MED 4.01 Approach to the Patient with Endocrine Disorders PDF

MEDICINE Approach to the Patient with Endocrine Disorders &​ Block 4 Mechanisms of Hormone Action​ ​ Trans 4.01...

MEDICINE Approach to the Patient with Endocrine Disorders &​ Block 4 Mechanisms of Hormone Action​ ​ Trans 4.01 Oliver Allan Dampil, MD | November 26, 2024​ ​ ​ OVERVIEW hypo- or hyperproduction of hormones; a problem in I.​ Approach to Patient with C.​ Receptor Transduction the target cell may indicate receptor problems) Endocrine Disorders D.​ Hormone and A.​ The Endocrine System Receptor Families Overview of Endocrine Disorders B.​ Scope of E.​ Hormone Synthesis ​ The endocrine system is evaluated primarily by Endocrinology and Processing measuring hormone concentrations C.​ Pathologic F.​ Hormone Secretion ​ Most hormones are synthesized and can be replaced– Mechanisms of and Transport it is the diagnosis that is often problematic Endocrine Disorders G.​ Hormone Degradation ○​ Usually evaluated by measuring hormones or D.​ Endocrine Testing H.​ Hormone Action E.​ Hormone Evaluation through Receptors doing dynamic testing F.​ Screening of Common I.​ Function of Hormones ​ In cases of hormone deficiency, you try to Endocrine Disorders J.​ Feedback Control stimulate the hormone to confirm the presence II.​ Mechanisms of Hormone III.​ Review Questions of deficiency Action IV.​ References ​ In cases of hormone excess, you try to A.​ Hormones V.​ Summary suppress the level of the hormone (such as in B.​ 5 Major Classes of VI.​ Appendix Cushing’s disease) Hormones ​ In cases where it is unsuppressable, then you 💬➕ ⭐ LEGEND : Important information are confirming the presence of an autonomous : Good-to-know info from lecturer hormone secretion ​ Most disorders of the endocrine system are amenable ❗ : Supplementary/Background Info : Exception to treatment once the correct diagnosis is determined ○​ Deficiencies are corrected with physiologic I. APPROACH TO PATIENT WITH ENDOCRINE hormone replacement DISORDERS ○​ Excesses are reduced medically or in cases of A. The Endocrine System(Trans 2027) tumors, surgically removed Table 1. Endocrine Terminologies HORMONE FUNCTION B. Scope of Endocrinology ​ Involves hormones secreted internally Table 2. Endocrine Glands Endocrine ​ Ductless; usually secreted directly into ENDOCRINE GLANDS the bloodstream Pituitary Parathyroid Adrenals ​ Involves hormones secreted externally or Thyroid Pancreatic Islets Gonads into a lumen (such as the GI tract) ​ Difficult to define along anatomic lines Exocrine ​ Secreted into a ductal system (such as ○​ For example, how do you define anatomically the pancreatic and salivary ducts) where fat is? ​ “To set in motion” ​ Fat is everywhere. ​ Elicit cellular responses and regulate ​ Interdigitation of endocrinology with other physiological processes through regulated physiologic processes in other specialties blurs the Hormones 💬 feedback mechanisms. role of hormones ​ Hormones have target cells or ○​ Ex: Hormones that can act as neurotransmitters receptors and neurotransmitters that can act as hormones ​ 💬 For a properly functioning endocrine system, you ○​ 💬 Cannot make a “logo” of endocrinology with only one endocrine gland must be secreting the right amount of hormones, 💬 Thyroid gland can also be a part of ENT 💬 functioning hormones, and an organ with a good ​ receptor to receive those hormones. One problem in ​ Testis may be Uro; Ovaries may be part of these three will result in an endocrine disorder. OB-GYNE ○​ 💬 For example: ​ Interdigitation examples: ○​ 1. Maintenance of blood pressure, intravascular ​ No insulin → DM type 1 ​ Defective hormone → Deficiency, etc. volume, and peripheral resistance in the ​ Insulin receptor defect → DM type 2 cardiovascular system ​ Vasoactive substances such as catecholamines, Hormonal Arc(Trans 2027) angiotensin II, endothelin, and nitric oxide → ​ Consists of: also involved in vascular tone ○​ Organ/ gland producing the hormone ​ Heart: Principal source of atrial natriuretic ○​ The hormone itself peptide → induce natriuresis at a distant target ○​ The effector/ target cell that produces the desired organ (kidney) effect ​ Kidney ​ Must have an appropriate receptor for the ↪​ Produces erythropoietin → stimulates specific hormone, allowing it to respond erythropoiesis in bone marrow through a cascade ↪​ Involved in the Renin-Angiotensin Axis ​ An insult to any part of the hormonal arc produces a ↪​ Primary target of parathyroid hormone problem (e.g.: a problem in the gland may lead to mineralocorticoids, fibroblast growth factor 23 (FGF23), and vasopressin. Page 1 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CABILING, CHAN, CO, JOYAS, MONZON. Checked & Verified: MJ&Zarina  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action ○​ 2. Gastrointestinal tract produces a vast array of peptide hormones, such as glucagon-like peptide 1 (GLP1), cholecystokinin, ghrelin, gastrin, secretin, and vasoactive intestinal peptide, among many others ​ Adipose tissue: Leptin → Control appetite ​ Inhibin, Ghrelin, Leptin Hormones ​ 💬 Interplay of feedback secretions, defects, and feedback ○​ a complex process ○​ more of a loop ​ 💬 Hormonal arcs completed by a feedback loop ○​ Not just the presence of an arc ⇒ there is also a loop ○​ The same hormones that you secreted will suppress the same, but sometimes not the same, hormone ○​ Ex: TSH secretion will be suppressed by free thyroxine (FT4) or free triiodothyronine (FT3) ○​ Insulin secretion will be suppressed by the glucose coming into the pancreas ⇒ there is almost always the presence of another loop ​ Outside the loop are the influences of other organs ○​ Ex: Control of appetite ​ Ghrelin: appetite stimulation; comes from the stomach ​ Leptin: white adipose tissue ➕ Figure 2. Pituitary Gland Hormones C. Pathologic Mechanisms of Endocrine Disorders ​ Look at the problem of hormones in terms of hormone excess, hormone deficiency, or hormone resistance Figure 1. The role of gut hormones Figure 3. Causes of Endocrine Dysfunction (Kindly also see Appendix for a clearer version) Hormone Excess (Hyperfunction) ​ Neoplastic growth ○​ Typically benign ○​ Sometimes malignant like adenocarcinoma or adrenocortical carcinoma ○​ Pituitary adenoma ○​ Adrenal adenoma ⇒ excess aldosterone ○​ Can produce Cushing syndrome or other hormonal excess ​ Impaired