Endocrine System.
The endocrine system consists of ductless glands called endocrine glands the secrete hormones,
as well as hormone secreting cells located in various organs, such as the brain, heart, kidneys, liver,
and stomach.
Hormones are chemical messengers that enter the blood, which carries them from the site of secretion,
to the cells upon which they act.
The cells a particular hormone influences are known as the target cells for that hormone.
Hormones functionally link various organs together.
As such, several of the general principles of physiology apply to the study of the endocrine system,
including the principle, that the functions of organ systems are coordinated with each other.
This coordination is key to the maintenance of homeostasis, which is important for health and survival.
In many cases, the action of one hormone can be potentiated, inhibited,
or counterbalanced by the actions of another.
This illustrates the general principle of physiology that most physiological functions,
are controlled by multiple regulatory systems, often working in opposition.
The binding of hormones to their carrier proteins and receptors,
illustrates the general principle of physiology that physiological processes,
are dictated by the laws of chemistry and physics.
The anatomy of the connection of the hypothalamus and the anterior pituitary,
demonstrates that structure is a determinant of - and has coevolved with -
function (hypothalamic control of anterior pituitary function).
The regulated uptake of iodine into the cells of the thyroid gland,
that synthesises thyroid hormones demonstrates the general principle of physiology,
that controlled exchange of materials occurs between compartments and cellular membranes.
The general principle of physiology is that information flow between cells, tissues,
and organs is an essential feature of homeostasis,
and allows for the integration of physiological processes.
Hormones and Endocrine glands.
Endocrine glands are distinguished from another type of gland in the body called exocrine glands.
Exocrine glands secrete their products into a duct, from where the secretions either exit the body,
(as in sweat) or enter the lumen of another organ, such as the intestines.
By contrast, endocrine glands are ductless and release hormones into the blood.
Hormones are actually released first into the interstitial fluid, from where they diffuse into the blood.
For simplicity we will often omit the interstitial fluid in our discussion.
Overview of major hormones.
Hypothalamus.
Secretes several neurohormones that stimulate or inhibit anterior pituitary gland function.
Synthesises two neurohormones that are stored in and released from the posterior pituitary.
Heart.
(sodium ion N a +, reads as Na+)
Makes arterial natriuretic peptide, which lowers blood Na+.
Adrenal glands (medulla and cortex).
Medulla.
Makes epinephrine and norepinephrine, which mediate the fight-or-flight response.
Cortex.
Makes aldosterone, which regulate Na+ and K+ balance.
Makes cortisol which regulate growth, metabolism, development, immune function,
and the response to stress.
Makes some androgens which play a role in reproduction.
Liver.
Produces insulin-like growth factor-1, which controls growth of bones.
Secretes angiotensinogen, a precursor required for production of angiotensin II.
Kidneys.
Secrete erythropoietin, which regulates maturation of red blood cells.
Produces the active hormone 1, 25 dihydroxyvitamin D.
Secretes the enzyme renin, which begins the synthesis of the hormone angiotensin II.
Pancreas.
Makes insulin, which decreases blood glucose, and glucogen which increases blood glucose.
Blood vessels.
Cells of many blood vessel walls express enzymes that are required to complete the synthesis,
of angiotensin II, which helps maintain normal blood pressure.
Adipose tissue.
Produces hormones (for example, leptin) which regulates appetite and metabolic rate.
Anterior pituitary gland.
Produces diverse actions related to metabolism, reproduction, growth and others,
(ACTH, FSH, LH, GH, PRL, TSH).
Posterior pituitary.
Secrets oxytocin, which stimulates uterine contractions during birth and milk secretion after birth.
Secrets antidiuretic hormone (also called vasopressin),
which increases water reabsorption in the kidneys.
Pineal.
Makes melatonin, which may play a role in circadian rhythmicity.
Parathyroids. (behind the thyroid).
(Calcium ion C a 2+, reads as Ca2+.)
Makes parathyroid hormone which increases Ca2+, and stimulates the production in the kidneys,
of the active form of vitamin D.
Thyroid.
Makes thyroid hormone, which regulates metabolic rate, growth, and differentiation.
Makes calcitonin, which plays a role in Ca2+ homeostasis in some species.
The role in humans is not clear.
Stomach and small intestine.
Secrete numerous hormones such as gastrin, secretin,
and colosystokini that regulate pancreatic activity, facilitate digestion, and control appetite.
Ovaries.
Produces oestrogens - such as estradiol - and progesterone, which controls female reproduction.
Testes.
Produce androgens, such as testosterone, which control male reproduction.
This summarises most of the endocrine glands and other hormones secreting organs,
the hormones they secrete, and some of the major functions the hormones control.
The endocrine system differs from most of the other organ systems of the body,
in that the various components are not anatomically connected.
However, they do form a system in the functional sense.
A single gland may secrete multiple hormones.
The usual pattern in such cases, is that a single cell secretes only one hormone,
so that multiple hormone secretion reflects the presence of different types of endocrine cells,
in the same gland.
In a few cases, however, a single cell may secrete more than one hormone,
or different forms of the same hormone.
In some cases, a hormone secreted by an endocrine gland cell may also be secreted by other cell types,
and serves in these other locations as a neurotransmitters or paracrine or autocrine substance.
For example, somatostatin, a hormone produced by neurons in the hypothalamus,
is also secreted by cells of the stomach and pancreas, where it has local paracrine actions.
Hormone structure and synthesis.
Hormones fall into three major structural classes.
- Amines.
- Peptides and proteins.
- Steroids.
Amine hormones.
The amine hormones are derivatives of the amino acid tyrosine.
They include thyroid hormones produced by the thyroid gland,
catecholamines epinephrine, and norepinephrine produced by the adrenal nebula.
Dopamine produced by the hypothalamus.
There are two adrenal glands, one above each kidney.
Each adrenal gland is composed of an inner adrenal medulla, which secretes catecholamines,
and a surrounding adrenal cortex, which secretes steroid hormones.
The adrenal medulla is actually a modified sympathetic ganglion whose cell bodies do not have axons.
Instead, they release their secretions into the blood, thereby fulfilling a criteria for a endocrine gland.
The adrenal medulla secretes mainly two catecholamines, epinephrine and norepinephrine.
In humans, the adrenal nebula secretes four times more epinephrine then norepinephrine.
This is because high amounts of an enzyme called PNMT,
which catalyses the reaction that converts norepinephrine into epinephrine.
Epinephrine and norepinephrine exerts actions similar to those of the sympathetic nerves,
which, because they do not express PNMT, make only norepinephrine.
The other catecholamine hormone, dopamine is synthesised by neurons in the hypothalamus.
Dopamine is released into a special circulatory system called a portal system,
which carries the hormone to the pituitary gland.
There it acts to inhibit the activity of certain endocrine cells.
Peptide and protein hormones.
Short polypeptides with a known function are often referred to as peptides.
Longer polypeptides with tertiary structure and a known function are called proteins.
Hormones in this class range in size from small peptides having only 3 amino acids to large proteins,
some of which contain carbohydrate and thus are glycoproteins.
For convenience we will refer to all these hormones as peptide hormones.
In many cases, peptide hormones are initially synthesised on the ribosomes of endocrine cells,
as larger molecules known as prehormones, which are then cleaved to prohormones.
The prohormones is then packaged into secretory vesicles by the Golgi apparatus.
In this process, the prohormone is cleaved to yield the active hormone,
and other peptide chains found in the prohormone.
Consequently, when the cell is stimulated to release the contents of the secretory vesicles by exocytosis, the other peptides are secreted along with the hormone.
In certain cases, this other peptides may also exert hormonal effects.
In other words, instead of just one peptide hormone, the cell may secrete multiple peptide hormones-
derived from the same prohormone - each of which differs in its effects on target cells.
One well studied example of this is the synthesis of insulin in the pancreas.
Insulin is synthesised as a polypeptide prehormone, then processed to the prohormone.
Enzymes clip off a portion of the prohormone resulting in insulin and another product called C-peptide.
Both insulin and C-peptide are secreted into the circulation in roughly equimolar amounts.
Insulin is a key regulated of metabolism,
while C-peptide may have several actions in a variety of cell types.
Steroid hormones.
Steroid hormones makeup the third family of hormones.
They have a ring like structure.
Steroid hormones are primarily produced by the adrenal cortex and the gonads (testes and ovaries),
as well as by the placenta during pregnancy.
In addition, vitamin D is enzymically converted in the body to a active steroid hormone.
In both the godowns and adrenal cortex, the hormone producing cells are stimulated,
by the binding of an anterior pituitary gland hormone to its plasma membrane receptor.
G subscript s reads as Gs.
Lower case c, upper case A M P reads as cAMP.
These receptors are linked to Gs proteins, which activate adenylyl cyclase and cAMP production.
The subsequent activation of protein kinase A by cAMP results in phosphorylation,
of numerous intra cellular proteins, which facilitate the subsequent steps in the process.
All of the steroid hormones are derived from cholesterol,
which is either taken up from the extracellular fluid by the cells,
or synthesised by intracellular enzymes.
The final steroid hormone product depends upon the cell type,
and the types and amounts of the enzymes it expresses.
Cells in the ovaries, for example, express large amounts of the enzyme,
needed to convert testosterone to estradiol,
where as cells in the testes do not express significant amounts of this enzyme,
and therefore make primarily testosterone.
Once formed, steroid hormones are not stored in the cytosol in membrane bound vesicles,
because the lipophilic nature of steroids allows them to freely diffuse,
across the plasma membrane into the circulation.
