ENDOCRINOLOGY General endocrinology

1. Define the concept of hormone! Hormones are chemical substances secreted from endocrine glands to the circulatory system that carries them to act on distant target cell. (!) 2. 3. Classify the hormones according to their chemical structures! Amines: thyroid hormones and the catecholamines (N, NE) originate from amino acid tyrosine. Steroids: adrenal cortical hormones, sex hormones and the active metabolites of Vit. D. Proteins: e.g. GH, glucogon and inslulin. (!) Briefly outline the mechanism of peptide hormone synthesis! The proteins / peptides are synthesized from mRNA to form the preprohormone. In the ER they undergo additional modification (usually cleavage) to form the prohormone > transfer to the Golgi, where prohormone is packed in secretory granules. In the granules proteolytic enzymes cleave the prehormone to form active hormone + small inactive fragment. In Golgi hormone also undergoes modification (glycosylation or phosphorylation) and proper packing to give the stored hormone.(!) 4. Which are the cellular actions of peptide and catecholamine hormones? Both the peptide hormones and catecholamines are stored in the secretory granules and released by exocytosis > blood stream > receptor and signal generating system are within or immediately adjacent to the PM of the cell > change in the receptor conformation > evoke several processes that influence the cAMP, PKA, PLC, DAG and IP3. Therefore, the hormones effect is trough the second messengers. (!) 5. Which are the cellular actions of steroid hormones? The cellular action of the steroid hormone is on the DNA level. The steroid hormone binds to an intracellular receptor > this complex interacts with DNA molecules in the nucleus. This binding activates / inactivates certain region in the DNA > induce or suppress formation of mRNAs. (!) 6. List 4 intracellular messengers acting as intermediaries of hormonal effects! Adenylate cyclase (AC) > cAMP. Ca++ > Calmodulin.

 7.

Plasma membrane bound proteins > phospatidylinostiol (IP3) and DAG. Tyrosine kinase > RAS system AC > cGMP > Protein Kinase G. (!)

Explain the principle of negative feedback control, the regulating mechanism of the physiological hormone levels in the blood! Certain stimulus cause release of the primary hormone from the cells being stimulated > causes affect in the target cells that release hormone, which causes the inhibition of the primary hormone secretion by acting on the cells secreting this hormone. (!)

8.

What is the mechanism responsible for the atrophy of an endocrine gland when its hormone is substituted artificially for an extended period of time? The mechanism that is responsible for the atrophy of an endocrine gland, when substitution of artificial analog takes place, is the negative feedback mechanism, because the introduction of the analog inhibits the production of the hormone by the endocrine gland itself (the hormones produced by the target cells will act on the endocrine cells, which responsible for natural formation of this activating hormone), thus will, eventually, cause atrophy of the gland. (!)

9.

List 4 hormones the secretion of which is regulated by changes in chemical components of the blood! Vitamin D: respond to Ca++ levels. ADH: respond to water, Na+ and K+. Aldestrone: response to K+ (slow) and Na+. Insulin: respond to K+ (rapid) and glucose levels. PTH: respond to the Ca2+ level. Calcitonine: activated by the high Ca2+ level and cause decrease in this level. (!)

10. List 4 endocrine organs that are examples for the double hypothalamic-pituitary - feedback mechanism! Testis Ovary Adrenal gland Thyroid gland. (!)

11. On which levels does negative feedback control occur in the hypothalamic-pituitary-target organ model? The short loop: the hormones secreted by the pituitary make (-) feedback on the hypothalamus The long loop: the hormones secreted by the peripheral endocrine glands make (-) feedback on the hypothalamus. [p. 877 B&L] (!) 12. What is the significance and the role of the portal circulation in the function of the hypothalamic-pituitary system? The significant role of the portal circulation (double capillarization) is to allow the relation between the hypothalamus and pituitary (by collecting the hormones produced by the hypothalamus and their transportation to the pituitary via long and short portal veins). The 1 st capillaries in the hypothalamus collect the hormones > 2nd capillaries distribute these hormones in the pituitary and pick the hormones released by the pituitary. This connection also allows the short loop feedback between the endocrine cells of pituitary and hormone secreting cells of the hypothalamus ones. (!)

Posterior pituitary gland

1. Where and in which form is ADH produced? The ADH is synthesize mostly in the supraoptic nucleus of hypothalamus, but some also by and paraventriculer nuclueus of the hypothalamus, as octapeptide. The ADH produced in the form of preprohormone > prohormone > hormone and it binds to neurophysin II (carrier protein) in the granule > moves down the nerve ending and when stimulation arrives it is being released form the neurophysin to the blood stream. (!)

2.

Give 2 physiologic (!) factors that enhance the secretion of ADH! Hyperosmomolarity (increase in the ionic [ ]) > mucula densa > renin > ATII > ADH secretion increases. Hypovolemia (decrease in the water content) > hyperosmolarity. Exercise. Hemorrhage. (!)

3. 4.

Give 2 physiologic (!) factors that inhibit the secretion of ADH! Hyposmolarity (decrease in the ionic [ ]) Hypervolemia (increase water content) > high blood pressure > secretion of the ANP > inhibits secretion of renin and ATII > decrease in ADH secretion. Excessive water uptake. (!) List the physiological effects of ADH! Increase in water re - absorption from the glomerular filtration > acts on the distal and collecting tubules > increase their permeability to water. Also acts on the medullary collecting ducts to increase urea reabsorption.

5.

Increase thirst sensation. Increasing vascular tone (sympathetic activation) in response to hemorrhage, via V1a receptor. Acts as ACTH releasing factor. Helps to contract the smooth muscles in the spermatic cord > sperm ejaculation. Facilitates memory. (*****)(1)

The cellular mechanism of action of ADH in the kidney. The ADH promotes the reabsorption of free water in the distal and collecting tubules of the nephron. ADH > binds to V2 receptor > activation of the adenilyl cyclase > increase in cAMP > activation of the PKA > phosphorylation of the membrane proteins and cytoskeleton components (microtubules and microfilaments) > cytoskeleton components transport vesicles containing water channels move to the PM (aquaporins II) > water re absorption increases. (!)

6. 7.

List 3 factors that enhance ADH secretion during blood loss. Hypovolemia Baroreceptor reflux due to decrease in the blood pressure (sympathetic activity). Hyperosmolarity. (!) How does high glucose concentration influence ADH-secretion a) in the presence of insulin b) in the absence of insulin? In absence of insulin the glucose cannot enter the cells > causes increase in osmolarity > increase in the ADH secretion.

In the case of insulin presence all the glucose is absorbed and moves into the cells > [glucose] decreases in the blood > decrease in osmolarity > decrease in ADH secretion. (!)

8.

What does the term diabetes insipidus refer to? Which are its characteristic symptoms? Diabetes insipidus is pathological state in which the body lacks the ability to concentrate urine. This situation can be provoked by the loss or deficiency of ADH production (destruction of the nuclei) or inability of the receptors to respond to ADH. The symptoms include highly diluted urine and high amount of the urine excretion, frequent urination and excessive drinking. (!)

9.

Where and in which form is oxytocin produced? The oxytocin is produced in posterior pituitary mostly in the paraventriculer nucleus, but also in the supraoptic nucleus, as octapeptide. Preprohormone > prohormone > hormone and it is bound to the neurophysin I (carrier protein). (!)

10. List 2 physiologic factors enhancing the secretion of oxytocin! Suckling (nipple > spinal cord > spinothalamic tract > midbrain > paraventricular nucleus of the hypothalamus) Stimulation of the cervix during labour > oxytocin > increase contraction of the uterus. (!)

11. How is the synthesis of oxitocin influenced by a) psychic stress b) ethanol? Both factors of psychic stress and ethanol inhibit the release of the oxytocin. (!)

12. The physiological effects of oxytocin Contraction of the myoepithelial cells of the alveoli of the mammary glands > allow milk ejection. Contraction of the uterus during labour. Decrease bleeding after the labour. (!)

Anterior pituitary gland and hormonal regulation of growth 1. List the hormones of the adenohypophysis (anterior pituitary gland)! Growth hormone (GH) Thyroid stimulating hormone (TSH) Adernocrticotropic hormone (ACTH) Lutenizing hormone (LH)

 2.

Follicle stimulating hormone (FSH) Prolactin (LTH). MSH by the pars intermedia. (!) How are the anterior pituitary hormones regulated by the hypothalamus? Through which factors? The hypothalamus secrets releasing or inhibitory hormones to the anterior pituitary. These hormones affect the cells (specific cells for each specific hormone) of the pituitary to release the stimulating hormone or cease release of the hormone. This stimulating hormone then travel to the periphery and cause affect on target cells. (!)

3.

Which are the symptoms of the pre-puberty ablation of the pituitary gland in mammals? Drawrfism Sexual immaturity Hypothyrodism Adrenal insufficiency. Impair metabolism. Inability to produce concentrated urine. (!)

4. 5.

The consequences of anterior pituitary gland loss in the adult Hypothyrodism Adrenal insufficiency. Impair metabolism. Cease of the menstrual cycle and lost of the secondary sexual characteristics / cease of the spermatogenesis. Explain the regulation of the secretion of the GH with a schematic diagram! [B&L 4th ed. Fig. 49-21 p.842] add figure from lecture. Hypothalamus secrete either GHRH or somatostatin (this process is induced by the sleep and stress, but inhibited by glucose, FFA, increase level of GHRH, as well by somatomedines and increased level of GH itself) > GHRH cause release of the GH from the anterior pituitary > liver and other tissues > produce somatomedins > cause inhibition of the GHRH and GH release (negative feedback to hypothalamus and pituitary respectively). (!)

6.

Through which substances does GH exert its influence on the growth? Where are those substances produced? The substances that influence the growth are the somatomedins (called also insulin-like growth factors, IGF > bind to specific IGFBP
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receptors > carry out GH effect). The somatomedins are

synthesized in the liver (mainly) and other tissues > somatomedins stimulate the proliferation of chondrocytes, muscles and appearance of osteoblasts. (!) 7. List 4 factors enhancing the secretion of the GH! GHRH. Starvation. Stress. Exercise. Sleep. Glucose and FFA decrease. (!)

8. 9.

List 4 factors inhibiting the secretion of the GH! Somatostatin. Glucose and FFA increase. Somatomedins. Obesity. GH and GHRH increase. Cortisol. (!) The general effects of GH on carbohydrate metabolism Decrease glucose uptake by the tissue (e.g. skeletal muscles and adipose tissue). Increase glucose production by the liver = gluconeogenesis. Increase insulin secretion. Increase insulin resistance. [Guyton; p. 850] (!)

10. The general effects of GH on lipid metabolism Increasing FFA in the plasma > enhanced formation of AcCoA from these FA. Increase lipolysis process in adipocytes. Decrease in lipogenesis. Increase formation of keton - bodies. [Guyton; p.850] (!)

11. The effects of GH on protein metabolism. Increases the synthesis of proteins. Free amino-acid will incorporate into proteins by increased transport which is mediated by the GH. Increase DNA transcription and RNA translation. Decrease in the protein and AA catabolism. [Guyton; p.850] (!)

12. How do a) insulin b) thyroxine c) glucocorticoids influence the secretion of GH? Insulin has dual effect: high insulin causes decrease in the transcription of the GH gene, on the other hand low / lack of insulin decreases GH effect. Thyroxine increases GH release. Glucocorticoids decrease GH release (cortisol increases mobilization of CH and FFA > GH release decreases). (!) 13. Describe acromegaly (reason, symptoms)! Acromaegaly is cause by excessive secretion of GH. It is occurs after puberty when the epiphyses of the long bones has fused with the shaft, but the soft tissue continue to growth > widened and enlarged fingers, toes, hands, feet, tongue and prominent lower jaw, prominent brow, cardiomegaly, hepatomegaly and renomegaly. Kyphosis of the back can also be observed [Guyton, p.854] (!) 14. What is gigantism? What may cause it? Gigantism caused by excessive GH secretion. If it occurs during childhood, while the epiphysisal plates are not closed, the persons height increases markedly. The cause for that excessive release of GH may be caused by tumor of the anterior pituitary gland that growth till the gland itself is destroyed > cause death in the early adulthood. [Guyton; p. 953] (!) 15. Which hormone has the strongest effect on prenatal growth? The main hormone affecting the pre - natal growth is HCS (human chorionic somatomammotropin) which is synthesized by the syncytiocytotropoblasts and it has 96% similarity to GH, but only 3% of its promoting activity. This hormone responsible for continuous flow of the substances to the fetus and it increases blood glucose concentration in the maternal blood > glucose to move to the fetal blood. [B&L; 4th p. 1005 1006] (!) 16. List the hormones necessary for normal postnatal growth! GH > normal growth. Thyroid hormone > normal metabolism.

Vitamin D > normal ionic composition > muscular activity. PTH Insulin Adrenal corticoids Androgens and estrogens (!)