feedback inhibition of adrenocorticotropic hormone (ACTH) secretion is associated with autonomous function Page 2 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action ​ However, the tumor cells are not completely tumor-suppressor gene, Menin. The affected resistant to feedback, as evidenced by ACTH individual inherits a mutant copy of the MEN1 suppression by higher doses of gene, and tumorigenesis ensues after a somatic dexamethasone (e.g., High-dose “second hit” leads to loss of function of the normal dexamethasone test) MEN1 gene (through deletion or point mutations). ​ Autoimmune disorders ​ B: MEN 2: activation of protooncogene ○​ Graves’ Disease ○​ MEN2 is caused by activating mutations in a single ​ Receptor autoantibodies mimic TSH action allele. In this case, activating mutations of the resulting in the overstimulation of TSH RET protooncogene, which encodes a receptor receptors tyrosine kinase, leads to thyroid C-cell hyperplasia ​ Causes thyromegaly and overproduction of in childhood before the development of medullary T3 & T4 thyroid carcinoma. ​ Iatrogenic / Excess administration ​ C: Grave’s disease: ○​ Cushing’s (excess steroids) ○​ Antibody interactions with TSH receptor → ○​ Hypoglycemia (inappropriate insulin) hormone overproduction. Autoantibodies induce ○​ Excess Thyroid Hormone Intake conformational changes in the TSH receptor that ○​ Osteonecrosis release it from a constrained state, thereby ​ Infectious / Inflammatory triggering receptor coupling to G proteins ○​ An escape or leakage of excess hormones ​ D: Activating mutations of the luteinizing hormone ○​ Most hormones are stored within the glands, and (LH) receptor when there are infectious processes, the initial ○​ Cause a dominantly transmitted form of reaction is NOT excess production but excess male-limited precocious puberty, reflecting DELIVERY premature stimulation of testosterone synthesis in ​ Activating receptor mutation Leydig cells. ○​ A defect (usually monogenic or a single gene ​ E: Activation of Gsα: defect) in the receptor causes it to auto-fire or ○​ (1) Mutations occur early in development → can auto-stimulate itself, resulting in hormone excess cause McCune-Albright syndrome; ○​ For example, mutations in the TSH receptor result ○​ (2) Occur only in somatotropes → GH-secreting in a receptor that is ALWAYS ON/ACTIVATED tumors and acromegaly. regardless of whether the hormone TSH is present or not Hormone Deficiency (Hypofunction) 💬 ​ would present as “hyper-“ ​ The majority are secondary to glandular destruction ○​ The most common is the Toxic Adenoma ​ Surgery ○​ Thyroidectomy Table 3. Hormone Excess (Hyperfunction) and Examples ⭐⭐⭐ ​ Infection Hormone Excess EXAMPLES ○​ Adrenal insufficiency secondary to TB Pituitary Adenoma ​ Inflammation Adrenal Adenoma ○​ Most common Benign Hyperparathyroidism ​ Infarction Autonomous Thyroid or Adrenal ○​ Pituitary apoplexy Nodules ○​ Disruption of blood supply of glands which are Adrenal Cancer highly vascularized are prone to infarction Malignant Medullary Thyroid Cancer ​ Hemorrhage Neoplas ○​ Hemorrhagic adrenalitis or some form of pituitary Carcinoid tic apoplexy can be because of hemorrhage Ectopic ACTH Ectopic ​ Tumor infiltration SIADH Secretion MEN1A: Parathyroid, Pancreatic Islet, ○​ In cases of advanced sarcoma Multiple Endocrine Neoplasia and Pituitary Tumors MEN2B: Medullary Thyroid Carcinoma, Table 4. Hormone Deficiency (Hypofunction) Examples ⭐⭐⭐ Pheochromocytoma, DEFICIENCY TYPE EXAMPLES (MEN) Hashimoto’s Thyroiditis Hyperparathyroidism (Thyroid Gland destruction) Autoimmune Graves’ DiseaseC Type 1 Diabetes Mellitus Cushing’s Syndrome Autoimmune (Pancreatic Islet β cells destruction) Iatrogenic Hypoglycemia Addison’s Disease Excess thyroid hormone intake (Adrenal Gland Destruction) Infectious/ Polyglandular Failure Subacute Thyroiditis Inflammatory Radiation-induced hypopituitarism Luteinizing Hormone (LH)D Iatrogenic Hypothyroidism Thyroid-stimulating hormone (TSH) Surgical Activating Receptor Ca2+ Infectious/ Adrenal Insufficiency secondary to TB Mutations Parathyroid hormone (PTH) Receptors Inflammatory Hypothalamic Sarcoidosis GsαE Growth Hormone (GH) ​ A: MEN1: Inactivation of tumor-suppressor gene Hormone Mutations Luteinizing Hormone β (LHβ) ○​ MEN1 gene (chromosome 11q13) encodes a Follicle-stimulating Hormone (FSHβ) Page 3 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action Vasopressin Leptin Resistance 21-Hydroxylase deficiency (Adrenal Abbreviations: ACTH, adrenocorticotropic hormone; AR, androgen receptor; ER, estrogen receptor; FSH, follicle-stimulating hormone; GH, hormone undergo corticosteroid growth hormone; GHRH, growth hormone–releasing hormone; GnRH, genesis type of transformation leading gonadotropin-releasing hormone; GR, glucocorticoid receptor; LH, Enzyme Defects to a defect and hormonal problems) luteinizing hormone; PPAR, peroxisome proliferator activated receptor; PTH, parathyroid hormone; SIADH, syndrome of inappropriate antidiuretic hormone; TR, thyroid hormone receptor; TSH, thyroid-stimulating Recall: ↓ 21-Hydroxylase → ↑ Sex hormone; VDR, vitamin D receptor. Hormones; ↓ Cortisol & Aldosterone Kallmann’s syndrome D. Clinical Evaluation of Endocrine Disorders Developmental Most Common: Turner’s syndrome ​ Thyroid and Gonads (testes): only two organs that Defects Transcription Factors can be palpated Nutritional/ Vitamin Vitamin D deficiency ○​ Problem with endocrinology: most organs are Deficiency Iodine Deficiency inaccessible on physical exam Sheehan’s syndrome ​ In the diagnosis of an endocrine condition, you must Hemorrhage/ Adrenal Insufficiency in patients with first ask 2 main questions: Infarction hemodynamic collapse ○​ Is it a condition of excess or deficiency? ○​ Is it a problem of the organ that produces the Hormone Resistance hormone, the hormone itself, or the receptor? ​ Due to INHERITED defects in membrane receptors, ​ Then you figure out the underlying problem: is it nuclear receptors or the pathways that transduce genetic, infectious, vascular, autoimmune, etc.? receptors signals ○​ PE should focus on manifestations of hormone ○​ Hormone production is normal but results in excess or deficiency, and not the organ itself defective hormone action ○​ How do you document insulin resistance? ​ Characterized by defective hormone action despite ​ Acanthosis nigricans