1. Describe the anatomical relationships between the hypothalamus and the pituitary.
- The pituitary gland, or hypophysis, lies in a pocket of the sphenoid bone (called the sella turcica) at the
- base of the brain, just below the hypothalamus. The pituitary gland is connected to the hypothalamus
- by the infundibulum, or pituitary stalk, containing axons from neurons in the hypothalamus and small
- blood vessels. In humans the pituitary gland is composed of two adjacent lobes—the anterior lobe
- usually referred to as the anterior pituitary gland or adenohypophysis and the posterior lobe usually
- called the posterior pituitary gland or neurohypophysis.
- The posterior pituitary is not actually a gland, but rather an extension of the neural components of
- the hypothalamus. The axons of the hypothalamic supraoptic and paraventricular nuclei pass down the
- infundibulum and end within the posterior pituitary in close proximity to capillaries. The axon
- terminals release hormones into these capillaries, which then collect into veins and the general
- The anterior pituitary is connected to the hypothalamus not by neural connections but by an
- unusual blood vessel connection. The capillaries in the median eminence at the base of the
- hypothalamus recombine to form the hypothalamo-pituitary (or hypothalamo-hypophyseal) portal
- vessels. They pass down the infundibulum connecting the hypothalamus and pituitary and enter the
- anterior pituitary where they drain into a second capillary bed, the anterior pituitary capillaries. Thus,
- the hypothalamo-pituitary portal vessels offer a local route for blood flow directly from the
- hypothalamus to the cells of the anterior pituitary.
2. Name the two posterior pituitary hormones and describe their site of synthesis and
- mechanism of release.
- Oxytocin and vasopressin (also known as antidiuretic hormone or ADH). These hormones are
- synthesized in the cell bodies of the neurons (one type of hormone per neuron) that form the supraoptic
- and paraventricular nuclei within the hypothalamus, and are then packaged into small vesicles, which
- move down the axon by axon transport to accumulate in the axon terminals of the posterior pituitary
- gland. 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 then enters
- capillaries in the posterior pituitary to be carried away by blood returning to the heart.
3. List all six well-established anterior pituitary hormones and their major functions.
- (1) Growth hormone (GH, somatotropin): Stimulates body growth, primarily by stimulating the
- secretion of insulin-like growth factor I (IGF-I) by target cells; also has direct effects on protein,
- carbohydrate, and lipid metabolism.
- (2) Thyroid-stimulating hormone (TSH, thyrotropin): Stimulates the growth of the thyroid gland and
- the secretion of thyroxine and triiodothyronine.
- (3) Adrenocorticotropic hormone (ACTH, corticotropin): Stimulates growth of the adrenal cortex and
- secretion of cortisol by that gland.
- (4) Prolactin: Stimulates breast growth and development and milk synthesis; may be permissive for
- certain reproductive functions in the male.
- (5 and 6) Follicle-stimulating hormone (FSH) and luteinizing hormone (LH)— collectively, the
- gonadotropins. They stimulate development of the gonads, the secretion of sex steroids by the gonads,
- and gamete production in them. These effects occur in both sexes, but the names are derived from some
- specific functions in females.
4. List the major hypophysiotropic hormones and the hormone whose release each controls.
- (1) Growth hormone-releasing hormone (GHRH): Stimulates secretion of GH.
- (2) Somatostatin (SS): Inhibits secretion of GH.
- (3) Thyrotropin-releasing hormone (TRH): Stimulates secretion of TSH.
- (4) Corticotropin-releasing hormone (CRH): Stimulates secretion of ACTH.
- (5) Gonadotropin-releasing hormone (GnRH): Stimulates secretion of both gonadotropins FSH and
- (6) Dopamine (DA): Inhibits secretion of prolactin.