17. In case of early puberty how is the stature of the child related to sex- and age-matched controls at the age of a) 10-12; b) 18? Give brief explanation! The sex hormone production peak in the normal state is in the ages 12 16, therefore if the peak of the hormone secretion is in the ages 10 12 the more developed appearance in this period of time is observed > the child is tall. But, in the same time the peak ceases earlier > the childs growth ceases earlier due to the closure of the epiphysial plates before the completion of the growth > short individual in adulthood (age 18). (!) 18. In case of delayed puberty how is the stature of the child related to sex- and age-matched controls at the age of a) 14 b) 18 ? Give brief explanation! The sex hormone production peak in the normal state is in the ages 12 16. In this case this is relatively delayed puberty, therefore the child will be short, but in the adulthood the person is high, because of the late disappearance of the epiphysial plate. [see graph in Viners notes] (!) 19. What is the significant difference between the dwarfed growths due to the thyroid-deficiency and that caused by GH-deficiency? If the dwarfism is due to GH - deficiency the person has normal body proportion, but decreased rate of growth and never secretes sufficient amounts of the gonadotropic hormones to develop adult sexual functions, while the thyroid deficiency causes dwarfism with abnormal body proportion. The person with GH dwarfism has normal intellect, while the person with thyroid dwarfism has mental retardations. [partly from Guyton, p. 853, p. 861] (!) 20. How is growth influenced by large-dose glucocorticoids administered in childhood?

As a result of glucocorticoids administration in the large doses causes inhibition of growth due to the inhibition of the GH secretion, therefore the growth in the child treated with glucocorticoids slowing or even stops. (!)

The hormonal control of calcium metabolism and physiology of the bone

1. What is the osteoid? Osteoblasts synthesize and extrude collagen monomers into extra cellular space > these collagen fibrils line up in the regular array and polymerize > form collagen fibers > the resultant tissue becomes osteoid. [Guyton, p. 902] (!) 2. Precursors of osteoclasts and osteoblasts The precursors of the osteoclasts are the monocytes / macrophages precursors that came from hemotopoietic stem cells. To form osteoclast these precursors fuse together to form big, multinuclear osteoclast. [B&L, 4th p. 852 drawing] The precursors of the osteoblasts are the osteoprogenitor cells that come from pluropotential primitive stem cells. (!) 3. What is the function of osteoblasts? The function of the osteblast is to form the bone. The active cell will release procollagen to the matrix > formation of the osteoid > calcium and phosphate from plasma incorporate into osteoid (by the help of Vitamin D) > addition of the hydroxide and bicarbonate ions > hydroapatite crystals are formed = bone formation. [B&L, 4th p. 852] 4. Produce osteocalcin and osteonectin required for the normal formation of the bone. (!) What is the function of the osteocytes? The osteocyte is the osteoblast surrounded by the bone matrix. The osteocyte is the inactive osteoblast. The osteocytes near the bone surface can initiate the cycle of remodeling in each osteoid. The osteocytes are connected to each other by the gap junctions and form osteocytic membrane system that provides a membrane that separates the bone itself from EC fluid. This membrane contains pumps Ca ions from the bone fluid into the EC fluid > cause low [Ca] in the bone fluid >

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in this way = osteocytic osteolysis the Ca and phosphate are absorbed from the bone. [p. 798B&L)] (!) 5. List the functions of osteoclasts! Decrease bone mass. Destroy the matrix of the bone by lytic enzymes. Solution of the bone salts by secreted acids. Phagocytosis of the minute particles of the bone. The main function of the osteoclast is the resorption of the bone on the bone surface. The resorption takes place by several processes: releasing of proteolytic enzymes, unmineralizing the surface and acidifying it. [Guyton, p. 903] (!) 6. The role of the osteoblast-produced osteonectin and osteocalcin in bone formation Osteonectin binds to collagen and this complex binds the hydroxyapaptite crystal. Ostecalcin has strong affinity to calcium (through -carboxyglutamate residues) and also strong affinity to uncrystalized hydroxyapatite. Both of them formed by the osteoblasts and help in the bone formation. [B&L, 4th p. 852] (!) 7. Why does Vitamin K deficiency lead to bone deformities? The deficiency in Vitamin K leads to the lack in -carboxyglutamate residues activity > deficiency in osteocalcin production (or lack with function) > the bone deformation. (!) 8. How much is the total serum calcium level? What fractions is it composed of? The total level of serum calcium is about 2.4 2.5 mmol / L. The fractions are: 50% are ionized (diffusible) 1.18 mmol / L; 41% are protein bounded (non diffusible) 1.16 mmol / L (0.92 bound to albomin and 0.24 to globulin); and 9% are complexed (diffusible, but bound to the anionic substances) 0.16 mmol / L. (!) 9. How is the free and the protein-bound Ca fraction of the plasma affected by an increase in the pH? As the blood becomes more alkali (increase pH) there is a swift from the ionized (free) calcium to the protein-bound calcium > increase in the protein bounded Ca. (!)

10. Explain the so-called hyperventillational tetany!

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As hyperventilation takes place the blood becomes more alkaline > swift from the ionized to the protein bound Ca > decrease in the free (extra cellular) calcium levels > cause nervous system to become more excitable, because increases membrane permeability for Na > cause tetanic muscle contraction mainly in the hands and feet = carpopedal spasm. [Guyton, p. 900] (!)

11. Can hypocalcaemia lead to blood coagulation disorder in vivo? Explain it briefly! The calcium is a major co - factor in the clotting mechanism. Lack in calcium leads to problems with activation of factors V, VIII, IX, X and XIII, which are essential in the blood coagulation mechanism. [B&L, 4th p. 322] (!) 12. List the humoral-hormonal factors regulating the serum calcium level! Where are they produced? PTH (parathyroid hormone): produced by the parathyroid glands. Vitamin D (1.25 Di OH Vit. D): produced by the skin, liver and kidney. Can also be digested. Calcitonin: produced by the thyroid gland in the C - cells between the follicles. [Guyton, p. 904 908] (!) 13. Where is parathyroid hormone produced? What is characteristic to its structure? The parathyroid hormone (PTH) is produced in the parathyroid gland by the chief cells. The PTH is synthesized as a single chain polypeptide of 110 AA = preprohormone > prehormone (90 AA) > active hormone (84 AA). Small compounds (about 34 AA long) attached to the N terminal exhibit full PTH activity. [Guyton, p. 906] (!) 14. What is the main stimulus of parathyroid hormone secretion? The main stimulus for the PTH is the high calcium level in the plasma that cause decrease in PTH secretion, while low calcium level causes increase in the PTH secretion. This is allowed due to the presence of the unique Ca receptors (G protein linked) within parathyroid cells that sense EC fluid [Ca]. In case of the high Ca it is binds to this receptor > activation of PLC and inhibition of the adenilyl cyclase > intracellular Ca increases, cAMP decreases > decrease in PTH exocytosis. (!)

15. Which organs are fundamentally affected by PTH? Bone: increase mobilization of calcium from the bone. Kidney: increase re - absorption of calcium in distal tubules, inhibit phosphate re - absorption and stimulate synthesis of Vitamin D. [NMS 4th ed. p.717, fig. 54-7], [Guyton, p. 906].

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Intestine: increase calcium absorption. (!)

16. List the target cells and of PTH in the bone! Osteoclast: osteoblast and osteocytes send secondary signals to osteoclasts (have no PTH receptor). > increase their activity and also increase in formation of the new osteoclasts. Osteocytes: ostiocytic osteolysis occur in response to PTH (activates Ca pumps) > increase in EC [Ca]. Osteoblast: stimulate osteclast cells. These cells have receptors for PTH > suppress the formation of collagen. [Guyton, p. 907] (!) 17. Calcium is mobilized from the bones by the parathyroid hormone. Explain the mechanism of action! The PTH acts by several mechanisms the first is increasing the transfer of calcium from the bone to the extracellaler fluid (osteocytic osteolysis) by acting on osteocytes (osteocytic osteolysis) > increase activity of the Ca pumps found on the osteocytic membrane. The second process is increasing the activation of the osteoclast > increase release of calcium and phosphate to the blood by resorption (the activation of osteclast needs the presence of osteoblast or osteocytes). [Guyton, p. 907] (!) 18. Which are the direct effects of parathyroid hormone on a) immature osteoclasts b) mature osteoclasts? The PTH will increase the fusion of osteoclast progenitors to form a multinuclear osteoclast. The action on the mature osteclasts includes the osteoblasts / osteocytes that send signals to osteoclasts > in their presence the osteoclasts increase production of collagnase and other lysosomal enzymes and acidic substances. [Guyton, p. 907] (!)

19. The effects of PTH and active Vitamin D on renal phophate reabsorption PTH increase phosphate excretion in the proximal tubules of the kidney. [Guyton, p. 907] Vitamin D increases phosphate absorption into the EC fluid. [Guyton, p.905] (!)

20. What is the mechanism that inhibits diffuse calcification due to the Ca2+ and PO43 mobilization by the PTH?

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The kidney extracts phosphate and preserves calcium, in order to prevent calcification. (!)

21. The main symptoms of parathormone overdose Hypercalcemia and hypercalcinuria. Hypophospatemia Kidney stones Bone fractures and deformation (pain) due to increased Ca and phosphate from the bones. [B&L 4th p. 864] (!) 22. What characteristic symptoms develop 23 days after parathyroidectomy? Decreased bone absorption. Low plasma PTH level > low Ca plasma level > increase in the excitability of the nervous system, due to increase in the permeability of the cell membrane to Na > titanic contractions can occur. Hyperphosphotemia. Decrease synthesis of vitamin D. Increased renal excretion of calcium > hypocalcemia and hypercalcinuria. [B&L, 4th p. 865] (*****) (2) 23. The characteristic alterations in the composition of blood and urine following parathyroidectomy. The blood calcium decreases while the phosphate levels increases, due to decreased (or none) formation of PTH. In the case of urine the increase in the Ca urine concentration, but decrease in the phosphate urine excretion. (!) 24. Describe the steps leading to the formation of the active Vitamin D3! The 7 dehydrocholesterol is formed by enzymatic activity from cholesterol > UV light of the sun produces the pre - vitamin D from 7-dehydrocholestrol in the kerationcytes, found in the epidermis of the skin > vitamin D then produced spontaneously driven by the thermal energy of the sunshine (3 days) > vitamin D goes to the liver and there undergoes hydroxylation of carbon number 25 > give 25-OH-vitamin D > move to the kidney where another hydroxyl is added (either to carbon 1 to give the active Vitamin D (1,25-di (OH) - vitamin D) or to give the inactive by hydroxylation of carbon 24). [B&L, 4th p. 855] (!) 25. Which organs are fundamentally affected by Vitamin D?

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Bone: increase absorption (in large amount of vitamin D) and mineralization (in small amount of vitamin D). Intestine: increase absorption of Ca by increasing the amount of the Ca binding proteins and also increase phosphate absorption. Kidney: increase phosphate and calcium re - absorption and decrease its own synthesis. [Guyton, p. 905 906] (!) Pancreatic islets, anterior pituitary, hypothalamus, placenta, ovary, aortic endothelium and skin fibroblasts. [B&L, 4th p. 859] (!)

26. How does parathyroid hormone influence the production of 1, 25-dihydroxicholecalciferol? The PTH hormone increases the production of 1, 25 di (OH) - Vitamin D by acting on 1- -hydroxalase. [B&L, 4th p. 865] (!) 27. How does 1, 25-dihydroxicholecalciferol influence the production of parathyroid hormone? The 1, 25 di (OH) vitamin D binds to the receptors of the parathyroid gland cells and inhibits the production of PTH in these cells by repressing the PTH genes. [B&L, 4th p.858] (!)

28. What mechanism is responsible for the increased Ca absorption from the intestines upon a decrease in the serum Ca level? The mechanism that increase the uptake of calcium in the intestine is regulated by PTH > activate 1 hydroxylase > activate 1, 25 di - (OH) - Vitamin D > increase the number of the Ca ATPase pumps in the basolateral membrane > allow Ca to enter the cell > increase in number of transporting proteins, called calbindin. [B&L, 4th p. 858] (!) 29. Explain why there is only a slight decrease in the plasma concentration of Ca and a marked decrease in the plasma concentration of phosphate in a child suffering in rickets. The rickets disease cause by decreased (or none) Vitamin D concentration or by mutation of vitamin D receptor. The Ca plasma concentration is slightly decreases, due to the regulatory effect done by PTH, which increase Ca re absorption by kidney > increase in plasma [Ca].

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In case of phosphate the deficiency in vitamin D causes decrease in phosphate absorption by the intestine, but there is no other regulatory mechanism to increase re absorption of phosphate. In addition presence of PTH increases phosphate excretion in the proximal tubules of the kidney. (!)

30. How is the gastro-intestinal absorption of a) calcium and b) phosphate influenced by dietary intake? The percentage of the dietary Ca absorbed from the intestine is inversely proportional to intake = adaptive regulation, therefore more Ca taken by diet > less absorbed to prevent Ca overload and vise versa. The absorption of the phosphate is relatively constant. The adaptive regulation also present, but it is less important than in Ca. [B&L, 4th p. 849 850] (!) 31. The Ca absorption from the intestines shows adaptational phenomena. What is meant by this? The meaning of this phenomena that if the Ca dietary uptake increases the absorption of the Ca decreases to prevent Ca overload, and opposite is true decrease in the dietary Ca intake cause increase in the Ca absorption to maintain normal Ca level. [B&L, 4th p. 849] (!)

