HOMEOSTASIS
"All the vital mechanisms, varied as they are, have only one object, that of preserving constant the conditions of life in the internal environment"
Claude Bernard, 1876
Homeostasis requires some sort of control system. The body must be able to both detect a change in the environment and to make the needed compensatory response.
Homeostatic control systems monitor the INTERNAL ENVIRONMENT. They are CLOSED LOOP systems and they incorporate NEGATIVE FEEDBACK (i.e. the deviation produces a corrective response in the opposite direction).
[Fig. 1-5] This slide illustrates the component parts and the closed loop nature of negative feedback control systems.
[see Figure] A thermoregulated water bath (here with a set point temperature of 30 C) is a good model of a homeostatic system.
Although homeostatic systems monitor the internal environment, information about the external environment may allow for anticipatory adjustments. For example, skin thermoreceptors monitoring ambient temperature allow thermoregulatory responses before internal temperature actually changes. This FEEDFORWARD REGULATION acts in conjunction with negative feedback control.
Homeostasis represents a relative, not an absolute, constancy. Some fluctuation about the set point is normal and natural. Also, the set point may change due to unusual circumstances (e.g. fever) or as part of a natural BIOLOGICAL RHYTHM.
Many such rhythms are CIRCADIAN (i.e. about 24 hr).
Biological rhythms are INTERNALLY DRIVEN; however, they can be constantly adjusted (i.e. ENTRAINED) by environmental cues.
[Fig. 1-8]
[see Figure] Cells communicate chemically with other cells in several different ways.
[Fig. 1-7] A HORMONE is a chemical substance produced by specific organs or tissues and transported by blood to other sites in the body where it produces an effect.
Hormones are secreted into the blood from ENDOCRINE glands, which are ductless.
[see Figure] Lipophilic molecules can directly enter cells; however, lipophobic molecules can not and thus require SIGNAL TRANSDUCTION.
CLASSES OF HORMONES:
Amines:
e.g. thyroid hormones, catecholamines
Peptides & Proteins:
e.g. pituitary hormones
Most hormones are peptides, and many of these are synthesized as larger molecules which are then cleaved.
Steroids:
e.g. cortisol & sex hormones
[Fig. 11-1] Amine hormones
[Fig. 11-3] Steroid hormones
Peptides and catecholamines circulate dissolved in the plasma. These hormones are lipophobic.
Thyroid and steroid hormones typically circulate bound to plasma proteins. These hormones are lipophilic.
[Fig. 5-4] Lipophilic hormones can enter the cell and bind with receptors in the nucleus (or cytosol), where they can affect the synthesis of specific proteins.
[Fig. 5-5]
[Fig. 5-5(a)] Lipophobic chemicals (the first messengers) bind to membrane receptors and induce changes inside the cell. In this example, by opening (or closing) specific ion channels.
[Fig. 5-5(c)] Lipophobic hormones may combine with membrane receptors which have PROTEIN KINASE activity (or which trigger such activity). This changes the activity of other proteins within the cell.
[Fig. 5-5(d)] Many lipophobic hormones bind with membrane receptors and the signal is then transduced via G PROTEINS, which activate other membrane proteins (which alter ion channels or act as enzymes).
[Fig. 5-6] The most famous example involves ADENLYL CYCLASE, which converts ATP to cyclic AMP (a SECOND MESSENGER) which then activates protein kinases within the cell.
One hormone molecule can (via SIGNAL AMPLIFICATION) generate a very large number of active molecules within the cell.
[Fig. 5-8]
[Fig. 5-9] A single type of second messenger can produce many different types of responses by activating different protein kinases.
[Fig. 5-11] Calcium can also act as a second messenger by combining with (and activating) CALMODULIN, which, in turn, can activate specific protein kinases.