Because of their lipid nature, steroid hormones are not highly soluble in blood.
Consequently, the majority of steroid hormones are reversibly bound in plasma to carrier proteins,
such as albumin and other specific proteins.
Hormones of the Adrenal Cortex.
The five major hormones secreted by the adrenal cortex are aldosterone, cortisol, corticosterone,
DHEA, and androstenedione.
Aldosterone is known as a mineralocorticoid because its effects are on salt balance,
mainly on the kidney’s handling sodium, potassium, and hydrogen ions.
Briefly, production of aldosterone is under the control of another hormone called angiotensin II,
which binds to the plasma membrane receptors in the adrenal cortex,
to activate the inositol triphosphate second messenger pathway.
This is different from the more common cAMP mediated mechanism,
by which most steroid hormones are produced.
Once synthesised, aldosterone enters the circulation and acts on the cells of the kidney’s to stimulate Na+ and H2O retention, K+ and H+ excretion in the urine.
.
Cortisol and the related less functional steroid corticosterone are called glucocorticoids,
because they have important effects on the metabolism of glucose and other organic nutrients.
Cortisol is the predominant glucocorticoid in humans.
In addition to its effects on organic metabolism, cortisol exerts many other effects,
including facilitation of the body’s response to stress and regulation of the immune system.
DHEA and androstenedione belong to the class of steroid hormones known as androgens.
This class also includes the major male sex steroid testosterone, produced by the testes.
The adrenal androgens are much less potent than testosterone,
and they are usually of little physiological significance in the adult male.
They do, however have functions in the adult female and in both sexes in the fetus and at puberty.
The adrenal cortex is composed of three distinct layers.
The cells of the outermost layers, express the enzymes required to synthesise corticosterone,
then convert it to aldosterone.
They do not express the genes that code for the enzymes,
required for the formation of cortisol and androgens.
Therefore this layer synthesises and secretes aldosterone,
but not the other major adrenocortical hormones.
In contrast, the other layers secrete no aldosterone, but do secrete cortisol and androgen.
Hormones of the Gonads.
Compared to the adrenal cortex, the gonads express different enzymes in their steroid pathways.
Endocrine cells in both the testes and the ovaries do not express the enzymes,
to produce aldosterone and cortisol.
They posses high concentration of enzymes in the androgen pathways,
leading to androstenedione as in the adrenal cortex.
In addition, the endocrine cells in the testes express large amounts of an enzyme that converts,
androstenedione to testosterone, which is the major androgen secreted by the testes.
The ovarian endocrine cell synthesises the female sex hormones, which are collectively known as estrogens.
Estradiol is the predominant estrogen present during a women’s lifetime.
The ovarian endocrine cells express large amounts of the enzyme aromatase,
which catalysis the conversion of androgens to estrogens.
Consequently, estradiol is the major steroid hormone secreted by the ovaries.
The major male and female sex hormones-testosterone and estradiol,
respectively are not unique to males and females.
The ratio of the concentration of the hormones, however, is very different in the two sexes.
Endocrine cells of the corpus luteum, an ovarian structure that arises following each ovulation,
secrete another major steroid hormone, progesterone.
This steroid is critically important for maintaining pregnancy.
Progesterone is also synthesised in other parts of the body - notably,
the placenta in pregnant women and the adrenal cortex in both males and females.
Review.
Amine hormones are amino acid derivatives.
- Iodine containing thyroid hormones.
- Catecholamines is secreted by the adrenal medulla and the hypothalamus.
Peptides and proteins are strings of amino acids.
- Typically synthesised as larger (inactive) molecules that are cleaved,
into active fragments by post-translation modification.
Steroid hormones are produced from cholesterol by the adrenal cortex and the gonads,
and from steroid precursors by the placenta.
- Adrenal cortex produces aldosterone, cortisol, and two androgens.
- Ovaries produce mainly estradiol and progesterone.
- Testes produce mainly testosterone.
Hormone transport in the blood.
Most peptide and all catecholamine hormones are water soluble.
Therefore, with the exception of a few peptides, these hormones are transported simply dissolved in plasma.
In contrast, steroid hormones and thyroid hormones are poorly soluble.
Consequently, they circulate in the blood largely bound to plasma proteins.
Small concentrations of these hormones do dissolve in the plasma.
The dissolved, or free, hormone is in equilibrium with the bound hormone.
Free hormone plus binding protein leads to hormone-protein complex.
This reaction is reversible.
This reaction is an excellent example of the general principle of physiology, that physiological processes,
are dictated by the laws of chemistry and physics.
The balance of this equilibrium will shift to the right as the endocrine gland secretes more free hormone,
and to the left in the target gland as hormone disassociates from its binding protein in plasma,
and diffuses into the target gland cell.
The total hormone concentration in plasma is the some of the free and bound hormones.
However, only the free hormone can diffuse out of the capillaries and encounter its target cells.
Therefore, the concentration of the free hormone is what is biologically important,
rather than the concentration of the total hormone, most of which is bound.
The degree of protein binding also influences the rate of metabolism and the excretion of the hormone.
Hormone metabolism and excretion.
Once a hormone is synthesised and secreted into the blood, has acted on target tissue,
and its increased activity is no longer required, the concentration of the hormone in the blood,
usually returns to normal.
This is necessary to prevent excessive, possibly harmful effects from the prolonged exposure,
of target cells to hormones.
A hormone’s concentration in the plasma depends upon:
- Its rate of secretion by the endocrine gland.
- Its rate of removal from the blood.
Removal of the hormone occurs either by excretion or metabolic transformation.
The liver and the kidneys are the major organs that metabolise or excrete hormones.
The liver and the kidneys, however, are not the only routes for eliminating hormones.
Sometimes, the hormone is metabolised by the cells upon which it acts.
In the case of some peptide hormones, for example, endocytosis of hormone receptor complexes,
on plasma membranes enables cells to remove the hormones rapidly from their surfaces,
and catabolise them intra cellularly.
The receptors are then often recycled to the plasma membrane.
In addition, enzymes in the blood and the tissues rapidly breakdown catecholamine and peptide hormones.
These hormones therefore, tend to remain in the blood stream for brief periods - minutes to an hour.
In contrast, protein bound hormones are protected from excretion or metabolism,
by enzymes as long as they remain bound.
Therefore, removal of the steroid and thyroid hormones generally takes longer, often several hours to days.
In some cases, metabolism of a hormone activates the hormone, rather than deactivate it.
In other words, the secreted hormone may be relatively inactive until metabolism transforms it.
One example, is T4 produced by the thyroid gland, which is converted to the much more active hormone T3, inside the target cell.
Mechanisms of hormone action.
Hormone receptors.
Because hormones are transported in the blood, they can reach all tissues.
Yet, the response to a hormone, is highly specific, involving only the target cells for that hormone.
The ability to respond depends on the presence of specific receptors for those hormones in the target cells.
The response of a target cell to a chemical messenger, is the final event in a sequence,
when the messenger binds to specific cell receptors.
The receptors for water soluble chemical messengers like peptide hormones and catecholamines,
are proteins located in the plasma membrane of the target cells.
In contrast, the receptors for lipid soluble chemical messengers like steroid and thyroid hormones,
are proteins mainly inside the target cells.
Hormones can influence the response of target cells by regulating hormone receptors.
The basic concepts of receptors modulation are up-regulation and down-regulation.
In the context of hormones, up-regulation is an increase in the number of hormones receptors in a cell,
often resulting from a prolonged exposure to a low concentration of the hormone.
Down regulation is a decrease in receptor number,
often from exposure to high concentrations of the hormone.
This temporally decreases the target cell responsiveness to the hormone,
thereby preventing overstimulation.
In some cases, hormones can down regulate or up regulate not only their own receptors,
but the receptors of other hormones as well.
If one hormone induces down regulation of a second hormone’s receptors,
the result will be a reduction of the second hormone’s effectiveness.
On the other hand, a hormone may induce an increase in the number of receptors for a second hormone.
In this case, the effectiveness of the second hormone is increased.
This latter phenomenon, in some cases,
underlies the important hormone-hormone interaction known as permissiveness.
In general terms, permissiveness means the hormone A must be present in order for hormone B,
to exert its full effect.
A low concentration of hormone A is usually all that is needed for this permissive effect,
which may be due to A’s ability to up regulate B’s receptors.
For example, epinephrine stimulates the release of fatty acids into the blood from adipocytes,
an important function in times of increased energy requirements.
However, epinephrine cannot do this effectively in the absence of permissive amounts of thyroid hormone.
One reason is that thyroid hormone stimulate the synthesis of beta-adrenergic receptors,
for epinephrine in adipose tissue:
As a result, the tissue becomes more sensitive to epinephrine.
However, receptor up regulation does not explain all the cases of permissiveness.
Sometimes, the effect may be due to changes in the signalling pathway,
that mediates the actions of a given hormone.
Events elicited by hormone-receptor binding.
The events initiated when a hormone binds to its receptor - that is,
the mechanisms by which the hormone elicits a cellular response -
are one or more of the signal transduction pathways that apply to all chemical messengers.
In other words, there is nothing unique about the mechanisms,
that hormones initiate as compared to those used by neurotransmitters,
and paracrine or autocrine substances.
Effects of peptide hormones and catecholomines.
The receptors for peptide hormones and catecholamines are located on the extra cellular surface,
of the target cells plasma membrane.