32. The site of calcitonin production; the direct stimulus of its secretion. Calcitonin is synthesized in the parafulicullar (or C) cells of the thyroid gland. Its release is stimulated by high level of calcium in the blood. In the case of the food stimulated calcitonin secretion the release is stimulated by several GI hormones (gastrin is the most important). [B&L, 4th p. 867] (!) 33. List the physiological roles of calcitonin! Osteoclast: inhibit bone resorption by binding to the receptor and elevating intra - cellular cAMP > skeletal re arrangement > detach from the bone surface > deactivated. Decrease plasma phosphate level by decrease in the bone resorption. Intestine: may be involved in the decrease of calcium uptake. [B&L, 4th p. 867] (*****)(3)

34. List the mechanisms that protect the organism against hypercalcemia. Calcitonin Inhibition of PTH production by negative feedback from 1, 25 di (OH) vitamin D

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Increased kidney extrusion and adaptive absorption. Decrease in Vitamin D synthesis by decrease in PTH that required for 1 hydroxylase activity.

The thyroid gland

1. 2. 3. List the organic iodine compounds (those with hormonal effects, as well as those without) that can be found in the thyroid! Monoiodothyrisine (MIT) Diiodothyrosine (DIT) Thyroglobulin Thyroxine (T4) (90%) Triiodothyronine (T3) (10%) Reverse triiodothyronine (rT3) (less than 1%). (!) What is the percentage distribution of the different iodinated tyrosine compounds in the hormones secreted by the thyroid? About 90% of the thyroid output is T4, 10% is T3 and only about 1% is rT3. [B&L, 4th p. 910] (!) How much is the weekly iodine requirement of the human body? In what form is iodine absorbed? The weekly iodine requirement is about 1mg per week (or 150 microgram per day) for adult. Iodine is taken by Na co transport mechanism (symport) against concentration gradient. The iodine takes up as iodine (I -) anion. This co transport requires energy and linked to Na / K pump. [B&L, 4 th p. 912] (!) 4. In the case of no dietary iodine intake, for what time interval can the iodide reserve of the body ensure thyroid hormone production? The reserve ensures the thyroid hormonal production for about 2 - 3 months if the body is deprived from the iodine. [Guyton, p. 859] (!) 5. Uptake of iodide by the thyroid cells. The iodide is taken by the cell through Na - I active symport in the basal membrane of the thyroid epithelial cells (against the [ ] gradient) coupled to the Na / K pump found in the plasma membrane that provide the energy for the Na / I co transport. [B&L, 4th p. 912] (!)

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6. 7.

What are the competitive inhibitors of the iodide transport in the thyroid gland? Thiocyanide (CNS-) Perchlorate (HClO-) Pertechnetate (TcO4-) [B&L, 4th p. 912] (!) What is the effect and the clinical use of the thiouracil derivatives? Thiouracil derivates are clinically used to treat hyperthyroidism, because they block the peroxidase that responsible for the conversion of the iodide and thyrosines into MIT and DIT, therefore in case of this blockage the thyroid hormones cannot be formed. (*****)(4)

8.

Through what mechanism does propil-thiouracil and sulfocyanate (SCN) induce the formation of goiter? Goiter is defined as enlargement of the thyroidal gland. Blockage of thyroid hormone synthesis induces increase in secretion of the TSH due to the absence of negative feedback from thyroid hormones > the gland swells as result of accumulation of TSH in the gland. (!)

9.

The mechanism of iodide oxidation in the thyroid gland. The thyroid enzyme, thyroid peroxidase (accompanying by hydrogen peroxide, which acts as the electron acceptor) converts the iodide anion to iodine (I 0) or I of thyroglobulin and form MIT and DIT. [B&L, 4th p. 913] (!)
3-

that is able to bind to AA tyrosine

10. Formation and role of H2O2 in the thyroid gland. The role of hydrogen peroxide is to accompany the thyroid peroxidase enzyme in convertion of the iodide ion into iodine, which is then able to bind with thyroglubolin. The hydrogen peroxide is formed in the cell by the calcium stimulated oxidase (formation of NADPH from NADP accompanied with conversion of O2 into H2O2). [B&L, 4th p. 913] (*****)(5) 11. What is the clinical use of the radioactive iodide ion? This procedure assists in the diagnosis of the biosynthetic defects in hormone synthesis. [B&L, 4th p. 913] (!)

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12. What is the chemical structure and the role of thyroglobulin? The chemical structure of thyroglobulin is glycoprotein that contains covalent bond of phosphate and sulfate. It is synthesized in the RER > moves to Golgi, where it is modified and packed into the vesicles > exocytosis from the apical membrane of the cell > within the thyroglobulin there are tyrosine molecules are found and iodine binds to these tyrosines by the tyrosine peroxidase activity > formation of T3, T4, MIT and DIT. [B&L 4th p. 913 914] (!)

In the thyroid cells, what is the fate of the colloid taken up by endocytosis? The colloid droplets that are taken by endocytosis (in luminal side) > moves toward basal membrane > during this way go through digestion by lysosomal proteases to release free T3 and T4 > leave the cell > blood stream; the MIT and DIT are deiodinated by the deiodinase enzyme. [B&L, 4 th p. 914] (!) 13. In the thyroid gland, what is the fate of MIT and DIT freed during the proteolysis of the colloid? The freed MIT and DIT will be rapidly deiodinated by the deiodinase enzyme. (!)

14. What is the role of selenium in the endocrine function of the thyroid gland? The selenium is a co-factor of some enzymes, e.g. 5-monodeiodinases isoenzyme found in the liver and kidney containing rare AA selenocysteine. This enzyme is responsible for the conversion of the T4 into T3 (active enzyme). [B&L, 4th p. 920] (!) 15. What is the role of tissue 5-monodeiodinase? The enzyme 5-monodeiodinase converts the T4 (thyroxine) into T3 molecule. [B&L, 4th p. 920] (!)

16. Why does hypophysectomy cause hypothyroidism? Hypophysis is responsible for the release of TSH in response to TRH. But in case of the hypophysectomy no TSH is released > no stimuli for the thyroid gland to produce hormones > hypothyrodism. (!)

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17. How is the plasma TSH level affected by the repeated injections of TRH, and why? At first increase in TSH levels observed, but after certain period of time, during which the amount of formed T3 and T4 reach the level causing short loop negative feedback the TSH release decreases. (!)

18. How is the histological picture of the thyroid gland altered by TSH in the hypothyroitic patient? This is the condition due to lack of iodine > there is no formation of T3 and T4 > no negative feedback to TSH secretion > large amounts of TSH secreted > thyroid cells secrete tremendous amount of thyroglobulin colloid into the follicles > gland grows larger and larger. [Guyton, p. 867] (!) 19. The hormonal regulating mechanisms responsible for the compensatory hypertrophy of the remnant thyroid tissue following partial thyroid excision. As a response to partial thyroid excision the decreased amount of TSH will be formed first > decrease in T3 and T4 release > negative feedback > increase in TSH secretion by the remnant thyroid tissue > hypertrophy of the remnant thyroid tissue. (!) 20. How is the function of the hypothalamo-hypophyseal TRH-TSH axis affected by a) starvation b) cold? In case of the cold the function of this axis increases = more TRH and TSH are released. In case of starvation the function of this axis also increases, because T3 and T4 stimulate gluconeogenesis, lipolysis and ketogenesis. [B&L, 4th p. 923 924] (!) 21. What is the effect of TSH on the thyroid cells? The TSH stimulates the entrance of thyroglobulin into the cells through endocytosis > colloid droplets occur inside the cells > also cause increase in the iodine intake and peroxidase activity. TSH stimulates glucose oxidation > increase in NADPH, which is needed for peroxidase reaction. [B&L, 4th p. 916] (!) 22. Which steps of the hormone synthesis of the thyroid are affected by the TSH?

20

Endocytosis of thyroglobulin Iodine uptake increase Peroxydase activity increase Transcription of thyroglobulin and pyroxidase genes Iodination [B&L, 4th p. 916] (!)

23. Which effects of TSH develop within minutes in the thyroid gland? Endocytosis of the thyroglobulin Increase in iodine uptake Increase in pyroxidase activity Glucose oxidation [B&L, 4th p. 916] (!)

24. Which are the effects of TSH in the thyroid gland that need a longer interval (hours, days) to develop? Thyroglubolin and pyroxidase gene transcription. Increase in the nucleic acid synthesis > support the local production of IGFs and epidermal GF. [B&L, 4th p. 916 917] (*****)(6) 25. How is the hormone secretion of the thyroid affected by the ingestion of a larger amount of iodide? How is it used in the clinical practice? The high levels of iodide uptake cause most activities of the thyroid gland to decrease (often it decreases for several weeks only) > less thyroid hormones are secreted. Due to this decreased activity the size of the thyroid gland decreases; therefore it is administrated to patients 2 3 weeks before surgical removal of the thyroid to decrease bleeding. [Guyton, p. 865] (!) 26. In which form are the hormones of the thyroid gland transported in the blood? Thyroxine binding globulin (TBG): 70% Transthyretin (TTR): 10 15% Albumin: 15 20 % Lipoproteins: 3% Some found in the free form (very small amount, less than 1%). (!)

27. What are the principal functions of the thyroxin-binding globulin (TBG) in the plasma?

21

TBG is a glycoprotein alpha-globlin synthesized in the liver. It has two main function; maintaining large T4 reservoir circulation in the blood (for acute changes), and to prevent loss of T4 through the urine (conserving iodide). [B&L, 4th p. 918] (!)

28. What are the short and long term effects of a decreased TBG content on the plasma level of free T4? Why? In short terms of decrease TBG causes an increase in the free T4 > cause negative feedback to TSH secretion > long term response is decrease in T4 to keep new, lower steady state of T4 (TBG) / free T4 = new equilibrium. [B&L, 4th p. 919] (!) 29. What are the short and the long term effect of an increased TBG content on the plasma level of free T4? Why? In the short term the decrease in T4 is observed > cause negative feedback to increase TSH secretion > increase in T4 secretion till the new equilibrium established, between T4 (TBG) and free T4. [B&L, 4th p. 919] (!) 30. How does the introduction of exogeneous thyroxine affect TSH secretion, the functional activity and the size of the thyroid gland? Introduction of exogeneous thyroxine cause decrease in secretion of TSH (short loop) > functional decrease in the thyroid gland > decrease in the size of the gland, due to decreased activity. (!) 31. What is the effect of alterations in the free thyroxine levels of the plasma on thyroxine secretion of the thyroid gland? The mechanism responsible is the negative feedback: if there is an increase in free thyroxine level the secretion of thyroxine from the thyroid gland is decreased, due to the negative feedback of free T4 on TSH secretion. The vise versa is true for decreased free T4 level. (!) 32. Where is the thyroid hormone receptor located on the target cell? To which form of thyroid hormone has the largest affinity? The thyroid hormone receptor of steroid hormone vitamin D family that located in the nucleus at least 3 forms exists). The T4 is carried through the plasma membrane by a specific carrier, there in the cytoplasm the T4 is converted into T3 (the receptor has the largest affinity to this form). The converted T3 then binds to the thyroid hormone receptor and generates the cascade. [B&L, 4th p. 920] (!)

22

33. What is the mechanism of action of T4 on the target cells? The T4 acts by the nuclear mechanism. First it is transported into the cell by carrier mediated, energy dependent process > converted into T3 > binds to specific nuclear receptor > activates gene expression > mRNA and proteins formation > increase the metabolic rate. [B&L, 4th p. 921 922] (!) 34. What is the fate of the thyroid hormones in the target cells? The thyroid hormones may undergo deiodination, oxidative deamination and decarboxylation, also T4 and T3 sulfates and glucoronides are formed in a small amounts > these last two secreted in bile. The liver, kidney and skeletal muscles are the major sites of T4 degradation. [B&L, 4th p. 919 920] (*****)(7) 35. What is the source of the greater part of the circulating T3? The main source for the circulating T3 is from T4 that was conversed into T3 in the periphery (tissues with the high blood flow: liver and possibly kidney) by 5- monodeiodinase > provide T3 to the other tissues. [B&L, 4th p. 918] (!) 36. List the effects of thyroid hormones on protein metabolism! Release of the amino acids from the muscles. Increase catabolism of the proteins. To lesser extend protein synthesis and urea formation. [B&L, 4th p. 924] (!)

37. List the effects of thyroid hormones on lipid metabolism! Increased lipid mobilization from the adipose tissue. Increased FFA plasma concentration. Increase beta - oxidation > more energy for the thermogensis effect. Decrease cholesterol (by increase in the LDL receptor activity), TAG and phospholipids concentrations in the plasma in case of the thyroid hormones increase and vise versa in case of thyroid hormones decrease. Decrease in the fat storage of the body. [Guyton, p.862] (!)

