Department of Physiology: Endocrine Physiology-Review & Illustrations

Hormone types (figure)

1. Steroid Hormones: Include hormones having chemical structure similar or derived from cholesterol e.g. adrenal cortex hormones, ovarian and testicular hormones.
2. Tyrosine derived hormones: Such as thyroid hormones and adrenal medulla hormones.
3. Protein and peptide hormone synthesis (figure)

Classification of Chemical Messengers (figure): Chemical messengers are classified into four types:

1. Endocrine messengers
2. Paracrine messengers
3. Autocrine messengers
4. Contact-dependent messengers.

1. Endocrine Messengers Endocrine messengers are the classical hormones. A hormone is defined as a chemical messenger, synthesized by endocrine glands and transported by blood to the target organs or tissues (site of action). Examples are growth hormone and insulin.

2. Paracrine Messengers Paracrine messengers are the chemical messengers, which diffuse from the control cells to the target cells through the interstitial ﬂuid. Some of these substances directly enter the neighboring target cells through gap junctions. Such substances are also called juxtacrine messengers or local hormones. Examples are prostaglandins and histamine.

3. Autocrine Messengers Autocrine messengers are the chemical messengers that control the source cells which secrete them. So, these messengers are also called intracellular chemical mediators. Examples are leukotrienes.

4. Contact-dependent messengers: They require cells to be in direct membrane-membrane contact.

Neurocrine or Neural Messengers Neurocrine or neural messengers are neurotransmitters and neurohormones. Neurohormone, any of a group of substances produced by specialized cells (neurosecretory cells) structurally typical of the nervous, rather than of the endocrine, system. The neurohormones pass along axons and are released into the bloodstream at special regions. Neurohormones thus constitute a linkage between sensory stimuli (events or conditions perceived by the nervous system) and chemical responses (endocrine secretions that act on other tissues of the endocrine system or on tissues of other systems, such as those involved with excretion or reproduction). The neurohormones in most mammals include oxytocin and vasopressin, both of which are produced in the hypothalamic region of the brain and secreted into the blood by the neurohypophysis (part of the pituitary gland). A second group of neurohormones, called releasing hormones, also originates in the hypothalamus. The members of this group, however, are transmitted within the neural cells to a second locus in the brain, from which they pass in the bloodstream to the adenohypophysis, which also is a part of the pituitary gland. There they either stimulate or inhibit the release of the various adenohypophysial hormones.A third group of neurohormones includes the enkephalins and other endorphins.

Mechanism of hormonal action (figure ): Refer to "Cell Physiology, Inter-cellular communication-Signal transduction". Hormone does not act on the target cell directly. It combines with receptor to form hormone-receptor complex. This complex executes the hormonal action by any one of the following mechanisms:

1. By altering permeability of cell membrane, such as neurotransmitters in synapse or neuromuscular junction act by changing the permeability of postsynaptic membrane.

2. By activating intracellular enzyme. Protein hormones and the catecholamines act by activating the intracellular enzymes through second messenger. Most common second messenger is cyclic AMP. In addition to cAMP, some other substances also act like second messengers for some of the hormones in target cells such as calcium ions and calmodulin, IP3, DAG, and cGMP.

3. By acting on genes such as Thyroid and steroid hormones execute their function by acting on genes in the target cells.

Regulation of hormone secretion

1. Negative feedback
■ is the most commonly applied principle for regulating hormone secretion.
■ is self-limiting.
■ A hormone has biologic actions that, directly or indirectly, inhibit further secretion of the hormone.
■ For example, insulin is secreted by the pancreatic beta cells in response to an increase in blood glucose. In turn, insulin causes an increase in glucose uptake into cells that results in decreased blood glucose concentration. The decrease in blood glucose concentration then decreases further secretion of insulin.
2. Positive feedback
■ is rare.
■ is explosive and self-reinforcing.
■ A hormone has biologic actions that, directly or indirectly, cause more secretion of the hormone.
■ For example, the surge of luteinizing hormone (LH) that occurs just before ovulation is a result of positive feedback of estrogen on the anterior pituitary. LH then acts on the ovaries and causes more secretion of estrogen.

Regulation of Hormone Receptors

Receptor proteins are not static components of the cell. Their number increases or decreases in various conditions. Generally, when a hormone is secreted in excess, the number of receptors of that hormone decreases due to binding of hormone with receptors. This process is called down regulation. During the defciency of the hormone, the number of receptor increases, which is called upregulation.

Thyroid gland (figure):

Thyroid gland secretes three hormones:

1. Tetraiodothyronine or T4 (thyroxine), 90% of the total secretion

2. Tri-iodothyronine or T3, 9% of the total secretion

3. Calcitonin.

T3 & T4 synthesis
Regulation of thyroid hormones secretion
After synthesis, the thyroid hormones remain in the form of vesicles within thyroglobulin and are stored for several months. So, when the synthesis of thyroid hormone stops, the signs and symptoms of deficiency do not appear for about 4 months.
Thyroid hormones are transported in the blood by three types of proteins: Thyroxine-binding globulin (TBG), Thyroxine-binding prealbumin (TBPA), and Albumin. In hepatic failure, TBG levels decrease and lead to an increase in free thyroid hormone levels. In pregnancy, TBG levels increase (due to high level of estrogen), leading to an increase in total thyroid hormone levels, but normal levels of free hormone (i.e., clinically, euthyroid).
In the peripheral tissues, T4 is converted to T3 by 5’-iodinase or to rT3 (rT3) is inactive. T3 is more biologically active than T4.
The iodide (I^–) pump, or Na⁺–I^– cotransport is inhibited by thiocyanate and perchlorate anions (see figure).
The peroxidase enzyme (step 3) is inhibited by propylthiouracil, which is used therapeutically to reduce thyroid hormone synthesis for the treatment of hyperthyroidism (see figure).
High levels of I^– inhibit organification and, therefore, inhibit synthesis of thyroid hormone (Wolff–Chaikoff effect).
More T4 than T3 is synthesized, although T3 is more active.
Iodinated thyroglobulin is stored in the follicular lumen until the thyroid gland is stimulated to secrete thyroid hormones.
TSH increases both the synthesis and the secretion of thyroid hormones by the follicular cells via an adenylate cyclase–cAMP mechanism.
Thyroid-stimulating immunoglobulins: They are components of the immunoglobulin G (IgG) fraction of plasma proteins and are antibodies to TSH receptors on the thyroid gland. They bind to TSH receptors and, like TSH, stimulate the thyroid gland to secrete T3 and T4. They circulate in high concentrations in patients with Graves’ disease, which is characterized by high circulating levels of thyroid hormones and, accordingly, low concentrations of TSH (caused by feedback inhibition of thyroid hormones on the anterior pituitary).

Effect of T3 & T4:

On CNS: Increased responsiveness to catecholamines with consequent increase in activation of the reticular activating system.The cerebral blood flow, O2 consumption and glucose are not affected by thyroid hormones. Thyroxin is very important to promote growth and development of the brain during fetal life and during the first few years of postnatal life. Thyroid deficiency in infants results in abnormal development of synapses, defective myelination and mental retardation.

One heart: Increase number and affinity of β1-adrenergic receptors and consequently increase their sensitivity to the inotropic and chronotropic effects of catecholamines on the heart. Therefore, a useful adjunct therapy for hyperthyroidism is treatment with a β-adrenergic blocking agent, such as propranolol.

On metabolism: Increase protein anabolism and catabolism with a net result of protein catabolism with consequent increase of N₂ excretion. In addition, T3 and T4 increase absorption of glucose by the GIT, stimulate glucose uptake by the cells, increase glycolysis, glycogenolysis and gluconeogenesis. Therefore, excess of thyroid hormones gives diabetogenic curve of oral glucose tolerance test (OGTT).

It increases milk secretion.
Thyroid hormones do not stimulate metabolism of the uterus but are essential for normal menstrual cycles and fertility. Hyperthyroidism causes impotance in male and oligominorrhoea in female while, hypothyroidsm causes loss of libido in male with menorhagia in female.

Applied physiology

Hypothyroidism: hypothyroidism of adult is called Myxedema. Hypothyroidism may arise [1] primarily from thyroid failure or [2] secondary to pituitary or hypothalamic failure (Pituitary hypothyroidism or hypothalamic hypothyroidism). In the latter two conditions, unlike the first, the thyroid responds to a test dose of TSH or TRH. Myxedema is characterized by a fall in BMR, weight gain, the hair is coarse and sparse, skin is dry and yellowish (carotenemia) with poor tolerance to cold, low cardiac output, hypoventilation. The voice is husky and slow. Mentation is slow, memory is poor and in some patients there are severe mental symptoms (myxedema madness), plasma cholesterol is elevated. Hypothyroidism in children who are hypothyroid from birth or before are called cretinism and the child is called cretins. They are dwarfed and mentally retarded, having potbellies with enlarged protruded tongues. Various congenital abnormalities of the hypothalamo-pituitary thyroid axis that causes enlarge thyroid size (goiter) can cause congenital hypothyroidism with cretinism. T4 crosses the placenta and unless the mother is hypothyroid, growth and development are normal until birth. When there is maternal iodine deficiency, the mental deficiency of the cretin is more severe and less responsive to treatment (deaf-mutism).

Hyperthyroidism (Thyrotoxicosis): is characterized by nervousness, weight loss, hyperphagia, heat intolerance, increase cardiac output, increased pulse pressure, a fine tremor of the outstretched fingers, sweating and variable increment in BMR.

Graves’ Disease: Also called exophthalmic goiter, characterized by diffuse hyperplastic enlargement of thyroid gland with protrusions of the eyeballs. Graves’ disease is an autoimmune disease in which circulating antibodies formed against TSH receptors will activate these receptors making the gland hyperactive (called TSH receptor stimulating antibodies).

Goiter:

Goiter means enlargement of the thyroid gland. It occurs both in hypothyroidism and hyperthyroidism, or physiological goiter.

Goiter in Hyperthyroidism – Toxic Goiter
Goiter in Hypothyroidism – Non-toxic Goiter: Non-toxic goiter is the enlargement of thyroid gland without increase in hormone secretion. It is also called hypothyroid goiter. Based on the cause, the non-toxic hypothyroid goiter is classified into two types.

1. Endemic colloid goiter: When the dietary intake is less tan 10 ug/day, the thyroid hormone synthesis is inadequate and T3 and T4 levels decline. As a resul TSH is stimulated leading the thyroid to be hypertrophied producing an iodine deficiency endemic goiter which may be very large. It occurs in certain areas around the great lakes and in inlands where the iodine is leached out of the soil by the rain so food will be grown in the soil is iodine deficient.

2. Idiopathic non-toxic goiter. Idiopathic non-toxic goiter is the goiter due to unknown cause. Enlargement of thyroid gland occurs even without iodine deficiency.

Physiological Goiter: Occurs during puberty due to increase stress and increase demand for T3 and T4 necessary for growth.

