OVERVIEW OF ENDOCRINOLOGY Cecilia A. Jimeno, M.D. UPCM Dept of Pharmacology UP-PGH Section of Endocrinology, Diabetes & Me...
Objectives <ul><li>To define endocrinology </li></ul><ul><li>To differentiate the types of cell-to-cell communication </li...
Endocrinology is a  fascinating specialty of medicine! <ul><li>Worldwide, endocrine diseases are prevalent </li></ul><ul><...
Diabetes Mellitus Type 2: A worldwide epidemic Nature 414:782-787  (2001) 2000: 151 million 2010: 221 million Increase: 46%
Obesity is usually measured as  Body Mass Index (BMI) BMI = Weight (kg) Height (m 2 ) World Health Organization, 1998 Clas...
FNRI 1987 to 1999 Food and Nutrition Research Institute (FNRI) Survey 1987-1999 Prevalence of OVERWEIGHT & OBESITY  among ...
(WHO vs. Asia Pacific), FNRI 1999  20.1% 23.3% 1999 (AP) 3.2% 16.9% 1999 (WHO) Obese Overweight Study Year Prevalence of  ...
Pituitary Gigantism <ul><li>Yao Defen  (Chinese:  姚德芬 ; Pinyin: Yáo Dé Fēn) of China, (born July 15, 1972) is the tallest ...
And who will forget these pts with hyperthyroidism due to Graves’ disease?
Sheehan’s Syndrome
Turner’s syndrome
Definitions & Scope of Endocrinology <ul><li>Endocrinology:  study of cell-to-cell communication by messenger molecules tr...
Definitions & Scope of Endocrinology <ul><li>Endocrine : process of secretion of biologically active substances into the b...
Endocrine vs Exocrine
What are Hormones? <ul><li>Hormone  (strict, classical definition):  an organic chemical agent liberated in  minute amount...
Mechanisms to maintain Homeostasis (Integrative Regulation) <ul><li>Neuronal (electrical, but chemical signaling across sy...
Types of cell-to-cell communication (by hormones) <ul><li>Autocrine – cells with themselves e.g.  in cancer cells (insulin...
Types of c-c comm; sites of hormone action
Comparison of Determinants of  Endocrine (A) & Paracrine (B) Signaling
Comparison of Determinants of  Endocrine (A) & Paracrine (B) Signaling
Endocrine System & Biologic Activities of Complex Organisms <ul><li>Food seeking & satiety </li></ul><ul><li>Metabolism & ...
Four Primary Arenas of Hormone Action Hormones Growth & Development Reproduction Maintenance of Internal Environment Energ...
Maintenance of internal environment (homeostasis) <ul><li>Na+ &  K+:  regulated by RAAS </li></ul><ul><li>Calcium: catecho...
Basic Attributes of the  Endocrine System <ul><li>Gland </li></ul><ul><li>Hormone  </li></ul><ul><li>Transport </li></ul><...
Endocrine Glands <ul><li>Hormones are  synthesized  as required on a daily, hourly or minute to minute basis with minimal ...
Basic Attributes of the Endocrine System:  Glands <ul><li>9 CLASSIC GLANDS </li></ul><ul><li>Hypothalamus </li></ul><ul><l...
Basic Attributes of the  Endocrine System <ul><li>Gland </li></ul><ul><li>Hormone   </li></ul><ul><li>Transport </li></ul>...
Characteristics of Hormones <ul><li>Present in low concentrations in the circ’n </li></ul><ul><li>Specific mechanisms dire...
Steps in Hormone Action <ul><li>Synthesis </li></ul><ul><li>Transport/movement in the plasma </li></ul><ul><li>Entry into ...
Chemical Nature of hormones <ul><li>150 known chemical mediators fall into 2 major categories </li></ul><ul><li>1.  Peptid...
Peptide Hormones <ul><li>Synthesized like other proteins e.g. large precursor molecules are shortened in distinct steps by...
Peptide Hormones <ul><li>Genes code for mRNA ----- translated into protein precursors </li></ul><ul><li>To form active hor...
Peptide Hormone <ul><ul><ul><li>PREHORMONE </li></ul></ul></ul><ul><ul><ul><li>Long strand of hormones formed within the e...
Structure of Insulin
Glucagon:  Insulin’s counter-regulatory hormone
Pro-opiomelanocortin (POMC) Pro-ACTH B- LPH N-POC ACTH JP  - MSH  - MSH CLIP  -LP H  -End
Pro-hormones exist for <ul><li>Insulin </li></ul><ul><li>Somatostatin </li></ul><ul><li>Glucagon </li></ul><ul><li>Enkepha...
Peptide Hormones <ul><li>Water soluble, readily transported by circulation </li></ul><ul><li>No specific transport mechani...
Patterns of Hormone Biosynthesis <ul><li>Glycoprotein Hormones  </li></ul><ul><li>(FSH, LH,HCG,TSH) </li></ul><ul><li>- 4 ...
Steroid hormones <ul><li>The precursor is cholesterol (for most steroid hormones) or 7-dehydrocholesterol (for Vit D metab...
Steroid hormones <ul><li>Lipid-soluble </li></ul><ul><li>Needs transport proteins e.g. albumin or binding globulins </li><...
Protein Binding of Cortisol Cortisol Transcortin (80%) Albumin (10%) Receptor DNA/mRNA Endoplasmic  Reticulum Glucocortico...
