development and milk production.
• Two gonadotropic hormones, follicle-stimulating hormone –FSH and luteinizing hormone -LH.
The two hormones secreted by the posterior pituitary play other roles
.Antidiuretic hormone -ADH(also called vasopressin).
• Oxytocin.


Secretion from the posterior pituitary is controlled by nerve signals that originate in the hypothalamus and terminate in the posterior pituitary.
In contrast, secretion by the anterior pituitary is controlled by hormones called hypothalamic releasing and hypothalamic inhibitory hormones .
In the anterior pituitary, these releasing and inhibitory hormones act on the glandular cells to control their secretion.

Hormones of the posterior lobe of the pituitary gland ADH (ANTIDIURETIC HORMONE) or Vasopressin ADH is formed primarily in the supraoptic nuclei and to a lesser extent the paraventricular nucleuse, in the hypothalamus and carried along the axons to be stored in the posterior pituitary gland.



It exerts its action on the kidney, it acts on the distal convoluted tubules and collecting ducts, it increases the permeability of the cellular membrane to water so water diffuses to the surrounding medullary tissues down its osmotic gradient. reduction in the volume of urine excreted to the outside and it will become more concentrated.
Conversely in the absence of ADH, extreme dilution of the urine.
This hormone is called Vasopressin
Above the physiological concentration , vasoconstriction of arteriols throughout the body→ increase the blood pressure.

Control of hormone secretion;

1- Plasma osmolarity:
If there is reduction in the plasma osmolarity (e.g. overhydration) → inhibition of ADH secretion → large amount of water excreted to the outside.
If we have increase in the osmolarity (e.g. dehydration) → stimulation of ADH secretion →increase reabsorption and retention of water thus plasma osmolarity returns back to normal.
Osmoreceptors

2- Blood volume:

e.gblood loss (heamorhage).
The atria have stretch receptors volume or low pressure receptors. that are excited by overfilling. When excited, they send signals to the brain to inhibit ADH secretion. Conversely, when the receptors are unexcited as a result of underfilling, the opposite occurs, with greatly increased ADH secretion.


Decreased stretch of the baroreceptors of the carotid, aortic, and pulmonary regions also stimulates ADH secretion.

3-Variety of stimuli:

Drugs like morphine, pethedine (tranquilizers), they act centrally and stimulate the release of ADH→ increase of the reabsorption of water and decrease in volume of water excreted to the outside.
Alcohol inhibits the secretion of ADH and increase in urination (so drunk people urinate a lot).

Clinical conditions result from disturbances in ADH secretion:

After car accidents we have decrease in secretion of ADH and as a result we have increase urination called polyuria
We have 2 types of D.I (diabetes insipidus).:
Central D.I.:
When we have tumor of the pituitary gland→ decrease ADH secretion.
Nephrogenic D.I.;
Congenital absence of the ADH receptors in the kidney, so high level of ADH but no response
We must differentiate between DI. and D.M. (diabetes mellitus in which also there is polyuria and polydepsia ,but the specific gravity of urine in DM is higher because of the presence of glucose.

Oxytocine:

Oxytocin is formed primarily in the paraventricular nuclei in the hypothalamus, carried along the axons to be stored in the posterior pituitary, it is present in male and female but its exact physiological action is not obvious in male. Its action in females is on both
1- the uterus
2- the mammary gland.


Effect on the uterus;
It causes contraction of the uterus at labour .It aids in the expulsion of fetus and placenta; it increases to the peak value during labour. HOW?

Progesterone usually inhibits the sensitivity of the uterus to oxytocin, but Estrogen increases the sensitivity of the uterus to oxytocin.

2-Effect on the mammary gland:

In lactation, oxytocin causes milk to be expressed from the alveoli into the ducts of the breast so that the baby can obtain it by suckling, so oxytocin causes ejection of milk not secretion of it, because the secretion is under the effect of prolactin. (it is a neurohormonal reflex).
milk letdown
Or milk ejection.