23

38. List the effects of thyroid hormones on carbohydrate metabolism! Enhance glycolysis. Enhance gluconeogenesis. Increase rate of the CH absorption from the GI tract Increase insulin secretion > increase in CH uptake by the cells. [Guyton, p. 862] (!)

39. How does thyroxine cause hyperglycaemia? The thyroxin potentiates the respective stimulatory effects of epinephrine, NE, glucogon, cortisol and GH on gluconeogenesis > increase the glucose blood levels > hyperglycemia. [B&L, 4th p. 924] Increase glucose uptake by the GI tract. Cause glycogenolysis > increase in the glucose release from the liver and kidney cells into the blood. (*****)(8) 40. How and by what mechanism do thyroid hormones alter the heart rate? The thyroid hormones increase the heart rate. The hormones increase the heart by direct and indirect way. [B&L, 4th p. 923] The indirect effect is due to increase in the heat and CO2 production > peripheral resistance decreases > diastolic BP decreases > reflex increase adrenergic stimulation > HR increases. The direct way the thyroid hormones increase the heart contractility by affecting the Ca-ATPase, myosin chains and other structures > increase ventricular contractility and function > HR increases. (*****)(9) 41. How and by what mechanism do thyroid hormones alter the stroke volume? The stroke volume increases by activity of the thyroid hormones. This affect (direct) is achieved by increasing the calcium uptake, Na / K ATPase and myosin heavy chain / ratio > increase ventricular contractility and function > increase in the stroke volume. [B&L, 4th p. 923] (!) 42. How does thyroxine alter systolic and diastolic blood pressure? Why? The thyroxine reduces the peripheral resistance > decrease the diastolic blood pressure, while the systolic pressure increases due to higher stroke volume. (!) 43. What pathological conditions may lead to the hyperfunction of the thyroid gland? Graves disease autoimmune disease in which Antibodies to TSH receptors are produced > activate TSH receptor independently of TSH secretion > hyper - function of thyroid gland. Toxic Goiter.

24

Thyrotoxicosis. Thyroid adenoma. Inflammation of the gland. Excessive pituitary secretion of TSH. (!)

44. How is the plasma TSH level altered in hyperthyroidism? The level of TSH is low due to the negative regulation effect by the T3 and T4 on the hypothalamus (decreased TRH secretion) and pituitary gland (decrease in TSH secretion). (!) 45. What is the reason for the increased T4, T3 secretion in Graves disease? In Graves disease the antibodies to TSH receptor are formed > bind to the TSH receptor and cause activation of adenylyl cyclase (the same effect as TSH has) > increase in T3 and T4 secretion. [B&L, 4th p. 917] (!) 46. What are the main symptoms of hyperthyroidism in the adult? List 6! Weight loss. Muscle weakness. Excessive sweating (due to increased heat production) Increased heart rate. Intolerance to heat. Diarrhea. Inability to sleep. Nervousness or other psychic disorder. [Guyton, p.866] (!)

47. What is exophtalmus? The over - production of which hormone is it combined with? Exophatalmus is pathological sign of overproduction of thyroid hormone and it is stated by the prominence of the eyeball as a result of the swelling of the retro orbital tissue, and degradation of the eye muscles. [Guyton, p. 866] (!) 48. What neurological functional changes may be observed in hyperthyroidism? Nervousness, Hyperkinesis = excessive muscular activity. Inability to sleep. Intolerance to heat. Tremor of the hands. [Guyton, p. 866] (!)

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49. How does the hyperthyroitic patient tolerate warm environment? Why? The hyperthyrodic patient intolerant to warm environment, due to increased production of heat by the patient. The patient, in warm climate, excessively sweats and increases water intake. (!) 50. What pathological conditions may lead to the hypofunction of the thyroid gland? Idiopathic atrophy, usually due to autoimmune inflammation reaction. Radiation damage Endemic colloid goiter as a result of dietary iodide deficiency Hypothalamic or pituitary distraction Autoimmunity against thyroid gland (*****)(10)

51. Why does long-term iodine deficiency cause goiter? The decreased iodine intake causes hypothyroidism, because in the long term deficiency the iodide pool is empting and as a result thyroid hormones cannot be produced > absence of the thyroid hormones causes negative feedback to increase TRH and TSH release > increase in TSH secretion then results in the increase in the endocytosis of the thyroglobulins into the thyroidal cell > accumulation of the thyroglobulin colloid follicles > swelling of the gland > Goiter. (!) 52. What are the main symptoms of hypothyroidism in the adult? List 6! Increased body weight. Decreased sweating. Increased sleeping time. Bradycardia = decreased heart rate + decreased other heart functions. Constipations. Slowed movement and speech. Intolerance to cold. Accumulation of fluid myxedema in severe cases. Hair loss. [Guyton, p. 867] (!)

53. List those symptoms of the hypothyroidic patient that develop as a consequence of the decreased oxidative metabolism! Intolerance to cold Slow movement and speech Sleepiness. Hair loss.

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Cardiovascular dysfunctions. Constipations. [Guyton, p. 867] (!)

54. How does the hypothyroitic patient tolerate cold environment? Why? Hypothyroidic patient intolerant to the cold since the process of thermogensis is decreased as a result of thyroid hormones deficiency. (!) 55. List the main symptoms of hypothyroidism in childhood! Marked mental retardation. Decreased body growth (mainly in the skeletal system with normal rate of the visceral growth). Enlargement of the tongue > can lead to choking. [Guyton, p. 868] (!)

56. What does the term endemic cretinism refer to? What is the reason of it? Endemic cretinism is the cretinism developed as a result of insufficient or lack of iodide in diet > thyroid gland is enable to produce thyroid hormones > mental retardation and decrease in the growth. [Guyton, p. 868] (!) 57. Why must TSH - levels be screened in neonatal period? The TSH levels must be screened to predict occurrence of hypo or hyperthyroidism. This hormone is essential for the normal development of the fetus. (!)

58. What is the reason for enriching table salt with iodide? Salt is very popular digestion product, so enrichment of the salt with iodide allows preventing hypothyroidism. (!) 59. Which features are characteristic of the growth disorder of a child with congenital hypothyroidism? This child has a decreased growth, especially in the skeletal system and with lesser extend in the visceral organs > the child has disproportional growth. A child suffering from congenital hypothyroidism has late growth development indicated by late walking, sitting and standing (!) 60. How is the basal metabolic rate and the tissue oxigen uptake of the hypothyroidic patient altered by T3 and T4?

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The BMR of hypothyroidic patients is low, as well as the oxygen uptake; therefore introduction of T3 and T4 as a replacement therapy to the patient increases BMR and oxygen uptake. (!)

61. What is myxedema? Myxedema is a symptom of hypothyroidism in which ground substances (mucopolysaccharides) accumulate as a result causing accumulation of fluid. Its symptoms include enlargement of the tongue, joints stiffness, nerves dysfunctions, and pleural, pericardial and peritoneal effusions. [B&L, 4th p. 927]. (*****)(12) 62. What neurological functional changes may be observed in hypothyroidism in the adult? Sleepiness. Decreased mental activity. Nervousness and other psychological disorders. Slow speech and movements. Intolerance to cold. Obesity. (!)

63. How is the glucose metabolism affected by hypothyroidism? Glucose metabolism decreases due to decrease in the promoting functions of the thyroid hormones, which cause potentiation of the effects of E, NE, glucogon, cortisol and GH > decrease in gluconeogenesis and glycogenolysis > decrease in the blood glucose level. [B&L, 4th p. 924]. Thyroid hormones increase metabolic rate, therefore in case of hypothyroidism the metabolic rate decreases > cause decrease in the glucose metabolism. (!) 64. How is the plasma cholesterol level affected by hypo- and hyperthyroidism in humans? Cholesterol levels decrease in hyperthyroidism due to increased fat metabolism resulting from increase in thyroid hormones secretion; while in the hypothyroidism the cholesterol levels increase, due to decrease in the fat metabolism caused by decrease in the thyroid hormones. [Guyton, p. 862] (!)

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The adrenal cortex

1. What are the characteristic features of the circulation of the suprarenal gland? The adrenal gland has one of the bodys highest rates of the body flow per gram of tissue. The adrenal gland receives blood form the aorta, renal and phernic arteries. Arterial blood enters the sinusoids in the cortex and then drains into the medullary venules. This arrangement exposes the adrenal medulla to relatively high concentration of corticosteroids from the cortex. [B&L, 4th p. 930] (!) 2. What is meant by the zonal theory of adrenal cortex hormone synthesis? Zonal theory states that each zone of the adrenal cortex synthesizes one type of steroid hormone: zona glomerulose (15%) > mineralocorticoids; zona fasiculata (75%) > glucocorticoides and zona reticularis (10%) > sex hormones. [Guyton, p. 869] (!) 3. 4. The site(s) of aldosterone and cortisol production in the adrenal gland. The aldesterone is synthesized by zona glumrolusa of the adrenal cortex. Cortisol is synthesized by zona fasiculata of the adrenal cortex. [Guyton, p. 869] (!) During the evolutionary process, the adrenal cortex of mesodermal origin and the adrenal medulla of ectodermal origin have united to form one organ. Explain the physiological expediency of this! The expediency of this arrangement ensures powerful relationship between endocrine cells of the cortex and neuroendocrine cells of the medulla related to the sympathetic NS. This relationship provides the influence of one type of the cells on the others > provide the proper reaction in case of different stimulations (e.g. stress). (!) 5. List, grouped according to their main effects, the hormones secreted by the human adrenal cortex! Glucocorticoides: cortisol (95%), corticosterone (4%), 11- deoxycortisol, 11- deoxycorticosterone. Mineralcorticoides: aldestorne (90%), 18 OH corticosterone. Sex hormone: testosterone (small amount), estradiol (small amount), androstenedione, DHEA (dehydroepiandrosterone) and DHEA-S. [B&L, 4th p. 931 935] (!) 6. What is the intracellular mechanism of action of the hormones produced by the adrenal cortex?

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The hormones enter the cell by diffusion (due to their lipid solubility) > in cytoplasm binds with specific receptor protein (type II glucocorticoid for cortisol, and type I for aldestorone) > this complex enters the nucleus > binds to specific site on the DNA (e.g. GRE - glucocorticoid regulation element) > inhibit or stimulate a reaction. [partly from Guyton, p. 874] (!)

7.

What pathological condition develops when the formation of hormones in the adrenal cortex is blocked due to a congenital 21-hydroxilase enzyme deficiency? What are the common and distinctive features of the disease on boys and girls?

The pathological condition which develops is CAH (congenital adrenal hyperplasia) due to 21hydoxilase enzyme deficiency > deficiency in cortisol and aldesterone, but excess in androgens > muscularization in female fetuses in utero + clitoris hypertrophy; and early secondary sexual changes in male infant and young boys. This pathological situation characterized by hyponatrimia, hyperkalemia, acidosis, hypocalcemia and hypotension. [B&L, 4th p. 935 936 + Stedmans] (!)

8.

What mechanism is responsible for the development of the adrenogenital syndrome in 11hydroxilase enzyme deficiency? Due to 11- hydroxilase enzyme deficiency is the lack of conversion from 11- deoxycortisol (DOC) to cortisol > break in the negative feed-back mechanism and more ACTH produced. In these patients volume expansion with hypertension can be observed and increase in the synthesis of DHEA > cause virilization, muscularisation and sexual ambiguity in girls and early appearance of the secondary male characteristics in boys. (!)

9.

The synthesis of which adrenal hormones is insufficient in case of 17-hydroxilase deficiency? Cortisol Androstendione DHEA and DHEA - S Testosterone and estradiol [B&L, 4th p. 932 934] (!)

10. What is the source of the 17-ketosteroids found in the circulation? Androgens. DHEA-S Etiocholanolone [B&L, 4th p. 939] (!)

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11. How much is the ratio of the daily 17 - ketosteroid excretion in the female and in the male? What is the reason for the difference? The normal value is about 5 to 14 mg/day in women and 8 20 mg/day in men. The difference is due to the higher androgen secretion in male, due to the presence of testis. [B&L, 4th p. 939] (!)

12. List 4 effects that stimulate renin secretion! Hemorrhage Hypovolemia Hyperosmolarity Decreased arterial blood flow and pressure Na+ deprivation Prostaglandins (PGI-2) (!) ACTH [B&L, 4th p. 949]

13. List the mechanism through which renin increases aldosterone secretion! Increase of secretion of renin from the kidney > cleaves the peptide angiotesinogen that is secreted from the liver > decapeptide angiotensin I is formed > another cleavage by the enzyme AngiotensinConverting-Enzyme (ACE) > octapeptide angiotensin II > receptor on plasma membrane of the cells in zona glumerulosa > transfer of cholesterol into the mitochondria and the enzymes activity increases > stimulates the secretion of aldosterone. [B&L, 4th p. 949] (!) 14. List the effects that stimulate angiotensin II production! Na depravation Renin secretion ACTH Hypovolemia Sympathetic activity Hemorrhage [B&L, 4th p. 949] (!)