Steroid hormones <ul><li>Clinical implications of synthetic pathways: </li></ul><ul><li>certain tissues, both malignant & ...
Chemical Nature of Hormones <ul><li>I. Peptides or amino acid derivatives  </li></ul><ul><li>a. complex polypeptide – LH, ...
Steps in Hormone action <ul><li>Synthesis </li></ul><ul><li>Transport/movement in the plasma </li></ul><ul><li>Entry into ...
Transport of Hormones <ul><li>Water-soluble hormones – no specific transport mechanism </li></ul><ul><li>Lipid-soluble hor...
Steps in Hormone action <ul><li>Synthesis </li></ul><ul><li>Transport/movement in the plasma </li></ul><ul><li>Entry into ...
Hormone to cell interactions <ul><li>Solubility of the hormone affects its interaction with the target cell(s) </li></ul><...
Target Cells as Active Participants <ul><li>Hormones determine  cellular target actions  by binding with high specificity ...
Lipid-soluble Hormones <ul><li>Gain entry into cells due to its miscibility w/ the lipid component of the cell membrane </...
Water-soluble Hormones <ul><li>Peptide hormones cannot cross plasma membrane </li></ul><ul><li>The receptors for  water so...
<ul><li>Second messengers: not single entities but represent a cascade of events set in motion by a hormone-receptor inter...
INSULIN SIGNALING MECHANISMS
 
Interaction of Hormones <ul><li>A. One Hormone Multiple Actions </li></ul><ul><li>Testosterone: </li></ul><ul><ul><ul><ul>...
Interaction of Hormones <ul><li>Most hormones do more than one thing e.g. </li></ul><ul><li>INSULIN </li></ul><ul><li>-  P...
 
Interaction of Hormones <ul><li>2. Receptor cross-talk </li></ul><ul><li>  T + estradiol receptor:  anti-estrogen </li></u...
Interaction of Hormones <ul><li>B. One Function, Multiple Hormones </li></ul><ul><li>e.g. Glucose maintenance, lactation <...
Glucose Regulation <ul><li>   Epinephrine: glycogenolysis </li></ul><ul><li>   Glucagon:  glycogenolysis, gluconeogenesi...
Clinical Implications <ul><li>Fine tuning of blood glucose is maintained within normal limits even under nutritional condi...
Types of Hormone Interactions <ul><li>Additive </li></ul><ul><li>Antagonistic </li></ul><ul><li>Preparative </li></ul>
Interaction of Hormones <ul><li>Hypoglycemia </li></ul><ul><li>Glucocorticoids   </li></ul><ul><li>     Gluconeogenesis <...
Interaction of Hormones <ul><li>2.  Hormone antagonism: Greater fine tuning of metabolism </li></ul><ul><li>   PTH </li><...
Interaction of Hormones <ul><li>Example of Hormone Antagonism </li></ul><ul><li>   Epinephrine </li></ul><ul><li>   Gluc...
Interaction of Hormones <ul><li>3. Preparation by one hormone for the action of another </li></ul><ul><li>Estradiol induce...
Hormonal regulation <ul><li>Hormones regulate thru negative feedback the concentration of their own  receptor  on target c...
Hormonal regulation <ul><li>Or hormones can regulate hormones  </li></ul><ul><li>In the classic loop, one or more conseque...
Peripheral feedback mechanism & a million-fold amplifying cascade of hormonal signals
Model for regulation of anterior pituitary hormone secretion by three tiers of control
Pituitary-thyroid axis Hypothalamus TRH
Feedback Systems <ul><li>There is a basal fluctuation but more complicated rhythms are usually superimposed on these  </li...
Control of Hormone Secretion <ul><li>Anatomically distinct endocrine glands are composed of  highly differentiated cells  ...
Rhythms of Feedback Systems <ul><li>1. Circhoral – rhythms occur about once an hour e.g. 90-min periods of basal gonadotro...
Hormone Measurement <ul><li>Endocrine function can be assessed by measuring levels of basal circulating hormone, evoked  (...
Endocrine Diseases <ul><li>Hormone Overproduction </li></ul><ul><li>Hormone Underproduction </li></ul><ul><li>Altered Tiss...
Patterns of Endocrine Pathology <ul><li>Subnormal hormone production </li></ul><ul><li>Excess hormone production </li></ul...
PROHORMONE HORMONE RECEPTOR EFFECTOR RESPONSE GLAND Degraded Degraded
PROHORMONE HORMONE RECEPTOR EFFECTOR RESPONSE GLAND Degraded Degraded HYPOFUNCTION Destruction Block BLOCK stimulation Ant...
Defects which may cause DM <ul><li>Pre-receptor event </li></ul><ul><ul><li>- Ab bind insulin before it binds to its recep...
PROHORMONE HORMONE RECEPTOR EFFECTOR RESPONSE GLAND Degraded Degraded HYPERFUNCTION Tumor, hyperplasia Ectopic production ...
Hormone Overproduction <ul><li>Genetic abnormalities that cause abnormal regulation of hormone synthesis </li></ul><ul><ul...
<ul><li>Inherited as autosomal dominant </li></ul><ul><li>may be asymptomatic, or may present with hypertension, weakness,...
Hormone Overproduction <ul><li>Hyperthyroidism of Graves’ disease: antibodies mimic TSH and activate TSH receptors on thyr...
Graves’ disease?