Cretin Vs dwarf: A cretin is different from pituitary dwarf. In cretinism, there is mental retardation and the different parts of the body are disproportionate. Whereas, in dwarfsm, the development of nervous system is normal and the parts of the body are proportionate. The reproductive function is affected in cretinism but it may be normal in dwarfsm.

Endocrine Functions of the Pancreas

Endocrine function of pancreas is performed by the islets of Langerhans. Human pancreas contains about 1 to 2 million islets. Islets of Langerhans consist of four types of cells:

A cells or alpha-cells, which secrete glucagon
B cells or beta-cells, which secrete insulin
D cells or delta-cells, which secrete somatostatin
F cells or PP cells, which secrete pancreatic polypeptide

Insulin

Insulin is a polypeptide containing two chains of amino acids A and B of 21 and 30 amino acid respectively linked by disulfide bridges. Insulin is synthesized in the endoplasmic reticulum of β-cells as single chain of amino acids called pre-proinsulin but it is then cleaved in the endoplasmic reticulum to form a proinsulin. Most of this is further cleaved and then folded with the formation of disulfied bonds in the Golgi apparatus and result in formation of insulin and C-peptide which are packed and stored in secretary granules or vesicles (figure). So for each molecule of insulin formed and secreted, an equivalent amount of C-peptide is formed and secreted as well, thus C-peptide measurement can provide an excellent index for endogenous insulin in insulin treated diabetics.

Insulin receptor
■ is found on target tissues for insulin.
■ is a tetramer with two α- subunits (entirely extracellular) and two β- subunits.
a. The β subunits has an extracellular domain, a transcellular domain, and an intracellular domain that express insulin-stimulated kinase activity (tyrosine kinase activity) directed toward its own tyrosine residues. When insulin binds to the receptor, tyrosine kinase autophosphorylates the β subunits. The phosphorylated receptor then phosphorylates intracellular proteins.
b. The insulin-receptor complexes enter the target cells.
c. Insulin down-regulates its own receptors in target tissues. Therefore, the number of insulin receptors is increased in starvation and decreased in obesity.

Glucose can enter the cells by:

1. Insulin-dependent Facilitated diffusion: In most of tissues by the aid of special glucose transporters (GLUT4) (skeletal and cardiac muscle, adipocytes. The glucose transport in skeletal and cardiac muscle, liver and in adipose tissue is facilitated by insulin (insulin-dependent) as insulin increases the number of glucose transporters in the cell membranes. So far, seven types of GLUT are identified (GLUT 1–7). Among these, GLUT4 is insulin sensitive and it is located in cytoplasmic vesicles. It is present in large numbers in muscle fibers and adipose cells. When insulin-receptor complex is formed in the membrane of such cells, the vesicles containing GLUT are attracted towards the membrane and GLUT is released into the membrane. Now, GLUT starts transporting the glucose molecules from extracellular ﬂuid (ECF) into the cell. Insulin increases the entry of glucose into liver cells by trapping glucose through the effect of hexokinase which phosphorylate glucose and keeping intracellular free glucose concentration low which will facilitate glucose entry to the cell by facilitated diffusion.

2. Insulin-independent Facilitated diffusion: RBCs, brain (except hypothalamus), renal tubules, mucous membrane of intestine, Lens of the eye, liver, and β-cells of pancreas, the glucose transport is occurred by GLUT insulin-independent mechanism.

3. Secondary active transport with Na⁺ by the aid of sodium dependent glucose transporter in the intestine and in the kidney.

A glucose molecule is too large to pass through a cell membrane via simple diffusion. Instead, cells assist glucose diffusion through facilitated diffusion and active transport.

Mechanism of insulin secretion & mechanism of action (signal transduction)

Glucose, the stimulant for insulin secretion, binds to the Glut 2 receptor on the beta cells.
Inside the beta cells, glucose is oxidized to ATP, which closes K+ channels in the cell membrane and leads to depolarization of the beta cells. Similar to the action of ATP, sulfonylurea drugs (e.g., tolbutamide, glyburide) stimulate insulin secretion by closing these K+ channels.
Depolarization opens Ca2+ channels, which leads to an increase in intracellular [Ca2+] and then to secretion of insulin.
Signal transduction is demonstrated in figure. The α subunits bind insulin and are extracellular, whereas the β subunits span the membrane. The intracellular portions of the β subunits have tyrosine kinase activity. Binding of insulin triggers the tyrosine kinase activity of the β subunits, producing autophosphorylation of the β subunits on tyrosine residues. The autophosphorylation, which is necessary for insulin to exert its biologic eﬀects, triggers phosphorylation of cytoplasmic protein (insulin receptor substrate, IRS) which in turn phosphorylates some cytoplasmic proteins and dephosphorylate others.

Action of insulin:

A. Insulin decreases blood glucose concentration by the following mechanisms

It increases glucose uptake into target cells by directing the insertion of glucose transporters into cell membrane (EXCEPT in Brain, RBCs, Kidney tubules, Liver, Lens of the eye, β-cells of pancreas, Intestinal mucosa). The liver does not require insulin for efficient uptake of glucose. This is because the liver cells don't use GLUT4 for importing glucose. The increase of the liver uptake of glucose is indirect because insulin has several effects in liver enzymes which increases the phosphorylation of glucose, so that the intracellular free glucose concentration stays low, facilitating the entry of glucose into the cell.
It promotes formation of glycogen from glucose in muscles and liver, and simultaneously inhibits glycogenolysis.
It decreases gluconeogenesis. Insulin increases the production of fructose 2,6 biphosphate, increasing phosphofructokinase activity. In effect, substrate is directed away from glucose formation.

After the meal is over and the blood glucose level begins to fall to a low level causing the pancreas to decrease its insulin secretion. The lack of insulin secretion then reverses all the effects listed above for glycogen storage and prevents further uptake of glucose by the liver from the blood. Furthermore, the lack of insulin (along with increase of glucagon) activates phosphorylase enzyme which causes the splitting of glycogen into glucose phosphate from which phosphate radical will split away from glucose by glucose phosphatase. Then the free glucose diffuse back into the blood. Therefore, the liver acts as glucose buffer system.

B. Insulin decreases blood fatty acid and keto acid concentrations.

In adipose tissue, insulin stimulates fat deposition and inhibits lipolysis.
Insulun inhibits keto acid formation in the liver because decreased fatty acid degradation provides less acetyl-Co A substrate for keto acid formation.

C. Insulin decreases blood amino acid concentration. Insulin stimulates amino acid uptake into cells, increases protein synthesis, and inhibits protein degradation. Thus, insulin is anabolic.

D. Insulin decreases blood K ion concentration by increasing K uptake into the cells.

The factors that affect insulin secretion are:

↑ Plasma Glucose Level
↑ amino acids
↑ fatty acids
Cyclic AMP: Stimuli that increase cAMP in β cells increases insulin secretion by increasing intracellular Ca⁺⁺. They include beta adrenergic agonists (epinephrine and norepinephrine), glucagon and theophylline. Catecholamines have a dual effect on insulin secretion (stimulation and inhibition) but the net effect of epinephrine and norepinephrine is inhibition.
Autonomic Nerves:
[a] Stimulation of parasympathetic Rt. vagus stimulates insulin secretion via muscarinic receptors.

[b] Sympathetic nerve stimulation to pancreas inhibits insulin secretion due to the release of norepinephrine.
GIT Hormones (glucagon, secretin, CCK, gastrin): Orally administered glucose and amino acids exerts greater insulin stimulating effect than i.v administration, this is due to the presence of GIT hormones (glucagon. secretin, CCK, gastrin)
Other hormones (glucagon, growth hormone, cortisol, and to lesser extent progesterone and estrogen). They are either directly increase insulin secretion or potentiate the glucose stimulus for insulin secretion. The prolong and high level of secretion of these hormones can occasionally lead to exhaustion of the beta cells of the islets of Langerhans and thereby cause diabetes.

Biphasic effect of glucose: Action of blood glucose on insulin secretion is biphasic (figure).

i. Initially, when blood glucose level increases after a meal, the release of insulin into blood increases rapidly. Within few minutes, concentration of insulin in plasma increases up to 100 uU/mL from the basal level of 10 uU/mL. It is because of release of insulin that is stored in pancreas. Later, within 10 to 15 minutes, the insulin concentration in the blood reduces to half the value, i.e. up to 40 to 50 uU/mL of plasma.

ii. After 15 to 20 minutes, the insulin secretion rises once again. This time it rises slowly but steadily. It reaches the maximum between 2 and 2½ hours. The prolonged increase in insulin release is due to the formation of new insulin molecules continuously from pancreas.

Applied physiology

Diabetes Mellitus: Is defined as a clinical syndrome characterized by sustained hyperglycemia which may result due to lack of insulin secretion or to an excess of factors that oppose it’s action.

Consequences of Insulin Deficiency: The fundamental defects to which most of the abnormalities are secondary to it are: Reduced entry of glucose to various peripheral tissues and increased liberation of glucose into the circulation from the liver (hepatic gluconeognesis) due in part to glucagon excess.

Hyperglycemia → glycosuria → osmotic diuresis → dehydration → hypovolemia → polydipsia and hypotension.
HyperphagiaI
Increased gluconeogenesis
Negative nitrogen balance
Excess formation of keton bodies.
Coma

Glycosylated Haemoglobin (HBA1c): When plasma glucose is episodically elevated over time, small amounts of hemoglobin A is glycosylated by non-enzymatic pathway to form HbAlc. Level of HbAlc is an index of control of diabetes for 6 - 10 weeks before measurement.

Case study: A woman is brought to the emergency room. She is hypotensive and breathing rapidly; her breath has the odor of ketones. Analysis of her blood shows severe hyperglycemia, hyperkalemia, and blood gas values that are consistent with metabolic acidosis.

Explanation:

a. Hyperglycemia

is consistent with insulin deficiency.
In the absence of insulin, glucose uptake into cells is decreased, as is storage of glucose as glycogen.
If tests were performed, the woman’s blood would have shown increased levels of both amino acids (because of increased protein catabolism) and fatty acids (because of increased lipolysis).

b. Hypotension

is a result of ECF volume contraction.
The high blood glucose concentration results in a high filtered load of glucose that exceeds the reabsorptive capacity (Tm) of the kidney.
The unreabsorbed glucose acts as an osmotic diuretic in the urine and causes ECF volume contraction.

c. Metabolic acidosis

is caused by overproduction of ketoacids (â-hydroxybutyrate and acetoacetate).
The increased ventilation rate is the respiratory compensation for metabolic acidosis.

d. Hyperkalemia

results from the lack of insulin; normally, insulin promotes K+ uptake into cells.

Glucagon

It is produced by the alpha-cells of pancreas and upper gastrointestinal tract. This hormone causes an increase in the plasma glucose level. This is achieved through the following effects:

Glycogenolytic effects, it causes glycogenolysis in liver (but not in the muscle).
Gluconeogenic effects in liver.
Lipolytic effects and inhibition of the storage of triglycerides in the liver. Consequently, It increases keton bodies formation (ketogenic effect).