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15. List 4 actions of angiotensin II! Stimulation of aldesterone release > increase Na re absorption [B&L, 4th p. 710] Inhibit angiotensin converting enzyme (ACE) [B&L, 4th p. 1080] Local vasoconstrictor of afferent and efferent arterioles in kidney > decrease RBF and GFR > diminish renal perfusion during hemorrhage [B&L, 4th p. 509] Stimulate secretion of ADH and ACTH > increase water re absorption [B&L, 4th p. 710] Stimulate thirst center [B&L, 4th p. 722] Stimulate the release of epinephrine and norepinephrine from the adrenal medulla. (!)

16. State 4 effects that increase the aldosterone secretion of the cells of the zona glomerulosa! Na+ deprivation = hyponatremia Hemorrhage > hypovolemia High K+ = hyperkalemia Angiotensin II Renin ACTH (!)

17. How does hyperkalaemia influence the production of a) renin b) aldosterone? Hyperkalaemia does influence the renin secretion directly, but the production of aldosterone increases due to direct effect. The increased potassium stimulates the release of aldesterone through membrane depolarization and opening of calcium voltage gates. Increase in the intacelluar calcium increases the release the aldosterone. (!)

18. In a patient with edema and congestive heart disease what kind of alteration is expected in aldosterone level? Why? In these patients increase level of aldosterone is observed, because the increased level of aldesterone causes increase in the Na re absorption > water follows the Na > accumulation of the extracellular fluid in the body > edema. In this case the load on the heart increases, due to increase in the blood volume (because plasma volume is high) > congenital heart disease. [B&L, 4th p. 952] (!) 19. What are the main physiological actions of aldosterone? The main function of aldesterone is to preserve normal Na level in the body > water follows Na > regulation of the blood pressure.

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Regulation of potassium levels at the body. Increase in the K in the body causes direct effect on the aldesterone secretion > cause increase in aldesterone secretion > cause increase in the K excretion. Excretion of the H coupled to the Na re absorption in the kidney. (!)

20. Under physiological conditions, which ionic and hormonal effects alter the secretion of aldosterone, and how? Na+ level decrease = hyponatremia: aldosterone level increase; through the RAS. K+ level increase = hyperkalemia: aldosterone level increase; direct effect of the producing cells. Angiotensin II: increase level of aldosterone. It binds to specific receptor on the PM of the cells in zona glomerulosa > secondary messengers activated > cause secretion of aldesterone (see also Na+). ANP: negative inhibitor of aldesterone secretion. This hormone is released from the atria of the heart in response to the increased volume > suppress RAS system > suppress ADH and aldesterone secretions. Renin: increase aldesterone secretion through RAS. (!)

21. Identify the main target organs of aldosterone (3 examples). On which organ does it have a substantial effect? GI: stimulate absorption of sodium and excretion of potassium in the intestine and especially in colon [Guyton, p. 873]. Sweat glands: increase NaCl re absorption and increase K and HCO3 secretion [Guyton, p. 873]. Salivary glands: increase NaCl re absorption and increase K and HCO3 secretion [Guyton, p. 873]. Vessels: cause vasoconstriction. Kidney: increases re - absorption of sodium, increase excretion of potassium. (*****)(13)

22. List the changes caused by aldosterone in the kidney tubular cells! Increase in Na re absorption (mostly in the distal tubular part) by increasing the number of the Na channels > increase in the water reabsorption. Increase excretion of the K (mostly in the distal tubular part). Increase H secretion (coupled to the Na re absorption). Increase activity of the mitochondria to provide energy required for the pumps activities. Increase ammonium secretion. Increase in Na-K ATPase activity on the basal membrane > secret Na to blood and take K into the cell. [B&L, 4th p. 952] (!)

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23. How is the excretion of Na+, K+ and H+ altered by a single dose of aldosterone? Na: decrease Potassium: increase. Hydrogen ions: increase (may cause mild alkolosis). [B&L, 4th p. 952] (!)

24. How is aldosterone secretion affected by a) Na-depletion b) Na-depletion and increased water load? Na depletion: increases Na depletion and increased water load: decrease in the secretion, due to inhibition of the RAS by ANP. (!) 25. Aldosterone deficiency may lead to circulatory insufficiency. Describe the mechanism! Aldesterone deficiency causes in decrease Na re absorption that causes in decrease in the water retention > result in the decrease in the amount of EC fluid > decrease in blood volume > circulatory insufficiency. (!) 26. The mechanism responsible for an increased plasma potassium level in aldosterone deficiency Deficiency in aldesterone causes hyperkalemia. This is due to decreased excretion of potassium in the kidney. The aldestorone increase the Na-K ATPase activity on the basal membrane and ATP production by mitochondria > more potassium can enter the cell > cell [K] increases > more K leave to the lumen due to the [ ] gradient = excretion. In the case of aldesterone deficiency this mechanism does not work; therefore the [K] remains high in EC fluid > hyperkalemia. (!) 27. Within the survival time following adrenalectomy, what alterations can be observed in the electolyte and water turnover of the organism? Increased water and sodium excretion by the kidney > polyurea. Decrease in the Na and water re absorption. Increased plasma levels of potassium and hydrogen. Decrease in the K and H excretion. (!)

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28. Explain the development of extracellular alkalosis in the case of aldosterone overdose (Conns syndrome)! As a result of the aldesterone overdose the H excretion from the EC fluid > less H remain in EC fluid > may cause EC alkalosis. The excretion of the H takes place in the kidney and it is coupled to the Na re absorption. (!) 29. How does aldosterone overdose influence blood pressure? Why? As a result of the aldesterone overdose the Na re absorption increases and it causes increase in the water re absorption as well > increase in water content in the EC fluid > increase in the blood volume > increase in the blood pressure. (!) 30. The serum Na-concentration is 134 mmol/l, the serum K-concentration is 6.7 mmol/l and the serum protein content is 8g/100 ml in a patient. What endocrine disorder may account for this? The endocrine disorder the may be accounted by decrease in aldesterone level, because [Na] is about normal (140 mmol / l), but there is an increase in the [K] (normal 3.3 4.9 mmol / l). (!) 31. Illustrate, through a comprehensive outline, the regulation of glucocorticoid secretion! [B&L, 5th p. 830 figure 43-9] (*****)(14)

32. List the characteristic acute and long-term adrenal effects of ACTH treatment! In the acute effect of the ACTH treatment is the increase in all processes inducing steroids synthesis through the cAMP mechanism > cause enzymes activation. In the long term affect the increase in the secretion of hormones, size and number of the cells secreting glucocorticoids is observed (especially in zona fasciculate and reticularis). As well production of MSH (melanin stimulating hormone) also increase > hyperpigmentation of the skin. [Guyton, p. 879] (*****)(15)

33. What is the intracellular mechanism of action of ACTH on steroid synthesis? The ACTH binds to a membrane receptor > activate the Adenylyl Cyclase > increase cAMP levels > activation of protein kinase A (PKA) (cholesterol > pregnenolone) and other enzymes > cause increase in the production of the required hormone. [Guyton, p. 879] (!)

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34. Metyrapone reversibly inhibits the 11-hydroxylase in the adrenal cortex. How is the biosynthesis of the corticoids and the secretion of ACTH affected by the administration of this substance? As metyrapone inhibition of the 11-hydroxylase in the adrenal cortex inhibits cortisol synthesis > no negative feedback to ACTH secretion > ACTH secretion from pituitary increases > 11deoxycortisol and DOC increase. [B&L, 4th p. 932] (!) 35. How does prolonged psychic stress influence the synthesis of ACTH and cortisol? Cortisol and ACTH secretions are highly increases when the body is found in the stress situation, but in case of the prolong stress levels of cortisol in the blood increase > cause negative feedback on ACTH secretion > decreased levels of ACTH in the blood. [Guyton, p. 879] (!) 36. The skin color of those suffering from adrenal cortex insufficiency is often dark (bronze disease). Why? As a result of inability of the cortisol production by adrenal cortex that result in the absence of the negative feedback higher amounts of the ACTH are released from the pituitary > result in the increased formation of MSH (melanocytes stimulating hormone) > acts on melanocytes of the skin to produce more melanin > hyperpigmentation of the skin. [B&L, 4th p. 886] (!) 37. How does adrenalectomy lead to increased ACTH secretion? Remove the adrenal gland causes absence of the cortisol and as a result there is no negative feedback for ACTH secretion from pituitary > ACTH secretion increases. (!) 38. How does the removal of one adrenal gland affect the weight of the contralateral one? Why? The size of the coltralateral gland increases, because it needs to compensate the absence of the removed one. This is caused due to the decreased levels of the cortisol production by the single gland > cause increase in ACTH secretion > increase in stimulation of the remained gland > increase in size of the gland and secretion to answer the requirements of the incoming stimuli. (!) 39. Explain the origin and the essence of compensatory adrenal hypertrophy! See question above. (!)

40. Why is it dangerous to stop administering glucocorticoids suddenly? As administration of the glucocorticoids increase the own body synthesis of these hormones decreases as well as ACTH secretion; therefore body needs time to return the ability to secrete the

36

hormones in the normal amounts; therefore the sudden cease in the administration of the glucocorticoids causes decrease in the amount of these hormones in the body > life threatening situation. (!) 41. Which is the most active natural glucocorticoid? The most active natural glucocorticoid is the cortisol. (!)

42. Where is cortisone produced in the organism? The cortisone is produced in the adrenal cortex in not significant amount. [Stedmans] It is produced from cortisol in the liver. [Fonyo, p. 798] (!)

43. What is transcortin, and what physiological significance does it poses? The transcortin is a corticosteroid - binding alpha globulin (CGB) which binds cortisol. The main physiological function of it is to increase cortisol solubility in the blood and increase half-life of the cortisol. [Guyton, p. 870] (!) 44. Where are the glucocorticoids metabolized in the organism? List the main biochemical reactions of inactivation! The glucocorticoids are metabolized by the liver (mainly) and kidney. The reactions that take place during this metabolic activity include conversion of the keto group on the C3 into hydroxyl group and reduction of the double bond between C4 and C5 > formation of tetrahydrocortisol / tetrahydrocortisone + glucoronides = 50% of the cortisol secreted in this form. The next step involves conversion of the keto group on C20 to hydroxyl group > cortol / cortolone production + glucoronides = another way for cortisol secretion. [B&L, 4th p. 939 - 940] (*****)(16) 45. In what form is cortisol excreted from the body? Cortisol is excreted from the body as tetrahydrocortisol or cortol bounded to glucuronides. [B&L, 4th p. 939 940] (!) 46. As opposed to glucocorticoids the metabolites of the hormone can be excreted through the kidneys. Why? The addition of glucoronic groups allows the solubility of the metabolites in the urine. The changes that take place in the metabolites allow the connection of glucorinic groups. The transcortin + cortisol complex is too big to be filtrated, while cortisol metabolites + glucoronides are small enough to be filtrated. (!)

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47. What is the effect of glucocorticoids on the blood cells and lymphatic organs? Cortisol inhibit the activities of WBC and lymphatic organs by inhibition of synthesis and release of the arachidonic acid, needed for tromboxans, leukotriens, prostaglandins synthesis > supress the inflammatory and immune response. [B&L, 4th p. 946] (!) 48. Describe the effects of cortisol on connective tissue! The cortisol inhibits the collagen synthesis > result with fragile blood vessel walls > easy rapture and intracutaneous hemorrhage; and fragile skin. [B&L, 4th p. 944] (*****)(17) 49. Describe the effects of glucocorticoids on gastric function! Cortisol increases gastric flow and gastric acid secretion, but decreasing gastric mucosa proliferation (decreased PG effect) > may lead to ulcer. (!) 50. How may the absence of cortisol to induce edema? The absence of the cortisol causes absence of the negative feedback for ACTH release > ACTH and ADH release increases > stimulates increase in aldesterone secretion > increase Na re absorption > increase in water re absorption > increase in EC fluid > may lead to edema. (!) 51. The effects of cortisol on renal function Cortisol increases GFR (glomerular filtration rate) by decreasing preglomerular resistance and increased RPF > increases urine dilution. Cortisol also increases PO4- excretion by decreasing its re absorption. [B&L, 4th p. 945] (*****)(18)

52. The effects of cortisol on central nervous system Decrease the taste, smell and auditory sensations, but on the other hand will increase the ability to integrate between them. Decreases REM, but increases slow waves sleep and time spending awake. Insomnia: inability to sleep without external impediments (noise, light ) Depressed or elevated moods Decreased memory function. [B&L, 4th p. 945] (*****)(19)

53. The effects of cortisol on protein metabolism

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Enhance mobilization of the muscle proteins for gluconeogenesis by accelerating protein degradation and inhibiting protein synthesis. [B&L, 4th p. 942] Depresses the mRNA synthesis in the extra - hepatic tissues. Increase protein synthesis in the liver > plasma. Decrease AA transport into the extra - hepatic tissue. [Guyton, p. 876] (*****)(20)

54. The effects of cortisol on lipid metabolism Mobilization of fat > increase FFA in the plasma. Enhance beta oxidation. Stimulates lipolysis. Stimulates ketogenesis. Increase differentiation of the adipose tissue cells and stimulates lipogenesis by increasing LPL and glucose 6 phosphetase activities. [B&L, 4th p. 942 and 944] (!) 55. How does cortisol change the fat distribution of the body? The fat distribution is changing due to overexposure to cortisol. We can see that there is accumulation of fat at the abdomen and the neck region and decrease in the muscle mass in the extremities. [B&L, 4th p. 945] (!)