5. What kinds of inputs control the secretion of the hypophysiotropic hormones?
- Some of the neurons that secrete hypophysiotropic hormones may have spontaneous activity. In
- addition, neurons of the hypothalamus receive stimulatory and inhibitory synaptic input from
- virtually all areas of the CNS, and specific neural pathways influence secretion of the individual
- hypophysiotropic hormones. A large number of neurotransmitters are released at the synapses on the
- hormone-secreting hypothalamic neurons, which explains why the secretion of hypophysiotropic
- hormones can be altered by drugs that influence these neurotransmitters.
- One example of neural control of hypophysiotropic hormone secretion is the increased secretion of
- CRH in response to a wide variety of physical and emotional stresses that act via neural pathways to
- the hypothalamus. Other neural control of CRH comes from the circadian-rhythm generator (see
- Chapter 1).
- The secretion of the hypophysiotropic hormones is also controlled by negative feedback exerted
- upon the hypothalamus by one or more of the hormones in the hypothalamo-anterior pituitary-target
- gland sequence. For example, rising levels of cortisol reduce the secretion of CRH by causing a decrease
- in the frequency of action potentials in the neurons secreting CRH.
6. Diagram the CRH-ACTH-cortisol system.
7. What is the difference between long-loop and short-loop negative feedback in the
- hypothalamo-anterior pituitary system?
- Long-loop negative feedback refers to the inhibitory effects exerted by the third hormone in a
- hypothalamo-anterior pituitary-target gland sequence (e.g., cortisol) on the secretion of the
- hypophysiotropic hormone (e.g., CRH) and the anterior pituitary gland hormone (e.g., ACTH). Shortloop
- negative feedback refers to the inhibitory effects (generally) of an anterior pituitary gland hormone
- on the secretion of the hypophysiotropic hormone that stimulates its secretion. (The case of prolactin is
- special because increased plasma levels of prolactin stimulate dopamine secretion. But because
- dopamine is inhibitory to prolactin secretion, the effect is one of negative feedback.)
1. Describe the steps leading to T3 and T4 production, beginning with the transport of iodide
- into the thyroid follicular cell.
- Synthesis of thyroid hormones begins when circulating iodide is cotransported with Na+ across the
- follicular cell plasma membrane. Once inside the follicular cell, the bulky iodide cannot diffuse back
- into the interstitial fluid; this is known as iodide-trapping. The trapped, negatively charged iodide ions
- diffuse down their electrical and concentration gradients to the lumenal border of the follicular cells.
- Inside of the colloid of the follicles, iodide is oxidized to iodine and attached to the phenolic rings of
- tyrosine molecules within the amino acid structure of the protein thyroglobulin by the enzyme thyroid
- peroxidase. Within the lumen of the follicle (in the colloid), additional diiodotyrosines are added to
- tyrosine residues on the thyroglobulin. If two diiodotyrosines are bound, the product is T4. If a
- monoiodotyrosine and a diidotyrosine are attached, the product is T3. When thyroid hormone is
- required in the blood, the thyroglobulin re-enters the follicular cell by endocytosis. Lysosomal enzymes
- then cleave molecules of T3 and T4, which diffuse out of the cell and into the blood.
2. What are the major actions of TSH on thyroid function and growth?
- TSH stimulates the synthesis of T3/T4. It also stimulates protein synthesis in follicular cells, increases
- DNA replication and cell division, and increases the amount of rough endoplasmic reticulum and
- other cellular machinery required by the follicular cells for protein synthesis.
3. What is the major way in which the TRH/TSH/TH pathway is regulated?
- TRH from the hypothalamus stimulates the secretion of TSH from the anterior pituitary gland which
- stimulates the secretion of T3 and T4 from the thyroid gland. T3 and T4 inhibit the secretion of TRH
- and TSH through long-loop and short-loop negative feedback mechanisms, respectively.
4. Explain why the symptoms of hyperthyroidism may be confused with a disorder of the
- autonomic nervous system.