Oxytocin evokes feelings of contentment, reductions in anxiety, and feelings of calmness and security
This suggests oxytocin may be important for the inhibition of the brain regions associated with behavioral control, fear, and anxiety.
Oxytocin also functions to protect against stress. Increasing trust and reducing fear

Objectives:

1-How do the anterior pituitary hormones be classified?
2-What are the effects of Growth hormone on metabolism and growth?
3-What are the effects of the disturbance in growth hormone secretion?

Anterior lobe of the pituitary gland:

It is a vascular organ .It receives its blood supply from superior and inferior hypophysial arteries. The superior arises from the internal carotid artery then it enters the median eminence, then break into numerous branches and capillary loops called the primary plexus then they reconverge to form parallel venules that descend along the stalk (the long portal vessels), descend along the stalk and penetrate the adenohypophysis and end on the sinusoids bathing the adenohypophysis

These five cell types are:

1. Somatotropes—human growth hormone (hGH), 50% of the anterior lobe.
2.Corticotropes—adrenocorticotropin (ACTH)
3. Thyrotropes—thyroid-stimulating hormone (TSH)
4. Gonadotropes—gonadotropic hormones, which include both luteinizing hormone (LH) and follicle stimulating hormone (FSH)
5. Lactotropes—prolactin (PRL), the number of these cells increase during pregnancy due to estrogen action.

We can classify the hormones of the anterior pituitary also into:

1-Glycoproteins: TSH, LH, FSH and Human Chorionic Gonadotropins(HCG) secreted during pregnancy from the placenta. Composed of 2 peptide chains α and β chains. Alpha chains are similar in all but beta is different so their action depends on beta chains.


2-Somatomammotrophins: (single peptide) prolactin and growth hormone, Human Placental Lactogen(HPL).

3-ACTH related peptide. These close related peptides are derived from parent compound known as (Big ACTH) which has120- 130 amino acid residues. This undergoes enzymatic cleavage → large fragment (β lipoprotein), this gives rise to smaller peptides, the most important of which is ACTH.

ACTH synthesized in basophilic cells and composed of 39 amino acids. The activity of ACTH resides in the first 24 a.a. (a property used in the synthesis of the synthetic ACTH).
The first 13 a.a resembles that of β –melanocyte stimulating hormone; therefore if we have increment of ACTH above the physiological level, we have increase in the pigmentation of the skin.
Other important fragment of β lipotrophes is β endorphin which is present in the brain and GIT and acts as a neurotransmitter (have analgesic property).

13 24 39↓

This is like MSH All the activity of the ACTH is due to this limit

TSH (thyroid stimulating hormone) :

TSH is a glycoprotein synthesized and stored in the thyrotroph cells (basophilic cells) ,its primary action is on the thyroid gland
Stimulate the synthesis and release of T3 and T4 after several mechanisms:
Stimulation of iodide pump in the cell membrane which transport the iodine from the blood to the cell against the electrochemical gradient.
It stimulates the synthesis of thyroid storage protein which is thyroglobulin.
Stimulates the synthesis of T3 and T 4.
Stimulates the release of T3 and T4 from the thyroglobulin complex.

If there is oversecretion of TSH there is enlargement of the thyroid gland (goiter).

FSH (follicle stimulating hormone) and LH (lutenizing hormone):
They are glycoproteins
They are responsible for development of the ovarian follicles and ovulation.
The production of LHRH (lutenizing hormone releasing hormone) is inhibited by estrogen and to lesser extent by progesterone; this phenomenon is used in the contraceptive pills,

While LHRH is stimulated by estrogen deficiency, so we can use antiestrogenic drugs like clomid.

In male FSH stimulates the development of sperms i.e spermatogenesis,

the release of peptide called inhibin ,which feeds back and inhibit the release of FSH
LH in male is called interstitial cell stimulating hormone (ICSH), it stimulates the interstitial cells to synthesize and release Testosterone. As the level of testosterone increase, we have inhibition of LH secretion.

Growth hormone:

It does not function through a target gland but exerts its effects directly on all or almost all tissues of the body.
It exerts an effect on metabolism and tissue growth. The effect on metabolism is a direct effect but on growth is indirect via a peptide called somatomedin.