[see Figure] CALMODULIN undergoes a conformational change when all four calcium binding sites are occupied. The resulting calcium - calmodulin complex can bind to many different target proteins, thereby modulating their activity
[see Figure] Calcium - colmodulin is involved in the excitation - contractikon coupling of smooth muscle (as we discussed earlier) and in the regulation of many other processes or enzymes within cells.
Additional second messengers include:
Cyclic GMP (acts similarly to cyclic AMP)
Diacylglycerol (DAG) – This also works by activating specific protein kinases.
Inositol triphosphate (IP
3) – This releases calcium ions from the endoplasmic reticulum.DAG and IP
3 are formed from phosphatidylinositol bisphosphate (PIP2) by the membrane enzyme phospholipase C, which is activated by G protein.[Fig. 11-2] Typical peptide hormones go through a multistage process beginning with synthesis and ending with secretion. Some hormones may skip some of these stages.
[Fig. 11-9] As indicated earlier, the rate of secretion can be either stimulated or inhibited by a variety of chemical and neural factors.
[Fig. 11-7] The amount of active circulating hormone depends on the rate of secretion and also on the rates of activation/inactivation and excretion. (Not all of the above processes apply to all hormones).
The responses of tissues to specific hormones are not rigidly fixed. Prolonged exposure to low concentrations can result in UP-REGULATION by the target cells (i.e. by an increase in the number of receptors). Conversely, prolonged exposure to high hormone concentrations can result in DOWN-REGULATION (a decrease in number of receptors).
[see Figure] We will focus on the following:
Hypothalamus, Anterior pituitary, Posterior pituitary, Thyroid, Parathyroids, Pancreas, Adrenal cortex, Adrenal medulla, Ovary, Testis.
PITUITARY
The ANTERIOR PITUITARY (ADENOHYPOPHYSIS) is derived from embryonic ENDODERM. It develops from an upgrowth of the roof of the primitive mouth (Rathke's pouch).
The POSTERIOR PITUITARY (NEUROHYPOPHYSIS) is derived from embryonic ECTODERM. It develops from a downgrowth from the floor of the primitive brain.
[see Figure] The pituitary is connected to the HYPOTHALAMUS by an infundibular stalk.
Blood from the hypothalamus flows through the hypothalamo-hypophyseal portal vessels to the anterior pituitary.
[Fig. 11-15] Although the pituitary has been called the "master gland", the release of anterior pituitary hormones is controlled by hypophysiotropic hormones from the hypothalamus. These are released into the blood and reach the anterior pituitary via the portal vessels.
ANTERIOR PITUITARY HORMONES
Thyroid Stimulating Hormone (TSH)
Adrenocorticotropic Hormone (ACTH)
Somatotropic (Growth) Hormone
(This stimulates the liver to secrete insulin-like growth factor I (IGF-I)
Three additional hormones are associated with reproduction. These are listed on the next slide.
Follicle-Stimulating Hormone (FSH)
Luteinizing Hormone (LH)
The above two hormones affect the gonads and are known as GONADOTROPINS. LH is also known as Interstitial Cell Stimulating Hormone (ICSH) in males.
Prolactin
(This stimulates the development of the mammary glands and the production of milk).
[Fig. 11-17] Releasing hormones from the hypothalamus act to stimulate or inhibit the release of anterior pituitary hormones.
NOTE: DA = Dopamine
[Fig. 11-19] Plasma concentrations of hormones are homeostatically controlled by negative feedback mechanisms involving feedback loops to the hypothalamus and/or anterior pituitary.
POSTERIOR PITUITARY HORMONES
Antidiuretic Hormone (ADH)
(This hormone affects water balance by regulating the permeability of the kidney collecting ducts. ADH also causes general vasoconstriction and is sometimes called VASOPRESSIN).
Oxytocin
(This hormone stimulates myoepithelial cells in the mammary glands to contract and "let down" milk. Oxytocin also stimulates uterine smooth muscle and can be used clinically to induce labor).