- A permissive action of T3 and T4 is to up-regulate beta-adrenergic receptors in many tissues, notably
- the heart and nervous system. Thus, symptoms of excess thyroid hormone concentration closely
- resemble some of the symptoms of excess epinephrine and norepinephrine (sympathetic nervous system
- activity). Although catecholamine levels are normal, they have a greater effect on target tissues in
- patients with hyperthyroidism because of the potentiating effect of increased T3 and T4.
5. Explain how both hypothyroidism and hyperthyroidism can result in the appearance of a
- A goiter develops if there is higher than normal stimulation of TSH receptors located within the
- thyroid gland. In primary hypothyroidism, there is no negative feedback to the anterior pituitary so
- TSH levels are elevated, and the excessive stimulation of the TSH receptors causes a goiter to develop.
- If the hyperthyroidism is caused by Graves' disease, antibodies stimulate the TSH receptor (even
- though actual TSH levels are lower than normal) causing the same effects as TSH itself; one of which
- is a goiter.
1. Diagram the CRH-ACTH-cortisol pathway.
2. List the physiological functions of cortisol.
- Cortisol has permissive actions on the reactivity to epinephrine and norepinephrine of smooth
- muscle cells that surround blood vessels such as arterioles. Partly for this reason, therefore, basal
- levels of cortisol help maintain normal blood pressure. Cortisol is also important for maintaining
- the cellular concentrations of certain enzymes involved in metabolic homeostasis. These key
- enzymes are mostly in the liver, and they act to increase hepatic glucose production between
- meals, thereby preventing plasma glucose levels from significantly decreasing below normal. Antiinflammatory
- and anti-immune actions are also essential functions of cortisol. Finally, during
- fetal and neonatal life, cortisol is an important developmental hormone. It has been implicated in
- the proper differentiation of numerous tissues and glands, including various parts of the brain, the
- adrenal medulla, the intestine, and the lungs.
3. Define stress, and list the functions of cortisol during stress.
- Stress is an environmental change that must be adapted to if health and life are to be maintained.
- It is an event that elicits cortisol secretion.
- (1) Cortisol affects organic metabolism in many ways. In general, it increases the amount of
- substrates available for energy metabolism. These include proteolysis in bone, lymph, muscle, and
- elsewhere, lipolysis in adipose tissue causing the release of glycerol and free fatty acids into the
- blood, amino acid uptake and gluconeogenesis in the liver, and maintenance of plasma glucose
- levels by insulin antagonism.
- (2) Cortisol causes enhanced vascular reactivity.
- (3) Cortisol causes inhibition of inflammation and adaptive immune responses.
- (4) Cortisol inhibits nonessential functions such as reproduction and growth.
- (5) Cortisol has unidentified protective effects against the damaging influences of stress.
4. Contrast the symptoms of adrenal insufficiency and Cushing’s syndrome.
- In adrenal insufficiency, cortisol levels are chronically lower than normal. This may be caused by
- destruction of the adrenal gland by disease (primary adrenal insufficiency) or because of a failure
- of the pituitary gland to secrete ACTH (secondary adrenal insufficiency). Adrenal insufficiency
- results in low blood pressure due to the loss of cortisol's permissive effects on the blood vessels. If a
- patient has primary adrenal insufficiency and the levels of aldosterone are also decreased, then the
- inability to retain salt and water can also lead to hypotension. Blood sugar levels are low because
- of the loss of cortisol's effects on organic metabolism.
- On the other hand, cortisol excess, possibly caused by a hormone-producing tumor of the
- adrenal gland or the anterior pituitary gland, is known as Cushing’s syndrome. Hypertension is
- often a symptom because of cortisol's permissive effect on the blood vessels. Hyperglycemia,
- muscle weakness, osteoporosis, and thinning of the skin can occur due to the excess breakdown
- and mobilization of organic molecules. Immunosuppression is brought about by cortisol excess.