Control of Secretion: The low blood glucose concentration is by far the most potent factor for stimulation of glucagon secretion.

Other factors which increase glucagon secretion:
i. Exercise
ii. Stress
iii. Gastrin
iv. Cholecystokinin (CCK)
v. Cortisol.

Factors which inhibit glucagon secretion:
i. Somatostatin
ii. Insulin
iii. Free fatty acids
iv. Ketones.

Somatostatin

This hormone is secreted from delta cells (δ-celIs) of pancreas. Somatostatin secretion is affected by same factors stimulating insulin secretion (increased blood glucose, increased amino acids, increased fatty acids, and increased concentration of several GIT hormones released in response to food intake).

Somatostatin acts within islets of Langerhans and, inhibits β and α cells:

As paracrine hormone by inhibiting the secretion of insulin, glucagon and pancreatic polypeptide.
Slows motility, and decreases secretion and absorption in the GIT including gallbladder (may cause gallbladder stones in excessive secretion).
Somatostatin is the same chemical substance as growth hormone inhibitory hormone that is secreted in the hypothalamus that inhibits the secretion of GH and TSH from anterior pituitary.

Pancreatic Polypeptide

Human pancreatic polypeptide is secreted by PP-cells of pancreas. It is closely related to other peptides found in intestine and may be a gastrointestinal hormone and the neuropeptide found in the brain and autonomic nervous system. PP secretion is increased by protein meal, fasting, exercise, and acute hypoglycemia. Its exact physiological function is uncertain but it slows the absorption of food and may smooth out the peak and valleys of absorption curves.

The Adrenal Medulla and adrenal Cortex

The inner adrenal medulla (constituting 20% of the gland) secretes catecholamines, the synthesis of them is shown in figure:

Epinephrine,
Norepinephrine, and
Dopamine

the outer adrenal cortex (constituting 80% of the gland) secretes,the synthesis of them is shown in figure.

Mineralocorticoids from zona glomerulosa (aldosterone,11-deoxycorticosterone),
Glucocorticoides from zona fasciculata (cortisol → more potent and predominantly secreted, and corticosterone).
Androgens or sex hormones secreted mainly by zona reticularis. Zona fasciculata secretes small quantities of sex hormones (dehydroepiandrosterone, androstenedione, and testosterone). Dehydroepiandrosterone is the most active adrenal androgen.

Catecholamines: The pathway for biosynthesis of epinephrine, norepinephrine and dopamine are shown. Half life of catecholamines is about 2 minutes in circulation. Then they are destroyed by catechol-O-methyl transferase in all tissues especially in the liver to vanillylmandelic acid (VMA). 50% of secreted catecholamines appear in urine as free or conjugated metanephrine and normetanephrine and 35% as VMA and small amounts as epinephrine and norepinephrine. Destruction of epinephrine and norepinephrine can occur in the nerve endings by enzymes one of them is monoamine oxidase.

Effects of Epinephrine and Norepinephrine:

Circulating adrenaline and noradrenaline have similar effect of sympathetic stimulation. But, the effect of adrenal hormones is prolonged 10 times more than that of sympathetic stimulation. It is because of the slow inactivation, slow degradation and slow removal of these hormones. Effects of adrenaline and noradrenaline on various target organs depend upon the type of receptors present in the cells of the organs. Adrenaline acts through both alpha and beta receptors equally. Nor-adrenaline acts mainly through alpha receptors and occasionally through beta receptors. Adrenaline inﬂuences the metabolic functions more than nor-adrenaline.

1. CVS and other effects:

2. On CNS: Increase alertness (epinephrine evokes anxiety and fear).

3. Effect on BMR (calorigenic hormone): The initial rise in BMR is due to cutaneous vasoconstriction that prevent heat loss or increase muscular activity followed by a smaller delayed rise in BMR due to oxidation of lactic acid in liver. Adrenaline increases the blood glucose level by increasing the glycogenolysis in liver and muscle. So, a large quantity of glucose enters the circulation. Adrenaline causes mobilization of free fatty acids from adipose tissues. Catecholamines need the presence of
glucocorticoids for this action.

4. Effect on K+: Initial rise in K⁺due to release of K⁺from liver followed by a prolonged fall in K⁺due to increased entry of K⁺ into skeletal muscles (as a result of stimulation of β-adrenergic receptors).

5. Other Effects of Catecholamines:

On salivary glands (via alpha and beta-2 receptors): Cause vasoconstriction in salivary gland, leading to mild increase in salivary secretion
On sweat glands (via beta-2 receptors): Increase the secretion of apocrine sweat glands.
On lacrimal glands (via alpha receptors): Increase the secretion of tears.
On ACTH secretion (via alpha receptors): Adrenaline increases ACTH secretion.
On nerve fbers (via alpha receptors): Adrenaline decreases the latency of action potential in the nerve fibers, i.e. electrical activity is accelerated
On renin secretion (via beta receptors): Increase the rennin secretion from juxtaglomerular apparatus of the kidney.

Dopamine

Actions:

Vasodilatation: In kidney and mesentry by acting on dopaminergic receptors.
Vasoconstriction in other sites due to release of norepinephrine.
Positive inotropic effect on the heart (through β receptors).
Increase in systolic B.P with no change in diastolic B.P.
Natriuresis by inhibiting the Na⁺- K⁺ATPase of the kidney.

ReguIation of adrenal medullarv secretion: Catecholamine secretion is under the effect of sympathetic nervous system and it is low at basal state. Secretions are decreased in recumbent subject and more reduction during sleep while increased in standing up. The metabolic effects of circulating catecholamines are important in exposure to cold or hunger. Increased adrenal medullar secretion is part of diffuse sympathetic discharge provoked by emergency situation (Fight or Flight). The output of norepinephrine is increased selectively as in emotional stress with which the individual is familiar where as epinephrine is selectively increased in hemorrhage (as it reduce peripheral resistance) and in situations in which the individual do not know what to expect.

Adrenal glucocorticoids

Control of glucocorticoid secretion

Glucocorticoids secretion is regulated by ACTH and by the free cortisol level.

1. Role of adrenocorticotrophic hormone (ACTH): The hypothalamus via release of corticotrophic releasing hormone (CRH), that will be transferred by hypothalamo-hypophyseal portal system to anterior pituitary gland. stimulates the release of ACTH. ACTH affects the inner two zones of adrenal cortex. Basal and stimulated secretion (stress) of glucocorticoids are dependent upon ACTH from anterior pituitary. ACTH bind to ACTH receptors and activate adenyl cvclase and increase cAMP which in turn increases the activity of enzymes responsible for increase free cholesterol formation resulting in increase pregnenolone. So ACTH leads to increase glucocorticoids formation and at the same time increases responsiveness of adrenal cortex to subsequent doses of ACTH. Severe stress (body injury, emotional stress, anxiet and fear) increases ACTH secretion which is mediated through hypothalamus via release of corticotrophic releasing hormone (CRH). ACTH is secreted in irregular burst throughout the day and plasma cortisol tends to rise and fall in response to these bursts. In humans, the bursts are most frequent in early morning and about 75% of the daily production of cortisol is secreted between 4 – 10 AM. The bursts are least frequent in the evening. This diurnal (circadian) rhythm in ACTH secretion is not due to stress or trauma or getting up in the morning as it occurs even before waking up. The biological clock responsible for the diurnal ACTH rhythm is located in the suprachiasmatic nuclei of the hypothalamus. Dexamethasone suppression test is based on the ability of dexamethasone (which is a potent synthetic glucocorticoid) to inhibit ACTH secretion. If the hypothalamic-piuitary-adrenocortical axis is normal, then the administration of dexamethasone inhibits the secretion of ACTH and cortisol.

2. Role of Cortisol: Free cortisol inhibits ACTH secretion and the degree of pituitary inhibition is proportional to the circulating glucocorticoid level. The inhibitory effect is exerted at both levels, pituitary and hypothalamic. This is called Glucocorticoid negative feedback. When prolonged treatment with glucocorticoids is stopped suddenly, not only the adrenal become atrophic and unresponsive after such treatment, but even if it’s responsiveness is restored, the pituitary may be unable to secrete normal amounts of ACTH for as long as a month, this is because of diminished ACTH synthesis.

Effects of Adrenal glucocorticoids:

[I]. Effect on carbohydrates: Glucocorticoids increase the blood glucose level and insulin resistance by two ways:. It increases blood glucose level due to:

Stimulation of gluconeogenesis. Therefore, deficiency of glucocorticoids causes a lowered fasting blood sugar which is largely the result of depressed gluconeogenesis
Decreases glucose utilization peripherally by blocking glucose transport in muscle and adipose tissue (it has an anti-insulin activity)
Increases glycogen deposition in the liver by promoting the conversion of amino acids to carbohydrates and the storage of carbohydrate as hepatic glycogen.

Hypersecretion of glucocorticoids increases the blood glucose level, resulting in hyperglycemia, glucosuria and adrenal diabetes. Hyposecretion of these hormones causes hypoglycemia and fasting during adrenal insuffciency will be fatal. It decreases blood glucose level to a great extent, resulting in death.

[II]. Effect on protein metabolism: Glucocorticoids promote the catabolism of proteins, leading to:

Decrease in cellular proteins
Increase in plasma level of amino acids
Increase in protein content in liver.

Glucocorticoids cause catabolism of proteins by the following methods:

i. By releasing amino acids from body cells (except liver cells), into the blood

ii. By increasing the uptake of amino acids by hepatic cells from blood. In hepatic cells, the amino acids are used for the synthesis of proteins and carbohydrates (gluconeogenesis). Thus, glucocorticoids cause mobilization of proteins from tissues other than liver. This gluconeogenesis is associated with increased urea production via the conversion of amino nitrogen to urea with consequent increase of urinary nitrogen excretion.

In hypersecretion of glucocorticoids, there is excess catabolism of proteins, resulting in muscular wasting and negative nitrogen balance.

[III]. Effects on Fat metabolism: Glucocorticoids are lipolytic hormones (with consequent increase in plasma free fatty acids) and favor the mobilization of fatty acids from adipose tissue to the liver to be oxidized (with consequent increase keton formation as in diabetes). Glucocorticoids inhibit fatty acid synthesis in the liver (an effect not observed in adipose tissue).

Glucocorticoids decrease the utilization of glucose. At the same time, these hormones mobilize fats and make the fatty acids available for utilization, by which energy is liberated. It leads to the formation of a large amount of ketone bodies. It is called ketogenic effect of glucocorticoids. Hypersecretion of glucocorticoids causes an abnormal type of obesity by increasing the deposition of fat in certain areas such as abdomen, chest, face and buttocks.

[IV]. Permissive action: Small amounts of glucocorticoids must be present for a number of metabolic reactions to occur although glucocorticoids do not produce the reactions by themselves. This effect is called the permissive action. It includes:

For glucagon and catecholamines to produce their calorigenic effect.
For catecholamine to induce lipolytic effect, bronchodilatation and vascular pressor responses.