This location is important because these hormones are too hydrophilic,
to diffuse through the plasma membrane.
When activated by hormone binding, the receptors trigger one or more of the signal transduction pathways,
for plasma membrane receptors.
That is, the activated receptors directly influence,
- enzyme activity that is part of the receptor.
- activity of cytoplasmic janus kinases associated with the receptor.
- G proteins coupled in the plasma membrane to effector proteins - ion channels and enzymes - that generate second messengers such as, cAMP and Ca2+.
The opening and closing of ion channels changes the electrical potential across the membrane.
When a Ca2+ channel is involved,
the cytosolic concentration of this important ionic second messenger changes.
The changes in enzyme activity are usually very rapid (example, due to phosphorylation),
and produce changes in the activity of various cellular proteins.
In some cases, the signal transduction pathways also lead to activation or inhibition of particular genes,
causing a change in the synthesis rate of proteins encoded by these genes.
Thus, peptide hormones and catecholamines may exert both rapid (nongenomic),
and slower (gene transcription) action on the same target cell.
Effects of steroid and thyroid hormone.
The steroid hormones and thyroid hormone are lipophilic, and their receptors, which are intracellular,
are members of the nuclear receptor superfamily.
In these lipid soluble messengers, the binding of the hormone to the receptors leads to the activation,
(or sometimes inhibition) of the transcription of certain genes.
The ultimate result of changes in the concentration of these proteins is an enhancement or inhibition,
of particular processes in the cell carries out for a change in the cell’s rate of protein secretion.
Evidence exists for plasma membrane receptors for these hormones,
but their physiological significance in humans is not established.
Pharmacological effects of hormones.
The administration of very large quantities of hormones for medical purposes,
may have effects on an individual that are not usually observed at physiological concentrations.
These pharmacological effects can also occur in diseases,
involving the secretion of excessive amounts of hormones.
Pharmacological effects are of great importance in medicine,
because hormones are often used in large doses as therapeutic agents.
Perhaps the most common example is that of very potent synthetic forms of cortisol,
such as prednisone, which is administered to suppress allergic and inflammatory reactions.
In such situations, a host of unwanted effects may be observed.
Review.
Receptors: bind to hormones and exert an action.
- Steroid and thyroid hormones: inside target cells.
- Peptide hormones and catecholamines: on plasma membrane.
- Up regulation and down regulation increases or decreases hormone’s effectiveness, respectively.
Inputs that control hormone secretion.
Hormone secretion is mainly under the control of three types of inputs to endocrine cells.
- Changes in plasma concentrations of mineral ions or organic nutrients.
- Neurotransmitters released from neurons ending on the endocrine cells.
- Another hormone (or, in some cases a paracrine substance) acting on the endocrine cell.
We must stress that more than one input may influence hormone secretion.
For example, insulin secretion is stimulated by the extracellular concentration of glucose or other nutrients,
and is either stimulated or inhibited by different branches of the atomic nervous system.
Thus, the control of endocrine cells illustrates the general principle of physiology,
that most physiological functions are controlled by multiple regulatory systems, often working in opposition.
The resulting output - the rate of hormone secretion -
depends on relative amounts of stimulatory or inhibitory inputs.
The term secretion applied to a hormone denotes its release by exocytosis from the cell.
In some cases, hormones such as steroid hormones are not secreted, per se,
but instead diffuse through the cell’s plasma membrane into the intra cellular space.
Secretion or release by diffusion is sometimes accompanied by increased synthesis of the hormone.
For simplicity, we will not distinguish between these possibilities,
when we refer to stimulation or inhibition of hormone secretion.
Control by plasma concentrations of mineral ions or organic nutrients.
The secretion of several hormones is directly controlled - at least in part - by the plasma concentrations,
of specific mineral or organic nutrients.
In each case, a major function of the hormone is to regulate through negative feedback,
the plasma concentration of the ion or nutrient controlling its secretion.
For example, insulin secretion is stimulated by an increase in plasma glucose concentration.
Insulin, in turn, acts on skeletal muscle and adipose tissue to promote diffusion of glucose,
into the plasma membranes into the cytosol.
Consequently, the action of insulin restores plasma, glucose concentration to normal.
Another example, is the regulation of calcium ion balance by parathyroid hormone, (PTH).
This hormone is produced by cells of the parathyroid glands,
which are located in close proximity to the thyroid gland.
But, decrease in Ca2+ concentration directly stimulates PTH secretion.
PTH then exerts several actions on bone and other tissue that increase calcium release into the blood,
thereby restoring Ca2+ to normal.
Control by neurons.
The adrenal medulla is a modified sympathetic ganglion,
and thus is stimulated by sympathetic preganglionic fibres.
In addition to controlling the adrenal medulla,
the autonomic nervous system influences other endocrine glands.
Both parasympathetic and sympathetic inputs into these other glands may occur,
some inhibitory and some stimulatory.
Examples are secretions of insulin and gastrointestinal hormones,
which are stimulated by the neurons of the parasympathetic nervous system,
and inhibited by the sympathetic neurons.
One large group of hormones - those secreted by the hypothalamus and posterior pituitary -
is under direct control of the neurons in the brain itself.
Control by other hormones.
In many cases, the secretion of a particular hormone is directly controlled by the blood concentration,
of an other hormone.
Often, the only function of the first hormone in a sequence is to directly stimulate the secretion of the next.
A hormone that stimulates the secretion of another hormone is often referred to as a tropic hormone.
The tropic hormones usually stimulate not only secretion but also the growth of the stimulated gland.
In addition to stimulatory actions,
however some hormones as those in a multihormone sequence inhibit secretion of other hormones.
Review.
Hormone secretion is controlled by different inputs.
- Ion or nutrient that the hormone regulates.
- Neural input to the endocrine cells.
- One or more other hormones .
Autonomic nervous system controls the secretion of many hormones.
- Neurons from the sympathetic and parasympathetic nervous system,
terminate directly on the cells within some endocrine glands, thereby regulating hormone secretion.
Types of endocrine disorders.
Because there is such a wide variety of hormones and endocrine glands,
the features of disorders of the endocrine system may vary quite considerably.
For example, endocrine disease may manifest as a imbalance in metabolism, leading to weight gain or loss,
as a failure to grow or develop normally in early life; as an abnormally high or low blood pressure;
as a loss of reproductive fertility; or as mental or emotional changes, to name a few.
Despite this varied features, which depend on the particular hormone affected,
essentially all hormone diseases can be categorised in one of the four ways.
- Too little hormone (hyposecretion).
- Too much hormone (hypersecretion).
- Decreased responsiveness to the target cells to hormone (hyporesponsiveness).
- Increased responsiveness of the target cells to hormone (hyperresponsiveness).
Control systems involving the hypothalamus and pituitary gland.
The pituitary gland, lies in a pocket at the base of the brain.
The pituitary gland is connected to the hypothalamus, by the pituitary stalk,
containing axons from neurons in the hypothalamus, and small blood vessels.
In humans, the pituitary gland is primarily composed of two adjacent lobes,
called the anterior pituitary gland, and the posterior pituitary gland.
The posterior pituitary gland is not actually a gland but, rather,
an extension of the neural components of the hypothalamus.
The axons of two well defined clusters of hypothalamic neurons, passed down the pituitary stalk,
and end in the posterior pituitary in close proximity to capillaries.
Capillaries are small blood vessels where exchange of solutes takes place,
between the blood and the interstitium.
These neurons do not form a synapse with the other neurons.
Instead their terminals end directly on the capillaries.
The terminals release hormones into these capillaries,
which then drain into veins and the general circulation.
In contrast to the neural connections between the hypothalamus and posterior pituitary,
there are no important neural connections between the hypothalamus and anterior pituitary gland.
There is however, a special type of vascular connection.
The junction of the hypothalamus and pituitary stalk is known as median eminence.
Capillaries in the median eminence recombine to form the portal veins.
The term portal denotes veins that connect two sets of capillaries.
Only in the portal system does one set of capillaries drain into the veins,
and then form a second set of capillaries before eventually emptying again into veins,
that return to the heart.
The portal veins offer a local route for blood to be delivered directly from the median eminence,
to the cells of the anterior pituitary gland.
This local blood system provides a mechanism for hormone synthesised in cell bodies of the hypothalamus,
to directly alter the activity of cells of the anterior pituitary gland, by passing the general circulation,
and thus efficiently and specifically regulating hormone release from that gland.
Posterior pituitary hormones.
The posterior pituitary is really a neural extension of the hypothalamus.
The hormones are synthesised not in the posterior pituitary itself, but in the hypothalamus -
specifically in the cell bodies of the supraoptic and paraventricular nuclei,
whose axons pass down the portal stalk and terminate in the posterior pituitary.
Enclosed in small vesicles, the hormone is transported down the axons to accumulate at the axon terminals, in the posterior pituitary.
Various stimuli activate inputs to these neurons, causing action potentials that propagate,
to the axon terminals and trigger the release of the stored hormone by exocytosis.
The hormone than enters capillaries to be carried away by the blood returning to the heart.
In this way the brain can receive stimuli and respond as if it were an endocrine organ.
By releasing its hormones into the general circulation, the posterior pituitary can modify,
the functions of distant organs.
The two posterior pituitary hormones are the peptides oxytocin and vasopressin.
Oxytocin is involved in two reflexes related to reproduction.
In one case, oxytocin stimulates contraction of smooth muscle cells in the breast,
with results in milk ejection during lactation.
This occurs in response to stimulation of the nipples of the breast during nursing of the infant.