- Cushing’s syndrome is often associated with loss of fat mass from the extremities, and with a
- redistribution of the fat in the trunk, face, and back of the neck. It can also lead to an increased
5. List the major effects of activation of the sympathetic nervous system during stress.
- (1) increased glycogenolysis in muscle and liver, (2) increased breakdown of adipose tissue
- triglyceride, (3) increased cardiac function including an increased heart rate, (4) redistribution of
- blood from the viscera to skeletal muscle by means of vasoconstriction in the former beds and
- vasodilation in the latter, (5) increased lung ventilation by stimulating brain breathing centers
- and dilating airways
1. Describe the process by which bone lengthens.
- Linear bone growth occurs at the ends, or epiphyses, of the bone. Chondrocytes within a region of
- actively proliferating cartilage called the epiphyseal growth plate continuously produce new
- cartilage. Osteoblasts along the shaft-side of the growth plate convert the cartilage to bone and
- push the epiphyseal plate away from the shaft resulting in growth.
2. What are the effects of malnutrition on growth?
- Proper nutrition is a requirement for growth. Sufficient levels of amino acids, fatty acids,
- vitamins, and minerals must be present not only during childhood but also during prenatal
- development. Improper nutrition will stunt growth.
3. List the major hormones that control growth.
- (1) growth hormone (which primarily works indirectly through the actions of the mitogen IGF-1),
- (2) insulin-like growth factor I, (3) insulin-like growth factor II, (4) T3 and T4, (5) insulin,
- (6) testosterone, (7) estradiol, (8) cortisol.
4. Describe the relationship between growth hormone and IGF-1 and the roles of each in
- Growth hormone is secreted by the anterior pituitary gland where it enters the bloodstream and
- acts on many tissues. In some tissues like muscle, growth hormone directly stimulates protein
- synthesis. In bones, growth hormone acts directly on prechondrocytes in the epiphyseal plate to
- differentiate into mature chondrocytes. However, many of the effects of growth hormone are
- mediated indirectly through the actions of insulin-like growth factor I (IGF-1). After growth
- hormone stimulates chondrocytes to mature, they begin to secrete IGF-1 and also become sensitive
- to it. IGF-1 works in a paracrine or autocrine manner to stimulate cell division. Besides its role in
- promoting bone growth, growth hormone also plays a role in 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 gluconeogenesis in the liver, and inhibits the
- ability of insulin to promote glucose transport into certain cells. Growth hormone, therefore, tends
- to increase circulating energy stores.
5. What are the effects of growth hormone on protein synthesis?
- Growth hormone stimulates protein synthesis especially in skeletal muscle. It does this by
- increasing amino acid uptake and both the synthesis and activity of ribosomes, all of which are
- essential for protein synthesis.
6. Give two ways in which short stature can occur.
- Short stature can occur because of a lack of growth hormone secretion by the anterior pituitary
- gland. It can also be caused by an inability to produce IGF-1 or an insensitivity of target tissues to
7. What is the status of growth hormone secretion at different stages of life?
- Growth hormone levels are moderate in children, peak during adolescence and are lowest during
8. State the effects of the thyroid hormones on growth.
- Thyroid hormones are essential for normal growth. They are required for both the synthesis and
- the growth-promoting effects of growth hormone.
9. Describe the effect of testosterone on growth, cessation of growth, and protein synthesis.
- Which of these effects does estrogen also exert?
- Testosterone promotes growth by stimulating the secretion of growth hormone and IGF-1.
- Testosterone also induces closure of the epiphyseal plates and thus stops growth. These effects are
- shared by estrogens. Testosterone alone has the added ability to stimulate protein synthesis in
- nonreproductive organs and tissues of the body.