In adrenal insufficiency, the vascular smooth muscles become unresponsive to catecholamines resulting in dilatation of the vessels, hypotension, and exudation. So glucocorticoids are necessary for restoration of vascular responses.

[V]. Effects on nervous system: Changes in the nervous system in adrenal insufficiency causes slow α waves rhythm on ECG, personality changes include irritability, apprehension and inability to concentrate.

[VI]. Effect on water metabolism: Glucocortiocoids probably help to maintain a normal rate of glomerular filtration and they promote free water excretion. In adrenal insufficiency,

water intoxication occurs due to high levels of vasopressin and low glomerular filtration rate (GFR), and is corrected by glucocorticoids. Water intoxication due to adrenal insufficiency can be seen in condition known as glucose fever in which glucose infusion may cause high fever (glucose fever) followed by collapse and death. Presumably the glucose is metabolized, the water will dilute the plasma resulting in high osmotic gradient between plasma and the cell causes the cells of thermo-regulatory centers in the hypothalamus to be swollen and disrupted function.

[VII] On Mineral Metabolism Glucocorticoids enhance the retention of sodium and to lesser extent, increase the excretion of potassium. Thus, hypersecretion of glucocorticoids causes edema, hypertension, hypokalemia and muscular weakness. Glucocorticoids decrease the blood calcium by inhibiting its absorption from intestine and increasing the excretion through urine.

[VIII]. Effects on blood cells and lymphatic organs:

Decrease number of eosinophils, basophils and lymphocytes.
Increase number of neutrophils, platelets and RBCs.
Inhibit lymphocyte mitotic activity so reduce the size of lymph node and thymus.
Inhibit production of IL-2 by T-lymphocyte so effectively stop lymphocyte proliferation.
Inhibition of IL-I by monocyte and macrophage.

[IX]. Resistance to stress: Stress is defined as any noxious stimuli that increases ACTH and so glucocorticoids are increased for vascular reactivity to occur in response to stress and also for their permissive action to catecholamines for full FFA mobilization (important emergency energy supply), so glucocorticoids are necessary to resist stress. Stress causes increase in plasma glucocorticoids to high pharmacologic levels that in short run are lifesaving but in long run are definitely harmful and disruptive.

[XI]. Other Effects:

Glucocorticoids in high doses leads to:

Decrease growth hormone secretion.
Decrease TSH secretion.
Accelerate the maturation of surfactant in the lungs of foetus.

[XII] Anti-Inflammatory and antiallergic effects of glucocorticoids: In large pharmacological doses, glucocorticoids inhibit the inflammatory response to tissue injury and also suppress the manifestation of allergic diseases that are due to histamine release from tissues. Glucocorticoids prevent the inﬂammatory changes by:

Inhibiting the release of chemical substances from damaged tissues and thereby preventing vasodilatation and erythema in the affected area
Causing vasoconstriction through the permissive action on catecholamines. This also prevents rushing of blood to the injured area
Decreasing the permeability of capillaries and preventing loss of ﬂuid from plasma into the affected tissue iv. Inhibiting the migration of leukocytes into the affected area
Suppressing T cells and other leukocytes, so that there is reduction in the reactions of tissues which enhance the inﬂammatory process.

This is achieved through the following mechanisms:

[l] The anti-allergic effects due to inhibition of release of histamine from mast cells in response to Ag-Ab reaction. Glucocorticoids do not affect the Ag-Ab combination and have no effects of histamine once it is released.

[2] Anti-inflammatory effect is due to:

[al Inhibition of phospholipase A2 resulting in decrease release of arachidonic acids from tissue phospholipids and decrease formation of leukotrienes, thromboxane, prostaglandins and prostacyclin and consequently decreased local inflammatory reaction. A decrease of prostaglandins and leukotriens formation decreases vasodilatation and reduce capillary permeability leading to decrease plasma loss and local swelling.

[b] Stabilization of lysosomal membrane and inhibit release of mediators of inflammation as leukotrienes in inflammed tissue.

[c] Slowing of degrading effect of collagenase in joint tissues in rheumatoid arthritis and this is the basis of their effectiveness in local intra-articular administration.

[dl It lowers fever by inhibit the release of IL-I from W.B.Cs. IL-I is one of the principal excitants of hypothalamic temperature control system.

[el Cortisol suppresses:

WBC migration to the inflammed area.
Phagocytosis of damaged cells.
The immune system by lowering the production of T-lyrnphocyte and reduce antibody formation.

[f1 inhibit fibroplastic activity.

[g] Cortisol increase the rate of resolution of inflammation (healing) due to increased amino acids, glucose and FFA necessary for resolution or by inactivating the inflammatory products.

Adrenal mineralocorticoids
They include aldosterone, deoxycorticosterone and corticosterone. Aldosterone is most potent while corticosterone is the weakest one. Aldosterone is very essential for life and it maintains the osmolarity and volume of ECF. It is usually called life-saving hormone because, its absence causes death within 3 days to 2 weeks.

Physiological Effects:

Increases renal reabsorption of Na+ (action on the principal cells of the late distal tubule and collecting duct). Thus, causing water retention. It also increases reabsorption of Na ions from the sweat, saliva, gastric juice and intestinal secretions.
Increase renal K+ secretion (action on the principal cells of the late distal tubule and collecting duct).
Increase renal H+ ions secretion (action on the α-intercalated cells of the late distal tubules and collecting ducts). Thus, causing urine acidity and decrease hydrogen ion concentration in the ECF.

Regulation of Aldosterone Secretion: Four different factors are presently known to play essential roles in the regulation of aldosterone. In the probable order of their importance these are:
[1] K ion concentration of the ECF: Even I meq/l increase in ECF K+ concentration can directly stimulate the zona glomerulosa cells to secrete aldosterone.
[2] Renin—angiotensin system: The injection of angiotensin II stimulates adrenocortical secretions and in small doses stimulate aldosterone secretion primarily.
[3] Quantify of body Na: Diminished Na leads to: Decrease ECF volume → decrease cardiac output → decrease renal blood flow → increase renin secretion → enhanced formation of angiotensin → stimulation of aldosteron secretion.
[4] ACTH: It causes stimulation of aldosterone output as well as that of glucoeorticoids and sex hormones. The effect is transient and aldosterone secretion declines in 1 - 2 days. ACTH also has a permissive effect on aldosterone secretion of all the above factors to stimulate zona glomerulosa.
Diurnal Changes: Plasma aldosterone concentration increases during upright position due to postural elevation of renin secretion. Individuals who are confined to bed, show a circadian rhythm in aldosterone secretion and renin with highest values in the early morning before awakening.
Mechanism of aldosterone escape: When aldosterone level increases, there is excess retention of sodium and water. This increases the volume of ECF and blood pressure. Aldosterone-induced high blood pressure decreases the ECF volume through two types of reactions:
i. It stimulates secretion of atrial natriuretic peptide (ANP) from atrial muscles of the heart: ANP causes excretion of sodium in spite of increase in aldosterone secretion
ii. It causes pressure diuresis (excretion of excess salt and water by high blood pressure) through urine. This decreases the salt and water content in ECF, in spite of hypersecretion of aldosterone.
Besides ANP, two more natriuretic peptides called brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) are also secreted by cardiac muscle. BNP and CNP also have similar actions of ANP on sodium excretion. Because of aldosterone escape, edema does not occur.

Adrenal sex hormones:

Adrenal sex hormones are secreted mainly by zona reticularis. Zona fasciculata secretes small quantities of sex hormones. Adrenal cortex secretes mainly the male sex hormones, which are called androgens. But small quantity of estrogen and progesterone are also secreted by adrenal cortex. In normal conditions, the adrenal androgens have insignifcant physiological effects, because of the low amount of secretion both in males and females.
In congenital hyperplasia of adrenal cortex or tumor of zona reticularis, an excess quantity of androgens is secreted. In males, it does not produce any special effect because, large quantity of androgens are produced by testes also. But in females, the androgens produce masculine features. Some of the androgens are converted into testosterone. Testosterone is responsible for the androgenic activity in adrenogenital syndrome or congenital adrenal hyperplasia.

Applied physiology
Aldosterone increases sodium absorption from the intestine, especially from colon and prevents loss of sodium through feces. Aldosterone defciency leads to diarrhea, with loss of sodium and water.In hypersecretion, it causes alkalosis and in hyposecretion, it causes acidosis.

A. Adrenocortical insufficiency
(1) Primary adrenocortical insufficiency—Addison’s disease
■ is most commonly caused by autoimmune destruction of the adrenal cortex and causes acute adrenal crisis.
■ is characterized by the following:
(a) ↓ adrenal glucocorticoid, androgen, and mineralocorticoid
(b) ↑ ACTH (Low cortisol levels stimulate ACTH secretion by negative feedback.)
(c) Hypoglycemia (caused by cortisol deficiency)
(d) Weight loss, weakness, nausea, and vomiting
(e) Hyperpigmentation (Low cortisol levels stimulate ACTH secretion; ACTH contains the MSH fragment.)
(f) ↓ pubic and axillary hair in women (caused by the deficiency of adrenal androgens)
(g) ECF volume contraction, hypotension, hyperkalemia, and metabolic acidosis (caused by aldosterone deficiency)
(2) Secondary adrenocortical insufficiency
■ is caused by primary deficiency of ACTH.
■ does not exhibit hyperpigmentation (because there is a deficiency of ACTH).
■ does not exhibit volume contraction, hyperkalemia, or metabolic acidosis (because aldosterone levels are normal).
■ Symptoms are otherwise similar to those of Addison’s disease.

B. Adrenocortical excess—Cushing’s syndrome
■ is most commonly caused by the administration of pharmacologic doses of glucocorticoids.
■ is also caused by primary hyperplasia of the adrenal glands.
■ is called Cushing’s disease when it is caused by overproduction of ACTH.
■ is characterized by the following:
(1) ↑ cortisol and androgen levels
(2) ↓ ACTH (if caused by primary adrenal hyperplasia or pharmacologic doses of
glucocorticosteroids); ↑ ACTH (if caused by overproduction of ACTH, as in Cushing’s disease)
(3) Hyperglycemia (caused by elevated cortisol levels)
(4) ↑ protein catabolism and muscle wasting
(5) Central obesity (round face, supraclavicular fat, buffalo hump)
(6) Poor wound healing
(7) Virilization of women (caused by elevated levels of adrenal androgens)
(8) Hypertension (caused by elevated levels of cortisol and aldosterone)
(9) Osteoporosis (elevated cortisol levels cause increased bone resorption)
(10) Striae
■ Ketoconazole, an inhibitor of steroid hormone synthesis, can be used to treat Cushing’s disease.