Somatomedin is synthesized in the liver and to lesser extent by the kidney under the effect of growth hormone.
.

Effect of GH on metabolism:

1-Effect on proteins: GH increase protein synthesis and tissue growth
1- Enhancement of Amino Acid Transport through the Cell Membranes increased protein synthesis.
2-Enhancement of RNA Translation to Cause Protein Synthesis by the Ribosomes.
3-Increased Nuclear Transcription of DNA to Form RNA.
4-Decreased Catabolism of Protein and Amino Acids.
5-Decrease urinary urea nitrogen.
6-The net effect is positive nitrogen balance.

2-Effect on fat metabolism

Growth hormone has a specific effect in causing the release of fatty acids from adipose tissue increasing the concentration of fatty acids in the body fluids, and increase in utilization of fat which promote a source of energy for tissues, increase in keton bodies formation by the liver
(ketogenic hormone).


3- Effect on carbohydrates:
including (1) decreased glucose uptake in tissues such as skeletal muscle and fat,
(2) increased glucose production by the liver, and
(3) increased insulin secretion.
This will cause increase in blood glucose concentration. So it is considered as a diabetogenic hormone.

4- Effect on electrolytes:

It decreases the elimination of all electrolytes in the body.
It increases the absorption of calcium by the intestine.
Na and K excretion through the kidney is reduced .
The electrolyte levels in blood and urine decrease. Why?

5-Effect on growth:

Increase size of the body. The effect of growth hormone is through
(1)increased deposition of protein by the chondrocytic and osteogenic cells that cause bone growth
(2) increased rate of reproduction of these cells,
and
(3) a specific effect of converting chondrocytes into osteogenic cells, thus causing deposition of new bone i.e stimulate osteoblast cells.
GH stimulates a second humeral factor which acts on the cartilage called somatomedine which is synthesized in the liver and to lesser extent in the kidney under the effect of GH.
Many of the somatomedin effects on growth are similar to the effects of insulin on growth. Therefore, the somatomedins are also called insulin-like growth factors (IGFs).


Regulation of Growth Hormone Secretion;

After adolescence, secretion decreases slowly with aging, finally falling to about 25 per cent of the adolescent level in very old age. Growth hormone is secreted in a pulsatile pattern, increasing and decreasing.
Factors affecting the release of GH:
State of nutrition ;( 1) starvation, especially with severe protein deficiency (under a chronic conditions is a good stimulator); (2) hypoglycemia (under acute conditions, it is a good stimulator) (3) low concentration of fatty acids in the blood.
Stress: exercise; excitement; and trauma.
Deep sleep: GH increases during the first 2 hours of deep sleep.
Feedback mechanism:
GHRH stimulated by hypoglycemia, emotion, stress, trauma, dopamine, serotonin.

GHRH passes through the hypothalamo hypophysial portal system to adenohypophysis, bind with receptors in the cell membrane of somatotroph cells leading to:
Immediate response to CAMP and have release of GH via Calcium enter the cell.
Late action of CAMP, stimulate GH synthesis.
GHIH (also called somatostatine) stimulated by hyperglycemia, increase free fatty acids, aging, obesity, exogenous injection of humeral GH.
The level of GH increases in the circulation→ feedback to the hypothalamus→ decrease the release of GHRH → decrease the release of GH (short loop negative feedback).

Abnormalities of Growth Hormone Secretion:

Reduction in GH secretion
Panhypopituitarism: as in case of tumor decreasing all the pituitary hormones.
Dwarfism. Results from deficiency of GH secretion during childhood.

Increase in GH secretion:

1-Gigantism.
Tumors occur in the pituitary gland. As a result, large quantities of growth hormone are produced. All body tissues grow rapidly, including the bones.
Occurs before adolescence, before the epiphyses of the long bones have become fused with the shafts, height increases so that the person becomes a giant. The giant ordinarily has hyperglycemia. Consequently, full-blown diabetes mellitus eventually develops.