Sensory cells within the nipples send stimulatory neural signals to the brain,
that terminate on the hypothalamic cells that make oxytocin,
causing the activation and thus release of the hormone.
In the second reflex, one that occurs during labor in a pregnant women,
stretch receptors in the cervix send neural signals back to the hypothalamus,
which releases oxytocin in response.
Oxytocin then stimulates contraction in uterine smooth muscle cells, until eventually the fetus is delivered.
Although oxytocin is also present in males, its systemic endocrine functions in males are uncertain.
Recent research suggests that oxytocin may be involved in various aspects of memory and behaviour,
in male and female mammals, possibly including humans.
These include such things as pair bonding, maternal behaviour, and emotions such as love.
If true, in humans, this is likely due to oxytocin containing neurons, in other parts of the brain,
as it is unclear whether any systemic oxytocin can cross the blood brain barrier and enter the brain.
The other posterior pituitary hormone, vasopressin, acts on smooth muscle cells around blood vessels,
to cause their contraction, which constricts the blood vessels and thereby increases blood pressure.
This may occur, for example, in response to a decrease in blood pressure,
that resulted from loss of blood due to an injury.
Vasopressin also acts within the kidneys to decrease water excretion in the urine,
thereby retaining fluid in the body and helping to maintain blood volume.
One way in which this could occur would be if a person were to become dehydrated.
Because of its kidney function, vasopressin is also known as antidiuretic hormone (ADH).
Anterior pituitary gland hormones and the hypothalamus.
Other nuclei of hypothalamic neurons secrete hormones that control the secretion,
of all the anterior pituitary gland hormones.
Several hypothalamic nuclei send axons whose terminals end in the median eminence.
The hypothalamic hormones that regulate anterior pituitary gland function,
are called hypophysiotropic hormones.
A hypophysiotropic hormone controls the secretion of an anterior pituitary gland hormone,
which controls the secretion of a hormone from some other endocrine gland.
The last hormone then acts on its target cells.
The adaptive value of such sequences is that they permit a variety of types of important hormonal feedback.
They also allow amplification of a response of a small number of hypothalamic neurons,
into a large peripheral hormone signal.
Overview of anterior pituitary gland hormones.
The anterior pituitary gland secretes at least six hormones that have well established functions in humans.
These six hormones - all peptides - are,
- follicle stimulating hormone (FSH).
- thyroid stimulating hormone (TSH).
- luteinising hormone (LH).
- growth hormone (GH).
- prolactin.
- adrenocorticotropic.
Each of the last four is secreted by a distinct cell type in the anterior pituitary gland.
FSH and LH, collectively termed gonadotropic hormones because they stimulate the gonads,
are often secreted by the same cell.
The major function of the six is to stimulate their target cells to synthesis and secrete other hormones.
Thyroid stimulating hormone induces the thyroid to secrete thyroxin and triiodothyronine.
Adrenocorticotropic hormone stimulates the adrenal cortex to secrete cortisol.
Three other anterior pituitary gland hormones also stimulate the secretion of another hormone,
that have additional functions as well.
Growth hormone stimulates the liver to secrete the growth promoting peptide hormone known as,
insulin like growth factor-1 (IGF-1), and in addition, exerts directs effects on bone and metabolism.
Follicle stimulating hormone and luteinising hormone to stimulate the gonads to secrete the sex hormones -
estradiol and progesterone from the ovaries, and testosterone from the testes.
In addition they regulate the growth and development of ova and sperm.
Prolactin is unique among the six classical anterior pituitary gland hormones,
in that its major function is not to exert control over the secretion of a hormone by another endocrine gland.
Its most important action is to stimulate the development of the mammary glands,
and milk production during lactation prolactin exerts a secondary action to inhibit gonadotropin secretion,
thereby decreasing fertility when a women is nursing.
In the male, the physiological functions of prolactin are still under investigation.
Hypophysiotropic hormone.
These hormones are secreted by neurons that originate in discrete nuclei of the hypothalamus,
and terminate in the median eminence.
The generation of action potential in these neurons causes them to secrete these hormones by exocytosis,
much as action potential cause other neurons to release neurotransmitters by exocytosis.
Hypothalamic hormones however, reach the anterior pituitary gland.
There they diffuse into the interstitial fluid.
Upon binding to specific membrane bound receptors, the hypothalamic hormones act to stimulate or inhibit, the secretion of the different pituitary gland hormone.
The hormones are synthesised in cell bodies of the hypothalamic neurons,
pass down axons to the neuron terminals, and are released in response to action potentials in the neurons.
Too crucial differences, however distinguish the two systems.
First, the axons of the hypothalamic neurons that secrete posterior pituitary hormones,
leave the hypothalamus and end in the posterior pituitary,
whereas those that secrete hypophysiotropic hormones, end in the median eminence.
Second, most of the capillaries into which the posterior pituitary hormones are secreted,
immediately drain into the general circulation,
which carries the hormones to the heart for distribution to the entire body.
In contrast, the hypophysiotropic hormones enter capillaries in the median eminence of the hypothalamus,
that do not directly join the main blood stream, but empty into the capillaries,
which carry them to the cells of the anterior pituitary gland.
When an anterior pituitary gland hormone is secreted,
it will diffuse in the same capillaries that delivered the hypophysiotropic hormone.
These capillaries drain into the veins, which enter the general blood circulation,
from which the anterior pituitary gland hormones come into contact with their target cells.
The portal circulatory system ensures that hypophysiotropic hormones can reach the cells,
of the anterior pituitary gland at a high concentration and with very little delay.
The small total blood flow in portal veins allows extremely small amounts of hypophysiotropic hormones, from the relatively few hypothalamic neurons to control the secretion of anterior pituitary hormones,
without dilution in the systemic circulation.
This is an excellent illustration of the general principle of physiology that structure is a determinant - ,
and has coevolved with - function.
By releasing hypophysiotropic factors into relatively few veins with a low total blood flow,
the concentration of hypophysiotropic factors can increase rapidly leading to a larger increase,
in the release of anterior pituitary hormones (amplification).
Also, the total amount of physiotropic hormones entering the general circulation is very low,
which prevents them having unintended effects in the rest of the body.
There are multiple physiotropic hormones, each influencing the release of one or, in at least one case,
two of the anterior pituitary gland hormones.
Several of the hypophysiotropic hormones are named for the anterior pituitary gland hormone,
whose secretion they control.
Thus, secretion of ACTH is stimulated by corticotropin releasing hormone (CRH).
Secretion of growth hormone is stimulated by growth hormone releasing hormone (GHRH).
Secretion of thyroid stimulating hormone is stimulated by thyrotropin releasing hormone (TRH).
Secretion of follicle stimulating hormone (the gonadotropins),
is stimulated by gonadotropin releasing hormone (GnRH).
Somatostatin (SST), inhibits the secretion of growth hormone.
Dopamine inhibits the secretion of prolactin.
Growth hormone is controlled by two hypophysiotropic hormones.
Somatastatin inhibits its release, and growth hormone releasing hormone, stimulates it.
The rate of growth hormone secretion depends, therefore,
upon relative amounts of the opposing hormones released by the hypothalamic neurons,
as well upon the relatively sensitivities to them of the GH producing cells of the anterior pituitary gland.
This is a key example of the general principle of physiology,
that most physiological functions are controlled by multiple regulatory systems, often working in opposition.
Such dual controls may also exists for other anterior pituitary gland hormones.
Given that hypophysiotropic hormones control anterior pituitary gland function,
we must explore what controls secretion of the hypophysiotropic hormones themselves.
Some of the neurons that secret hypophysiotropic hormones may posses spontaneous activity,
but the firing of most of them requires neural and hormonal input.
Neural control of hypophysiotropic hormones.
Neurons of the hypothalamic receive stimulatory and inhibitory synaptic input,
from virtually all areas of the central nervous system, and specific neural pathways influence the secretion,
of the individual hypophysiotropic hormones.
A large number of neurotransmitters, such as catecholamines and serotonin,
are released at synapses on the hypothalamic neurons that produce hypophysiotropic hormones.
Not surprisingly, drugs that influence these neurotransmitters,
can alter the secretion of the hypophysiotropic hormones.
In addition, there is a strong circadian influence over the secretion of certain hypophysiotropic hormones.
The neural inputs to these cells arise from other regions of the hypothalamus,
which in turn are linked to inputs from visual pathways that recognise the absence of light.
A good example of this type of neural control is that of CRH,
the secretion of which is tied to the day/night cycle in mammals.
This pattern results in ACTH and cortisol concentration in the blood,
that begin to increase in the hours just prior to awakening.
Hormonal feedback control of the hypothalamus and the anterior pituitary gland.
A prominent feature of each of the hormonal sequences initiated by hypophysiotropic hormone,
is negative feedback exerted upon the hypothalamo-hypophyseal system,
by one or more hormones its sequence.
Negative feedback is a key component of most homeostatic control systems.
In this case, it is effective in dampening hormonal responses - that is,
in limiting the extremes of hormonal secretive rates.
For example, when a stressful stimulus elicits, increase secretion of CRH, ACTH, and cortisol,
the resulting increase in plasma cortisol concentration feeds back to inhibit the CRH secreting neurons,
of the hypothalamus and the ACTH secreting neurons of the hypothalamus,
and the ACTH secreting cells of the anterior pituitary gland.
Cortisol negative feedback is also critical in terminating the ACTH response to stress.