Hormone Overproduction <ul><li>Pituitary and parathyroid tumors are usually monoclonal expansions in which somatic mutatio...
Acromegaly
Acromegaly
Cushing’s Syndrome
 
 
 
Cushing’s disease
Cushing’s Syndrome
 
Hormone Underproduction <ul><li>Surgical removal of parathyroid glands during neck surgery, tb destruction of adrenal glan...
 
Altered Tissue Responses <ul><li>Resistance to hormones can be caused by a variety of genetic disorders (e.g. Laron dwarfi...
Therapeutic Strategies <ul><li>Hormones are given pharmacologically for replacement and suppressive effects </li></ul><ul>...
Therapeutic Strategies <ul><li>Novel formulations of receptor-specific hormone ligands (e.g. estrogen agonists/antagonists...
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Overview 2009

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Overview of endocrinology:definitions, hormonal regulation, hormone action and pathology

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  • 3 Xenical Slide Kit August 1998 Section 1 3 Slide 3: Obesity is usually measured as body mass index (BMI) The most common measure of obesity is the body mass index (BMI). BMI is the ratio of body weight (kg) divided by height (m 2 ). Both weight and height can be measured very simply in the clinic and the BMI determined by calculation of the formula. Using BMI, it is possible to determine obesity by reference to internationally accepted “Grades”, commencing with “normal” (Grade 0) for individuals with a BMI &lt;25 kg/m 2 and rising to “severely obese” at Grade 3 (BMI &gt;40 kg/m 2 ).
  • Prevalence of Overweight / Obesity in Adult Filipinos Applying the NIH / WHO guidelines to the results of the surveys conducted by the Food and Nutrition Research Institute of the Philippines from 1987 to 1999, one can see that the prevalence of overweight has increased in a 12 year period from 12% to 17%. Likewise, prevalence of obesity has almost doubled from 1.7% to 3.2%.
  • Prevalence of Overweight / Obesity in Adult Filipinos (WHO vs.. AP) However, when the Asia-Pacific guidelines is used instead as it is more appropriate for our population, then one can appreciate the magnitude of the health problem we are currently facing. With the lower cutoff BMIs for obesity (&gt;25) and overweight (&gt;23), about 20% of adult Filipinos are considered obese, and an additional 23% are considered overweight. This means that 43% of adult Filipinos, or roughly 17 million, are either overweight or obese.
  • Some neurotransmitters are also hormones (e..g dopamine, catecholamines) while some hormones are also neurotransmitters
  • Transcript of "Overview 2009"

    1. 1. OVERVIEW OF ENDOCRINOLOGY Cecilia A. Jimeno, M.D. UPCM Dept of Pharmacology UP-PGH Section of Endocrinology, Diabetes & Metabolism
    2. 2. Objectives <ul><li>To define endocrinology </li></ul><ul><li>To differentiate the types of cell-to-cell communication </li></ul><ul><li>To list the functions of hormones </li></ul><ul><li>To explain the different attributes of the endocrine system: gland, hormone, transport, action & feedback </li></ul>
    3. 3. Endocrinology is a fascinating specialty of medicine! <ul><li>Worldwide, endocrine diseases are prevalent </li></ul><ul><li>See one, know one … </li></ul>
    4. 4. Diabetes Mellitus Type 2: A worldwide epidemic Nature 414:782-787 (2001) 2000: 151 million 2010: 221 million Increase: 46%
    5. 5. Obesity is usually measured as Body Mass Index (BMI) BMI = Weight (kg) Height (m 2 ) World Health Organization, 1998 Classification BMI (kg/m 2 ) Risk co-morbidities Normal range 18.5  24.9 Average Overweight  25 Pre-obese 25  29.9 Increased Obese class I 30.0  34.9 Moderate Obese class II 35.0  39.9 Severe Obese class III  40.0  Very severe
    6. 6. FNRI 1987 to 1999 Food and Nutrition Research Institute (FNRI) Survey 1987-1999 Prevalence of OVERWEIGHT & OBESITY among Filipino Adults 3.2% 16.9% 1999 2.6% 14.0% 1993 1.7% 11.8% 1987 BMI > 30 BMI 25-29.9 Study Year
    7. 7. (WHO vs. Asia Pacific), FNRI 1999 20.1% 23.3% 1999 (AP) 3.2% 16.9% 1999 (WHO) Obese Overweight Study Year Prevalence of OVERWEIGHT & OBESITY among Filipino Adults Food and Nutrition Research Institute (FNRI) Survey 1987-1999
    8. 8. Pituitary Gigantism <ul><li>Yao Defen (Chinese: 姚德芬 ; Pinyin: Yáo Dé Fēn) of China, (born July 15, 1972) is the tallest woman in the world confirmed by the Guiness Book of World Records. </li></ul><ul><li>After 3 days of measuring (in the morning, afternoon, at midnight) it was confirmed that she is, generally, 7 foot 9 inches tall </li></ul>
    9. 9. And who will forget these pts with hyperthyroidism due to Graves’ disease?