2-Acromegaly. If the tumor occurs after adolescence— that is, after the epiphyses of the long bones have fused with the shafts—the person cannot grow taller, but the bones can become thicker and the soft tissues can continue to grow.
Enlargement of he bones of the hands and feet and in the membranous bones, including the cranium, nose, bosses on the forehead, supraorbital ridges, lower jawbone, and portions of the vertebrae, because their growth does not cease at adolescence.
Many soft tissue organs, such as the tongue, the liver, and especially the kidneys, become greatly enlarged.

The concentration of GH in different ages

5 to 20 years 6 ng/ml
20 to 40 years 3 ng/ml
40 to 70 years 1.6 ng/ml

Prolactin hormone:

It is secreted by lactotroph cells. In female it causes milk secretion after estrogen and progesterone priming effect.
During pregnancy there is no prolactin secretion because of the presence of estrogen and progesterone secreted by the placenta in addition to prolactin inhibiting factor.
After delivery the effect of estrogen and progesterone will be gone and no suppression of prolactin so milk secretion will occur.
Sometimes we have increase in prolactin in pathological way which leads to inhibition of LH and FSH → estrogen and progesterone inhibition → amenorrhea (no menstrual cycle).
In case of dead fetus, we don’t need milk so we give antiprolactin drugs (parlodel).

Objectives:

1- What are the hormones secreted from thyroid gland?
2- Describe the physiological actions of thyroid hormones?
3-What are the physiological effects of hypothyroidism and hyperthyroidism?

Thyroid gland:

The thyroid secretes two major hormones,
thyroxine(T4)or tetraiodothyronin and triiodothyronine,(T3),these concerned with metabolism. The thyroid gland also secretes calcitonin, an important hormone for calcium metabolism.
Thyroid gland has got a characteristic feature in trapping iodide from the circulation. This feature is also present in salivary gland, intestinal mucosa, mammary gland, ciliary body and choroid plexuses, but cannot synthesize thyroid hormone.

Iodide Pump (Iodide Trapping):

1- transport of iodides from the blood into the thyroid glandular cells and follicles. This is called iodide trapping.
The rate of iodide trapping by the thyroid is influenced by the concentration of TSH; which stimulates the pump and hypophysectomy greatly diminishes the activity of it.

2- Oxidation of the Iodide Ion.

Iodide Iodine
(peroxidase).
3-Iodination of Tyrosine and Formation of the Thyroid Hormones. Oxidized iodine will be secreted to the lumen of the follicle , bind directly with the amino acid tyrosine. Tyrosine is first iodized to monoiodotyrosine and then to diiodotyrosine. 2 molecules of diiodotyrosine will form thyroxin (T4), and one monoiodotyrosine with one diiodotyrosine, will form triiodothyronin(T3).
All these forms will attach to a protein called Thyroglobulin, When needed thyroxin and triiodothyronine must first be cleaved from the thyroglobulin molecule, and then released.





On entering the blood, over 99 per cent of the thyroxine and triiodothyronine combines immediately with plasma proteins.
They combine mainly with thyroxine-binding globulin (TBG), binds mainly to T4, and much less so with thyroxine-binding prealbumin (TBPA)bound mainly to T3 and albumin.
Thyroxine (T4) — are released to the tissue cells slowly, has high affinity for binding with blood proteins.
While triiodothyronine—because of its lower affinity to binding with blood proteins—is released to the cells easier.


The physiological action of thyroid hormone:
1- Thyroid hormones increase the transcription of large numbers of genes;
So there will be generalized increase in functional activity throughout the body. Before acting on the genes, one iodide is removed from almost all the thyroxine, thus forming triiodothyronine.
Intracellular thyroid hormone receptors have a very high affinity for triiodothyronine.

2-Thyroid hormones increase cellular metabolic activity:

The thyroid hormones increase the metabolic activities of almost all the tissues of the body. Increase the number and activity of mitochondria, Increases the rate of formation of (ATP) .
Increase the activity of enzyme Na+-K+- ATPase, which increases heat production.
Basal metabolic rate BMR is the quantity of energy production at rest during optimal temperature, measured 12 hours after last meal.