56. List the effects of cortisol on carbohydrate metabolism! Increase the blood glucose level. Stimulate gluconeogenesis and enzymes required for it. Preventing uptake of glucose by muscle or adipocytes (anti-insulin effect). (!) Glycogen storage. [Guyton, p. 875]

57. What basic alterations can be observed in the carbohydrate metabolism following adrenalectomy (within the survival time)? Decreased gluconeogenesis Decreased blood glucose level. Decrease in glycogen storage. Increase in glucose uptake by the adipose tissue. (!)

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58. May diabetes mellitus of pancreatic origin develop in the case of prolonged cortisol treatment? Why? Yes, because cortisol increases blood glucose level > enhance insulin release to decrease glucose level > this high level of insulin secretion not as effective in maintaining plasma glucose as they are under normal conditions, due to decrease in the sensitivity of the tissues to insulin in the presence of glucocorticoids > diabetes mellitus. [Guyton, p. 875] (!) 59. How are the circulatory effects of the glucocorticoids and the catecholamine interconnected? The blood stream moves from the cortex to the medulla, therefore increase in cortisol level enhances the secretion of catecholamine from the medulla in response to stress. Cortisol also enhances the formation of E from NE by methylation. (*****)(21) 60. Why the circulatory effect of adrenalin (epinephrine) is less marked in cortisol deficiency? Cortisol is one of the factors enhancing E release, therefore in case of cortisol deficiency the amount of E in the circulation decreases. (!) 10%

Pancreas
1. List the hormone producing cells of the pancreas and the hormones they secrete! Insulin by beta () cells. Glucagon by alpha () cells. Somatostatin by delta () cells. Pancreatic polypeptide by PP cell type. Amylin. Pancreastatin. [B&L, 5th p. 766] (!)

2. Demonstrate the interactions between the pancreatic hormones with a simple diagram! NMS p. 671, figure 52-1. (*****)(22)

3. The chemical nature of the pancreatic hormones. The hormones secreted by the pancreas are peptide hormones.

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Insulin made up of two peptide chains: A + B connected by two disulfide bridges. [B&L, 5th p. 768] Glucogon made up by a single peptide chain (29 AA). [B&L, 5th p. 785] Somatostatin: small peptide of 14 AA. [B&L, 5th p. 790] Pancreatic peptide: single chain, 36 AA. [B&L, 5th p. 790] (!)

4. Describe the main characteristics of the insulin receptor! The insulin receptor is the subclass II tyrosine type receptor. It made up of two subunits; two subunits extracellular; and two subunits intracellular. These subunits are connected by the disulfide bonds. Binding of insulin to units cause conformational change of the receptor > result in activation of the tyrosine kinase activity > subunits undergo autophosphorylation > RAS family activation (GTP binding proteins) > activation of IRS 1 and IRS 2 > intracellular effect. [B&L, 5th p. 72] (!)

5. The main steps of insulin synthesis in the cells. The insulin synthesized first as preproinsulin containing N terminal signal peptide, A, B and C chains > N terminal signal peptide is cleaved in the site of the synthesis (before the completion of the translation) > proinsulin is formed > transferred to the ER by SRP > moves to Golgi > formation of the disulfide bridges and removal of the C peptide > achievement of the final conformation > packaging into the granules together with the C peptide. [B&L, 5th p. 769 770] (!) 6. List 4 effects that stimulate the secretory function of the pancreatic cells! Glucose, galactose, mannose, glyceraldehydes. Amino acids: argenine, lysine, leucine and alanine. FFA and ketone bodies. K, Ca. Glucagon and glucogon like peptide I. Secretin, GIP and chylocystokinin. Acetylcholine and vagal activity. Beta adrenergic activity of sympathetic NS. [B&L, 5th p. 771, table 41- 1] (!)

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7. List 4 factors inhibiting insulin secretion! Somatostatin and pancreastatin. Low glucose level. Interleukin 1. Prostaglandin E2. Starvation. Exercise. Leptin. Alpha adrenergic activity of sympathetic NS. [B&L, 5th p. 771, table 41- 1] (!)

8. When glucose is administered orally, it stimulates insulin secretion to a greater degree than when administered intravenously. What is the reason for this? The main reason for greater secretion in case of oral administration is the additional stimuli for insulin secretion caused by the release of glucogon like peptide 1, GIP, secretin and chylocystokinin. While insulin is given IV these substances are not secreted > no additional stimuli for insulin secretion. [B&L, 5th p. 773] (!) 9. The role of GIP in fending off the sudden postprandial rise in the blood glucose level. The GIP cause increase in the insulin secretion after meal (postprandial) > decrease glucose level due to the insulin release caused by GIP. (!) 10. The effect of insulin on the ion homeostasis. Insulin increases the re absorption of K+, Na+ and PO4- in the tubules of the kidney. Decreases K, Mg and PO4- serum levels in response to glucose load by entering these electrolytes into the cells of the muscles and liver. [B&L, 5th p. 782] (!) 11. Give a brief description of the effects of insulin on protein (amino acid) metabolism! Insulin is anabolic hormone > increases the amino acid uptake by the muscle tissue (lowers AA plasma levels) and increase the synthesis of proteins. Activate the Na-AA co - transport.

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Inhibits proteolysis. [B&L, 5th p. 782] (!)

12. Give a brief description of the effects of insulin on lipid metabolism! Enhance storage of the FA by adipose tissue. Block FA mobilization. Block oxidation of the FA by inhibiting hormone sensitive lipase activity first enzyme of the beta oxidation. Lowers the levels of circulating FFA and ketoacids (due to decrease in delivery of the FA to the liver). Has positive affect on LPL. May reduce levels of circulating TAG. [B&L, 5th p. 781] (!)

13. List three hormones that have effects antagonistic to that of insulin in the carbohydrate metabolism! Glucagons. Cortisol. Epinephrine. GH (!)

14. What is the normal fasting glucose level in the plasma? What plasma glucose level can be considered as a sign of diabetes mellitus? The normal fasting glucose level is between 80 - 90 mg / dl in the morning before breakfast, diabetic patient have circulating glucose level above 250 mg / dl and it can even reach 1200 mg / dl. [Guyton, p. 893 894] (!) 15. Plot a glucose tolerance curve (calibrate the axes!)! See lecture notes. The plot present glucose concentration as a function of time. At first glucose concentration rises from its fasting value of 80 90 mg / ml till it reaches the level of about 125 150 mg / ml. At this point maximal insulin secretion takes place (about 1 hour) > the curve moves down, even below its normal value (because it takes time to decrease insulin secretion through the negative feedback) (about after 2.5 hours and continues for about 2 hours = 4.5 hours after meal). After this time the glucose slightly rises again to its normal fasting concentration. (!)

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16. After what time interval does the normal glucose tolerance curve fall below the baseline? What is the reason for this decrease? After about 2 - 2 hours the glucose tolerance curve drops below the baseline and it continues for about 2 hours, because it takes time to decrease insulin production through the negative feedback. (!)

17. What characterizes the glucose tolerance curve of a thyrotoxic individual? Thyrotoxicosis is the condition of the increased level of thyroid hormones secretion. These hormones increase blood glucose level (these hormones increase BMR), therefore in case of increased thyroid secretion glucose level in the blood increases > the maximal point of the glucose concentration on the plot will be higher than normal. The high increase in blood glucose level requires higher amount of insulin to be secreted and this process takes more time > as a result the decrease in the glucose concentration is more prolonged that in the normal case. (!) 18. List the general symptoms of pancreatic diabetes! High plasma glucose level. Glucourea glucose in the urea. Polyuria. Thirst due to hyperosmolarity and hypovolemia. Loss of body mass. Increased N, K, PO4 and Mg excretion. Swelling of the lens of the eyes and blurred vision and even cataract. Ketoacidemia. [B&L, 5th p. 784 785] (*****)(23)

19. What is the immediate cause of pancreatic diabetes? Type I diabetes: the body produces antibodies against the islet cells, this is so called IDDM. This is an immediate cause of the pancreatic diabetes. [B&L, 5th p. 784] Type II diabetes: in this case the body develops resistance against insulin, this is so called NIDDM. (!)

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20. Characterize the type II (non-insulin dependent; NIDDM) diabetes mellitus. In case of NIDDM the sensitivity of the target cells is greatly diminished = insulin resistance. In this type ketoacidosis is usually NOT present. It usually occurs after age 40 and develops gradually. In type II diabetes there are increase in the plasma insulin, but tissues does not respond to this insulin > hyperglycemia. This type of diabetes is usually present in the obese individuals. [Guyton, p. 895 896] (!) 21. How does ablation of the pituitary gland affect the blood glucose level of a diabetic (pancreas eradicated) animal (Houssay animal)? Why? The ablation of the pituitary causes decrease in ACTH secretion that > decreases cortisol, GH and TSH levels. Cortisol is the antagonist of insulin and it increases plasma glucose level. As a result of its deficiency the level of glucose decreases. GH and thyroid hormones are responsible for increase in the blood glucose level, therefore in case of their absence blood glucose level decreases. (!) 22. The pathomechanism of the development of metahypophysael diabetes. The mechanisms for the development of metahypophyseal diabetes is due to the increased secretion of the GH. This hormone cause decrease in uptake of glucose by the tissues, increase in glucose production (these two effects cause increase in the blood glucose level) by the liver and increase in the insulin secretion (but this amount of insulin decrease sensitivity of the tissue to insulin) all these effects promote appearance of the insulin resistance = type II diabetes. [Guyton, p. 850] (!) 23. The pathomechanism of the development of metathyroid diabetes. In the case of metathyroid diabetes increased amount of thyroid hormones are released. These hormones promote glycolysis and gluconeogenesis, increase rate of the glucose absorption from GI. All these effects cause increase in blood glucose level and even increase in insulin secretion as a secondary effect of thyroid hormones is not able to decrease glucose level to its normal blood concentration > development of diabetes. [Guyton, p. 862] (!) 24. Porcine insulin used in the treatment of diabetes may become ineffective. Why? The porcine insulin is similar, but no identical to the human one, therefore there is a possibility of awaking immune response against porcine insulin, as a result use of this insulin may become ineffective. (!)

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25. Too large doses of insulin given in the evening can lead to hyperglycaemia at dawn. Why? This is called Somogy effect. In this case increased dose of the insulin injected in the evening causes first decrease in the blood glucose level, but after some time this low glucose level stimulate increase in glucagon and epinephrine (mainly) secretion as a contra mechanism to the increase glucose level. The action of these two hormones is to increase glucose level; therefore they cause hyperglycemia at dawn. [consultation] (!) 26. How does muscle work (e.g. physical exercise) produce hypoglycaemia in the diabetic patient treated with insulin? In diabetic patient who inject insulin regularly, the injected insulin promote glucose uptake to the tissues. In addition exercise promotes increased glucose utilization by skeletal muscles for the energy generation; therefore combination of these two effects can result in hypoglycemia. (!) 27. What disorders may be observed in the electrolyte and water homeostasis in diabetes? Polyuria = increase urine, due to decrease in electrolytes and glucose re absorption. Increase in the K, Na and PO4 excretions. Increase in the K, PO4 and Mg serum levels by entering these electrolytes into the muscle and liver cells. [B&L, 5th p. 782] (!) 28. Where is glucagon produced? Glucagon is produced at the alpha () cells of the pancreas. [B&L, 5th p. 785] (!)

29. List 4 substances (effects) that inhibit glucagon secretion! Insulin. Somatostatin. High glucose level. High FFA levels. Ketoacids. Secretin and GLP 1 (a proglucogon product of intestine). [B&L, 5th p. 785 786] (!)

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30. List at least 4 effects that stimulate glucagon secretion! Low glucose level. Starvation. Exercise. Stress. Low levels of FFA and ketoacids Epinephrine and norepinephrine. Amino acids: especially alanine and arginine. [B&L, 5th p. 786] (!)

31. List the metabolic effects of glucagon! Increase blood glucose level. Increase FFA levels in the blood. Enhance oxidation. Increase mobilization of AA. Enhance gluconeogenetic pathway. Increase formation of the ketoacids. [B&L, 5th p. 786] (!)

32. Glucagon stimulates the phosphorylase kinase enzyme in the hepatic cells. What is the cellular mechanism of action? When the ratio of the glucogon : insulin favors insulin the enzyme phosphorylase kinase is activated. Glucogon binds to receptor > activation of the G protein > activates adenylyl cyclase > increase in cAMP > activates PKA > phosphorylation of the phosphorylase kinase > activates phosphorylase (promote release of the glucose from glycogen) > enhance gluconeogenetic pathway. [B&L, 5th p. 787] (!) 33. Which organs are capable of burning ketone bodies a) under normal conditions b) in fasting? In the normal state all peripheral organs (except liver, adipose tissue and kidney cortex) are able to use ketone bodies, while during fasting the main tissues using the KB are brain, RBC, kidney medulla and the heart. (!)