    10. 10. Sheehan’s Syndrome
    11. 11. Turner’s syndrome
    12. 12. Definitions & Scope of Endocrinology <ul><li>Endocrinology: study of cell-to-cell communication by messenger molecules traversing an extra-cellular space </li></ul><ul><li>Hormones: Greek “hormao” – to rouse </li></ul><ul><li>Exert regulatory function typically in cells other than those in w/c they are produced </li></ul>
    13. 13. Definitions & Scope of Endocrinology <ul><li>Endocrine : process of secretion of biologically active substances into the body </li></ul><ul><li>vs exocrine - refers to external secretion, generally via anatomically identifiable ducts e.g. GIT </li></ul>
    14. 14. Endocrine vs Exocrine
    15. 15. What are Hormones? <ul><li>Hormone (strict, classical definition): an organic chemical agent liberated in minute amounts by living cells of a restricted area of an organism into tissue fluids or vascular system , generally effective at a distance from its source and resulting in coordination of parts of the organism (homeostasis) or for regulation of body functions </li></ul>
    16. 16. Mechanisms to maintain Homeostasis (Integrative Regulation) <ul><li>Neuronal (electrical, but chemical signaling across synapses) </li></ul><ul><li>Endocrine/immune (chemical, but electrical excitability of the cells) </li></ul><ul><li>These categories are not exclusive or dichotomous in nature, but are representative of a continuum of types. </li></ul>
    17. 17. Types of cell-to-cell communication (by hormones) <ul><li>Autocrine – cells with themselves e.g. in cancer cells (insulin, dihydrotestosterone) </li></ul><ul><li>Paracrine – have actions in cells in the same tissues in which they are formed or with adjacent neighbors e.g. somatostatin from pancreatic delta cells suppress insulin release by beta cells & glucagon release by alpha cells </li></ul><ul><li>Endocrine – with distant cells via the circulatory system </li></ul>
    18. 18. Types of c-c comm; sites of hormone action
    19. 19. Comparison of Determinants of Endocrine (A) & Paracrine (B) Signaling
    20. 20. Comparison of Determinants of Endocrine (A) & Paracrine (B) Signaling
    21. 21. Endocrine System & Biologic Activities of Complex Organisms <ul><li>Food seeking & satiety </li></ul><ul><li>Metabolism & caloric economy </li></ul><ul><li>Growth & Differentiation </li></ul><ul><li>Reproduction </li></ul><ul><li>Homeostasis </li></ul><ul><li>Response to environmental change </li></ul><ul><li>Arousal, defense, flight & secluding behaviors </li></ul>
    22. 22. Four Primary Arenas of Hormone Action Hormones Growth & Development Reproduction Maintenance of Internal Environment Energy Production, Utilization & Storage
    23. 23. Maintenance of internal environment (homeostasis) <ul><li>Na+ & K+: regulated by RAAS </li></ul><ul><li>Calcium: catecholamines, PTH, calcitonin </li></ul><ul><li>BP: catecholamines & RAAS </li></ul><ul><li>Temperature: catecholamines & thyroids </li></ul><ul><li>Body fluids: aldosterone & ADH </li></ul><ul><li>Deficiency in insulin: may cause ketoacidosis </li></ul>
    24. 24. Basic Attributes of the Endocrine System <ul><li>Gland </li></ul><ul><li>Hormone </li></ul><ul><li>Transport </li></ul><ul><li>Action </li></ul><ul><li>Feedback </li></ul>
    25. 25. Endocrine Glands <ul><li>Hormones are synthesized as required on a daily, hourly or minute to minute basis with minimal storage </li></ul><ul><li>Various feedback signaling systems provide hormonal homeostasis characteristic of virtually all endocrine systems </li></ul><ul><li>Regulation may be CNS or local signal recognition (as in Ca++ sensing receptor of the parathyroid cell) </li></ul>
    26. 26. Basic Attributes of the Endocrine System: Glands <ul><li>9 CLASSIC GLANDS </li></ul><ul><li>Hypothalamus </li></ul><ul><li>Pineal gland </li></ul><ul><li>Pituitary gland </li></ul><ul><li>Thyroid gland </li></ul><ul><li>Parathyroid glands </li></ul><ul><li>Pancreas </li></ul><ul><li>Adrenal gland </li></ul><ul><li>Ovary </li></ul><ul><li>Non-classical glands </li></ul><ul><li>Thymus </li></ul><ul><li>Heart </li></ul><ul><li>Gut </li></ul><ul><li>Kidney </li></ul><ul><li>Placenta </li></ul><ul><li>Skin </li></ul><ul><li>Endothelial cells </li></ul>
    27. 27. Basic Attributes of the Endocrine System <ul><li>Gland </li></ul><ul><li>Hormone </li></ul><ul><li>Transport </li></ul><ul><li>Action </li></ul><ul><li>Feedback </li></ul>
    28. 28. Characteristics of Hormones <ul><li>Present in low concentrations in the circ’n </li></ul><ul><li>Specific mechanisms directing hormones to sites of action </li></ul><ul><li>a. Specific receptors with high affinity or numbers </li></ul><ul><li>b. Delivery within restricted circulation OR </li></ul><ul><li>c. Direct diffusion to adjacent sites: testosterone (Leydig cells) diffuses into adjacent spermatogenic tubules </li></ul><ul><li>d. Local formation of hormone within the tissue from </li></ul><ul><li> circulating precursors </li></ul><ul><li> Testosterone---  DHT ---  prostate </li></ul>