3-Calorigenic Action:

T4 and T3 increase the O2 consumption and heat production of almost all metabolically active tissues. The exceptions are the adult brain, testes, uterus, lymph nodes, spleen, and anterior pituitary.

4-Effect on carbohydrates ,fat and protein:

Carbohydrates, It stimulates rapid uptake of glucose by the cells, enhanced glycolysis, enhanced hepatic gluconeogenesis, increased rate of absorption from the gastrointestinal tract, and even increased insulin secretion. So we have increase in blood glucose concentration.

Fat, it has a lipolytic action.

This also increases the free fatty acid concentration in the plasma.
It also decreases the concentrations of cholesterol, phospholipids, and triglycerides in the plasma,
-increase the rate of secretion in the bile and consequent loss in the feces.
-increased formation of LDL (low density lipoprotein) receptors in the liver -Indirectly (lipolysis) through potentiation of the effect of other hormones like adrenaline, glucagon and glucocorticoids.


Protein, it stimulates the synthesis of specific proteins.
This anabolic action occurs when TH is within the physiological limits. But if we have increase in the level of thyroid hormone this anabolic will to catabolic action, especially in muscles and causes muscle weakness (thyrotoxic myopathy),.
The plasma creatinin increases and causes excessive amino acids in blood (creatinurea).
In hypothyroidism, there will be deposition of mucoprotein subcutaneously which sucks water and causes swelling (edema) differ from heart failure edema because it is not pitting.

Vitamins, thyroid hormone causes increased need for vitamins. Therefore, a relative vitamin deficiency can occur when excess thyroid hormone is secreted.

3- Effect of Thyroid Hormones on the Cardiovascular System;

Increased Blood Flow and Cardiac Output. The increase metabolism causes vasodilatation in most body tissues, thus increasing blood flow (increase in metabolism will cause accumulation of metabolites and vasodilatation). The rate of blood flow in the skin especially increases because of the increased need for heat elimination from the body. As a result of increase blood flow, the cardiac output increases.

The heart rate increases considerably, so it is one of the sensitive physical signs

The systolic blood pressure increases because thyroid hormone enhances the effect of chatcholamines.
While peripherally the vasodilatation due to the increase in BMR will cause decrease in the peripheral resistance that means drop in the diastolic blood pressure.
As a result of that we have increase in the pulse pressure (pulse pressure= systolic blood pressure- diastolic pressure).
The mean arterial pressure usually remains about normal because the rise in systolic is equal to the drop in diastolic.
The heart muscle strength becomes depressed because of long-term excessive protein catabolism.

Effect on respiration:

The increased rate of metabolism increases the utilization of oxygen and formation of carbon dioxide;
increase the rate and depth of respiration to get rid of the accumulated CO2.
Effect on GIT:
increase in the absorption of food stuffs and an increase in the rate of secretion of digestive juices and increase in the motility of GIT. Excessive thyroid hormone results in diarrhea and associated with increase appetite due to increase of BMR and increase of consumption of ATP and sometimes loss of weight.
.


Effect on sexual function:
In men, lack of thyroid hormone is likely to cause loss of libido
great excesses of the hormone, however, sometimes cause impotence.
In women, lack of thyroid hormone often causes menorrhagia and polymenorrhea
A hypothyroid woman, like a man, is likely to have greatly decreased libido. While in the hyperthyroid woman, oligomenorrhea, and occasionally amenorrhea results.

Effect on growth (effect on the bone):

Thyroid hormones are essential for normal growth and skeletal maturation.
In congenital hypothyroidism, bone growth is slowed and epiphysial closure delayed.
In the absence of thyroid hormones, growth hormone secretion is also depressed, and thyroid hormones potentiate the effect of growth hormone on the tissues.
In those who are hyperthyroid, excessive skeletal growth often occurs, causing the child to become considerably taller at an earlier age. However, the bones also mature more rapidly and the epiphyses close at an early age, so that the duration of growth and the eventual height of the adult may actually be shortened.