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34. Which hormones induce protein anabolism and protein catabolism (2-2 examples)? The hormones that induce protein anabolism are: insulin and GH. The hormones that induce protein catabolism are: glucagon and cortisol. (!)

35. List 3 hormones affecting the hormone sensitive lipase enzyme of the lipocytes! Insulin: decrease the activity of this enzyme. Glucogon: increase activity of this enzyme. GH: increase the activity of this enzyme. Cortisol: increase the activity of this enzyme. Epinephrine: increase activity of this enzyme. (!)

36. How do insulin and growth hormone influence the a) protein synthesis b) lipolysis c) blood glucose level? (!) Protein synthesis Lipolysis Blood glucose level Insulin Increase Decrease Decrease Growth Hormone Increase Increase Increase

37. How is the activity of the lipoprotein lipase enzyme affected by insulin and by epinephrine? Epinephrine (hormone that promotes gluconeogenesis) inhibits the lipoprotein lipase in order to increase the mobilization of FFA and decrease lipogenesis. Insulin (enhance lipid storage) increases the activity of lipoprotein lipase in order to preserve and form lipids (lipogenesis). (!) 38. In which organs is the breakdown of glycogen regulated by a) epinephrine b) glucagon? In liver the glycogen breakdown is mainly regulated by the glucagon (through glucogon receptor) with augmented effect by the epinephrine (through adrenergic receptor). In muscle tissue the epinephrine is the regulator: mainly by decreasing the uptake of glucose. [Devlin, p. 625 628] (!)

39. Which step of the breakdown of glycogen is regulated by a) epinephrine b) glucagon?

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Glucagon > activates G protein > activation of adenylyl cyclase > increase in cAMP level > activation of PKA > activation of phosphorylase kinase > activation of phosphorylase > cause glycogen breakdown.

Epinephrine > adrenergic receptor > activates G protein > activation of adenylyl cyclase > increase in cAMP level > activation of PKA > activation of phosphorylase kinase > activation of phosphorylase > cause glycogen breakdown. (!)

40. How does the epinephrine-induced breakdown of glycogen in the a) liver b) skeletal muscle affect blood glucose level? Epinephrine increase glycogen breakdown in the liver and increase blood glucose level. [Devlin, p. 623 624] In the muscle tissue the epinephrine increases glycogen breakdown in order to provide glucose to the muscle cell (the action is mediated by decreasing uptake of glucose by these cells), but this glucose released in the muscle does not effect the blood glucose level. (!)

The gonads
1. 2. 3. What are the main physiological functions of the ovaries? Hormones production and secretion (sex steroids and proteins). Site of ovarian follicle proliferation. Formation of the corpus luteum. Control and maintenance of pregnancy. [B&L, 5th p. 947 949] (!) List the physiologically active estrogen hormones! What are the common characteristics of their chemical structures? Estradiol (major estrogen secreted directly by the follicle) Esterone (converted estradiol / androstendione in the peripheral tissue) Estriol (a weak estrogen converted from estradiol or esterone mainly in the liver). All these hormones are derivatives of cholesterol, therefore steroids and they are converted by aromatase to their final form. (!) Which organs and tissues synthesize estrogens? Where does the most intensive synthesis occur? Ovaries Placenta. Testis (mainly the Sertolli cells in small amounts).

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In zona reticularis of the adrenal cortex. The most of endrogens are synthesized by the ovaries in female and by adrenal cortex in male. [Stedmans] (!)

4.

The physiologic effects of estrogens (list 6)! Growth and development of the reproductive organs (increase in size of the ovary, uterus, vagina; change in vaginal epithelium; increase in the size of the labia majora and minora) = primary sexual characteristics.

Increase protein and fat deposition. Decrease in the osteoclast formation and activity, due to inhibition of IL 1 and TNF . Increase in the formation, differentiation and activity of osteoblasts. Due to the last two effects the increase in bone resorption takes place in females after menopause(due to decrease in Estrogen levels)

5.

Stimulate hepatic synthesis of thyroxin binding globulin, steroid binding globulin, renin substrate, angiotensinogen, VLDL and HDL. Increase in release of the local vasodilators, such as NO and prostaglandin E2. Induce the development of the lactiferous duct at the mammary gland and development of the stromal tissue. Improves the memory and coordination. [B&L, 5th p. 962] Increase growth of the myometrium. Stimulate growth of the ductal system of the breast. [B&L, 5th p. 969] (!) The effects of progesterone (list 4)! Inhibits uterine contractions by inhibiting production of prostaglandins. [B&L, 5th p. 968] Increase body temperature by 0.5o shortly after ovulation. Increase appetite. Induce natriuresis increased Na excretion. Decrease LH and FSH synthesis. [B&L, 5th p. 962] Increase the mucosa secretion in the fallopian tube Immunosuppressive effect during pregnancy. Increase ventilation in the pregnant woman to increase release of CO2 produced by the woman and her fetus. Contribute to proliferation and enlargement of the lobules and alveoli of the breast. [B&L, 5th p. 968] Decrease the quantity of the cervical mucous. [B&L, 5th p. 961] (!)

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6.

How does LH and FSH secretion in the pituitary gland change in case of continuous GnRH administration? Explain the effect! In the case of continues GnRH administration the secretion of LH and FSH increases, where the LH increase more sharply (biphasic release: first peak after 30 min, while the second after about 90 min this one is continuous for hours after) than the FSH (uniphasic release). [B&L, 5th p. 837, 43-16]

In case of the continuous administration of the GnRH first the increase in the LH and FSH is observed, but these hormones then induce the production of the androgens and estrogens that in turn inhibition to their secretion > decrease in the LH and FSH secretion through negative feedback. [B&L, 5th p.838] (!)

7.

List the effects of the LH in males and females! In male: stimulates the Leydig cells to produce testosterone > promote spermatogenesis and onset of puberty. [B&L, 5th p. 938] In female: stimulates the theca cells of the ovaries to produce estrogen; involved in ovulation; increase growth and secretion from the corpus luteum; increase progesterone synthesis by granulosa cells, promote puberty onset. [B&L, 5th p. 954 955] (!)

8.

List the effects of the FSH in males and females! In male: promote spermatogenesis, facilitate the normal structural changes during spermatogenesis, insures proper acrosomal activity and motility of the sperm. The FSH affects Sertolli cells > miotic and miotic division of sperm > spermatogenesis. [B&L, 5th p. 938]

In female: FSH stimulates growth of the granulosa cells of the ovarian follicle > increase in aromatase activity; enhance estrogen synthesis from androgen precursors; stimulate follicular growth and estradiol production; induce LH receptors of the granulosa cells. [B&L, 5th p. 954 955] (*****)(24)

9.

What type of chemical structures do the FSH and LH have? Both FSH and LH are small glycoproteins that share the same (binds to the receptor) unit, but different units. [Guyton, p. 930]

10. How is progesterone metabolized and excreted from the body? The progesterone is mainly bound to albumin (mainly) and to cortisol binding protein. It is reduced to urine metabolite pregnanediol in the liver through conjugation by glucoronic acid > secreted in the urine. [B&L, 5th p. 962] (!)

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11. How does estrogen metabolism change in case of impaired liver function? The liver is responsible for the conversion of estrogen into urine metabolite by oxidation and conversion to glucuronide and sulphate conjugates, therefore impaired liver reduces the metabolism of estrogen and increase its blood levels. (!)

12. List 4 different methods that may be used to determine the phases of the menstrual cycle! Measuring the basal body temperature: temperature increases by 0.5o shortly after ovulation as a result of increase in progesterone level. Measuring the LH and FSH levels: their plasma levels are the lowest during luteal phase. Measuring the levels of estradiol, LH and FSH: their level increases during ovulatory phase, as a preparation for possible pregnancy. Measuring the levels progesterone: its level is very high during the luteal phase. Measuring the levels of the inhibin B: increase during follicular phase, very low during luteal phase. Measuring the level of the inhibin A: increases during luteal phase, but low during follicular phase. [B&L, 5th p. 952 953]. Measurement of the cervical mucous quality: its quality is decreased during luteal phase. (!)

13. Draw the changes of the plasma concentrations of estradiol during a normal menstrual cycle. Calibrate the timescale! At the days 0 7 there are constant level of estradiol of about 36 pg / ml, on the days 8 14 increase takes place till the level reaches maximum of about 380 pg / ml and then sharp decrease with the minimum on the day 18. After that for 2 days (days 18 20 of the cycle) additional increase takes place with the peak of about 250 pg / ml and this peak continues till the day 27 of the cycle and then it decreases to the basic 36 pg / ml. [B&L, 5th p. 953 figure 46-25] (!)

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14. Draw the changes of the plasma concentrations of progesterone during a normal menstrual cycle. Calibrate the timescale! At the days 0 8 there is a decrease from the original 1ng / ml to approximately 0 ng / ml level of progesterone and till day 12 this level remains about 0 ng / ml. On the day 12 short increase takes place for about 1 day that increase the level of the hormone to about 1 ng / ml and then decrease in the same day to about 0.5 ng / ml. After that, on the day 14, the increase begin till day 20 of the cycle that bring the level of progesterone to about 6 7 ng / ml. This level of hormone remains for 4 days (day 24 of the cycle), then it return to its basic level of 1 ng / ml [B&L, 5 th p. 953, figure 46 25] (!)

15. Draw the changes of FSH and LH plasma levels during a normal menstrual cycle. Calibrate the timescale! LH: small increase in the first 10 days of cycle, then sharp increase till day 14 of the cycle and then sharp decrease in one day (day 15). From the day 15 to 28 small continues decrease till the hormone level returns to its basic level. FSH: small decrease in the hormone level in the first 12 days of the cycle, then sharp increase (not as sharp as LH) for 2 days and then sharp decrease for another day (day 15 of the cycle). From day 15 to 28 there is small gradual decrease in the hormone level with small increase in the last 3 days (25 28) of the cycle. [B&L, 5th p. 953, figure 46 25] (!) 16. What is the magnitude of peak estradiol and progesterone plasma levels during a normal menstrual cycle? The estradiol reaches peak of 380 pg / ml on day 13 of the cycle (close to the end of follicular phase). The peak of progesterone is 6 -7 ng / ml and it occurs on the 20th day of the cycle (beginning of the luteal phase). [B&L, 5th p. 953, figure 46 25] (!) 17. What is the magnitude of peak LH and FSH plasma levels during a normal menstrual cycle? The magnitude of the LH peek is about 70 mlU / ml and it occurs on about 13 - 14th day of the cycle.

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The FSH peak is about 25 mlU / ml and it also occurs on 13 - 14 th day of the cycle. [B&L, 5th p. 953] (!)

18. Draw the alterations of the body temperature during a normal menstrual cycle! In the first 12 days only small temperature changes, while on the days 12 13 decrease of about 0.2o takes place and then for 3 days (13 16 days of the cycle) increase takes place that cause elevation of the body temperature by about 0.5o (this is due to increased progesterone level). This increase remains as long as high level of progesterone present (till about day 24), with the peak on days 16 18 of the cycle. [B&L, 5th p. 942, figure 81 11] (!)

19. How does the structure of endometrium change during a normal menstrual cycle? During the menstrual cycle the endometrium prepares itself for possible pregnancy = proliferating phase > the glands become more coiled and increase in vascularization due to the growth of the spiral arteries. Secretion phase > the endometrium in the beginning is enlarged, but if fertilization do not occur the endometrium sheds (menses) > menstrual phase. [B&L, 5th p. 960 961, also see figure 46 30] (!) 20. What is the cause of the menstrual flow? The cause for the menstrual flow is the shedding of the endromtrial tissue as a result of a sharp decline in the estrogen and progesterone > spasmodic contractions of the spiral arteries and uterine muscle due to the local production of prostaglandins and leukotriens > result in ischemia > necrosis > stroma condense and degenerate > superficial endometrial cells are sloughed > menstruation. [B&L, 5th p. 961] (!) 21. Describe the mechanism, which inhibits menstruation if fertilization has occurred! In case of fertilization secretion of HCG (Human chorionic gonadotropin) from syncytiotropoblast cells takes place that increase the life span of the corpus luteum and it increases the secretion of estrogen and progesterone from corpus luteum > emdometrium continue to grow > no menstruation. [B&L, 5th p. 967 968] (!) 22. What is the menopause? When does it occur and what are the concomitant principal endocrine changes?

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The menopause is a state in which the woman loss her ability to reproduce and it is stated by the cease of the menstrual cycle (usually occurs around age of 50). This is a gradual process in which first the cycles become irregular, then the time between the cycles increases and ovulation falls to occur in many of these cycles, and later the cycles cease.

This condition is stated by low estradiol plasma levels (ovaries do not secrete it anymore), low inhibin A and B levels, increase in gonadotropin levels due to absence of the negative feedback from estradiol and inhibin. [B&L, 5th p. 964] (!)