    29. 29. Steps in Hormone Action <ul><li>Synthesis </li></ul><ul><li>Transport/movement in the plasma </li></ul><ul><li>Entry into cells – cell membrane, cytosol, nuclear receptors </li></ul><ul><li>Hormone action </li></ul>
    30. 30. Chemical Nature of hormones <ul><li>150 known chemical mediators fall into 2 major categories </li></ul><ul><li>1. Peptides or amino acid derivatives </li></ul><ul><li>2. Steroids </li></ul>
    31. 31. Peptide Hormones <ul><li>Synthesized like other proteins e.g. large precursor molecules are shortened in distinct steps by “cleavage” enzymes </li></ul><ul><li>One or a few structural genes code for the amino acid sequence of the peptide, & other genes are responsible for the alteration of the peptide to its final form </li></ul>
    32. 32. Peptide Hormones <ul><li>Genes code for mRNA ----- translated into protein precursors </li></ul><ul><li>To form active hormones recognized by target tissues, proteins undergo post-translational cleavage </li></ul><ul><li>OR processing e.g. thyroglobulin -----  thyroxine ----  triidothyronine </li></ul>
    33. 33. Peptide Hormone <ul><ul><ul><li>PREHORMONE </li></ul></ul></ul><ul><ul><ul><li>Long strand of hormones formed within the endoplasmic reticulum </li></ul></ul></ul><ul><ul><ul><li>PROHORMONE </li></ul></ul></ul><ul><ul><ul><li>Formed from the breakdown of the prehormone that occurs during storage in the Golgi apparatus </li></ul></ul></ul><ul><ul><ul><li>HORMONE : secreted </li></ul></ul></ul>
    34. 34. Structure of Insulin
    35. 35. Glucagon: Insulin’s counter-regulatory hormone
    36. 36. Pro-opiomelanocortin (POMC) Pro-ACTH B- LPH N-POC ACTH JP  - MSH  - MSH CLIP  -LP H  -End
    37. 37. Pro-hormones exist for <ul><li>Insulin </li></ul><ul><li>Somatostatin </li></ul><ul><li>Glucagon </li></ul><ul><li>Enkephalin </li></ul><ul><li>ADH </li></ul><ul><li>Gastrin </li></ul><ul><li>Parathyroid hormones </li></ul><ul><li>Calcitonin </li></ul><ul><li>ACTH </li></ul>
    38. 38. Peptide Hormones <ul><li>Water soluble, readily transported by circulation </li></ul><ul><li>No specific transport mechanism </li></ul><ul><ul><li>“Free” fraction of the circulating hormone is taken up by the cell </li></ul></ul><ul><li>Need 2 nd messengers to exert action </li></ul><ul><li>Clinical Implications: simpler synthesis enables it to be formed ectopically in certain malignancies of non-endocrine origin e.g. carcinoma of the lungs </li></ul>
    39. 39. Patterns of Hormone Biosynthesis <ul><li>Glycoprotein Hormones </li></ul><ul><li>(FSH, LH,HCG,TSH) </li></ul><ul><li>- 4 hormones with common A chain (“overlap effect”), different B chains (“specificity) </li></ul><ul><li>- Clinical implications </li></ul><ul><li>1. hCG- used clinically for its LH-like effect & can be used to stimulate ovulation </li></ul><ul><li>2. Hyperthyroidism with hydatiform mole </li></ul>
    40. 40. Steroid hormones <ul><li>The precursor is cholesterol (for most steroid hormones) or 7-dehydrocholesterol (for Vit D metabolites) </li></ul><ul><li>Precursor undergoes a series of enzymatic transformations to form the final products </li></ul><ul><li>At least six enzymes, and consequently a minimum of 6 genes are required to transform cholesterol to estradiol </li></ul>
    41. 41. Steroid hormones <ul><li>Lipid-soluble </li></ul><ul><li>Needs transport proteins e.g. albumin or binding globulins </li></ul><ul><li>In the corculation, is b ound to 50 to 60-kd carrier plasma glycoproteins such as TBG, SHBG and CBG, as well as albumin </li></ul><ul><li>Serve as reservoir </li></ul><ul><li>Cytosol/Nuclear receptors </li></ul>
    42. 42. Protein Binding of Cortisol Cortisol Transcortin (80%) Albumin (10%) Receptor DNA/mRNA Endoplasmic Reticulum Glucocorticoid response Ribosomes Glucocorticoid response Free Cortisol (5 -8%) (Macrocortin/lipomodulin)
    43. 43. Steroid hormones <ul><li>Clinical implications of synthetic pathways: </li></ul><ul><li>certain tissues, both malignant & nonmalignant that cannot synthesize steroid hormones contain enzymes that convert circulating steroids to other hormones </li></ul><ul><li>Examples: conversion of androgens to estrogens by trophoblastic tumors and by normal adipocytes </li></ul>
    44. 44. Chemical Nature of Hormones <ul><li>I. Peptides or amino acid derivatives </li></ul><ul><li>a. complex polypeptide – LH, FSH, hCG (glycoproteins) </li></ul><ul><li>b. intermediate sized – insulin, glucagon </li></ul><ul><li>c. small peptides -TRH </li></ul><ul><li>d. dipeptides – T 4 and T 3 </li></ul><ul><li>e. derivatives of single amino acid (tyrosine)– </li></ul><ul><li>catecholamines (Epi/NE), serotonin, histamines </li></ul><ul><li>II. Steroid derivatives of cholesterol </li></ul><ul><li>a. intact steroid nucleus – adrenal, gonadal steroids </li></ul><ul><li>b. cleavage of steroid nucleus – Vit D & metabolites </li></ul>