[see Figure] The hormones released by the posterior pituitary are actually synthesized by hypothalamic neurons. These neurons also control the release of the hormones.
ADRENAL GLANDS
These glands have a dual origin. The CORTEX arises embryologically from the same MESODERM tissue that gives rise to the gonads. The MEDULLA arises from ECTODERM tissue associated with ganglia of the sympathetic division of the ANS.
The hormones of the cortex are STEROIDS, whereas those of the medulla are CATECHOLAMINES.
[Fig. 11-5]
[Fig. 11-3 (part)]
The hormones of the adrenal cortex fall into three general categories:
GLUCOCORTICOIDS – These hormones affect carbohydrate metabolism. The major example is CORTISOL.
MINERALOCORTICOIDS – These hormones affect salt and water balance. The major example is ALDOSTERONE.
SEX HORMONES – These hormones affect sexual characteristics. The major example is DEHYDROEPIANDROSTENE (a weak androgen, which can be converted to TESTOSTERONE in peripheral tissue).
[Fig. 11-18] CORTISOL is involved in responses to stress. Its release is controlled by CRH via ACTH, with negative feedback regulation.
In response to stimulation by preganglionic sympathetic neurons, the adrenal medulla releases EPINEPHRINE plus smaller amounts of NOREPINEPHRINE.
THYROID GLAND
The element IODINE is an essential component of the thyroid hormones THYROXINE (T
4) and TRIIODOTHYRONINE (T 3). The latter is the active form. These hormones are transported in the blood bound to plasma proteins. Most of the secreted hormone is T4; however, many cells convert T4 to T3. T3 affects protein synthesis. This hormone influences growth and has a pronounced CALORIGENIC effect (and is thus a major determinant of an individual's BMR).[see Animation]
[see Figure] Iodine deficiency can lead to decreased levels of thyroid hormones, which can, in turn, reduce feedback inhibition of TRH, which can promote a marked hypertrophy of the thyroid (=GOITER).
C cells in the thyroid gland secrete the hormone CALCITONIN in response to increased blood calcium. This hormone acts to decrease bone resorption and to increase renal excretion of calcium. Calcitonin is most important during childhood growth, pregnancy, and lactation.
[Fig. 11-8]. In some cases (as in the example above), one hormone will induce an increase in the number of receptors for a second hormone. This phenomenon is called PERMISSIVENESS.
PARATHYROID GLANDS
These small glands, embedded in the thyroid, are essential for life. They secrete parathyroid hormone (= PARATHORMONE or PTH), which is released in response to decreased plasma calcium. PTH reduces renal excretion of calcium, enhances bone resorption, and stimulates the production of a hormone from VITAMIN D, which promotes intestinal absorption of calcium.
PANCREAS
The pancreas has both an exocrine (i.e. digestive enzymes, etc.) and an endocrine function. The hormones are produced by cells in the ISLETS OF LANGERHANS. The two major hormones are INSULIN (produced by beta cells) and GLUCAGON (produced by alpha cells). These hormones affect metabolism, and the ratio between them is very important.
[see Figure] Insulin is a hormone of the fed state. It promotes the uptake of glucose from the plasma to the cells. It is an ANABOLIC hormone, promoting glycogen, protein, and fat synthesis.
Glucagon increases dkuring fasting and raised blood glucose concentration by promoting glycogenolysis and gluconeogenesis.
[Fig. 11-10] Too little plasma glucose = HYPOGLYCEMIA, and too much = HYPERGLYCEMIA.
The hyperglycemia associated with insulin deficiency is associated with one common form of the disease, DIABETES MELLITUS.
[see Figure] In the absorptive postprandial (i.e. fed) state, insulin dominates and promotes anabolic processes.
In the postabsorptive (fasted) state, glucagon works to maintain circulating levels of plasma glucose (typically at around 100 mg/dL (aka 100 mg%).
[Fig. 11-11] This slide illustrates the several ways by which the nervous system interacts and controls the endocrine system.