C. Hyperaldosteronism—Conn’s syndrome
■ is caused by an aldosterone-secreting tumor.
■ is characterized by the following:
(1) Hypertension (because aldosterone increases Na+ reabsorption, which leads to increases in ECF volume and blood volume)
(2) Hypokalemia (because aldosterone increases K+ secretion)
(3) Metabolic alkalosis (because aldosterone increases H+ secretion)
(4) ↓ renin secretion (because increased ECF volume and blood pressure inhibit renin secretion by negative feedback)

D. 21β-Hydroxylase deficiency
■ is the most common biochemical abnormality of the steroidogenic pathway.
■ belongs to a group of disorders characterized by adrenogenital syndrome.
■ is characterized by the following:
(1) ↓ cortisol and aldosterone levels (because the enzyme block prevents the production of 11-deoxycorticosterone and 11-deoxycortisol, the precursors for cortisol and aldosterone)
(2) ↑ 17-hydroxyprogesterone and progesterone levels (because of accumulation of intermediates above the enzyme block)
(3) ↑ ACTH (because of decreased feedback inhibition by cortisol)
(4) Hyperplasia of zona fasciculata and zona reticularis (because of high levels of ACTH)
(5) ↑ adrenal androgens (because 17-hydroxyprogesterone is their major precursor) and ↑ urinary 17-ketosteroids
(6) Virilization in women
(7) Early acceleration of linear growth and early appearance of pubic and axillary hair
(8) Suppression of gonadal function in both men and women

E. 17α-Hydroxylase deficiency is characterized by the following:
(1) ↓ androgen and glucocorticoid levels (because the enzyme block prevents the production of 17-hydroxypregnenolone and 17-hydroxyprogesterone)
(2) ↑ mineralocorticoid levels (because intermediates accumulate to the left of the enzyme block and are shunted toward the production of mineralocorticoids)
(3) Lack of pubic and axillary hair (which depends on adrenal androgens) in women
(4) Hypoglycemia (because of decreased glucocorticoids)
(5) Metabolic alkalosis, hypokalemia, and hypertension (because of increased mineralocorticoids
(6) ↑ ACTH (because decreased cortisol levels stimulate ACTH secretion by negative
feedback).

Calcium metabolism and bone physiology

40% of the total Ca2+ in blood is bound to plasma proteins.
60% of the total Ca2+ in blood is not bound to proteins and is ultrafilterable. Ultrafilterable Ca2+ includes Ca2+ that is complexed to anions such as phosphate and free, ionized Ca2+.
Free, ionized Ca2+ is biologically active.
Serum [Ca2+] is determined by the interplay of intestinal absorption, renal excretion, and bone remodeling (bone resorption and formation). Each component is hormonally regulated (see figure).
To maintain Ca2+ balance, net intestinal absorption must be balanced by urinary excretion.

1. Positive Ca2+ balance is seen in growing children. Intestinal Ca2+ absorption exceeds urinary excretion, and the excess is deposited in the growing bones.
2. Negative Ca2+ balance is seen in women during pregnancy or lactation. Intestinal Ca2+ absorption is less than Ca2+ excretion, and the deficit comes from the maternal bones.

Hvpocalcemia: A decrease of plasma calcium (free and bound forms).
1.It can cause muscle tetany (occurs at a blood Ca level of about 6 mg/dl) and subsequently increases motor nerves excitability leading to carpopedal spasm and laryngeal spasm.
2.It can cause prolongation of ST-segment and prolonged QT-interval in ECG.
Hypercalcemia: An increase of plasma calcium (free and bound forms). It is associated with depressed nervous system activity, sluggish reflex activity, shortened QT-interval in ECG, enhanced myocardial contractility, constipation and reduced appetite, and predispose to renal stone formation.
Phosphorus: About 90% of which is found in skeleton. Plasma phosphorus is about 12 mg/dI, two third of it is present in organic compounds and the rest is inorganic phosphorus (Pi) mostly in PO43-., HPO42- and H2PO41-Pi is absorbed in duodenum and small intestine by active transport and passive diffusion. Absorption is linearly correlated with dietary intake. 1,25 dihydrocholecalciferol increases Pi absorption. Pi is filtered in glomeruli, 85% - 90% is reabsorbed by proximal tubules and the active transport is powerfully inhibited by PTH.

Absorption and excretion of calcium: Calcium taken through dietary sources is absorbed from GI tract into blood and distributed to various parts of the body. Depending upon the blood level, the calcium is either deposited in the bone or removed from the bone (resorption). Calcium is excreted from the body through urine and feces.

Absorption from Gastrointestinal Tract: Calcium is absorbed from duodenum by carrier mediated active transport and from the rest of the small intestine, by facilitated diffusion. Vitamin D is essential for the absorption of calcium from GI tract.
Excretion: While passing through the kidney, large quantity of calcium is filtered in the glomerulus. From the filtrate, 98% to 99% of calcium is reabsorbed from renal tubules into the blood. Only a small quantity is excreted through urine. Most of the filtered calcium is reabsorbed in the distal convoluted tubules and proximal part of collecting duct. In distal convoluted tubule, parathormone increases the reabsorption. In collecting duct, vitamin D increases the reabsorption and calcitonin decreases reabsorption. About 1,000 mg of calcium is excreted daily. Out of this, 900 mg is excreted through feces and 100 mg through urine.

Physiology of bone:

Bone or osseous tissue is a specialized rigid connective tissue that forms the skeleton. It consists of special type of cells and tough intercellular matrix of ground substance. The matrix is formed by organic substances like collagen, proteoglycans (chondroitin sulfate and hyaluronic acid) and it is strengthened by the deposition of mineral salts like calcium phosphate and calcium carbonate, and hydroxyapatites (a complex phosphate of calcium Ca5(PO4)3OH that occurs as a mineral and is the chief structural element of vertebrate bone). Throughout the life, bone is renewed by the process of bone formation and bone resorption.

Functions of bone:

1. Protective function: Protects soft tissues and vital organs of the body 2. Mechanical function: Supports the body and brings out various movements of the body by their attachment to the muscles and tendons 3. Metabolic function: Plays an important role in the metabolism homeostasis of calcium and phosphate in the body. 4. Hemopoietic function: Red bone marrow in the bones is the site of production of blood cells.

Classification of bone
Depending upon the size and shape, the bones are classified into five types:
1. Long bones: Bones of the limbs
2. Short bones: Bones in the wrist and ankle
3. Flat bones: Skull bones, mandible, scapula, etc.
4. Irregular bones: Vertebra
5. Sesamoid bones: Patella.

Parts of bone: Long bones are formed by a cylindrical tube of bone tissue, which has three portions:

Diaphysis: Midportion or midshaft.
Epiphysis: Wider extremity or the head on either end.
Metaphysis: Portion between the diaphysis and the epiphysis. In growing age, a layer of cartilage called epiphyseal cartilage or epiphyseal plate or growth plate is present in between epiphysis and metaphysis. Epiphyseal plate is responsible for the longitudinal growth of the bones

Types of cells in bone: Bone has three major types of cells:
1. Osteoblasts: Osteoblasts are responsible for the synthesis of bone matrix. Osteoblasts are rich in enzyme alkaline phosphatase, which is necessary for deposition of calcium in the bone
matrix (calcifcation).
2. Osteocytes: Help to maintain the bone as living tissue because of their metabolic activity and maintain the exchange of calcium between the
bone and ECF.
3. Osteoclasts: Responsible for bone resorption during bone remodeling. They synthesis and release of lysosomal enzymes necessary for bone resorption into the bone resorbing compartment.

Bone formation and resorption: Through the life, bone is a dynamic rather than static organ, being constantly resorbed and new bone being formed. The calcium in bone turns over at a rate of 100% per year in infants and 18% per year in adults. Bone remodeling is mainly a local process carried out in small areas by populations of cells called bone-remodelling units. First osteoclasts resorb bone forming a tunnel of few millimeters in length, then ostoblasts lay down new bone in the same area in successive layers of concentric circles (Larnellae). If blood vessels run through the tunnel it is called Haversian Canal. The benefit of remodeling is to adjust the shape and strength of bone in response to stress (bone thickened when subjected to heavy load and resorbed in long bed rest). The calcium precipitates in bone when it exceeds the saturation point.Osteoblasts secrete an alkaline phosphatase that hydrolyzes phosphate esters, thus providing the necessary phosphate for new bone formation (precipitation of Ca-P04).
Regulation of Ca metabolism: Three hormones are primarily concerned with the regulation of calcium metabolism (see also the figure and figure):

1-25 Dihydroxycholecalciferol (calcitriol): Is a steroid hormone formed from inactive vit. D (cholecalciferol or D3, and ergocalciferol or D2) by successive hydroxylation in kidney and liver (see figure). It’s primary function is to increase Ca absorption from GIT.

Action:
1. Increased Ca++ and phosphate absorption from intestine.
2. Increased Ca++ and phosphate reabsorption in the kidney.
3. The most important net effect of vit. D is to ensure that newly formed bone is calcified by stimulation osteoclasts to provide Ca++ and phosphate ions from “old bone” to mineralize “new bone”. Without vit. D, the bone matrix remains uncalcified leading to the development of rickets in children and osteomalacia in adults.

The net results of the previous effects are increased plasma Ca++ and phosphate levels

Parathyroid hormone (PTH): Parathormone (PTH) is secreted by the chief cells of the parathyroid glands. Circulating ionized Ca acts directly on parathyroid glands in a negative feedback fashion to regulate the secretion of PTH. PTH is stimulated by low Ca, Mg, and high phosphate. While it is inhibited by high Ca, Mg, and active Vit D.

Actions:

I. Bone resorption: This is achieved by stimulation of osteoclasts and consequently increase Ca and phosphate mobilization to the blood.

2. Increases renal of reabsorption of Ca⁺⁺ increases renal excretion of PO₄^3- (phosphaturic action).

3. Increases the renal formation of 1,25 (OH)2 D3 and consequently increases Ca⁺⁺ reabsorption in the intestine.

The net results of the previous effects are increased Ca⁺⁺ plasma level and a decreased phosphate plasma level.

Hyperparathyroidism:
1. Primary Hyperparathyroidism: Usually increased PTH level in functioning parathyroid tumor is characterized by hypercalcemia, hypophosphatemia, demineralization of bone (increase bone resorption), hypercalcuria, increase urinary phosphate excretion, and calcium containing renal stones.
2. Secondary Hyperparathyrodism: In disease of kidney and in rickets, chronic low Ca++ level exert a feedback stimulation on PTH.

Hypoparathyroidism: PTH is essential for life. After parathyroidectomy, steady decline in plasma Ca++ level causes hyperecitability followed by hypocalcemic tetany. Can occur following thyroid surgery. Signs of tetany in human include:
1. Chvostek’s sign: Quick contraction of ipsilateral facial muscles elicited by tappinu on facial nerve at jaw.
2. Trousseau’s sign: Spasm of the muscles of upper extremities, flexion of the wrist and thumb and extension of the fingers, can be produced by occluding the circulation for few minutes with sphygmomanometer cuff.