    45. 45. Steps in Hormone action <ul><li>Synthesis </li></ul><ul><li>Transport/movement in the plasma </li></ul><ul><li>Entry into cells – cell membrane, cytosol, nuclear receptors </li></ul><ul><li>Hormone action </li></ul>
    46. 46. Transport of Hormones <ul><li>Water-soluble hormones – no specific transport mechanism </li></ul><ul><li>Lipid-soluble hormones - transport proteins </li></ul><ul><li>a. Albumin & transthyretin – bind small </li></ul><ul><li> ligands; general transport molecules </li></ul><ul><li>b. Specific transport proteins </li></ul><ul><li> TBG Thyroxine-binding globulin </li></ul><ul><li> TeBG Testosterone-binding globulin </li></ul><ul><li> CBG Corticosteroid binding globulin </li></ul>
    47. 47. Steps in Hormone action <ul><li>Synthesis </li></ul><ul><li>Transport/movement in the plasma </li></ul><ul><li>Entry into cells – cell membrane, cytosol, nuclear receptors </li></ul><ul><li>Hormone action </li></ul>
    48. 48. Hormone to cell interactions <ul><li>Solubility of the hormone affects its interaction with the target cell(s) </li></ul><ul><li>Water-soluble hormones are excluded from the interior of the cell & must interact with cell-surface or “membrane-bound” receptors </li></ul><ul><li>Hormones interact with the nucleus through the medium of “second messengers ” </li></ul>
    49. 49. Target Cells as Active Participants <ul><li>Hormones determine cellular target actions by binding with high specificity to receptor proteins. </li></ul><ul><li>Polypeptide hormone receptors are cell membrane associated whereas soluble intracellular proteins selectively bind to steroid hormones. </li></ul><ul><li>Intracellular signaling is mediated by soluble second messengers (e.g. c AMP) or by activation of intracellular signaling molecules </li></ul>
    50. 50. Lipid-soluble Hormones <ul><li>Gain entry into cells due to its miscibility w/ the lipid component of the cell membrane </li></ul><ul><li>Interact with cytosol or nuclear receptors that recognize & interact with specific gene-regulatory sequences </li></ul><ul><li>This interaction leads to a hormone action mediated by new protein synthesis </li></ul><ul><li>e.g the receptor for lipophilic steroid hormone progesterone resides in the cell nucleus </li></ul><ul><li>Binds the hormone and becomes activated and capable of directly modulating target gene transcription </li></ul>
    51. 51. Water-soluble Hormones <ul><li>Peptide hormones cannot cross plasma membrane </li></ul><ul><li>The receptors for water soluble polypeptide hormones (LH, IGF-1) are integral membrane proteins located at cell surface </li></ul><ul><ul><li>Bind the hormone-utililizing extracellular sequences and transduce a signal by the generation of second messengers, (cAMP for the LH receptor, tyrosine-phosphorylated substrates for the IGF-1 receptor) </li></ul></ul>
    52. 52. <ul><li>Second messengers: not single entities but represent a cascade of events set in motion by a hormone-receptor interaction ----  alteration in the conc’n of molecular species interacting with “hormone-responsive” gene regulatory elements (GRE’s) </li></ul>Water-soluble Hormones
    53. 53. INSULIN SIGNALING MECHANISMS
    54. 55. Interaction of Hormones <ul><li>A. One Hormone Multiple Actions </li></ul><ul><li>Testosterone: </li></ul><ul><ul><ul><ul><li>Fusion of labioscrotal folds </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Male differentiation of Wolffian ducts </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Growth of male urogenital tracts </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Muscle growth </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Control of erythropoietin synthesis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Temporal regression of scalp hair </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Prostatic hyperplasia </li></ul></ul></ul></ul>
    55. 56. Interaction of Hormones <ul><li>Most hormones do more than one thing e.g. </li></ul><ul><li>INSULIN </li></ul><ul><li>- Promotes glucose utilization </li></ul><ul><li>- Inhibits glycogenolysis & gluconeogensis </li></ul><ul><li>- Promotes amino acid uptake </li></ul><ul><li>- Inhibits lipolysis </li></ul><ul><li>- Regulates growth (nuclear events) </li></ul>
    56. 58. Interaction of Hormones <ul><li>2. Receptor cross-talk </li></ul><ul><li> T + estradiol receptor: anti-estrogen </li></ul><ul><li> High [ T ] – anabolic effects </li></ul><ul><li>- binds to the glucocorticoid receptor </li></ul><ul><li>thus blocking the catabolic effects of </li></ul><ul><li>glucocorticoids (muscle wasting) causing </li></ul><ul><li>an increase in muscle bulk </li></ul>
    57. 59. Interaction of Hormones <ul><li>B. One Function, Multiple Hormones </li></ul><ul><li>e.g. Glucose maintenance, lactation </li></ul><ul><li>Lactation </li></ul><ul><li>1. Prolactin </li></ul><ul><li>2. Placental lactogen </li></ul><ul><li>3. Estrogen & Progesterone </li></ul>