Excess thyroid hormone secretion result in excessive demineralization of the bone and a resultant increase in urinary loss of calcium and phosphate and this effect is apart from the effect of parathyroid hormone but it is due to the catabolic effect of TH on the proteins as part of the matrix of the bone.

Effect on the central nervous system:

An important effect of thyroid hormone is to promote growth and development of the brain .
If the fetus does not secrete sufficient quantities of thyroid hormone, growth and maturation of the brain both before birth and afterward are greatly retarded. Without thyroid therapy within days or weeks after birth, the will remain mentally deficient throughout life.
In general, thyroid hormone increases the rapidity of cerebration.
The hyperthyroid individual is likely to have extreme nervousness, irritability, exaggerated response to environmental stimuli and many psychoneurotic tendencies, such as anxiety complexes, extreme worry, and paranoia (always suspect) ,
TH results in hyperexcitibilty due to increase in synaptic transmission .


Effect on Sleep. Because of the exhausting effect of thyroid hormone on the musculature and on the central nervous system, the hyperthyroid subject often has a feeling of constant tiredness, but because of the excitable effects of thyroid hormone on the synapses, it is difficult to sleep. Conversely, extreme somnolence is characteristic of hypothyroidism.

Effect on Other Endocrine Glands.

increases the rates of secretion of most other endocrine glands, but it also increases the need of the tissues for the hormones.
e.g increases the rate of glucose metabolism everywhere in the body and therefore causes a corresponding need for increased insulin secretion by the pancreas.
Also, thyroid hormone increases many metabolic activities related to bone formation and, as a consequence, increases the need for parathyroid hormone.
Thyroid hormone also increases the rate at which adrenal glucocorticoids are inactivated by the liver. This leads to feedback increase in adrenocorticotropic hormone.

Objectives:

1-What is goiter? Enumerate the causes of iodine deficiency?
2-Explain the physiological influence of hypothyroidism and hyperthyroidism?
3-Describe the action of parathyroid hormone

Clinical conditions:

Enlargement of the thyroid gland for any reason is called goiter. The metabolic function of the gland is either increased or decreased (hyper or hypothyroidism).

Endemic goiter
Usually in places where iodine is insufficient in food, so there is inadequate formation of the TH.
As a result, no hormone is available to inhibit production of TSH by the anterior pituitary; this causes the pituitary to secrete excessively large quantities of TSH. .
The TSH then stimulates the thyroid cells to secrete tremendous amounts of thyroglobulin colloid into the follicles, and the gland grows larger and larger.

Idiopathic Nontoxic Colloid Goiter.

Can also occur in people who do not have iodine deficiency. These goitrous glands may secrete normal quantities of thyroid hormones, but more frequently, the secretion of hormone is depressed
Most of these patients show signs of mild thyroiditis.
Iodine deficiency is due to:
1-Deficiency of iodine intake.
2-Substances interfere with absorption of iodide from GIT.
3-Substances interfere with the taken up by follicular cells such as thiocynate ions. Some foods contain goitrogenic substances, thus leading to TSH-stimulated enlargement of the thyroid gland. Such goitrogenic substances are found especially in some varieties of turnips and cabbages.
4- Substances interfering with its transforming to iodine.

Abnormality of the enzyme system required for formation of the thyroid hormones.

1-Deficient iodide-trapping mechanism,
2. Deficient peroxidase system, in which the iodides are not oxidized to the iodine state
3. Deficient coupling of iodinated tyrosines in the thyroglobulin molecule,
4. Deficiency of the deiodinase enzyme, which prevents recovery of iodine from the iodinated tyrosines that are not coupled to form the thyroid hormones

Hypothyroidism:

The cause is either in the thyroid gland or in pituitary or hypothalamus
Hypothyroidism, probably is initiated by autoimmunity against the thyroid gland. The thyroid glands of most of these patients first have autoimmune “thyroiditis,”.
Several other types of hypothyroidism also occur, often associated with development of enlarged thyroid glands, called thyroid goiter, as discussed.
So the causes for hypothyroidism:
thyroiditis, endemic colloid goiter, idiopathic colloid goiter, destruction of the thyroid gland by irradiation, or surgical removal of the thyroid gland


Physiologic Characteristics of Hypothyroidism.