ELEVATED hormone levels ​ Central obesity ​ Involves receptor downregulation and post-receptor ○​ What would be the sign of hypothyroidism? desensitization ​ Physical signs of a low metabolic rate ​ A common example is Type 2 Diabetes Mellitus ​ Thyromegaly ○​ Insulin resistance caused by a defect in the ​ Edema receptor since the target organ is not responding ​ Mental slowing well ​ Fatigue ​ May be a result of receptor downregulation ​ Dry skin ○​ When exposed to repeatedly high levels of ○​ How do you document Cushing's Syndrome? hormones, the body downregulates the ​ Striae production and translocates the receptors ​ Buffalo hump ​ Typically 2 receptor types in general ​ Moon facies ○​ Transmembrane/Membrane receptor (cytosolic) ​ Central Fat Redistribution ​ Exposure to high or long duration of hormones ​ Proximal Muscle Weakness results in ⇒ DOWNREGULATION of receptors ​ Astute clinical skills are required to detect subtle ​ Even in excess amounts, no receptors present signs and symptoms on the submembrane, there will be an effect ○​ Often history and PE alone are insufficient in ↪​ Ex: Contraceptive pills: giving high doses making a diagnosis, in contrast to examination of of hormones like estradiol, disrupts the the heart and brain wherein much of the diagnosis cyclic regulation resulting in its lies in PE downregulation ○​ Nuclear receptors Clinical significance: Primary vs. Secondary ​ In complete androgen resistance, for example, Hypocortisolism [Guyton 14th; Harrison’s 21st; TRANS 2027 ] mutations in the androgen receptor result in a female Question: What PE finding will help differentiate them? phenotypic appearance in genetic (XY) males, even ​ Hyperpigmentation is more common in primary though LH and testosterone levels are increased. hypocortisolism ​ More common acquired forms of functional hormone resistance: ○​ Insulin Resistance in Type 2 Diabetes Mellitus Physiology ⭐⭐⭐ ○​ Leptin Resistance in Obesity PRIMARY SECONDARY ○​ GH Resistance in Catabolic States problem lies in the adrenal problem lies in the pituitary glands Table 5. Hormone Resistance ⭐⭐⭐ ↓Cortisol → stimulation of pituitary ACTH secretion → ↓ACTH → ↓Cortisol RESISTANCE TYPE EXAMPLES GH, Vasopressin, LH, FSH, ACTH, ↑ACTH Receptor Membrane ​ Large amounts of ACTH probably cause most of GnRH, GHRH, PTH, Leptin, Ca2+ Mutations the pigmenting effect because they can stimulate Nuclear AR, TR, VDR, ER, GR, PPARγ Signaling Pathway Albright’s hereditary formation of melanin by the melanocytes in the Mutations osteodystrophy same way that melanocyte-stimulating hormone Postreceptor Type 2 diabetes mellitus (MSH) does [Guyton 14th ed.] Page 4 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action ​ Aldosterone - higher when standing up due to ​ Excess ACTH and other pro-opiomelanocortin decreased blood pressure when blood flows (POMC) cleavage products have stimulatory toward lower extremities effects on melanocyte pigment production [Harrisons ​ Normal hormones are age and sex specific 21st ed.] ○​ Males have higher testosterone as compared to females ​ Laboratory testing plays an essential role ⭐ ○​ In other specializations: labs confirm the diagnosis ○​ TSH level increases with age ○​ Level of sex hormones decrease with age made upon physical examination ​ Utilizing the correct normative database are essential ○​ In endocrinology: diagnosis can only be done with for interpretation laboratory testing since you cannot rely on PE ​ Normal range usually broad ​ Imaging studies are generally employed after ​ Pulsatile nature of hormones and factors that affect biochemical testing them also have to be considered ○​ Imaging studies are only done to confirm the ○​ Eg: cortisol, testosterone, estradiol during diagnosis made during the assessment of reproductive cycle laboratory tests ​ More information can be gathered when different ○​ Only done to locate the abnormality anatomically components of the endocrine system are tested simultaneously E. Hormone Measurements and Endocrine Testing Immunoassays Basal Hormone Testing ​ The most important diagnostic tool in endocrinology ​ More information can be gained from basal hormone ​ Allows sensitive, specific, and quantitative testing, particularly when different components of an measurement of steady state and dynamic changes of endocrine axis are assessed simultaneously hormones ○​ Assessment for hyperthyroidism ​ Utilize specific antibodies to detect specific hormones ​ Test TSH, T3 and T4 ​ Sensitive enough to detect hormones in the picomolar ​ Elevated T3 and T4 in hyperthyroidism or nanomolar range ​ TSH differentiates primary and secondary hyperthyroidism (↓ TSH = primary) ​ Different management in primary and secondary Figure 4. ICMA (not discussed but was in the powerpoint) Figure 6. Basal Hormonal Testing Thyroid ○​ Assessment of patient with amenorrhea ​ Estrogen, FSH, LH, Prolactin, thyroid function Figure 5. IRMA (not discussed but in the powerpoint) test Samples ​ 24 hour urine collection provides integrated assessment of hormone production and its metabolites, including its daily variations: ○​ 24 hour urine cortisol ○​ Urine metanephrine determination Principles ​ Values depends on correct interpretation in a clinical context ○​ Time of the day sample was extracted ​ Cortisol - highest in the morning; lowest in the evening ○​ Positional variation Page 5 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action Figure 7. Basal Hormonal Testing Gonads ​ Feedback Loop Measurement ○​ Gather different components and test them simultaneously ​ Do not just measure thyroid hormone, measure TSH ​ If ↑ thyroid hormone, TSH is suppressed ​ If TSH is not suppressed, TSH is probably overstimulated ​ Hypothyroidism but TSH and thyroid hormones are decreased → receptor problem (Autoactivation of TSH receptor) ​ Basement levels may overlap with pathologic levels ○​ Normal TSH is 0.5-5 mU/L ○​ FT4 is elevated but TSH is 4.5 ​ Even if TSH is in the normal range, since FT4 is elevated you expect TSH to be suppressed. Such, TSH is considered elevated ○​ Blood pressure slowing down during stress ​ Normal cortisol is 18 and below Figure 8. Dexamethasone Suppression Test ​ During hypotension cortisol should increase ​ Cortisol level is 5 upon examination Stimulation Tests ​ Considered abnormal because when there is ​ Used to assess endocrine hypofunction