This is important because of the potentially damaging effects of excessive cortisol on immune functions,
and metabolic reaction, among others.
The situation described for cortisol, in which the hormone secreted by the third endocrine gland,
in a sequence exerts a negative feedback over the anterior pituitary gland and/or hypothalamus,
is known as long-loop negative feedback.
Long-loop feedback does not exist for prolactin because this is one anterior pituitary gland hormone,
that doesn’t have major control over another endocrine gland - that is,
it does not participate in a three hormone sequence.
Nonetheless, there is negative feedback in the prolactin system,
for this hormone itself acts upon the hypothalamus to stimulate the secretion of dopamine,
which then inhibits the secretion of prolactin.
The influence of an anterior pituitary gland hormone on the hypothalamus,
is known as a short-loop negative feedback.
Like prolactin, several other anterior pituitary gland hormones, including growth hormone,
also exert such feedback on the hypothalamus.
The role of ‘non sequence’ hormones on the hypothalamus and anterior pituitary gland.
There are many stimulatory and inhibitory hormonal influences on the hypothalamus,
and/or the anterior pituitary gland other than those that fit the feedback patterns just described.
In other words, a hormone that is not itself in a particular hormonal sequence,
may nevertheless exert important influences on the secretion of hypophysiotropic,
or anterior pituitary gland hormones in that sequence.
For example, estradiol markedly enhances the secretion of prolactin by the anterior pituitary gland,
even though estradiol secretion is not normally controlled by prolactin.
Thus, the sequences we have been describing should not be viewed as isolated units.
Review.
Pituitary gland: anterior and posterior pituitary.
- Connected to the hypothalamus by a stock containing neuron axons and blood vessels,
called portal veins.
Axons with cell bodies in the hypothalamus,
- Terminate in the posterior pituitary.
- Release oxytocin and vasopressin (anti diuretic hormone) into the blood (not into the portal circulation).
Anterior Pituitary gland secretes:
- Growth hormone (GH).
- Thyroid stimulating hormone (TSH).
- Adrenocorticotropic hormone (ACTH).
- Prolactin (PRL).
- Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (gonadotropins).
Anterior pituitary gland hormone control:
- Hypophysiotropic hormones:
- Stimulatory or inhibitory hormones secreted into capillaries in the median eminence of the hypothalamus,
and reaching the anterior pituitary gland via the portal vessels.
- Hypophysiotropic hormone control:
Neuronal and hormonal input into the hypothalamic neurons.
The thyroid gland.
Synthesis of thyroid hormone.
Thyroid hormone exerts diverse effects through out much of the body.
The actions of this hormone are so widespread -
and the consequences of the imbalance in its concentration so significant -
that it is worth examining the thyroid gland function in detail.
The thyroid gland produces to iodine containing molecules of physiological importance,
thyroxin (called T4 because it contains 4 iodines) and triiodothyronine (T3).
A considerable amount of T4 is converted to T3 in the target tissues by enzymes known as deiodinases.
We will therefore consider T3 to be a major thyroid hormone,
even though the concentration of T4 in the blood is usually greater than that of T3.
We can think of T4 as a reservoir for additional T3.
Because of its lower clearance rate, T4 is typically prescribed in situations,
where thyroid function is decreased in a person for any reason.
The thyroid gland sits within the neck in front of and straddling the trachea.
It first becomes functional early in fetal life.
Within the thyroid gland are numerous follicles, each composed of an enclosed sphere of epithelial cells, surrounding a core containing a protein rich material called the colloid.
The follicular epithelial cells participate in almost all phases of the thyroid hormone synthesis and secretion.
Synthesis begins when circulating iodide is actively cotransported with sodium ions,
across the basolateral membranes of the epithelial cells, a process known as iodine trapping.
The Na+ is pumped back out of the cell.
The negatively charged iodide ions are transported into the colloid by a protein called pendrin.
Pendrin is a sodium independent chloride/iodine transporter.
The colloid of follicles contains large amounts of a protein called thyroglobulin.
Once in the colloid, iodide is rapidly oxidised to iodine,
which is then attached to the phenolic rings of tyrosine residues within the thyroglobulin.
This process is called organification of iodine.
Thyroglobulin itself is synthesised by the follicular epithelial cells.
The enzyme responsible for oxidising iodides and attaching them to thyroglobulin in the colloid,
is called thyroid peroxidase.
It too, is synthesised by follicular epithelial cells.
D I T is read as DIT.
A tyrosine with one iodine attached is called MIT.
If two iodines are attached, it is called DIT.
Next, the phenolic ring of a molecule of MIT or DIT is removed and coupled to another DIT,
on the thyroglobulin molecule.
If two DIT molecules are coupled the result is thyroxine (T4).
If one MIT or one DIT is coupled, the result is T3.
Therefore, the synthesis of T4 and T3 is unique in that it actually occurs,
in the extra cellular (colloidal ) space within the thyroid follicles.
Finally, the thyroid hormone to be secreted into the blood, extensions of the colloid facing membranes,
of follicular epithelial cells engulf portions of the colloid by endocytosis.
The thyroglobulin, which contains T4 and T3, is brought into contact with lysosomes in the cell interior.
Proteolysis of thyroglobulin releases T4 and T3, which then diffuse out of the follicular epithelial cells,
into the interstitial fluid and from there to the blood.
There is sufficient iodinated thyroglobulin stored within the follicles of the thyroid,
to provide thyroid hormone for several weeks even in the absence of dietary iodine.
This storage capacity makes the thyroid gland unique about endocrine glands,
but is essential adaptation considering the unpredictable intake of iodine in most animals.
These processes are an important example of the general principle of physiology,
that controlled exchange of materials between compartments and across cellular membranes.
A pump is needed to transport iodide from the interstitial space against a concentration gradient,
across the cell membrane into the cytosol of the follicular cell,
and pendrin is necessary to mediate the efflux of iodide from the cytoplasm into the colloidal space.
Review.
Thyroid hormones (T3 and T4).
- Sequential additions of iodine (catalysed by thyroid peroxidase),
to tyrosines within the thyroglobulin molecule sequence in the thyroid follicle lumen (colloid),
a process called organification of iodine.
- Iodinated tyrosines on thyroglobulin are coupled to produce either T3 or T4.
- T4:Main secretory product.
- T3: Active hormone produced from T4, in target tissue.
Control of thyroid function.
Essentially all the actions of the follicular epithelial cells or stimulated by TSH, which is stimulated by TRH.
The basic control mechanism of TSH production is the negative feedback action of T3 and T4,
on the anterior pituitary gland and to a lesser extent, the hypothalamus.
However, TSH does more than just stimulate T3 and T4 production.
TSH also increases protein synthesis in the follicular epithelial cells,
increases DNA replication and cell division, and increases the amount of rough endoplasmic reticulum,
and other cellular machinery required by follicular epithelial cells for protein synthesis.
Therefore, if thyroid cells are exposed to greater TSH concentrations than normal,
they will undergo hypertrophy - that is, they will increase in size.
An enlarged thyroid gland from any cause is called a goiter.
Actions of thyroid hormone.
Receptors for thyroid hormone are present in the nuclei and most of the cells of the body,
unlike receptors for many other hormones, whose distribution is more limited.
Therefore, the actions of T3 are widespread and affect many organs and tissues.
Like steroid hormones, T3 acts by inducing gene transcription and protein synthesis.
Metabolic actions.
T3 has several effects on carbohydrate and lipid metabolism,
although not to the extent of other hormones like insulin.
Nonetheless, T3 stimulates carbohydrate absorption from the small intestine,
and increases fatty acid release from adipocytes.
These actions provide energy that helps maintain metabolism at a high rate.
Much of that energy is used to support the activities of Na+/K+- pump through out the body.
These enzymes are stimulated by T3.
The cellular concentration of ATP, therefore is critical for the ability of cells,
to maintain Na+/K+- pump activity in response to thyroid hormone stimulation.
ATP concentrations are controlled in part by negative feedback mechanism.
ATP negatively feeds back on the glycolytic enzymes within cells that participate in ATP generation.
A decrease in cellular stores of ATP, therefore, releases the feedback and triggers an increase in glycolysis.
This results in the metabolism of additional glucose that restores ATP concentration.
One of the by-products of these processes is heat.
Thus, as ATP is consumed in cells Na+/K+- pump at a high rate due to T3 stimulation,
the cellular stores of ATP must be maintained by increased metabolism of fuels.
This calorigenic action of T3 represents a significant fraction of the total heat produced,
each day in a typical person.
This action is essential for body temperature homeostasis,
just one of the many ways in which the actions of thyroid hormone,
demonstrates the general principle of physiology that homeostasis is essential for health and survival.
Without thyroid hormone, heat production would decrease and body temperature,
and most physiological processes, would be compromised.
Permissive actions.
Some of the actions of T3 are attributable to its permissive effects on the actions of catecholamines.
T3 up-regulates beta - adrenergic receptors in many tissues, notably the heart and the nervous system.
It should not be surprising, therefore, that the symptoms of extra thyroid hormone concentration,
closely resemble some of the symptoms of excess adrenalin and noradrenalin,
(sympathetic nervous system activity).
That is because the increase T3 potentiates the actions of the catecholamines,
even though the latter or within normal concentrations.
Because of this, potentiating effects, people with excess T3 are often treated with drugs,
that block beta-adrenergic receptors to alleviate the anxiety, nervousness,
and ‘racing heart’ associated with excessive sympathetic activity.
Growth and development.