10. What is the effect of cortisol on growth?
- In high concentrations, cortisol inhibits growth by inhibiting DNA synthesis and promoting
- protein catabolism in many organs. Cortisol also inhibits bone formation and growth hormone
1. Describe bone remodeling.
- Throughout life, bone is being constantly remodeled by the combined actions of osteoblasts—the boneforming
- cells that secrete collagen to form a surrounding matrix called osteoid, which then becomes
- calcified—and osteoclasts—the cells that break down (resorb) previously formed bone by secreting
- hydrogen ions, which dissolve the crystals of calcium, phosphate, and hydroxyl ions, and hydrolytic
- enzymes, which digest the osteoid. In remodeling, osteoclasts resorb old bone, and then osteoblasts
- move into the area and lay down new matrix, which becomes mineralized. Osteoblastic activity is
- stimulated by the stresses imposed on bone by gravity and muscle tension. It is also affected by many
- hormones and a variety of autocrine/paracrine growth factors produced locally in bone.
2. Describe the handling of Ca2+ by the kidneys and the gastrointestinal tract.
- About 60 percent of plasma Ca2+ is filterable at the renal corpuscle (the rest is bound to plasma
- proteins), and most of this filtered Ca2+ is reabsorbed. There is no tubular secretion of Ca2+. The control
- of Ca2+ excretion is exerted mainly on reabsorption; that is, reabsorption is reflexly decreased when
- plasma Ca2+ goes up, and reflexly increased when plasma Ca2+ goes down.
- In contrast to the absorption of almost 100 percent of ingested Na+, K+, and water from the
- gastrointestinal tract, a considerable amount of ingested Ca2+ is not absorbed. Moreover, the active
- transport system that achieves Ca2+ absorption is under important hormonal control. Accordingly,
- there can be large regulated increases or decreases in the amount of Ca2+ absorbed from the diet.
- Hormonal control of this absorptive process is the major means for homeostatically regulating totalbody
- calcium balance, more important than the control of renal Ca2+ excretion.
3. What controls the secretion of parathyroid hormone, and what are this hormone’s major
- Parathyroid hormone secretion is controlled by the extracellular Ca2+ concentration acting directly on
- the secretory cells via a plasma membrane Ca2+ receptor of the parathyroid glands. Decreased plasma
- Ca2+ concentration stimulates parathyroid hormone secretion, and an increased plasma Ca2+
- concentration does the opposite.
- Parathyroid hormone:
- (1) Directly increases the reabsorption of bone by osteoclasts, which results in the movement of
- calcium (and phosphate ions) from bone into extracellular fluid.
- (2) Directly stimulates the formation of 1,25-dihydroxyvitamin D, which then increases the intestinal
- absorption of calcium (and phosphate ions). Thus, the effect of parathyroid hormone on the intestinal
- tract is indirect.
- (3) Directly increases tubular Ca2+ reabsorption in the kidneys, thereby decreasing urinary Ca2+
- (4) Directly reduces the tubular reabsorption of phosphate ions in the kidneys, thus increasing its
- urinary excretion. This keeps plasma phosphate ions from increasing at a time when parathyroid
- hormone is simultaneously causing increased release of both calcium and phosphate ions from bone and
- when 1,25-dihydroxyvitamin D is increasing both calcium and phosphate ion absorption in the
4. Describe the formation and action of 1,25-(OH)2D. How does parathyroid hormone influence
- the production of this hormone?
- The term vitamin D denotes a group of closely related compounds. Vitamin D3 is formed in the body
- by the action of ultraviolet radiation on 7-dehydrocholesterol in the skin. Another form of vitamin D
- that is very similar to vitamin D3 is ingested in food (vitamin D2). Both forms must be activated by
- the addition of two hydroxyl groups. The first addition occurs in the liver by the enzyme 25-
- hydroxylase and results in the formation of 25-hydroxyvitamin D3. The second addition occurs in
- certain kidney tubule cells by the enzyme 1-hydroxylase and results in the active form of the
- hormone—1,25-dihydroxyvitamin D (1,25-(OH)2D). The major action of 1,25-(OH)2D is to
- stimulate absorption of Ca2+ by the intestine.
- Parathyroid hormone stimulates the enzyme (1-hydroxylase) that catalyzes the second
- hydroxylation step that occurs in the kidneys