Fatigue with sleeping up to 12 to 14 hours a day,

Extreme muscle sluggishness(decrease tone)
slowed heart rate, decreased cardiac output
sometimes increased body weight, constipation, mental sluggishness, dryness of the hair and skin, development of husky voice, slowness of speech



and, in severe cases, development of an edematous appearance throughout the body called myxedema.

Myxedema.

such a patient, demonstrating bagginess under the eyes and swelling of the face.
increased quantities of hyaluronic acid and chondroitin sulfate bound with protein.
Because of the gel nature of the excess fluid, it is mainly immobile, and the edema is the nonpitting type(hard),while in case of for example renal and liver failure it is pitting.


Atherosclerosis in Hypothyroidism. Lack of thyroid hormone increases the quantity of blood cholesterol
which in turn results in peripheral vascular disease, deafness, and coronary artery disease with consequent early death.

Diagnostic Tests in Hypothyroidism.

The free thyroxine in the blood is low. The basal metabolic rate low. And the secretion of
TSH by the anterior pituitary is usually greatly increased

Cretinism

It is caused by extreme hypothyroidism during fetal life, infancy, or childhood. This condition is characterized especially by failure of body growth and by mental retardation.
1- congenital lack of a thyroid gland (congenital cretinism),
2- genetic defect of the gland, or from iodine lack in the diet especially of the pregnant woman (endemic cretinism).
3- treatment of the hyperthyroid mother with antithyroid drugs that passes placental barrier to fetus.

We have to treat the child during the first few weeks after birth . Disproportionate rate of growth,





So in critisim we have short stature and mental retardation, while in GH deficiency we also have short stature but without mental retardation.
Occasionally the tongue becomes so large in relation to the skeletal growth that it obstructs swallowing and breathing.

Hyperthyroidism

Excessive thyroid secretion.
In hyperthyroidism, the level of TSH is reduced, but it is not accompanied by the decrease in thyroid hormone.
Because there are substances which have similar action to that of TSH found in the blood of almost all patients, these are immunoglobulin antibodies. These antibodies are called thyroid-stimulating immunoglobulin (TSI).
Thyroid Adenoma. Hyperthyroidism occasionally results from a localized adenoma (a tumor) that develops in the Thyroid tissue and secretes large quantities of thyroid hormone.

Symptoms of Hyperthyroidism

(1) a high state of excitability, (2) intolerance to heat, (3) increased sweating, (4) mild to extreme weight loss, (5) varying degrees of diarrhea, increase appetite (6) muscle weakness, (7) nervousness or other psychic disorders, (8) extreme fatigue but inability to sleep, and (9) tremor of the hands.10) vitamin deficiency especially D.

Exophthalmos. It is protrusion of the eyeballs, sometimes becomes so severe that the eyeball protrusion stretches the optic nerve enough to damage vision. As a result, the epithelial surfaces of the eyes become dry and irritated and often infected, resulting in ulceration of the cornea.
The cause of the protruding eyes is edematous swelling of the retro-orbital tissues and degenerative changes in the extraocular muscles.

Muscle Tremor.

fine muscle tremor. This is not the coarse tremor that occurs in Parkinson’s disease or in shivering, because it occurs at the rapid frequency of 10 to 15 times per second. The tremor can be observed easily by placing a sheet of paper on the extended fingers and noting the degree of vibration of the paper.
This tremor is believed to be caused by increased reactivity of the neuronal

Calcitonin:

This peptide hormone is synthesized and secreted by the parafollicular cells (c- cells), it is also called calcium lowering hormone it is not under the control of pituitary or the hypothalamus. It is affected by the level of calcium in the blood.
It mobilizes the calcium from the blood to the bone and enhances the osteoblastic activity, so it opposes the parathyroid hormone.
We have increase in its level when there is need to calcium i.e growth, pregnancy, lactation.