T3 is required for normal production of growth hormone from the anterior pituitary gland.
Therefore, when T3 is very low, growth in children is decreased.
In addition, T3 is a very important developmental hormone for the nervous system.
T3 exerts many effects on the central nervous system during development,
including the formation of axon terminals and the production of synapses,
the growth of dendrites and dendritic extensions, called spines, and the formation of myelin.
Absence of T3 results in the syndrome called congenital hypothyroidism.
This syndrome is characterised by a poorly developed nervous system,
and severely comprised intellectual function.
With neonatal screening, it can be treated with T4 at birth.
The most common cause of congenital hypothyroidism is dietary iodine deficiency in the mother.
The availability of iodised salt has essentially eliminated congenital hypothyroidism in many countries.
T3 is required for proper nerve and muscle reflexes and for normal cognition in adults.
The endocrine response to stress.
Physiological functions of cortisol.
The body’s response to stress is a real or perceived threat to homeostasis.
Thus, any change in external temperature, water intake,
or other homeostatic factors sets into motion responses designed,
to minimise a significant change in some physiological variable.
These threats to homeostasis comprise of a large number of situations, including physical trauma,
prolonged exposure to cold, prolonged heavy exercise, infection, shock, decreased oxygen supply,
sleep deprivation, pain and emotional stresses.
It may seem obvious that the physiological response to cold exposure,
must be very different from that to infection or emotional stresses such as fright,
but in one respect the response to all these situations is the same.
Invariably, the secretion from the adrenal cortex of the hormone cortisol is increased.
Activity of the sympathetic nervous system, including release of the hormone adrenalin,
also increases in response to many types of stress.
The increased cortisol secretion during stress is mediated by the hypothalamus -
anterior pituitary gland system.
Neural input into the hypothalamus from portions of the nervous system responding,
to a particular stress induces secretion of CRH.
This hormone is carried to the anterior pituitary gland, where it stimulates ACTH secretion .
ACTH in turn circulates through the blood, reaches the adrenal cortex, and stimulates cortisol release.
The secretion of ACTH, and therefore of cortisol, is also stimulated to a lesser extent by vasopressin,
which usually increases in response to stress, and which may reach the anterior pituitary gland,
from the general circulation or by the short portal vessels.
Some of the cytokines (secretion from cells that comprise the immune system),
also stimulate ACTH secretion both directly and by stimulating the secretion of CRH.
This cytokines provide a means for eliciting an endocrine stress response,
when the immune system is stimulated in, for example, systemic infection.
Although the effects of cortisol are best illustrated during the response to stress,
cortisol is always produced by the adrenal cortex and exerts many important actions,
even in non stress situations.
For example, cortisol has permissive actions on the responsiveness,
to adrenaline and noradrenaline of smooth muscle cells,
that surround the lumen of blood vessels such as arterioles.
Partly for this reason, cortisol helps maintain normal blood pressure.
When cortisol secretion is greatly decreased, low blood pressure can occur.
Likewise, cortisol is required to maintain the cellular concentrations of certain enzymes,
involved in metabolic homeostasis.
These enzymes are expressed primarily in the liver,
and they act to increase hepatic glucose production between meals,
thereby preventing the plasma glucose concentration from significantly decreasing below normal.
Two important systematic actions of cortisol are its anti-inflamantory and anti-immune functions.
The mechanism by which cortisol inhibits immune system function are numerous and complex.
Cortisol may serve as a ‘brake’ on the immune system,
which may over react to minor infections in the absence of cortisol.
During foetal and neonatal life, cortisol is also important developmental hormone.
It has been implicated in the proper differentiation of numerous tissues and glands.
Cortisol is very important for the production of surfactant, a substance that decreases surface tension,
in the lungs, thereby making it easier for the lungs to inflate.
Maintenance of homeostasis in the absence of external stress is also a critical function of cortisol.
Functions of cortisol in stress.
Effects of increased plasma cortisol concentration during stress.
1. Effects of organic metabolism.
A. Stimulation of protein catabolism in bone, lymph, muscle, and elsewhere.
B. Stimulation of liver uptake of amino acids and their conversion to glucose.
C. Maintenance of plasma glucose concentrations.
D. Stimulation of triglycerides catabolism in adipose tissue with release of glycerol and fatty acids,
into the blood.
2. Enhanced vascular reactivity (increased ability to maintain vasoconstriction,
in response to noradrenaline and other stimuli).
3. Unidentified protective effects against the damaging influences of stress.
4. Inhibition of inflammation and specific immune responses.
5. Inhibition of nonessential functions (example, growth and reproduction).
The effects on organic metabolism are to mobilise energy sources,
to increase the plasma concentrations of amino acids, glucose, glycerol, and free fatty acids.
These effects are ideally suited to meet a stressful situation.
First, an animal faced with a potential threat is often forced to forgo eating,
making these metabolic changes adapting for coping with stress while fasting.
Second, the amino acids liberated by catabolism of body protein,
not only provide a potential source of glucose, via hepatic gluconeogenesis,
but also constitute a potential source of amino acids for tissue repair should injury occur.
Cortisol has important effects during stress other than those on organic metabolism.
For example, it increases the ability of vascular smooth muscle to contract in response to noradrenaline,
thereby improving cardiovascular performance.
We still do not know the other reasons that increased cortisol is so important,
for the body’s optimal response to stress.
What is clear is that a person exposed to sever stress can die, usually of circulatory failure,
if plasma cortisol concentration is abnormally low; the complete absence of cortisol is fatal.
The administration of large amounts of cortisol or its synthetic analog,
profoundly reduces the inflammatory response to injury or infection.
Because of this effect, the synthetic analogs of cortisol are useful in the treatment of allergy, arthritis,
other inflammatory diseases.
These anti inflammatory and anti immune effects of cortisol have been classified,
as pharmacological effects of cortisol.
It is now clear that anti inflammatory and anti immune effects also occur, albeit to lesser degree,
at the plasma cortisol concentration achieved during stress.
Thus, the increased plasma cortisol typical of infection or trauma exerts a dampening effect,
on the body’s immune responses protecting against possible damage from excessive inflammation.
This effect explains the significance of the fact, that certain cytokines (immune cells secretions),
stimulate the secretion of ACTH and thereby cortisol.
Such stimulation is part of a negative feedback system in which the increased cortisol,
then partially inhibits the inflammatory process in which the cytokines participate.
Moreover, cortisol normally dampens the fever and infection causes.
Whereas the acute cortisol responses to stress are adaptive, it is now clear that chronic stress,
including emotional stress, can have deleterious effects on the body.
Chronic stress results in sustained increases in cortisol secretion.
In such a case, the abnormally high cortisol concentrations,
sufficiently decrease the activity of the immune system to reduce the body’s resistance to infection.
It can also worsen the symptoms of diabetes mellitus because of its effects on blood glucose concentrations.
In summary, stress is a broadly defined situation,
in which there exists a real or potential threat to homeostasis.
In such a scenario, it is important to maintain blood pressure, to provide extra energy sources in the blood,
and to temporarily reduce nonessential functions.
Cortisol is the most important hormone that carries out these activities.
Cortisol enhances vascular reactivity, catabolises protein and fat to provide energy,
and inhibits growth and reproduction.
The price the body pays during stress is that cortisol is strongly catabolic.
Thus, cells of the immune system, bone, muscles, skin,
and numerous other tissues undergo catabolism to provide substrates for gluconeogensis.
In the short term, this is not of any major consequence.
Chronic stress, however, can lead to sever decreases in bone density, immune function,
and reproductive fertility.
Other hormones released during stress.
Other hormones that are usually released during many kinds of stress are aldosterone, vasopressin,
growth hormone, glucagon, and beta endorphin.
Insulin secretion usually decreases.
Vasopressin and aldosterone act to retain water and Na+ within the body,
an important response in the face of potential losses by dehydration, hemorrhage, or sweating.
The overall effects of the changes in growth hormone, glucagon and insulin are,
like those of cortisol and adrenaline,
to mobilise energy stores and increase the plasma concentration of glucose.
The function in humans, if any, of beta-endorphin and stress may be related to its pain killing effects.
In addition, the sympathetic nervous system has a key function in stress response.
Activation of the sympathetic nervous system during stress is often termed as the fight or flight response.
It releases noradrenaline primarily from sympathetic neuron terminals.
These actions are:
- Increased hepatic and muscle glycogenolysis, which provides a quick source of glucose.
- Increased breakdown of adipose tissue triglyceride, which provides a supply of glycerol for gluconeogensis, and of fatty acids for oxidation.
- Increased heart rate.
- Diversion of blood from viscera to skeletal muscles by means of vasoconstriction in the viscera,
and vasodilation in the skeletal muscles.
- Increased lung ventilation by stimulating brain breathing centres and dilating airways.
This almost constitutes a guide on how to meet emergencies in which physical activity maybe required,
and bodily damage may occur.
This description of hormones whose secretion rates are altered by stress is by no means complete.
It is likely that the secretion of almost every known hormone maybe influenced by stress.
For example, prolactin is increased, although the adaptive significance of this change is unclear.
By contrast, the pituitary gonadotropins and the sex steroids are decreased,
as reproduction is not an essential function during a crisis.
The response to stress is a classic example of the general principle of physiology,
that the functions of organ systems are coordinated with each other.
The target organs of this extensive number of hormones must respond in a coordinated way,
to maintain homeostasis.
Endocrine control of growth.
One of the major functions of the endocrine system is to control growth.