23. What is the menarche? When does it occur and what are the concomitant principal endocrine changes? The menarche is the beginning of the cycles of menstruation, it occurs around the age of 11 to 15. It occurs due to gradual increase in the GhRH (begins at about 8 10 years old), which cause elevation in the levels of LH and FSH > after about 1 - 2 years the levels of these hormones reach the level that can cause significant estrogen secretion > menarche. [Guyton, p. 939] (!) 24. For how long do human spermatozoa and ovum keep their fertility? The spermatozoa can keep his fertility from 24 - 48 hours, some as long as 5 days. The ovum keeps her fertility for about 24 hours; therefore the fertilization must take place in the day of the ovulation. [Guyton, p. 941] (!) 25. Where does fertilization usually take place in humans? When does the implantation occur? The fertilization of the ovum and the sperm takes place in the ampulla of the uterine tube. The implantation occurs about 5 6 days after fertilization and it takes place in the uterus (3 days in the ampulla + another 2 - 3 days in the uterus > implantation), most commonly in the dorsal wall. [B&L, 5th p. 965] (!) 26. In the case of a normal menstrual cycle, when is pregnancy a) the most likely; b) the least likely to occur subsequent to intercourse? The pregnancy is most likely in the day of ovulation or one day after it (days 15 - 16 of cycle). The least likely days are the days during the menses. (!)

27. Draw the changes of the plasma levels of estrogen during a normal pregnancy! Calibrate the timescale!

55

The levels of estradiol increase gradually and more than all the other estrogens, such as estriol and estriole. From the ovulation till the 8th week the rise is small and the level is 10IU / ml > sharper rise till week 18th and the level reaches 20IU / ml > continue to rise sharp from week 20 till the week 36 with the peak on the week 36th and level of about 80IU / ml > gradually decrease. [B&L 5 th p. 948 figure 82 - 6] (!)

28. Draw the changes of the plasma levels of progesterone during a normal pregnancy! Calibrate the timescale! The levels of progesterone increase in almost linear manner. Moderate increase in the level till week 20 with the level of about 15IU / ml > sharp increase till the week 40 with the peak at this week and level of 100IU / ml. On the week 26th progesterone level become greater that estrogen level (lines cross). [B&L 5th p. 948 figure 82 - 6] (!) 29. Which estrogen hormone is secreted in the greatest amount into the maternal bloodstream during the second and third trimesters of pregnancy? In which organs and tissues is this hormone synthesized, and what are the main steps of its synthesis? The estradiol is the most secreted estrogen hormone in pregnancy. In the second and third trimesters the estrogen is synthesized by the placenta form the precursor DHEA S formed by the fetal liver. Placenta synthesize prognenolone > moves into the fetus > fetus synthesize DHEA S and 16 - OH DHEA S by hydroxylation in the fetal liver > back to placenta > sulfation and aromatization in placenta > estradiol + estrone (from DHEA S) and estriol (from 16 OH DHEA S) are formed in placenta. [B&L p. 968 - 969, figure 46 - 35] (*****)(25) 30. Which cells produce the hormone hCG, and what are its effects? The syncytiotrophoblast cells of placenta produce the hCG hormone. hCG is glycoprotein with alpha and beta subunits (like FSH and LH). Its main effect is to maintain the function of the corpus luteum. Increase secretion of estrogens and progesterone by corpus luteum > allows maintenance of pregnancy. HCG that reaches the fetus stimulates essential DHEA S production. In male fetus it stimulates the Lyedig cells to produce testosterone. Stimulate production of relaxin that helps in the relaxation of the ligaments in the female pelvis and relaxation of the pubic symphysis > it causes easier delivery, Inhibit maternal secretion of LH by the pituitary. In addition this hormone inhibits uterine contraction.

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Increase the thyroid activity (have similar structure as the thyroid hormone). [B&L, 5th p. 968] (*****)(26)

31. What is the principal effect of the human placental lactogen (human chorionic somatomammotropin)? This hormone is synthesized by the syncyciocytotropoblast. The main effect of the hCS is to act as maternal growth hormone of pregnancy = promotes anabolism in the pregnant woman. Lactogenic activity, but it is usually not needed due to the high levels of prolactin during pregnancy. Stimulates maternal lipolysis. Increase maternal plasma glucose level > energy source for fetal growth. [B&L, 5th p. 969] (!)

32. What are the important hormonal changes that take place between the 10th12th weeks of pregnancy (about the end of the first trimester)? During this period placenta takes over the estrogen and progesterone production (till this period corpus luteum was providing these hormones). The level of HCG decreases, because no need to sustain the activity of the corpus luteum. HCS secretion increases to increase glucose supply to the growing fetus and participate in the preparation of the breast for lactation. Prolactin secretion increases to promote the breast proliferation for the future lactation. Marked increase in the estrogen and progesterone secretions. (!)

33. List the main physiological functions of the cervix! Cervix allows the sperm to pass into the uterus. Sperm undergoes capacitation in the cervical crypts. [B&L, 5th p. 963 964] During pregnancy the cervix is hardening and closes in order to prevent the fall of the fetus. [B&L, 5th p. 972] (!) 34. In humans, what mechanisms are responsible for the initiation and the maintenance of the myometrial contractions during parturition? The main step causing the contraction of the uterus is the decrease in progesterone level. The decrease in the level of progesterone activates the Ca - channels in the myometrium causing contractions. Prostaglandins (secreted as a result of progesterone decrease) also increase the Ca level in the myometrium increasing the contractions effect.

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Oxytocin hormone induces / reinforces the contraction of the uterus. Increase in the size of the uterus activates stretch receptors activities that in response cause contractions to occur. Increase in catecholamines also stimulates uterine contraction through adrenergic receptors. [B&L, 5th p. 972] (!)

35. List those hormones that are necessary for the development of normal lactation! Prolactin: promotes milk synthesis by the mammary glands. Oxytocin: cause contraction of the ducts > promotes transport of the milk in the ducts. HCS: promote lactation, but usually not needed due to the presence of prolactin. Cortisol, GH, parathyroid hormones and insulin: provide substances for the milk production, support the breast tissue and milk secretion, induction of functions of the GI of the infant. [B&L, 5th p. 974 975] Progesterone and estrogens: physical development of the breast during pregnancy, but their specific effect is to inhibit actual secretion of milk. [Guyton, p. 955] (!) 36. List the physiological effects of prolactin! Development of the mammary glands. Promotes androgen production through the prolactin receptors on the surface of the Leydig cells. [B&L, 5th p. 939] Decrease responsiveness of the ovaries to FSH. Production of milk. Inhibit LH secretion by the pituitary. Promotes development of the maternal behavior by acting on the brain through the prolactin receptors. Stimulates maternal appetite. Decrease in maternal response to stress. Help to depress the immune responses in the uterus. [B&L, 5th p. 974] (*****)(26)

37. It is an old observation that the chances of a new pregnancy are decreased during lactation. What is the explanation for this? This is the result of prolactine hormone secretions that reduce the levels of LH (mainly) secreted by pituitary and also decrease responsiveness of the ovaries to FSH. These two effects prevent normal ovulation. [B&L, 5th p. 974] (!)

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38. Briefly describe the main physiologic functions of the testis! Spermatogenesis, Spermiogenesis - This is the site for the production, maturation and storage of sperms. Site of the testosterone synthesis by the Leydig cells, which is the hormone required for spermatogenesis and development of the secondary male characteristics. Also produce DHT (dihydrotestesterone) and estrogens. Site of the AMH production by the Sertolli cells. (!)

39. Which hormones regulate gametogenesis in the male? FSH > acts on Sertolli cells. Prolactine increases number of the LH receptors on the surface of the Leydig cells. LH > stimulate testosterone secretion > essential for the growth and division of the germinal cells. GH required for the normal onset of the reproductive functions (stimulates growth of Wolffian duct structures, penis and prostate gland). Testosterone. Estrogens help mitotic and miotic divisions. [B&L, 5th p. 938 939] (!)

40. Which cells produce androgens in the testes? The cells producing androgens are Leydig cells of the testes. These cells produce testosterone, DHT and androstendione hormones (stimulated by the pituitary LH). [B&L, 5th p. 938] (!)

41. List 6 effects of testosterone! Spermatogenesis. Primary male characteristics (testis formation, suppress the formation of the female genitalia). Secondary male characteristics (voice, hear ). Anabolism - Enlargement in the muscle mass. Increase levels of VLDL and LDL, but decrease levels of HDL. Stimulate erytropoiesis by stimulating erythropoietin synthesis. Suppress mamillary glands growth. Stimulate aggressive behavior. Increase Na re - absorption in the kidney. Increase libido and erectile function. [B&L, 5th p. 946] (!)

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42. In what form can testosterone be found in the plasma? Free form: 1 2%. Bound to the liver derived glycoprotein called sex steroid - binding globulin (SSBG): 65%. Rest is bound to the other proteins, mainly albumin. Converted to DHT and 5 - androstendiol. [B&L, 5th p. 943] (!)

43. What is the exact mechanism of testosterone effect in the peripheral tissues? Testosterone diffuses into the target cell > reduction to dihydrotestosterone (much more biologically active than testosterone) or to 5 - androstendiol by 5 reductase > binds to its cytoplasmic receptor > nucleus > bind to DNA > more mRNA and enzymes activated > increase the synthesis of proteins. [B&L, 5th p. 944] (!)

44. How is spermatogenesis affected by the administration of a pharmacological dose of testosterone? What is the mechanism of action? The production of sperm increases in case of administration of pharmacological dose of testosterone. Testosterone causes decrease in the production of FSH and LH (negative feed back) > decrease in the production of inhibin > more sperm is produced due to increased basal level of testosterone. (?????)(26)

45. What are the characteristic consequences of testosterone - insensitivity (receptor - mutation)? The characteristic consequences of testosterone receptor mutations are male genotype (XY) (still develop testes) with female phenotype (no muscularization of external genitalia and breast development due to the estrogens actions). [B&L, 5th p. 925] (!) 46. List 4 functions of Sertoli-cells! Secretion of the AntiMullerian hoemone (AMH). Maintain blood - testis barrier by forming tight junctions. Secrete androgen - binding protein. Regulation of sperm maturation (gematogensis). Formation of the blood testis barrier. Conversion of small amount of testosterone into estradiol Synthesis of inhibin: cause negative feedback for FSH release. Production of watery, solute rich fluid to the semineferous ducts. [B&L, 5th p. 933 938] (!)

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47. Describe the environment in which the maturation of the spermatozoa takes place! The spermatozoa move from the seminiferous tubules to the epididymis, where it completes its maturation and it is stores there till the ejaculation. The temperature in the testis is 1 2o below normal body temperature and it is required for the appropriate spermatogenesis. In addition Sertolli cells secrete fluid containing nutrition for the spermatozoa. (!) 48. What temperature is required for normal gametogenesis in the male? The temperature that is required for normal gametogenesis in male is about 34 - 35 degrees; this is the reason that testes are outside the human body. [Guyton, p. 920] (!) 49. Describe the mechanism responsible for the erection of the penis! The mechanism of erection of the penis is dialation of the arterioles in response to parasympathetic activity (from sacral part of the spinal cord) that cause secretion of the vasodilator substances (NO, Ach, vasoactive intestinal peptide). In addition the relaxation of the cavernous sinusoids takes place and they also become filled with the blood > compression of the veins > accumulation of the blood in the penis > erection. [Guyton, p. 921] (!) 50. What is the volume and sperm count of a normal human ejaculate? A typical ejaculation contains in average 120 million spermatozoa and its volume is about 3.5 ml. [Guyton, p. 920] (!) 51. What pathway must the spermatozoa travel and what layers must they traverse to achieve fertilization? The sperm passes the vagina, cervix and uterus to reach the ovum, usually in the ampulla of the fallopian tube. There the sperm must penetrate the layers surrounding the ovum: the corona radiate and the zona pellucida this action is due to the activity of the hyaluronidase and other proteolytic enzymes released from the head of the sperm cell (acrosomal reaction) > only the head is goes into the ovum, while the body and the tail of the spermatozoid are remain outside. The entering sperm allows the ovum to complete second meiotic division = fertilization. (!) 52. What are the functions of the seminal vesicles? The function of the seminal vesicles is to secrete fluid containing fructose, citric acid, fibrinogen and prostaglandins. The fructose and citric acid provide the energy for the sperm movement, while prostaglandins promote movement of the sperm by promoting uterine and fallopian tubes

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contractions. As well prostaglandins react with the cervical mucous to make it more receptive to sperm movement. [Guyton, p. 918] In addition it secretes enzyme vasculase that avoid the backflow of the sperm. (!) 53. What are the elements of the blood - testis barrier? The elements of the blood - testis barrier are the tight junctions between adjacent Sertolli cells and the lamina limitans around the seminiferous tubules. [B&L, 5th p. 940] (!) 54. The physiological significance of the blood - testis barrier. The physiological significance of the blood - testis barrier is to prevent sperms to reach the blood, because it can provoke immune responds. The barrier also excludes different substances to act on spermocytes. Maintenance proper composition of the fluid inside the seminiferous tubules: low protein and glucose levels, but high androgen, estrogen, K levels. [B&L, 5th p. 940] (!) 9%

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