hypotension it is expected that the cortisol ​ Ex. ACTH Stimulation Test to assess adrenal gland level would be elevated in suspected adrenal insufficiency ​ Stress induced relative corticosteroid ○​ Patients are given cosyntropin/ACTH then tested insufficiency for cortisol levels ○​ Normal is normal when the condition is normal ​ ↑ cortisol = not a true deficiency ○​ Normal values is abnormal when the condition is ​ ↓ cortisol = true deficiency abnormal ​ Ex. Growth Hormone Stimulation ○​ Take into consideration the feedback regulation ○​ Used to test for growth hormone insufficiency among patients with pituitary problems Dynamic Testing ○​ Growth hormone (stress hormone) increases ​ Baseline hormone testing may overlap with IGF-1 during stress pathologic levels ○​ Patient is given insulin to induce hypoglycemia ​ May be required to differentiate 2 groups (stressor) up to a point nearing seizures → blood ○​ Ex: Cases of excess or deficiency of adrenal or is drawn and tested for HGH or IGF-1 pituitary hormones ​ Based on the principle of feedback regulation stimulate ⭐ ​ If there is excess, suppress it. If there is deficiency, ○​ True excess: elevated results despite suppression ○​ True deficiency: deficiency despite stimulation Suppression Tests ​ Used in suspected endocrine hyperfunction ​ Ex. Dexamethasone Suppression Test to evaluate Cushing’s Syndrome ○​ Patient is given 0.5mg dexamethasone (steroid) to suppress cortisol production/peak during morning ○​ Given at night → ↓ ACTH in the morning → ↓ cortisol Figure 9. ACTH Stimulation Test ○​ ↑ cortisol = Cushing’s Syndrome ​ Ex. Saline Suppression Test ○​ Used to test for aldosterone hypersecretion ○​ Infuse patient with 2L saline rapidly Page 6 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action F. Screening of Common Endocrine Disorders (TRH) ​ Somatostatin ​ Vasopressin (ADH) ​ Growth hormone (GH)* ​ Oxytocin* ​ Insulin Large ​ Luteinizing hormone (LH) proteins ​ Parathyroid hormone (PTH) Steroid hormones ​ Cortisol (Synthesized from ​ Estrogen cholesterol-based ​ Testosterone* proteins) ​ Aldosterone* ​ Vitamin D Vitamin derivatives ​ VitaminA (retinoids)* *not included in the PPT C. Receptor Transduction Table 8. Receptor interaction Interact with plasma Interact with intracellular membrane receptors receptors Generates signal that Ligand-receptor complex regulates various directly provides the signal intracellular functions Polypeptides Steroid Catecholamines Retinoid Protein hormones Thyroid hormone 💬 Can be intranuclear or 💬Require signaling 💬 intracytoplasmic Intracytoplasmic has pathways such as GPCR to ligand-receptor complex that produce an effect will place the hormone intranuclear Figure 10. Screening and Testing Recommendations for different disorders. Doc mentioned that these would not be asked in the exam and that there’s no need to memorize since we would focus on principles for his lecture. II. MECHANISM OF HORMONE ACTION A. Hormones ​ Integrate physiologic systems in the body ​ Hormones essentially interact with every organ to regulate: Figure 11. (Left) Hormones with receptors located in the plasma membrane (Right) Hormones with receptors located in the ○​ Growth and development cytoplasm and nucleus ○​ Maintenance of homeostasis ○​ Reproduction Table 6. 3 Hormones Essential to Life HORMONE DEFINITION Insulin ​ Death within 7-14 days Cortisol ​ Death within hours ​ Death within months Thyroid ​ Slow and progressive debilitation → Hormones coma → death B. Five Major Classes of Hormones Table 7. Major classes of hormones Hormone Class Examples ​ Dopamine Amino acid derivatives ​ Catecholamines ​ Thyroid hormone Small ​ Gonadotropin-releasing Peptides neuro- hormone (GnRH) peptides ​ Thyrotropin-releasing hormone Page 7 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action D. Hormone and Receptor Families Table 10. Nuclear receptor types Type I Type II Binds Vitamin D, Thyroid hormone, Binds steroids Vitamin A, retinoid acid Figure 12. Receptor families and signaling pathways Glycoprotein Hormone Family Table 9. Glycoprotein hormone family Glycoprotein Hormones Figure 14. Example of Nuclear receptor signaling. (Top) Figure Thyroid-stimulating hormone ​ Shares alpha subunit shows how a Type I receptor binds to steroids like aldosterone to Luteinizing hormone ​ Beta subunit confers transcribe and translate it to ENac aka your Na+ channels. (Bottom) Follicle Stimulating hormone B-hCg ⭐️ specific biologic activity Figure shows how the different nuclear receptors bind can be responsive or unresponsive to other steroids. E. Hormone Synthesis and Processing Figure 13. Glycoprotein hormone family cascade ​ 💬 Sometimes the mere presence of the alpha subunit can suppress the production of the other hormones. ○​ e.g. very high B-hCg can suppress the production Figure 15. Steps involved in hormone synthesis and processing of TSH ​ 💬In practice, it can also stimulate production when ​ The synthesis of peptide hormones and their they are overly high ○​ e.g. during molar pregnancy, it can present with receptors occurs through a classic pathway of gene hyperthyroidism because they have enough expression: transcription → mRNA → protein → post structural similarity that the b-hCg can also bind translational protein processing → intracellular to the TSH receptor and can stimulate FT3 and sorting followed by membrane integration or secretion FT4 production ○​ 💬 Problem in any step of the synthesis can render the product (hormone) defective Nuclear Receptor Family ​ Found at the nucleus ○​ 💬 Hormone production and regulation are tightly ○​ Functional domains in the nuclear receptors are controlled by enzymes, and deficiencies or highly conserved meaning their specificity is very malfunctions can lead to diverse outcomes: high ​ Deficiency in production enzymes = Hormone ○​ Hormone binding domains are more variable deficiency. ​ Deficiency in processing enzymes = Hormonal imbalances, including hypersecretion or Page 8 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action accumulation. ​ Many hormones are embedded within larger precursor polypeptides that are proteolytically processed to yield the biologically active hormone. ​ Synthesis of most steroid hormones is based on modifications of the precursor, cholesterol. ​ Endocrine genes contain regulatory DNA elements but their exquisite control