At least, half a dozen hormones directly or indirectly have important functions,
in stimulating or inhibiting growth.
This complex process is also influenced by genetics and a variety of environmental factors,
including nutrition.
It provides an illustration of the general principle of physiology,
that most physiological functions are controlled by multiple regulatory systems,
often working in opposition.
The growth process involves cell division and net protein synthesis throughout the body,
but a person’s height is determined specifically by bone growth,
particularly of the vertebral column and legs.
Bone is a living metabolically active tissue consisting of a protein (collagen) matrix upon which calcium salts, particularly calcium phosphate is deposited.
A growing long bone is divided, into the ends, or epiphyses, and the remainder, the shaft.
The portion of each epiphyses in contact with the shaft is a plate of actively proliferating cartilage,
(connective tissue composed of collagen and other fibrous proteins) called epiphyseal growth plate.
Osteoblasts, the bone forming cells at the shaft edge of the epiphyseal growth plate,
convert the cartilaginous tissue at this edge to the bone,
while cells called chondrocytes simultaneously lay down new cartilage in the interior of the plate.
In this manner the epiphyseal growth plate widens and is gradually pushed away from the centre,
of the bony shaft as the shaft lengthens.
Linear growth of the shaft can continue as long as the epiphyseal growth plates exist,
but ceases when the growth plates themselves are converted to bone,
as a result of other hormonal influences towards the end of puberty.
Children manifest two periods of rapid increase in height, the first during the first two years of life,
and the second during puberty.
The pubertal growth spurt lasts several years in both sexes, but growth during this period is greater in boys.
In addition, boys grow more before the start of puberty because they began puberty,
approximately two years later than girls.
These factors account for the differences in average height between men and women.
Environmental factors influencing growth.
Adequate nutrition and good health are the primary environmental factors influencing growth.
Lack of sufficient amounts of protein, fatty acids, vitamins, or minerals interferes with growth.
The growth inhibiting effects of malnutrition can be seen at any time of development,
but are most profound when they occur early in life.
For this reason, maternal malnutrition may cause growth retardation in the foetus.
Because low birth weight is strongly associated with increased infant mortality,
prenatal malnutrition causes increased numbers of prenatal and early postnatal deaths.
Moreover, irreversible stunting of brain development maybe caused by prenatal malnutrition.
During infancy and childhood, too, malnutrition can interfere with both intellectual development,
and total body growth.
Following a temporary period of stunted growth due to malnutrition or illness,
and given proper nutrition and recovery from illness, a child can manifest a remarkable growth spurt,
called catchup growth that brings the child to within the range of normal heights expected for his or her age.
The mechanisms that account for this accelerated growth are unknown,
but recent evidence suggests that it may be related to the rate of stem cell differentiation,
within the growth plates.
Hormonal influences of growth.
The hormones most important to human growth are growth hormone, insulin like growth factor-1,
and insulin like growth factor-2, T3, insulin, testosterone and estradiol, all of which exert widespread effects.
In addition to all these hormones, a large group of peptide growth factors exert effects,
most of them acting in a paracrine or autocrine manner to stimulate differentiation and/or cell division,
of certain cell types.
Molecules that stimulate cell division are called mitogens.
The various hormones and growth factors do not all stimulate growth at the same periods of life.
For example, fetal growth is less dependent on growth hormone, thyroid hormone, and the sex steroids,
then are the growth periods that occur during childhood and adolescence.
Growth hormone and insulin like growth factors.
Growth hormone, secreted by the anterior pituitary gland, has little effect on fatal growth,
after the age of 1 to 2 years.
Its major growth promoting effect is stimulation of cell division in many target tissues.
Thus, growth hormone promotes bone lengthening by stimulating maturation and cell division,
of the chondrocytes in the epiphyseal plates,
thereby continuously widening the plates and providing more cartilaginous material for bone formation.
Importantly, growth hormone exerts most of its mitogenic effects not directly on cells,
but indirectly through the mediation of mitogenic hormone IGF-1,
whose synthesis and release by the liver are induced by the growth hormone.
Despite some structural similarities to insulin (from which its name is derived),
this messenger has its own unique effects distinct from those of insulin.
Under the influence of growth hormone, IGF-1 is secreted by the liver, enters the blood,
and functions as a hormone.
In addition, growth hormones stimulates many other type of cell, including bone, the secrete IGF-1,
where it functions as an autocrine or paracrine substance.
The importance of IGF-1 in mediating the major growth promoting effect of growth hormones,
illustrated by the fact that short stature can be caused not only by the decreased growth hormone secretion, but also by decreased production of IGF-1.
The secretion and activity of IGF-1, can be influenced by the nutritional status of the individual,
and by many hormones other than growth hormone.
For example, malnutrition during childhood can inhibit the production of IGF-1,
even if plasma growth hormone is increased.
In addition to its specific growth promoting effect on cell division via IGF-1,
growth hormone directly stimulates protein synthesis in various tissues and organs, particularly muscle.
It does this by increasing amino acid uptake, and both the synthesis and activity of ribosomes.
All of these events are essential for protein synthesis.
This anabolic effect on protein metabolism facilitates the ability of tissues and organs to enlarge.
Growth hormone also contributes to energy homeostasis.
It does this in part by facilitating the breakdown of triglycerides that are stored in adipose cells,
which then release fatty acids into the blood.
It also stimulates gluconeogensis in the liver and inhibits the ability of insulin,
to promote glucose transport into the cells.
Growth hormone, therefore, tends to increase circulating energy sources.
Not surprisingly, therefore, situations such as exercise, stress, or fasting,
for which increased energy availability is beneficial,
result in stimulation of growth hormone secretion into the blood.
The metabolic effects of growth hormone are important throughout life,
and continue in adulthood long after bone growth has ceased.
Major effects of growth hormone.
1. Promotes growth:
Induces precursors cells in bone and other tissues,
to differentiate and secrete insulin like growth factor-1 (IGF-1), which stimulates cell division.
Also stimulates liver to secrete IGF-1.
2. Stimulates protein synthesis, predominantly in muscle.
3. Anti insulin effects (particularly at high concentrations):
a. Renders adipocytes more responsive to stimuli that induce breakdown of triglycerides,
releasing fatty acids into the blood.
b. Stimulates gluconeogensis.
c. Reduces the ability of insulin to stimulate glucose update by adipose and muscle cells,
resulting in higher blood glucose concentrations.
Control system for growth hormone begins with two of the hormones secreted by the hypothalamus.
Growth hormone secretion is stimulated by growth hormone releasing hormone,
and inhibited by somatostatin (SST).
As a result of changes in these two signals, which are usually out of phase with each other,
(that is, one is high when the other is low), growth hormone secretion occurs in episodic bursts,
and manifests a striking daily rhythm.
During most of the day, little or no growth hormone is secreted,
although burst maybe elicited by certain stimuli, such as exercise.
In contrast, one to two hours after a person falls asleep, one or more larger,
prolonged bursts of secretion may occur.
Negative feedback controls the growth hormone and IGF-1,
which influences the hypothalamus and anterior pituitary gland.
In addition to hypothalamic controls, a variety of hormones - notably, the sex steroids, insulin,
and thyroid hormones - influence the secretion of growth hormone.
The net result of all these inputs is that the secretion rate of growth hormone is highest during adolescence,
(the period of most rapid growth), next highest in children, and lowest in adults.
The decreased growth hormone secretion associated with aging is responsible, in part,
for the decrease in lean body and bone mass, the expansion of adipose tissue,
and the thinning of the skin that occur as people age.
The availability of human growth hormone produced by recombinant DNA technology,
has greatly facilitated the treatment of children with short stature due to growth hormone deficiency.
There is another messenger - insulin like growth factor-2 (IGF-2), which is closely related to IGF-1.
IGF-2, the secretion of which is independent of growth hormone,
is also a crucial mitogen during the prenatal period.
It continues to be secreted throughout life, but its postnatal function is not definitely known.
Recent evidence suggest a link between IGF-2 concentrations,
and the maintenance of skeletal muscle mass and strength in elderly persons.
Thyroid hormone.
Thyroid hormone is essentially for normal growth because it facilitates the synthesis of growth hormone.
T3 also has direct actions on bone, where it stimulates chondrocyte differentiation,
growth of new blood vessels in developing bone, and responsiveness of bone cells to other growth factors, such as fibroblast growth factor.
Consequently, infants and children with hypothyroidism have slower growth rate than would be predicted.
Insulin.
Insulin is an anabolic hormone that promotes the transport of glucose and amino acids,
from the extra cellular fluid into adipose tissue and skeletal and cardiac muscle cells.
Insulin stimulates storage of fat and inhibits protein degradation.
Thus, it is not surprising that adequate amounts of insulin are necessary for normal growth.
Its inhibitory effects on protein deviation is particularly important with regard to growth.
In addition to this general anabolic effect, insulin exerts direct growth promoting effects,
on cell differentiation and cell division during fetal life and, possibly during childhood.
Sex steroids.
Sex steroid secretion (testosterone in the male and estradiol in the female),
begins to increase between the ages of 8 to 10 and reaches a plateau over the next 5 to 10 years.
A normal pubertal growth spurt, which reflects growth of the long bone and vertebrae,
requires this increased production of the sex steroids.
The major growth promoting effect of the sex steroids is to stimulate the secretion,
of growth hormone and IGF-1.
Unlike growth hormone, however, the sex steroids not only promote bone growth,
but ultimately stop it by inducing epiphyseal closure.