Parathyroid Hormone:

Normally there are four parathyroid glands in humans; they are located immediately behind the thyroid gland.
It controls the level of calcium and phosphate in the blood by the movement of calcium and phosphate from the bone to blood and excretion of po4 by the kidney.
Usually 99% of calcium is in the bone and small fraction is ionized and circulates in the blood and this is the active form which performs the physiological action. .
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Calcium level is controlled by:
1-Parathyroid hormone.
2-Calcitonin
3-Metabolites of vitamine D “1,25 dihydroxycholecalceferol”.

The level of calcium is 10 mg/dl(9.4 mg/dl) or 5 meq/L in SI units and is present in 3 forms:
1- Non diffusible through the capillary membrane form 41%: bound to protein albumin, Globulin.
Hyperventilation→ alkalosis→ increase protein→ increase number of non diffusible form→ decreased ionized form→ increase the excitability of nerve and muscle→ tetany.
2-About 9 per cent of the calcium is diffusible through the capillary membrane but is combined with anionic substances of the plasma and interstitial fluids(non ionized).
3-The remaining 50 per cent of the calcium in the plasma is both diffusible through the capillary membrane and ionized.

The diffusible form is performing physiological functions.

1-Maintain membrane permeability.
2-Activation of enzymatic process involved in muscular contraction.
3-Release of neurohormones and neuropeptides.
4-Excitability of neuromuscular system.
5-Involvement in clotting mechanism.
6- It acts as hydroxyapetite in the bone, responsible for the strength of the bone so if there is decrease in the Ca in the bone it will become liable for fractures as in case of old age.

Calcium is absorbed from the first half of the small intestine partly by active transport and partly be the help of vitamin D.

The phosphate level is 3-4 mg/dl as follows:

85% in bone, 14% intracellular, 1% extracellular fluid.
If we multiply the concentration of calcium by the concentration of phosphate we will get the figure 40, this is a constant figure .so whenever we have hypercalciemia we have hypophosphatemia.

Parathyroid hormone acts on calcium and phosphate through:

1- Parathyroid Hormone Increases Calcium and Phosphate Absorption from the Bone:
It mobilizes both calcium and phosphate from the bone to the extracellular fluid; as a result we have increase in calcium and phosphate in the plasma.

2-Parathyroid Hormone Increases Intestinal Absorption of Calcium and Phosphate:

It increases the absorption leading to increase in calcium and phosphate in plasma this effect is enhanced by metabolite of vitamine D.


3-Parathyroid Hormone Decreases Calcium Excretion and Increases Phosphate Excretion by the Kidneys
It increases phosphate excretion in the urine and decreases renal tubular reabsorption of phosphate and increase reabsorption of calcium so we get rid of the excess phosphate in the body , so still there is equilibrium between the calcium and phosphate.

Clinical conditions:

Hypofunction of the parathyroid hormone(hypoparathyroidism):
This leads to decrease in calcium concentration in the blood → abnormal function of the neuromuscular system → hyperexcitibilty of the nerves and muscle.
In children and may lead to laryangeal spasm →asphyxia and death.
Hypoparathyrodism may be mild and we have twitching of the facial muscles elicited by mild stimuli, this condition is called chvostek' s sign .
The other sign we can see it by occlusion of blood flow to the hand like by a sphygmomanometer, so we have flexion of the wrist and thumb, extension of the fingers this is called trousseau's sign.

2-Hyperparathyroidism:

The cause may be:
Primary: tumor in the gland (mainly in women because of lactation and pregnancy which predispose for tumors).
Secondary: vitamin D deficiency or chronic renal failure.
Excessive mobilization of calcium and phosphate from the bone to the extracellular fluid .If we take x ray to the bone we will see a cyst filled with fibrous tissue so we call this condition osteitis fibrosa cystica.
The most important complication is renal calculi (stones).
Other complications: CNS excitability, constipation, weakness and hypophosphatemia.