by hormones reflects the presence of specific hormone response elements. F. Hormone Secretion and Transport ​ Circulating level of a hormone is dependent on (1) rate of secretion and (2) circulating half life ○​ The longer the half life, the longer the stimulating ○​ action 💬 Peptides have very short half-life due to the ⭐️Figure 16.hormones Example of the different half lifes of different types of in association with protein binding. ubiquitousness of the peptidases that degrade Harrison’s 21st: T4 or Thyroxine ½ life: 7 days them ​ E.g Insulin’s half life is rapid (in less than 5 ​ Thyroid hormones: among the longest half-life ⭐️ minutes, half of the insulin secreted is already deactivated) Hormone Binding Proteins ​ Hormone transport and degradation dictate the ​ Provides reservoirs of free hormones rapidity with which a hormonal signal decays. ​ Prevents rapid degradation of hormones ​ Some signals are pulsatile but long acting (i.e. TSH: ​ Restricts entry /access of hormones to other sites effect specific to thyroid) ​ Modulates levels of free hormones ​ Acts as regulator Table 11. Differences in secretion and transport between protein ○​ 💬 A patient can have hypersecretion, but if they and peptide hormones vs. steroid hormones are bound to proteins, they are rendered inactive Protein and Peptide ○​ In pregnancy a patient, there can be a high Steroid Hormones Hormones secretion of FT4, but most of the T4 are tightly Secretion Determined by rate of Proportional to rate protein bound, they will not have hyperthyroid. Rate exocytosis of synthesis ○​ In a patient who exhibits stunting, there is an Storage Stored in secretory vesicles Secreted as soon as they are synthesized the hormone secretion is normal. ⭐️ excess of growth hormone binding protein even if ○​ The first action of insulin is suppress the Neural or hormonal Factors Enzyme activity and affecting release signals that induce rapid changes in voltage gated availability of precursors production of glucagon, the second is suppress the production of glucose by your liver ​ Hence exogenous insulin dosage is always ⭐️ channel LH, ACTH* → higher compared to endogenous Examples Insulin, GH, GnRH Steroidogenesis *LH and ACTH are both proteins. They induce steroidogenesis by G. Hormone Degradation stimulating the activity of the steroidogenic acute regulatory (StAR) ​ Important mechanism for regulating local hormone protein, which transports cholesterol into the mitochondrion, along action with other rate-limiting steps (e.g., cholesterol side-chain cleavage ○​ To lessen hormone action enzyme, CYP11A1) in the steroidogenic pathway. Table 12. Difference in half life between peptides and ⭐️ ​ Insulin is rapidly degraded by peptidases, reducing its T1/2 to 7-8 mins ​ D3 (Thyroid hormone deiodinases) - rapidly catecholamines vs steroids and thyroid hormone degrades T3 or rT3 Steroids and Thyroid Peptides and Catecholamines ​ 11β-hydroxysteroid dehydrogenase - Hormone inactivates glucocorticoids in renal tubule Very short half life (seconds to Long half life (hours) ​ During development, degradation of retinoic minutes) acid by Cyp26b1 prevents primordial germ Evanescent: Somatostatin exerts cells in the male from entering meiosis, as effects in virtually every tissue, a occurs in the female ovary Bound to plasma short half-life allows its ​ Circulating hormone half-life is important for protein concentrations and actions to be achieving physiologic hormone replacement controlled locally. ​ Frequency of dosing and the time required to reach steady state are intimately linked to rates of hormone decay. ​ Rapid hormone decay is useful in certain clinical settings ○​ Short half-life of PTH allows the use of intraoperative PTH levels to confirm successful removal of a parathyroid adenoma. Page 9 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action H. Hormone Action through Receptors ​ Divided into 2 major classes ○​ Membrane receptors ○​ Nuclear receptors Membrane Receptors Figure 18. G protein signaling Figure 17. Membrane receptor signaling ​ Primarily bind peptide hormones and catecholamines ​ Membrane receptors for hormones can be divided into several major groups ○​ Seven transmembrane GPCRs ○​ Tyrosine kinase receptors ○​ Cytokine receptors ○​ Serine kinase receptors Seven Transmembrane GPCR ​ Binds a huge array of hormones, including ○​ Large proteins (i.e. LH, PTH) ○​ Small peptides (i.e. TRH, somatostatin) ○​ Catecholamines (i.e. epinephrine, dopamine), and ○​ Minerals (i.e. calcium) ​ Extracellular domains of GPCRs vary in size and are the major binding site for large hormones ​ The transmembrane-spanning regions are composed of hydrophobic α-helical domains that traverse the lipid bilayer. These domains are thought to circularize and form a hydrophobic pocket into which certain small ligands fit. ​ Hormone binding induces conformational changes in these domains, transducing structural changes to the intracellular domain, which is a docking site for G proteins. ​ G protein–coupled receptors (GPCRs) signal via the family of G proteins, so named because they bind guanylyl nucleotides. ​ In figure 20, GPCR bound to a ligand induces GDP dissociation, allowing Gsα to bind GTP and dissociate from the βγ complex. ○​ GTP-bound Gsα increases cAMP production by adenylyl cyclase and activates the protein kinase A pathway. ○​ When GTP is converted to GDP by an intrinsic GTPase, the βγ subunits reassociate with Figure 19. Genetic Causes of G Protein Disorders GDP-bound Gsα and the complex returns to an Tyrosine Kinase Receptors inactive state. ​ Transduces signals for insulin, and other growth ○​ Mutations in Gsα that eliminate GTPase activity factors such as, IGF1, EGF (epidermal growth factor), result in constitutive activation of receptor NEGF (nerve growth factor), PDGF (platelet-derived signaling pathways because GTP-bound Gsα growth factor), FGF (fibroblast growth factors) cannot be converted to its GDP-bound inactive ​ Plays a prominent role in cell growth and state. differentiation and intermediary metabolism ​ The cysteine-rich extracellular domains contain Page 10 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action binding sites for the growth factors Table 13. Nuclear receptor types ​ After ligand binding, TK receptors undergo TYPE I RECEPTOR TYPE I RECEPTOR autophosphorylation, inducing interactions