    58. 60. Glucose Regulation <ul><li> Epinephrine: glycogenolysis </li></ul><ul><li> Glucagon: glycogenolysis, gluconeogenesis </li></ul><ul><li> Glucocorticoids: gluconeogenesis </li></ul><ul><li> Growth Hormone: gluconeogenesis </li></ul><ul><li> </li></ul><ul><li>  Insulin </li></ul>
    59. 61. Clinical Implications <ul><li>Fine tuning of blood glucose is maintained within normal limits even under nutritional conditions that vary in the extreme </li></ul><ul><li>Complex internal mechanisms provide add’nal level of safety e.g. during stress/ surgery/ accidents ---  epinephrine,  cortisol,  Insulin because glucose is needed as subtrate </li></ul>
    60. 62. Types of Hormone Interactions <ul><li>Additive </li></ul><ul><li>Antagonistic </li></ul><ul><li>Preparative </li></ul>
    61. 63. Interaction of Hormones <ul><li>Hypoglycemia </li></ul><ul><li>Glucocorticoids </li></ul><ul><li>  Gluconeogenesis </li></ul><ul><li>  glucose uptake in </li></ul><ul><li>the peripheral circ’n </li></ul><ul><li>  Lipolysis </li></ul><ul><li>Glucagon </li></ul><ul><li> Glycogenolysis </li></ul><ul><li>Epinephrine </li></ul><ul><li>  Gluconeogenesis </li></ul><ul><li>  Glycogenolysis </li></ul><ul><li>  Lipolysis </li></ul><ul><li>Growth hormone </li></ul><ul><li> Anti-insulin effects </li></ul>1. Hormone synergism- recruitment of multiple hormones for coordinated response
    62. 64. Interaction of Hormones <ul><li>2. Hormone antagonism: Greater fine tuning of metabolism </li></ul><ul><li> PTH </li></ul><ul><li> Calcitonin </li></ul>
    63. 65. Interaction of Hormones <ul><li>Example of Hormone Antagonism </li></ul><ul><li> Epinephrine </li></ul><ul><li> Glucagon </li></ul><ul><li> Glucocorticoids </li></ul><ul><li> Growth Hormone </li></ul><ul><li>  Insulin </li></ul>
    64. 66. Interaction of Hormones <ul><li>3. Preparation by one hormone for the action of another </li></ul><ul><li>Estradiol induces progesterone binding </li></ul><ul><li> protein </li></ul><ul><li>FSH induces androgen binding protein </li></ul>
    65. 67. Hormonal regulation <ul><li>Hormones regulate thru negative feedback the concentration of their own receptor on target cells </li></ul><ul><li>e.g. hyperinsulinemia – “down regulation” </li></ul><ul><li> “ desensitization” </li></ul><ul><li>Substrate conc’n can alter hormone levels </li></ul><ul><li>e.g. Insulin - Glucose concentration (major) </li></ul><ul><li>Amino acid conc’n (minor) </li></ul><ul><li> PTH - Calcium levels </li></ul>
    66. 68. Hormonal regulation <ul><li>Or hormones can regulate hormones </li></ul><ul><li>In the classic loop, one or more consequences of hormone action are “sensed” at some level, & the hormone secretory process is modulated to preserve a given “normal” level of hormone action </li></ul><ul><li>Phenomenon of NEGATIVE FEEDBACK </li></ul>
    67. 69. Peripheral feedback mechanism & a million-fold amplifying cascade of hormonal signals
    68. 70. Model for regulation of anterior pituitary hormone secretion by three tiers of control
    69. 71. Pituitary-thyroid axis Hypothalamus TRH
    70. 72. Feedback Systems <ul><li>There is a basal fluctuation but more complicated rhythms are usually superimposed on these </li></ul><ul><li>Endocrine rhythms have been named for the duration of the period </li></ul>
    71. 73. Control of Hormone Secretion <ul><li>Anatomically distinct endocrine glands are composed of highly differentiated cells that synthesize, store and secrete homones. </li></ul><ul><li>Circulating hormone concentrations are a function of glandular secretory patterns and hormone clearance rates. </li></ul><ul><ul><li>E.g. Longitudinal bone growth is initiated and maintained by GH, whereas mild hypersecretion results in gigantism and GH deficiency causes growth retardation </li></ul></ul><ul><li>Hormone secretion adheres to rhythmic patterns . </li></ul><ul><li>Hormone secretion is induced by multiple specific biochemical and neural signals. </li></ul>
    72. 74. Rhythms of Feedback Systems <ul><li>1. Circhoral – rhythms occur about once an hour e.g. 90-min periods of basal gonadotrophin secretion </li></ul><ul><li>2. Circadian – rhythms have a cycle of 24-hrs e.g. daily rhythm of cortisol conc’n </li></ul><ul><li>3. Circatrigantan – about once a month e,g, monthly period of the reproductive cycle in women </li></ul><ul><li>4. Circannual- annual priod of seasonal breeding in ungulates, hibernation </li></ul>
    73. 75. Hormone Measurement <ul><li>Endocrine function can be assessed by measuring levels of basal circulating hormone, evoked (ACTH and TSH) or suppressed hormone (glucose suppression of GH) or hormone-binding proteins. </li></ul><ul><li>Alternatively, peripheral hormone receptor function can be assessed. </li></ul><ul><li>Meaningful strategies for timing hormonal measurements vary. </li></ul><ul><ul><ul><li>E.g. thyroid hormone, prolactin and IGF-1: fasting morning serum samples </li></ul></ul></ul><ul><ul><ul><li>Episodic: Early morning and late evening cortisol </li></ul></ul></ul>