Chronic renal failure: It is characerized by decreased glomerular filtration rate which leads to:

Decreased filtration of phosphate, phosphate retention, and increased serum phosphate concentration.
Increased serum phosphate complexes Ca++ and leads to decreased ionized Ca++ concentration.
Decreased production of active vitamine D3 by the diseased renal tissues also contributes to the decreased ionized Ca++ concentration.
Decreased Ca++ concentration causes secondary hyperparathyroidism.

The combination of increased PTH levels and decreased active vit D3 produces renal osteodystrophy, in which there is increased bone resorption and osteomalacia.

Calcitonin: It is a calcium lowering enzyme in plasma. Calcitonin receptors are mainly found in bones and kidneys. It’s main action is to inhibit bone resorption.

Action:

Direct (immediate) effect by inhibiting the activity of osteoclasts (inhibit bone resorption).
Indirect (prolonged) effect by reducing the formation of new osteoclasts.
Increases Ca++ and phosphate excretion in urine.

The net results of the previous effects are decreased Ca⁺⁺ and phosphate plasma levels

Applied physiology – diseases of bone

1. Osteoporosis: Osteoporosis is the bone disease characterized by the loss of bone matrix and minerals. Osteoporosis means ‘porous bones’.

Causes of osteoporosis: Osteoporosis occurs due to excessive bone resorption and decreased bone formation. Osteoporosis is common in women after 60 years. The various risk factors are given in Box.

Manifestations of osteoporosis Loss of bone matrix and minerals leads to loss of bone strength, associated with architectural deterioration of bone tissue. Ultimately, the bones become fragile with high risk of fracture. Commonly affected bones are vertebrae and hip.

2. Rickets: Rickets is the bone disease in children, characterized by inadequate mineralization of bone matrix. It occurs due to vitamin D deficiency. Vitamin D deficiency develops due to insufficiency in diet or due to inadequate exposure to sunlight. Deficiency of vitamin D affects the reabsorption of calcium and phosphorus from renal tubules, resulting in calcium deficiency. It causes inadequate mineralization of epiphyseal growth plate in growing bones. This defect produces various manifestations.

Causes of rickets: Causes of rickets are given in Table.

Features of rickets: i. Collapse of chest wall: Due to the ﬂattening of sides of thorax with prominent sternum. This deformity of the chest with projecting sternum is called pigeon chest or chicken chest or pectus carinatum. ii. Rachitic rosary: A visible swelling where the ribs join their cartilages. It is because of the development of nodules at sternal end of ribs, which forms the rachitic rosary iii. Kyphosis: Extreme forward curvature of the upper back bone (thoracic spine) with convexity backward (forward bending). Severe kyphosis causes formation of a hump (protuberance) which is called humpback, hunchback or Pott curvature Lordosis: Extreme forward curvature of back bone in lumbar region: also called hollow back or saddle back Scoliosis: Lateral curvature of spine Harrison sulcus: A groove in rib cage due to pulling of diaphragm inwards Bowing of hands and legs Enlargement of liver and spleen Tetany: In advanced stages, the patient may die because of tetany, involving the respiratory muscles.

3. Osteomalacia: Rickets in adults is called osteomalacia or adult rickets.

Causes of osteomalacia: Osteomalacia occurs because of defciency of vitamin D. It also occurs due to prolonged damage of kidney (renal rickets).

Features of osteomalacia i. Vague pain ii. Tenderness in bones and muscles iii. Myopathy leading to waddling gait (gait means the manner of walking). In waddling gait, the feet are wide apart and walk resembles that of a duck iv. Occasional hypoglycemic tetany.

The pituitary gland (figure)

There are vascular connections (hypothalamic–hypophysial portal system) between the hypothalamus and the anterior lobe and Neural connections between the hypothalamus and the post. pituitary lobe of the pituitary gland. The nerve cell bodies are located in hypothalamic nuclei. Posterior pituitary hormones are synthesized in the nerve cell bodies, packaged in secretory granules, and transported down the axons to the posterior pituitary for release into the circulation.

Releasing and Inhibitory Hormones Secreted by Hypothalamus:

1. Growth hormone-releasing hormone (GHRH): Stimulates the release of growth hormone

2. Growth hormone-releasing polypeptide (GHRP): Stimulates the release of GHRH and growth hormone

3. Growth hormone-inhibitory hormone (GHIH) or somatostatin: Inhibits the growth hormone release

4. Thyrotropic-releasing hormone (TRH): Stimulates the release of thyroid stimulating hormone

5. Corticotropin-releasing hormone (CRH): Stimulates the release of adrenocorticotropin

6. Gonadotropin-releasing hormone (GnRH): Stimulates the release of gonadotropins, FSH and LH

7. Prolactin-inhibitory hormone (PIH): Inhibits prolactin secretion. It is believed that PIH is dopamine

The anterior pituitary (adenohypophysis) secretes,

ACTH (adrenocorticotrophic hormone),
FSH (follicular stimulating hormone).
LH (luteinizing hormone)
Prolactin and
GH (growth hormone).
TSH (thyroid stimulating hormone),

The posterior pituitary lobe (neurohypophysis) secretes

Oxytocin and
Vasopressin (antidiuretic hormone, ADH).

Vasopressin (antidiuretic hormone, ADH)

Originates primarily in the supraoptic nuclei of the hypothalamus.
Regulates serum osmolarity by increasing the H2O permeability of the late distal tubules and collecting ducts.

Actions:

Antidiuretic effect by increasing renal late distal tubule and collecting duct cells reabsorption of H2O.
Vasoconstriction causing an increase the arterial blood pressure at moderate and high concentrations.

Control of Secretion

Osmotic Stimuli
Volume effect
Other Stimuli include: pain, nausea, surgical stress, and emotions increase ADH secretion while alcohol decrease ADH secretion.

Diabetes insipidus generally develops because the posterior lobe of the pituitary gland no longer releases adequate amounts of ADH. Water conservation by the kidneys is impaired, and excessive amounts of water are lost in the urine. As a result, the person is constantly thirsty, but the body does not retain the fluids consumed. Mild cases of diabetes insipidus may not require treatment if fluid and electrolyte intake keep pace with urinary losses. In severe cases, the fluid losses can reach 10 liters per day, and dehydration and electrolyte imbalances are fatal without treatment. This condition can be effectively treated with desmopressin, a synthetic form of ADH.

Oxytocin

Action:

milk ejection reflex
On gravid uterus: Oxytocin acts on gravid uterine muscles directly or indirectly through prostaglandin formation. Oxytocin, therefore, can be used to induce labor and reduce postpartum bleeding.
On non gravid uterus: Genital stimulation during coitus causes oxytocin release leading to uterine contraction which help in pushing sperms upward. In males: oxytocin increases at time of ejaculation which causes smooth muscle contraction of vasdeference, so propelling the sperms toward the urethra.

Regulation of oxytocin secretion
(1) Suckling
■ is the major stimulus for oxytocin secretion.
■ The sight or sound of the infant may stimulate the hypothalamic neurons to secrete oxytocin, even in the absence of suckling.
(2) Dilation of the cervix and orgasm.

Prolactin

is the major hormone responsible for lactogenesis.
participates, with estrogen, in breast development.
is structurally homologous to growth hormone.

Regulation of prolactin secretion

(1) Hypothalamic control by dopamine- and thyrotropin-releasing hormone (TRH). Prolactin secretion is tonically inhibited by dopamine [prolactin-inhibiting factor (PIF)] secreted by the hypothalamus. Thus, interruption of the hypothalamic –pituitary tract causes increased secretion of prolactin and sustained lactation. TRH increases prolactin secretion.
(2) Negative feedback control: Prolactin inhibits its own secretion by stimulating the hypothalamic release of dopamine.
Actions of prolactin
(1) Stimulates milk production in the breast (casein, lactalbumin)
(2) Stimulates breast development (in a supportive role with estrogen)
(3) Inhibits ovulation by decreasing synthesis and release of gonadotropin-releasing hormone (GnRH)
(4) Inhibits spermatogenesis (by decreasing GnRH)

Pathophysiology of prolactin
(1) Prolactin deficiency (destruction of the anterior pituitary)
■ results in the failure to lactate.
(2) Prolactin excess
■ results from hypothalamic destruction (due to loss of the tonic “inhibitory” control by dopamine), or from prolactin-secreting tumors (prolactinomas).
■ causes galactorrhea and decreased libido.
■ causes failure to ovulate and amenorrhea because it inhibits GnRH secretion.
■ can be treated with bromocriptine, which reduces prolactin secretion by acting as a dopamine agonist.
Growth Hormone (GH), also called somatotropic hormone (SH) or somatotropin.
Is the most important hormone for normal growth to adult size. It is a single-chain polypeptide that is homologous with prolactin and human placental lactogen.

Regulation of growth hormone secretion.

Growth hormone is released in pulsatile fashion.
Secretion is increased by sleep, stress, hormones related to puberty, starvation, exercise, and hypoglycemia.
Secretion is decreased by somatostatin, somatomedins, obesity, hyperglycemia, and pregnancy.
GH acts on bones, growth and protein metabolism through somatomedins secreted by liver. GH stimulates the liver to secrete somatomedins. Somatomedins are of two types: i. Insulin-like growth factor-I (IGF-I), ii. Insulin-like growth factor-II (IGF-II). IGF-I acts on the bones and protein metabolism. IGF-II plays an important role in the growth of fetus.