w/ intracellular adaptor proteins such as Shc and insulin Interaction with co-repressors Interaction with co-repressors receptor substrates. still induces interactions with silences gene transcription ​ In the insulin receptor, multiple kinases are activated, coactivators Mediate dynamic changes in including the Raf-Ras-MAPK and the Akt/protein the level of gene activity kinase B pathways. ​ Nuclear receptor mutations = endocrine disease ​ Receptor Coactivator Complex- stimulates gene Cytokine Receptors transcription by several pathways ​ Ligand binding induces receptor interaction with ○​ Recruitment of enzymes that modify chromatin intracellular kinases structure ○​ JAKs (Janus kinases) are activators of transcription ○​ Interactions with additional TFs on the target gene (STAT) family, as well as with other signaling ○​ Interactions with the general transcription pathways (Ras, PI3-K MAPK) apparatus enhance the rate of RNA polymerase ○​ Activated STAT proteins translocate to the II-mediated transcription nucleus and stimulate expression of target genes ​ Includes GH and Prolactin receptors I. Function of Hormones Growth and Differentiation Serine Kinase Receptors ​ Complex interplay of hormones and nutrition mediate ​ Mediate the actions of activins, transforming growth growth factor β, müllerian-inhibiting substance (MIS; also ○​ GH deficiency, hypothyroidism, Cushing's known as anti-müllerian hormone [AMH]), and bone Precocious puberty, sex steroids can all lead to morphogenic proteins (BMPs) short stature ​ Consist of type I and II subunits signals through proteins termed SMADs Homeostasis ○​ SMADs serve a dual role of transducing the Table 14. Hormones and their functions in homeostasis receptor signal and acting as transcription factors HORMONE FUNCTION ​ Acts primarily in a local (paracrine or autocrine) manner Controls ~25% of basal metabolism in Thyroid Hormone ​ Includes TGF and MIS most tissues ​ Binding proteins, such as follistatin, function to Has direct effects and permissive action Cortisol inactivate the growth factors and restrict their for many hormones distribution. Regulates calcium and phosphorus PTH levels Nuclear Receptors Regulates serum osmolality via control Vasopressin ​ Bind small molecules that can diffuse across the cell of renal free-water clearance membrane (steroids and vitamin D) Controls vascular volume and serum Mineralocorticoids ​ Nearly 100 members electrolyte 3(Na, K+) concentrations ​ Majority are orphans (have unidentified ligands) Maintains euglycemia in the fed and Insulin ​ Classified on the basis of their ligands fasting states ​ Function ​ Insulin = suppressed in fasting state (falling blood ○​ Increase or decrease gene transcription glucose) ○​ In the cytoplasm: repress or stimulate signal ○​ Decreased glucose uptake transduction, providing cross talk between ○​ Mobilize fuel sources membrane and nuclear receptors ​ Enhanced glycogenolysis, lipolysis, proteolysis, and gluconeogenesis ○​ In hypoglycemia (usually from insulin administration or sulfonylureas) a counterregulatory response occurs ​ Glucagon and epinephrine rapidly stimulate glycogenolysis and gluconeogenesis ​ GH and cortisol: raise glucose levels and antagonize insulin action ​ Type of endocrine and cytokine pathway activation depend on stress severity and acuteness ○​ Acute (trauma or shock) sympathetic nervous system is activated, and catecholamines are released ​ Increased cardiac output and a primed Figure 20. Nuclear Receptor signaling musculoskeletal system ​ Catecholamines also increase mean blood pressure and stimulate glucose production. ​ Multiple stress induced pathways converge on the hypothalamus, stimulating several hormones Page 11 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action ○​ ACTH = increases cortisol to sustain blood ​ ↓ Thyroid hormones → ↑ TRH, TSH → ↑ thyroid gland pressure and dampens the inflammatory response stimulation, thyroid hormone production ○​ Vasopressin = conserves free water ○​ Upon reaching normal thyroid hormone levels → ↓ TRH, TSH → steady state Reproduction ​ Other examples of feedback regulation ​ Stages of reproduction involves an interplay of ○​ Calcium feedback on PTH hormones ○​ Glucose inhibition of insulin secretion ○​ Sex determination (fetus) ○​ Leptin feedback on the hypothalamus ○​ Sexual maturation (puberty) ​ Example of positive feedback ○​ Conception, pregnancy, lactation, and child rearing ○​ Estrogen-mediated stimulation of the midcycle LH ○​ Cessation of reproductive capability at menopause surge ​ 28-day menstrual cycle illustrate dynamic hormonal changes ○​ Early follicular phase: LH, FSH pulsatile secretion → ovarian follicle maturation ​ ↑ Estrogen & progesterone → ↑ pituitary sensitivity to GnRH & ↑ secretion of GnRH → LH surge, mature follicle rupture ○​ Inhibin produced by granulosa cells → ↑ follicular growth, ↓ FSH ​ Inhibin DO NOT affect LH ○​ Growth factors (i.e., EGF, IGF1) modulate follicular responsiveness to gonadotropins ○​ VEGF, PGs → follicle vascularization and rupture ​ Pregnancy ○​ ↑ PRL & placentally derived steroids (e.g., estrogen, progesterone) → prepares breast for lactation ○​ Estrogens → ↑ progesterone receptors ​ ↑ responsiveness to progesterone ○​ Oxytocin = suckling response and milk release Figure 22. Feedback regulation of endocrine axes Paracrine and Autocrine Control ​ Local regulatory system and anatomic relationships regulate hormonal exposure Table 16. Autocrine and paracrine regulation PARACRINE AUTOCRINE Factors released by one cell Factors that act on the same that act on an adjacent cell in cell from which it is produced the same tissue Somatostatin secretion by IGF-1 acts on many cells that pancreatic islet δ cells inhibits Figure 21. Relationship between gonadotropin, follicle produce it, including: insulin secretion from nearby development, gonadal secretion, and endometrial changes ​ Chondrocytes β cells: ​ Breast epithelium ​ Insulin suppress J. Feedback Control ​ Gonadal cells glucagon production ​ Negative and positive feedback control is a by α-cell fundamental feature of endocrine systems ​ Anatomic relationships of glandular systems also ​ Each of the major hypothalamic-pituitary hormone greatly influence hormonal exposure axes is governed by negative feedback ○​ Physical organization of islet cells enhances their ○​ Examples: intercellular communication ​ Thyroid hormones on the TRH-TSH axis ○​ Portal vasculature of the hypothalamic-pituitary ​ Cortisol on the CRH-ACTH axis system exposes the pituitary to high ​ Gonadal steroids on the GnRH-LH/FSH axis concentrations of hypothalamic releasing factors ​ IGF1 on the GHRH-GH axis ○​ Testicular seminiferous tubules gain exposure to ○​ These regulatory loops include the following for high testosterone levels produced by the exquisite control of hormone levels interdigitated Leydig cells ○​ Pancreas receives nutrient information and local Table 15. Positive & negative components of regulatory exposure to peptide hormones (incretins) from the loops gastrointestinal tract POSITIVE NEGATIVE ○​ Liver is the proximal target of insulin action TRH T4 because of portal drainage from the pancreas TSH T3 Page 12 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action ➕ releasing hormone ( affecting secretion of luteinizing hormone and follicle stimulating hormone= preventing ovulation) which would lead to the patient being infertile ○​ Parathyroid hormone ​ Function: Increase calcium level through bone resorption ​ When parathyroid hormone is elevated what can be expected from the bone if there is excess? It can become brittle and osteoporotic ​ Peri- Parathyroid : treatment for osteoporosis synthetic form of PTH ​ Why is one of the best treatments for osteoporosis a synthetic form of PTH? (Part of “quiz”) Figure 23. Paracrine regulation in glucose homeostasis Hormonal Rhythms Endocrine Testing and Treatment[Harrison’s page 2891 & Trans2027] ​ Feedback regulatory systems described above are Cushing's Syndrome superimposed on hormonal rhythms that are used for ​ Elevated midnight cortisol compared with normal adaptation to the environment individuals ○​ Seasonal cycle ​ Morning cortisol levels are similar in both groups, ​ TH higher in cold season as cortisol is normally high at this time of day ○​ Sleep wake cycles HPO Axis (control cortisol) ○​ Light-dark cycles More susceptible to suppression by glucocorticoids ​ Cortisol higher in the morning administered at night as they prevent the early morning ○​ Meals rise of ACTH (ACTH triggers cortisol production) ○​ Stress Glucocorticoid replacement that mimics diurnal ​ Menstrual Cycle is based on a 28 day cycle, reflecting production time needed for the following: Administer larger doses in the morning than in the ○​ Follicular maturation afternoon ○​ Ovulation Disrupted sleep rhythms can alter hormonal regulation ○​ Potential implantation Sleep deprivation causes mild insulin resistance, food craving and hypertension which are reversible at least in Pituitary Hormone Rhythms the short term ​ Linked to sleep and circadian cycle ○​ Generates reproducible patterns that are repeated LH and FSH secretion are exquisitely sensitive to GnRH approximately every 24 hours pulse frequency ​ HPA axis ​ Pulsatile GnRH= normal ○​ Exhibits characteristic peaks of ACTH and cortisol ​ Continuous GnRH = desensitization production in the early morning with a nadir ○​ Basis for treatment of long acting GnRH for (lowest point/ level) during the night precocious puberty or to decrease testosterone levels in the management of prostate cancer CASE ANALYSIS ​ Mary is a 37-year-old patient experiencing recurrent vague abdominal pain for the past 3 months. She has taken proton pump inhibitors (Esomeprazole) and prokinetics (Domperidon) for a week but without significant relief of symptoms. Figure 24. Pictures/Flowcharts/Concept Maps/Other Visual Aids ​ She also complains of progressive weight gain over the ​ ⭐When is the best time to check if the patient has past 3 years despite repeated attempts to control her diet high cortisol? ​ She is hypertensive and controlled on losartan 50 mg ○​ Night time once daily. She also takes simvastatin 20 mg once daily. ​ It should be low at night this confirms elevated Her menses are irregular, often skipping 2-3 months. cortisol She has no other known comorbidity. ○​ Do a Midnight Salivary Cortisol Test ​ Previous laboratory exams revealed a slightly elevated ​ Saliva has 3 forms of cortisol LDL and ALT, and an elevated FBS of 116 mg/dl. ​ Has Pulsatile secretions and the action ​ Slightly elevated LDL and ALT signifies that the patient depends on the pulsatility ​ 💬Examples from doc: ​ probably has metabolic syndrome. She has a normal electrolyte level and normal renal ○​ Oral Contraceptives parameters. ​ Disrupts the pulsatile release of gonadotropin ​ Both her parents and her eldest sister are Page 13 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action hypertensives and diabetics. ​ Quite large nodule, and notably the right kidney and adrenal gland is anatomically lower 1. You asked if the patient experiences vaginal or inguinal itchiness? She revealed that in fact, she had been using 6. What is your clinical impression? anti-fungal cream for this, but the condition has become ANSWERS recurrent. What might explain this condition? 1: A A.​ Impairment of cellular immunity due to 2: A hyperglycemia 3: Any question that is usually asked in history (family B.​ Impairment of the mucosal barrier due to history of endocrine disorders) peri-menopausal hormonal changes leading to 4: A dryness 5: C.​ Statin-induced suppression of humoral immunity 6: Metabolic syndrome or Cushing syndrome as supported by the elevated ALT D.​ Impairment of both humoral and cellular immunity RATIONALE due to suppressed cortisol level 1: B is not possible since the patient is not in the menopausal age. C is not correct because this is not a case 2. She told you that she has a very disturbed sleeping of statin-induced suppression. D is also not correct because pattern because she wakes up 3 to 4 times at night to this case is most likely from an increase in cortisol level. urinate. What might explain this condition? 2: Same as 1 A.​ The capacity of the kidneys to reabsorb sugar has 3: You may ask questions that will be relevant to the chief been exceeded due to hyperglycemia complaint of the patient or anything that will narrow down B.​ Impairment of thirst regulation due to your findings peri-menopausal hormonal changes leading to 4: Her symptoms, including central obesity, acanthosis sensation dryness leading to polydipsia and nigricans, hypertension, elevated blood sugar, and subsequent polyuria dyslipidemia, point toward metabolic syndrome, which C.