    74. 76. Endocrine Diseases <ul><li>Hormone Overproduction </li></ul><ul><li>Hormone Underproduction </li></ul><ul><li>Altered Tissue Responses to Hormones </li></ul><ul><li>Tumors of Endocrine Glands </li></ul>
    75. 77. Patterns of Endocrine Pathology <ul><li>Subnormal hormone production </li></ul><ul><li>Excess hormone production </li></ul><ul><li>Production of abnormal hormone </li></ul><ul><li>Disorders of hormone receptors </li></ul><ul><li>Abnormalities of hormone transport or metabolism </li></ul><ul><li>Multiple endocrine abnormalities </li></ul><ul><li>Benign or malignant tumors that produce hormones </li></ul>
    76. 78. PROHORMONE HORMONE RECEPTOR EFFECTOR RESPONSE GLAND Degraded Degraded
    77. 79. PROHORMONE HORMONE RECEPTOR EFFECTOR RESPONSE GLAND Degraded Degraded HYPOFUNCTION Destruction Block BLOCK stimulation Antibodies Antagonists DEFECT Tissue damage
    78. 80. Defects which may cause DM <ul><li>Pre-receptor event </li></ul><ul><ul><li>- Ab bind insulin before it binds to its receptor </li></ul></ul><ul><li>Receptor event </li></ul><ul><ul><li>- Down regulation of receptors or  affinity of receptors for insulin </li></ul></ul><ul><li>Post-receptor event </li></ul><ul><ul><li>-  GLUT-4 translocation </li></ul></ul>
    79. 81. PROHORMONE HORMONE RECEPTOR EFFECTOR RESPONSE GLAND Degraded Degraded HYPERFUNCTION Tumor, hyperplasia Ectopic production Iatrogenic BLOCK Antibodies Tissue damage STIMULATION
    80. 82. Hormone Overproduction <ul><li>Genetic abnormalities that cause abnormal regulation of hormone synthesis </li></ul><ul><ul><li>Glucocorticoid-remediable hyperaldosteronism (GRA) </li></ul></ul>
    81. 83. <ul><li>Inherited as autosomal dominant </li></ul><ul><li>may be asymptomatic, or may present with hypertension, weakness, and failure to thrive due to hypokalemia </li></ul>Causes of Mineralocorticoid Hypertension GCC-REMEDIABLE HYPER-ALDOSTERONISM <ul><li>PRIMARY ALDOSTERONISM </li></ul><ul><li>aldosterone-producing adenoma </li></ul><ul><li>Bilateral adrenal hyperplasia </li></ul><ul><li>GCC remediable aldosteronism </li></ul><ul><li>Familila hyperaldosteronism II </li></ul><ul><li>Aldosterone-producing adenoCA </li></ul><ul><li>Ectopic aldosterone producing CA </li></ul><ul><li>SECONDARY ALDOSTERONISM </li></ul><ul><li>renal artery stenosis </li></ul><ul><li>fibromuscular dysplasia </li></ul><ul><li>Renin-producing CA </li></ul><ul><li>SYNDROME OF APPARENT MINERALOCORTICOID EXCESS </li></ul><ul><li>CUSHING’S SYNDROME </li></ul><ul><li>CONGENITAL ADRENAL HYPERPLASIA </li></ul>
    82. 84. Hormone Overproduction <ul><li>Hyperthyroidism of Graves’ disease: antibodies mimic TSH and activate TSH receptors on thyroid cells </li></ul>
    83. 85. Graves’ disease?
    84. 86. Hormone Overproduction <ul><li>Pituitary and parathyroid tumors are usually monoclonal expansions in which somatic mutations occur in multiple tumor suppressor genes and proto-oncogenes </li></ul><ul><ul><li>E.g. mutant G s proteins in somatotrophs led to increased cellular proliferation and increased secretion of growth hormone </li></ul></ul>
    85. 87. Acromegaly
    86. 88. Acromegaly
    87. 89. Cushing’s Syndrome
    88. 93. Cushing’s disease
    89. 94. Cushing’s Syndrome
    90. 96. Hormone Underproduction <ul><li>Surgical removal of parathyroid glands during neck surgery, tb destruction of adrenal glands, iron deposition in beta cells in hemochromatosis </li></ul><ul><li>Autoimmune destruction of beta cells (T1DM) and thyroid cells (Hashimoto’s thyroiditis) </li></ul>
    91. 98. Altered Tissue Responses <ul><li>Resistance to hormones can be caused by a variety of genetic disorders (e.g. Laron dwarfism, pseudohypoparathyroidism, type 1a) </li></ul><ul><li>Insulin resistance in muscle and liver central to the etiology of Type 2 DM appears to be polygenic in origin </li></ul>
    92. 99. Therapeutic Strategies <ul><li>Hormones are given pharmacologically for replacement and suppressive effects </li></ul><ul><li>May be used for diagnostic stimulatory effects (e.g. hypothalamic hormones) </li></ul><ul><li>In general, steroid and thyroid hormones are replaced orally, whereas peptide hormones (e.g. insulin) require injection </li></ul>
    93. 100. Therapeutic Strategies <ul><li>Novel formulations of receptor-specific hormone ligands (e.g. estrogen agonists/antagonists, somatostatin receptor subtype ligands) result in selective therapeutic targeting </li></ul><ul><li>Improved hormone delivery systems inclue computerized minipumps, intranasal sprays (DDAVP, insulin), pulmonary inhalations and depot IM injections </li></ul>

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