(1) Hypothalamic control—GHRH and somatostatin
■ GHRH stimulates the synthesis and secretion of growth hormone.
■ Somatostatin inhibits secretion of growth hormone by blocking the response of the anterior pituitary to GHRH.
(2) Negative feedback control by somatomedins
■ Somatomedins are produced when growth hormone acts on target tissues.
■ Somatomedins inhibit the secretion of growth hormone by acting directly on the anterior pituitary and by stimulating the secretion of somatostatin from the hypothalamus.
(3) Negative feedback control by GHRH and growth hormone
■ GHRH inhibits its own secretion from the hypothalamus.
■ Growth hormone also inhibits its own secretion by stimulating the secretion of somatostatin from the hypothalamus.
The actions of GH are:
1. GH increases the length of the bones, until epiphysis fuses with shaft, which occurs at the time of puberty. GH increases the size and mitotic activity of the cells of most of tissues especially the bones by increasing the length of long bones by: a. Increases deposition of protein by chondrocytes and osteogenic cells and increases the rate of reproduction of these cells. b. Increases osteoblasts activity and inhibits osteoclastic activity. Hypersecretion of GH before the fusion of epiphysis with the shaft of the bones causes enormous growth of the skeleton, leading to a condition called gigantism. Hypersecretion of GH after the fusion of epiphysis with the shaft of the bones leads to a condition called acromegaly .
2. Effects on Carbohydrates: Enhance glycogen deposition in the cells, diminished glucose uptake by cells, increases hepatic glucose output, it decreases the number and affinity of insulin receptors causing the condition called (Pituitary Diabetes).
3. Effect on Fat: ↑ lipolysis, GH increases FFA and keton body formation with subsequent utilization of them for energy. Therefore, metabolic rate is increased. In addition. GH decreases cholesterol (decrease body fat) .
4. Effect on Protein: GH has anabolic effect on protein. Therefore, it has a positive nitrogen.
5. Effects on Electrolytes: Increase GIT absorption of calcium and phosphate, reduced excretion of Na+ and K+ due to shift of electrolyte from kidney to growth tissues.
Pathophysiology of growth hormone
(1) Growth hormone deficiency
■ in children causes failure to grow, short stature, mild obesity, and delayed puberty.
■ can be caused by:
(a) Lack of anterior pituitary growth hormone
(b) Hypothalamic dysfunction (↓ GHRH)
(c) Failure to generate IGF in the liver
(d) Growth hormone receptor deficiency
(2) Growth hormone excess
■ can be treated with somatostatin analogs (e.g., octreotide), which inhibit growth hormone secretion.
■ Hypersecretion of growth hormone causes acromegaly.
(a) Before puberty, excess growth hormone causes increased linear growth (gigantism).
(b) After puberty, excess growth hormone causes increased periosteal bone growth, increased organ size, and glucose intolerance.
Physiology of Growth
Affected by:
- Genetic factors
- Nutrition
- Hormonal effect
1. GH: The effects of GH on protein synthesis and cellular growth are most apparent in children. GH supports their muscular and skeletal development. In adults, growth hormone helps to maintain normal blood glucose concentrations and to mobilize lipid reserves in adipose tissue. GH is not the primary hormone involved, however. An adult with a GH deficiency but normal levels of thyroxine (T4), insulin, and glucocorticoids will have no physiological problems.
2. Sex hormones increase growth hormone and IGF-I secretion. Sex hormones also increases GH response to stimuli such as insulin and arginine.
3. Thyroid hormones: The action of thyroid hormone is permissive to that of growth hormone via
  the potentiation of somatomedins. Normal growth also requires appropriate levels of thyroid hormones. If these hormones are absent during fetal development or for the first year after birth, the nervous system fails to develop normally, and developmental delay results. If T4 concentrations decline later in life but before puberty, normal skeletal development does not continue.
4. Insulin: Growing cells need adequate supplies of energy and nutrients. Without insulin, the passage of glucose and amino acids across plasma membranes stops or is drastically reduced.
5. Adrenocortical hormones: Normal levels of adrenocortical hormones are needed for normal growth and they are having permissive action on growth. The presence or absence of reproductive hormones (androgens in males, estrogens in females) affects the activity of osteoblasts in key locations and the growth of specific cell populations. Androgens and estrogens stimulate cell growth and differentiation in their target tissues, but their targets differ. The differential growth induced by each accounts for gender-related differences in skeletal proportions and secondary sex characteristics.
6. Parathyroid Hormone (PTH) and Calcitriol: Parathyroid hormone and calcitriol promote the absorption of calcium salts from the bloodstream for deposition in bone. Without adequate levels of both hormones, bones can still enlarge, but are poorly mineralized, weak, and flexible. For example, rickets is a condition typically caused by inadequate calcitriol production due to vitamin D deficiency in growing children. As a result, the lower limb bones are so weak that they bend under the body’s weight
The Male reproductive system
The testes are made up of loops of convoluted seminiferous tubules.
blood—testis barrier
- Prevent large molecules from passing to lumen of tubule, allowing germ cells to pass only.
- Maintains the composition of fluid in the lumen of seminiferous tubule.
- Protects the germ cells from blood borne noxious agents.
- Prevents antigenic products of germ cell division and maturation from entering the circulation and generating an autoimmune response.
- Helps to establish an osmotic gradient that facilitate movement of fluid into tubular lumen.
Hormones essential for spermatogenesis (see figure):
1. Testosterone: necessary for maturation of spermatids to spermatozoa.
2. FSH:
- Acts on sertoli cell to facilitate last step of spermatid maturation.
- Stimulates production of ABP.
3. LH: stimulates the production of androgen from interstitial cells of Leydig.
4. Estrogen.
5. Growth hormones: necessary for controlling background metabolic function of testes and promote early maturation of spermatogonla.
Testosterone secretion in different periods of life: Testosterone secretion starts at 7th week of fetal life by fetal genital ridge. Fetal testes begin to secrete testosterone at about 2nd to 4th month of fetal life. In fetal life, testosterone secretion from testes is stimulated by human chorionic gonadotropins, secreted by placenta. But in childhood, practically no testosterone is secreted approximately until 10 to 12 years of age. Afterwards, the testosterone secretion starts and it increases rapidly at the onset of puberty and lasts through most of the remaining part of life. The secretion starts decreasing after 40 years and becomes almost zero by the age of 90 years (Figure).
In addition to androgens, female sex hormones are also produced in testes. Small amount of estrogen is produced in males. Estrogens have three sources of production in males, adrenal cortex, testes (up to 20% of estrogen in males is produced in testes), and estrogen is formed from androgens in Sertoli cells of testes, by the inﬂuence of the enzyme aromatase, other organs of which about 80% of estrogen is formed from androgens in other organs, particularly liver. Progesterone is also produced from androgens in males though the quantity is very less.
Male andropause or climacteric: Male andropause or climacteric is the condition in men, characterized by emotional and physical changes in the body, due to low androgen level with aging. It is also called viropause. After the age of 50, testosterone secretion starts declining. It is accompanied by decrease in number and secretory activity of Leydig cells. Low level of testosterone increases the secretion of FSH and LH, which leads to some changes in the body. It does not affect most of the men. But some men develop symptoms similar to those of female menopausal syndrome. Common symptoms are hot ﬂashes, illusions of suffocation and mood changes.
Endocrine Function of Testes:
Testosterone, the principal hormone of the testes. It is synthesizedfrom cholesterol in the Leydig cells and also formed from androsterone secreted by adrenal cortex. Secretion of testosterone is under the control of LH (see figure).
Actions of Testosterone are:
1. Development of secondary sexual characters of males at puberty .
2. Anabolic Effects.
- Increase synthesis and decrease breakdown of protein,
- Increase musculature and bone growth after puberty,
- Increase of BMR by 5 - 10%,
- Increase number of RBCs by 15 - 20%.
- It has a feedback mechanism to inhibit pituitary LH secretion and GnRH secretion from hypothamaus.
Female reproductive system
Control of ovarian functions & their changes
[1] Hypothalamus (Arcuate nucleus) control through pulsatile (every 1-3 hours) release of GnRH.
[2] Pituitary control through pulsatile release of FSH and LH: FSH from pituitary is responsible for maturation of ovarian follicles. The ovarian follicles, under the effect of FSH, secrete estrogen. Then at the end of follicular phase, a burst of LH secretion occurs (LH surge) which is responsible for ovulation and initial formation of corpus luteum.
[3] Cyclic control: Small amounts of estrogen had – ve Feedback on FSH, LH and GnRH, while large amounts of estrogen had + ve Feedback on the FSH, LH and GnRH. Progesterone and inhibin had – ve feedback effect on FSH, LH, and GnRH.

Ovarian (menstrual) cycle: Ovarian cycle has 3 phases:
1. The Follicular phase: The follicular phase extends from the 5th day of the cycle to the 14th day during which FSH will induce maturation of the primordial follicles > vesicular follicles > mature follicles (called Graffian follicles). FSH stimulates Graffian follicles to secrete estrogen. During this phase, LH secretion is held in check by the negative feedback of the rising plasma estrogen level.
2. The second phase: Ovulation: Occurs 14 days before menses, regardless of the cycle length. In ovulation, rupture of Graafian follicle occurs under the effect of LH. 36 – 48 h. before ovulation, the excess of estrogen level change the estrogen feedback to become positive leading to burst in LH secretion (LH surge) that produce ovulation. FSH also peaks despite little rise of inhibin level probably because of strong stimulation of FSH and LH by GnRH.
3. The third phase: Luteal phase: Begins from the 14th –28th day of the cycle, under the control of LH. The high levels of estrogen, progesterone and inhibin lead to – ve feedback so result in low FSH and LH.
Uterine cycle :
1. Proliferative phase (estrogen phase): Under the influence of estrogen from the developing follicle, the endometrium increases rapidly in thickness and uterine glands increases in length from the 5th to the 14th days of menstrual cycle.
2. Secretory or luteal phase (progestational phase): After ovulation the endometrium becomes more vascular and slightly edematous and the glands start to secrete clear fluid this occurs under the influence of estrogen and progesterone from corpus luteum during the 14th to 28th days of menstrual cycle.
3. Desquamation of endometrium (menstruation): Approximately, two days before the end of the monthly cycle, regression of corpus luteum occurs and leads to a sharp hormonal withdrawal of estrogen and progesterone leading to shedding of endometrial tissue resulting in spotty hemorrhages that become confluent and produce the menstrual flow.
Ovarian Hormones:
Regulation
Estrogens
[A] Effects on female genitilia:
- Estrogens facilitate growth of ovarian follicle.
- Increase motility of fallopian tubes
- Cyclic changes of endometrium, cervix and vagina as mentioned previously.
- Increases uterine blood flow.
- Increases the amount of uterine muscle and it’s content of contractile proteins.The muscle becomes active and more excitable.
- Estrogen makes uterus more sensitive to oxytocin.
- Vaginal epithelium is changed from cuboidal to startified columnar epith.
[B] Effect on development of secondary sexual characters:
- Female body configuration: Narrow shoulder, broad hip, converged thigh, diverged arm. Fat distribution in buttocks and breast.
- Larynx: Voice becomes high pitched.
- Skin: Soft, smooth, but thicker than childhood, more vascular, therefore, the skin is warm and bleed more than male, less body hair, more scalp hair, pubic hair is flat topped pattern (axillary and pubic hair is due to effect of adrenal androgen).
- Sebaceous glands secretions become more fluid so reduced acne formation.
- Breasts Become enlarged due to growth of stromal tissue, ductal system deposition of fat, pigmentation of areola and apperance of mature female breast.
[C] Behavioral effects: Estrogens are responsible for estrous behavior in animals and they increase libido in human due to effects on special neurons in hypothalaumus.

[D] Effect on skeleton: Estrogen had osteoblastic activity so it causes increase in bone length but later
causes early closure of epiphyseal plate so low estrogen levels lead to ostroporosis, decrease bone matrix and decrease bone Ca+ and PO4-.