​ Statin-induced suppression of the sodium-glucose involves a combination of these risk factors. (CHAT GPT) co-transporter leading to dilute and higher than ​ Other differentials you may consider include normal volume of urine Cushing’s Syndrome and T2DM D.​ Impairment of both renal and neural regulation of 5: You can do a CT Scan. You can also do a confirmatory test water balance due to suppressed cortisol level such as Salivary Cortisol Test or High Dose Dexamethasone Suppression Test 3. What other details in the history would you like to 6: Same as 4 inquire about and why? III. REFERENCES CASE: ​ Dampil, Oliver Allan, MD. Notes from Approach to the ​ BP: 130/80 Patient with Endocrine Disorders, Mechanisms of ​ CR: 72 bpm Hormone Action ​ BMI: 32 (elevated) ​ Harrison’s Principles of Internal Medicine (21st ed). ​ + acanthosis nigricans ​ + central obesity w/ 1 cm wide silvery striae IV. REVIEW QUESTIONS (abdomen and axillae) ​ Dexamethasone Cortisol Test- low 1. What determines the secretion rate of proteins and peptide hormones like insulin, GH, and GnRH? A. Proportional to rate of synthesis B. Rate of exocytosis C. Both A and B D. Neither A or B 2. Which subunit confers specific biological activity of 4. Based on the history and PE, what is your clinical glycoprotein hormone? impression? A.​ Metabolic Syndrome due to the presence of A. alpha hypertension, elevated blood sugar, and B. beta dyslipidemia C. gamma B.​ FSH – Estradiol disproportion due to D. delta perimenopausal syndrome C.​ Statin-induced hormonopathy 3. T/F. MEN1 syndrome usually causes tumors in the D.​ Cushing Syndrome due to suppressed cortisol pituitary gland, parathyroid gland, or pancreas. While level MEN2 syndrome usually causes tumors in the thyroid gland, parathyroid gland, or adrenal gland. 5. Because of suppression of cortisol level. What will be your next examination? 4. For hormone resistance, an example of a membrane receptor mutation comes from which of the ff? On CT Scan: 2.1 x 1.8 cm adrenal nodule, right Page 14 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action A. ACTH 5. [D]. Pituitary adenomas are tumors that arise from the B. GR pituitary gland, and they can cause excess secretion of C. Leptin resistance hormones. Depending on the type of cells involved in the D. T2DM adenoma, it can lead to overproduction of various hormones, such as growth hormone, prolactin, ACTH 5. Which of the following diseases is caused by excess (adrenocorticotropic hormone), and others. hormones? A. Hashimoto’s thyroiditis 6. [B]. Suppress the production of glucagon. The second B. Albright’s hereditary osteodystrophy function is suppress the production of glucose in the liver C. Addison’s disease D. Pituitary adenoma 7. [B]. Protein binding hormones decrease the potency of hormone action 6. What is the first function of Insulin? A. Suppress the production of glucose in the liver 8. [C]. Recall B. Suppress the production of glucagon C. Promote the production of glucagon 9. [D]. TSH has a proportional relationship with age D. Promote the production of glucose in the liver 10. [D]. Recall 7. What is the effect of excess hormone binding protein in Thyroxine VI. SUMMARY A. It will increase its action action on the thyroxine Endocrine Terminologies receptor B. It will decrease its affinity on thyroxine receptor HORMONE FUNCTION C. It has no effect ​ Involves hormones secreted internally D. It will cause hyperthyroidism Endocrine ​ Ductless; usually secreted directly into the bloodstream 8. Which test is used to detect/evaluate Cushing’s ​ Involves hormones secreted externally or Syndrome? into a lumen (such as the GI tract) Exocrine A. Saline Suppression Test ​ Secreted into a ductal system (such as B. ACTH Stimulation Test the pancreatic and salivary ducts) C. Dexamethasone Suppression Test ​ “To set in motion” D. Growth Hormone Stimulation Test ​ Elicit cellular responses and regulate physiologic processes through regulated Hormones 9. What is the relationship between TSH and age? A. Normal range is usually broad ​ 💬 feedback mechanisms. Hormones have target cells or receptors B. Unaffected by age C. Decreases with age D. Increases with age Hormonal Arc Consists of: 10. What is the most important diagnostic tool in ​ Organ/gland producing the hormone (right amount) endocrinology? ​ The hormone itself (functioning) A. Basal hormone testing ​ The effector/target cell that produces the desired B. Dynamic testing effect (good receptor) C. Imaging tests A problem in any of these would result to an endocrine D. Immunoassays disorder Overview of Endocrine Disorders V. RATIONALE ​ Usually evaluated by measuring hormones or doing 1. [B]. Recall dynamic testing ○​ Hormone deficiency: stimulate hormone → 2. [B]. Recall confirm deficiency ○​ Hormone excess: suppress hormone (i.e., 3. [T]. TRUE. These are the two main types of MEN Cushing’s disease) → unsuppressable → presence syndromes (MEN1 and MEN2). of autonomous hormone secretion ​ Most disorders of the endocrine system are amenable 4. [A]. Recall. Refer to Appendix 1 for the complete to treatment once the correct diagnosis is determined table. Leptin Resistance (post-receptor) is different from ○​ Deficiencies are corrected with physiologic membrane resistance. The former (post-receptor) is an hormone replacement acquired form (Leptin resistance in obesity). While, ○​ Excesses are reduced medically or in cases of membrane resistance is due to inherited defects in tumors, surgically removed membrane receptors. (*See Appendix 1 or p.2882 of Harrison’s 21st ed. ) Endocrine Glands ENDOCRINE GLANDS Pituitary Parathyroid Adrenals Page 15 of 21 | TH: TAMAYO, A., URBANO, A. | RTG 4 & 13 | AGANINTA, CHAN, JOYAS, CABILING, CO, MONZON.  MED 4.01 Approach to the Patient with Endocrine Disorders & Mechanisms of Hormone Action Thyroid Pancreatic Islets Gonads Cushing’s Syndrome Hypoglycemia Scope of Endocrinology Iatrogenic Excess thyroid hormone ​ Difficult to define along anatomic lines intake ​ Interdigitation of endocrinology with other OCT physiologic processes in other specialties blurs the Infectious/ Inflammatory Subacute Thyroiditis role of hormones LHD ○​ Ex: Hormones that can act as neurotransmitters TSH Activating Receptor and neurotransmitters that can act as hormones Ca2+ Mutations PTH Receptors Interdigitation examp