The dual effects of the sex steroids explain the pattern seen in adolescence:
rapid lengthening of the bones culminating in completion cessation of growth for life.
In addition to this dual effects on bone, testosterone exerts a direct anabolic effect,
on protein synthesis in many non reproductive organs and tissues of the body.
This accounts, at least in part, for the increased muscle mass in men in comparison to women.
This effect of testosterone is also why athletes sometimes use androgens,
called anabolic steroids in an attempt to increase muscle mass and strength.
However, these steroids have multiple potential toxic side effects, such as liver damage,
increased risk of prostrate cancer, infertility, and changes in behaviour and emotions.
Moreover, if females, they can produce virilization.
Cortisol.
Cortisol, the major hormone the adrenal cortex secretes in response to stress,
can have potent antigrowth effects under certain conditions.
When present in high concentrations, it inhibits DNA synthesis and promotes protein catabolism,
in many organs, and it inhibits bone growth.
Moreover, it breaks down bone and inhibits the secretion of growth hormone and IGF-1.
For all these reasons, in children, they increase in plasma cortisol that accompanies infections,
and other stressors is, at least in part, responsible for the decrease growth that occurs with chronic illness.
Endocrine control of Ca2+homeostasis.
Many of the hormones of the body control functions that, though important,
are not necessarily vital for survival.
By contrast, some hormones control functions so vital that the absence of the hormone,
would be catastrophic, even life threatening.
One such function is calcium homeostasis.
Calcium exists in the body fluids in its soluble, ionised form (Ca2+) and bound to proteins.
For simplicity, we will refer to the physiologically active, ionic form of Ca2+.
Extracellular Ca2+concentration normally remains within a narrow homeostatic range.
Large deviations in either directions can disrupt neurological and muscular activity, among others.
For example, a low plasma Ca2+ concentration,
increases the excitability of neuronal and muscle plasma membranes.
A high plasma Ca2+ concentration causes cardiac arrhythmias and depresses neuromuscular excitability,
via effects on membrane potential.
We will discuss the mechanism by which Ca2+ homeostasis is achieved and maintained,
by action of hormones.
Effector sites for Ca2+ homeostasis.
Ca2+ homeostasis depends on the interplay among bone, the kidneys, and the gastrointestinal tract.
The activities of the gastrointestinal tract and kidneys determine the net intake and output of Ca2+, for the entire body, thereby the overall Ca2+ balance.
In contrast, interchanges of Ca2+ between extracellular fluid and bone do not alter the total body balance,
but instead change the distribution of Ca2+ within the body.
We will first discuss the cellular and mineral composition of bone.
Bone.
Approximately 99% of total body calcium is contained in bone.
Therefore, the movement of Ca2+ in and out of bone is critical in controlling the plasma Ca2+ concentration.
Bone is a connective tissue made up of several cell types surrounded by collagen matrix called osteoid,
upon which are deposited minerals, particularly the crystals of calcium,
phosphate and hydroxyl ions known as hydroxyapatite.
In some instances the bones have central marrow cavities where blood cells form.
Approximately one third of a bone, by weight, is osteoid, and two thirds is mineral.
The bone cells contribute negligible weight.
The three types of bone cells involved in bone formation and breakdown are osteoblasts, osteocytes,
and osteoclasts.
Osteoblasts are bone forming cells.
They secrete collagen to form a surrounding matrix, which then become calcified,
a process called mineralisation.
Once surrounded by calcified matrix, the osteoblasts are called osteocytes.
The osteocytes have long cytoplasmic processes that extend throughout the bone,
and form tight junctions with other osteocytes.
Osteoclasts are large, multinucleated cells that break down (reabsorb) previously formed bone,
by secreting hydrogen ions, which dissolve the crystals, and hydrolytic enzymes, which digest the osteoid.
Throughout life, bone is constantly remodelled,
by the osteoblasts (and osteocytes) and osteoclasts working together.
Osteoclasts reabsorb old bone, and then osteoblasts move into the area and lay down new matrix,
which become mineralised.
This process depends in part on the stress that gravity and muscle tension impose on the bones,
stimulating osteoblastic activity.
Summary of major hormonal influences on bone mass.
Hormones that favour bone formation and increased bone mass.
- Insulin.
- Growth hormone.
- Insulin like growth factor (IGF-1).
- Estrogen.
- Testosterone.
- Calcitonin (physiological role unclear in humans).
Hormones that favour increased bone reabsorption and decreased bone mass.
- Parathyroid hormone (chronic increases).
- Cortisol.
- Thyroid hormone T3.
These hormones and the variety of autocrine and paracrine growth factors produced locally in the bone,
also have functions.
Of the hormones listed, only parathyroid hormone is controlled primarily by the plasma Ca2+ concentration. Nonetheless, changes in the other listed hormones have important influences on bone mass,
and plasma Ca2+ concentration.
Kidneys.
The kidneys filter the blood and eliminate soluble wastes.
In the process, cells in the tubules that make up the functional units of the kidneys,
reabsorb most of the necessary solutes that were filtered, which minimises their loss in urine.
Therefore, the urinary excretion of Ca2+ is the difference between the amount filtered into the tubules,
and the amount reabsorbed and returned to the blood.
The control of Ca2+ excretion is exerted mainly on reabsorption.
Reabsorption decreases when plasma Ca2+ concentration increases,
and it increases when plasma Ca2+ decreases.
The hormonal controllers of Ca2+ also regulate phosphate ion balance.
Phosphate ions, too, are subject to a combination of filtration and reabsorption,
with the latter hormonally controlled.
Gastrointestinal tract.
The absorption of solutes such as Na+ and k+ from the gastrointestinal tract into the blood,
is normally about 100%.
In contrast, a considerable amount of ingested Ca2+ is not absorbed from the small intestine,
and leaves the body along with the feces.
Moreover, the active transport system that achieves Ca2+ absorption from the small intestine,
is under hormonal control.
Therefore, large regulated increases or decreases can occur in the amount of Ca2+ absorbed from the diet.
Hormonal control of this absorptive process is the major means of regulating total body calcium balance.
Hormonal controls.
The two major hormones that regulate Ca2+ concentration,
are parathyroid hormone and 1,25-dihydroxy vitamin D.
A third hormone, calcitonin, has a very limited function in humans, if any.
Parathyroid hormone.
Bone, kidneys, and the gastrointestinal tract are subject, directly or indirectly,
to control, by a protein hormone called parathyroid hormone(PTH), which is produced by parathyroid glands.
These endocrine glands are in the neck, embedded in the posterior surface of the thyroid gland,
but are distinct from it.
PTH production is controlled by extracellular Ca2+ acting directly on the secretory cells,
via a plasma membrane Ca2+ receptor.
Decreased plasma Ca2+ concentration stimulates PTH secretion,
and an increased Ca2+ concentration does just the opposite.
PTH exerts multiple actions that increase Ca2+ concentration,
thereby compensating for the decreased concentration that originally stimulated secretion of this hormone.
1. It directly increases the reabsorption of bone by osteoclasts,
which causes calcium (and phosphate) ions to move from bone into extracellular fluid.
2. It directly stimulates the renal formation of 1,25-dihydroxy vitamin D,
which then increases intestinal absorption of calcium (and phosphate) ions.
Thus, the effects of PTH on the intestine is indirect.
3. It directly decreases Ca2+ reabsorption in the kidneys, thereby decreasing urinary Ca2+ excretion.
4. It directly decreases the reabsorption of phosphate ions in the kidneys,
thereby increasing their excretion in urine.
This keeps plasma phosphate ions from increasing when PTH causes an increased reabsorption of both calcium and phosphate ions from bone, and an increased production of 1,25-dihydroxy vitamin D,
leading to increased calcium and phosphate ion absorption in the intestine.
1,25-dihydroxy vitamin D.
The term vitamin D denotes a group of closely related steroid compounds.
Vitamin D3 is formed by the action of ultraviolet radiation from sunlight on a cholesterol derivate in skin.
Vitamin D2 is derived from plants.
Both can be found in vitamin pills and enriched foods and collectively called vitamin D.
For this reason, it was originally classified as a vitamin.
Regardless of source, vitamin D is metabolised by the edition of hydroxyl groups, first in the liver,
and then in certain kidney cells.
The end result is 1,25-dihydroxy vitamin D, the active hormonal form of vitamin D.
The major action of 1,25-dihydroxy vitamin D is to stimulate the intestinal absorption of Ca2+.
Thus, the major consequence of vitamin D deficiency is decreased intestinal Ca2+ absorption,
resulting in decreased plasma Ca2+.
The blood concentration of 1,25-dihydroxy vitamin D is subject to physiological control.
The nature control point is the second hydroxylation step in the kidneys, which is stimulated by PTH.
Because a low Ca2+ concentration stimulates the secretion of PTH,
the production of 1,25-dihydroxy vitamin D is increased as well under such conditions.
Both hormones work together to restore plasma Ca2+ to normal.
Calcitonin.
It is a peptide hormone secreted by cells that are within the thyroid gland.
Calcitonin decreases plasma Ca2+ concentration, mainly by inhibiting osteoclasts,
thereby reducing bone reabsorption.
Its secretion is stimulated by increased Ca2+ concentration, just the opposite of the stimulus for PTH.
Unlike PTH and 1,25-dihydroxy vitamin D, however,
calcitonin has no function in normal day to day regulation of plasma Ca2+ in humans.
It may be a factor in decreasing bone resorption when the plasma Ca2+ concentration is very high.