[E] Matabolic effects:
- On proteins it causes protein anabolic effect on specific target organs like breast, skeleten, uterus and certain fatty areas.
- On fat it causes increase in BMR, increases deposition of fat in subcutaneous tissues and has significant plasma cholesterol lowering action (less atherosclerosis).
[F] Other effects:
- Mild Na and H2O retention (significant in pregnancy only).
- Has positive and negative feedback effect on LH and FSH secretion.
- Increase size of pituitary.
- Increase secretion of angiotensinogen and thyroid binding protein.
Progesterone
It is secreted mainly from corpus luteum, placenta and less by the follicle. Small amounts enter circulation from testes and adrenal cortex.
The effects of progesterone are:
[A] On uterus:
- Cyclic changes on vagina and cervix.
- Progestational changes on endometrium.
- Antiestrogenic effect on myometrium including decreasing excitability of myometrium cells and their spontaneous electrical activity by increasing their membrane potential, also decrease number of estrogen receptors in endometrium and increase conversion of estradiol to less active estrogen.
[B] On fallopian tubes: Promotes secretory changes in mucosal membrane which are necessary for nutrition of fertilized ovum.
[C] On breast: Stimulate the development of lobules and alveoli and increase fluid in subcutaneous tissue leading to breast swelling. It induces differentiation of estrogen-prepared ductal tissues and support the secretory function of breast during lactation.
[D] On hypothalamus and pituitary: High does of progesterone causes feedback effect and inhibit LH secretion and potentiate the inhibitory effect of estrogen preventing ovulation (the action of contraceptive pills).
[E] Other effects: Large doses produce natriuresis by blocking the action of aldosterone on the kidney. It has thermogenic effect causing rise in basal body temperature at time of ovulation. Progesterone causes stimulation of respiration and therefore, alveolar PaCO2 falls as progesterone secretion rises. The hormone does not have a significant anabolic effect.

Relaxin
Polypeptide hormone produced by corpus luteum, uterus, placenta and mammary glands in women and from prostate in man. During pregnancy it relaxes pubic symphysis and other pelvic joints and softens and dilates uterine cervix to facilitate delivery. It also inhibits uterine contractions and may play a role in the development of mammary glands. In non–pregnant woman it’s function is unknown. In men relaxin is found in semen and it may help to maintain sperm motility and aid sperm penetration to the ovum.

Inhibin
A polypeptide produced by the granulosa cells and inhibits FSH secretion.

Hormones secreted from placenta
[1] Human Chorionic gonadotropin (hCG): acts on same receptors of LH. It appears in blood 6 days after conception and in urine after 14 days (so used as pregnancy test). It is secreted by the kidney and liver of fetus in small amounts. The rate of secretion reaches maximum about 10 – 12 weeks of gestation and decrease to much lower value by 16-20 week, and continues at this level for the rest of pregnancy. hCG:
- stimulates corpus luteum to continue secretes estrogen and progesterone until the 16th week of gestation after that the placenta secrete estrogen and progesterone. The function of Corpus luteum begins to decline after 8 weeks of pregnancy but it persist throughout pregnancy.
- exerts an interstitial cell stimulating effect on the testes thus resulting in production of testosterone in male fetus until the time of birth.
[2] Human Chorionic somatomammotropin (hCS, or human placental lactogen): The amount of hCS secreted is proportional to the size of placenta, which normally weights 1/6 of fetal weight. Therefore, low hCS levels indicates placental insufficiency. Functions of hCS are:
- Has Lactogenic effect with slight increase in breast development.
- It has most actions of GH (due to similar structure) but less potent than GH. It causes retention of nitrogen, K+ and Ca++. Secretion of GH from maternal pitutary is reduced by the hCS.
- Causes reduced insulin sensitivity and decrease utilization of glucose in maternal tissues thus making large quantities of glucose available to the fetus.
[3] Estrogen: It is formed by corpus luteum in early pregnancy and by placenta in late pregnancy. It differs from the estrogen secreted by the ovaries by:
a. Most of this estrogen is estriol (very weak type).
b. It is not secreted purely from placenta but interaction between placenta and fetal Adrenal cortex (fetoplacental unit). Functions of estrogen in pregnancy are:
- Development of maternal uterus, breasts and external genitilia.
- Relaxes various pelvic ligaments.
- Affects general aspects of fetal development as the rate of cell reproduction of early embryo.
[4] Progesterone: Secreted by corpus luteum in early pregnancy or by placenta in late pregnancy. The functions of progesterone during pregnancy are:
- Development of decidual cells in uterine endometrium which are important for nutrition of embryo in early stages.
- Decreases contractility of gravid uterus and prevent abortion.
- Increases the secretion of fallopian tubes and uterus to provide approperiate nutritive matter for the developing morula and blastocyst.
[5] Other Placental Hormones: Hormones secreted by the placenta also include: Proopiomelarocartin (POMC), melanocyte stimulating hormone, B-endrophin, dynorphin, GnRH and inhibin (which stimulates and inhibits hCG), also prolactin and prorenin hormones.
Pathways for placental exchange
NOTES:
During the first trimester of pregnancy (i.e., during the first 12 weeks of gestation), the corpus
luteum (stimulated by hCG) is responsible for the production of estradiol and progesterone. During second and third trimesters, progesterone is produced by the placenta while estrogens are produced by theinterplay of the fetal adrenal gland and the placenta.

Endocrinal changes during Pregnancy:
1- Pitutary gland: Increase In size, increased secretion of ACTH, TSH and prolactin. In addition,
decreased levels of FSH and LH.
2- Adrenal glands: Increased secretion of glucocorticoids, aldosteron and estrogen causes water and Na+ retention.
3- Thyroid gland: Increased size of the gland with increased thyroxin due to the thyrotropic effect of hCG and human chorionic thyrotropin (from placenta).
4- Parathyroid gland: Increase in the size of the gland. Increase PTH during pregnancy and lactation to meet the increased Ca+ demand of the fetus.
5- Relaxin: Secreted by corpus luteum and then by the placenta. It helps to relax the pelvic joints.
Uterine Blood Flow
Maternal Cardiovascular System

Parturition (delivery of the baby or labour)
In the last month of pregnancy irregular uterine contractions increases in frequency. This is due to:
[1] The number and sensitivity of oxytocin receptors in myometrium and decidua increases more than 100 folds during pregnancy and reach a peak during early labour. This is due to estrogen and uerine distention in late pregnancy which increases the formation of oxytocin receptors. Oxytocin increases uterine contractions by:
- Acts directly on uterine smooth muscles.
- Stimulation of PG formation in decidua. the PG enhances the oxytocin – induced contractions.
[2] Mechanical factors increases uterine contractions are:
- Stretch of uterine musculature caued by fetal movements.
- Stretch of cervix, leads to increase in oxytocin secrection. As plasma oxytocin level rises, more oxytocin acts on uterus, and positive feedback loop is established that aids delivery and is terminated when products of conception are expelled.
Development of breasts and lactation
[1] During puberty: Estrogen are primarily responsible for proliferation of mammary ducts while progesterone is necessary for development of lobules. Other hormones like insulin, GH and prolactin are necessary for mammary developmant but by themselves do not cause breast growth.
[2] During pregnancy: Enlargment of breast occur due to high circulating levels of estrogen,
progesterone, prolactin and hCG. Milk is secreted as early as the Fifth month but in small amounts.
[3] After Delivery: The drop in estrogen and progesterone after placental expulsion initiates lactation under the effect of prolactin. Estrogen antagonizes milk producing effect of prolactin.

Hormonal control of milk Production and secretion
1. Oxytocin as mentioned before.
2. Prolactin: Prolactin is secreted from anterior pituitary gland. It is tonically inhibited by hypothalamic
prolactin–inhibiting hormone (PIH). It causes milk production and inhibits gonadotropin in females and causes impotence in males. Prolactin is increased by
- Exercise.
- Sleeping.
- Surgical and psychological stress.
- Nipple stimulation.
- TRH
- Estrogen.
- Dopamine antagonist (drugs like metochlopramide, plasil).
Each time the mother nurses her baby, nervous signals from the nipple to hypothalamus causes
increase prolaction secretion and hence milk production is increased. When nursing is stopped, the PIH is secreted so prolactin level is reduced and milk production also decrease. So prolactin level increases in cycles during the peroid of nursing.
Milk ejection reflex:
It is a neuroendocrine reflex, initiated by by touching the touch receptors at areolas (the area around the nipples) and nipples, stimulated by sucking the mother nipples by the baby. Impulses generated in these receptors are then relayed to the suproptic and paraventricular nuclei. Discharge of the oxytocin-containing neurons causes secretion of oxytocin from the posterior pituitary gland. Oxytocin causes contraction of myoepithelial cells lining the duct walls leading to milk ejection. Suckling not only evokes reflex oxytocin release and milk ejection, it also maintains and augments the sectetion of milk because of prolactin stimulation as well.

Effect of lactation on menstrual cycles
Women who do not nurse their infants usually have their 1st mense 6 weeks after delivery. Women regularly nursing have their 1st cycle 25-30 weeks after delivery. Prolactin stimulated by nursing inhibits GnRH serection > inhibition of gonadotropin of pitutary gland > antogonize the action ofgonadotropin on ovary > ovulation is inhibited > inactive ovaries > estrogen and progesteron levels fall to low values. Only 5-10 % of women become pregnant again during suckling peroid also 50 % of the cycles in the first 6 months after return of menses are anovulatery cycles.

Hormone types (figure)

Regulation of hormone secretion

Regulation of Hormone Receptors

Thyroid gland (figure):

Effect of T3 & T4:

Applied physiology

Endocrine Functions of the Pancreas

Insulin

Mechanism of insulin secretion & mechanism of action (signal transduction)

Action of insulin:

Applied physiology

Glucagon

Somatostatin

Pancreatic Polypeptide

The Adrenal Medulla and adrenal Cortex

Effects of Epinephrine and Norepinephrine:

Dopamine

Adrenal glucocorticoids

Adrenal mineralocorticoids

Adrenal sex hormones:

Applied physiology

Calcium metabolism and bone physiology

Physiology of bone:

The net results of the previous effects are increased plasma Ca++ and phosphate levels

Actions:

The net results of the previous effects are increased Ca++ plasma level and a decreased phosphate plasma level.

The net results of the previous effects are decreased Ca++ and phosphate plasma levels

Applied physiology – diseases of bone

The pituitary gland (figure)

Vasopressin (antidiuretic hormone, ADH)

Oxytocin

Prolactin

Pathophysiology of prolactin

Growth Hormone (GH), also called somatotropic hormone (SH) or somatotropin.

Pathophysiology of growth hormone

Physiology of Growth

The Male reproductive system

Hormones essential for spermatogenesis (see figure):

Endocrine Function of Testes:

Actions of Testosterone are:

Female reproductive system

Control of ovarian functions & their changes

Ovarian (menstrual) cycle: Ovarian cycle has 3 phases:

Uterine cycle :

Ovarian Hormones:

Estrogens

Progesterone

Relaxin

Inhibin

Hormones secreted from placenta

Pathways for placental exchange

NOTES:

Endocrinal changes during Pregnancy:

Parturition (delivery of the baby or labour)

Development of breasts and lactation

Hormonal control of milk Production and secretion

Milk ejection reflex:

The net results of the previous effects are increased Ca⁺⁺ plasma level and a decreased phosphate plasma level.

The net results of the previous effects are decreased Ca⁺⁺ and phosphate plasma levels