1-ENDOCRINOLOGY-Part-I.PPT PART OF THE HUMAN BODY

What Is Endocrinology?
The Basics

Endocrinology is a branch of medicine that deals with the endocrine system, which controls the hormones in your body. An endocrinologist is a physician who specializes in the field of endocrinology. Endocrinologists diagnose and treat a wide range of conditions affecting the endocrine system, including diabetes mellitus, thyroid disorders, osteoporosis, growth hormone deficiency, infertility, cholesterol problems, hypertension (high blood pressure), obesity and more.

How the Endocrine System Works

The endocrine system’s glands and organs release hormones that regulate a number of vital functions of our body. These glands include the hypothalamus, pineal body, pituitary, thyroid, parathyroids, adrenals, pancreas, testes and ovaries.

The hormones in your body all have specific jobs to complete. There are up to 40 different hormones circulating in your blood at any time. Once released into the bloodstream, a hormone travels throughout the body until it reaches its specific destination(s) to perform its function. These destinations, called targets, can be located either on other endocrine glands or on other organs and tissues in the body.

When a hormone reaches its target, it tells that part of your body what work to do, when to do it and for how long. Hormones are often referred to as the “messengers” because they help different parts of the body communicate. Overall, they are involved in many different processes in the body, including:

Blood sugar control
Growth and development
Metabolism (the process of getting and maintaining energy in the body)
Regulation of heart rate and blood pressure
Sexual development and function
Reproduction
Mood
What Happens When the Endocrine System Does Not Work?

Hormonal function is a balancing act. Too much or too little of one hormone can have an impact on the release of other hormones. If this hormonal imbalance occurs, some of your body’s systems will not work properly.

These imbalances can often be corrected by the body itself. Your body has built-in mechanisms to keep track of and respond to any changes in hormone levels to bring them back to normal and restore the balance.

Sometimes, however, this system goes wrong and there can be a problem that the body can’t fix itself. In this case, a primary care physician will refer you to an endocrinologist, who is an expert in treating frequently complex (and often chronic) conditions which can involve several different systems within the body.

The Anatomy of the Endocrine System

The endocrine system is made up of a collection of glands. Each gland has a specific function in the body, and all these glands work together to regulate vital functions of our body.

Adrenal glands

Located just above the kidneys, adrenal glands are responsible for the secretion of several hormones which maintain the body’s salt and water balance that in turn regulate blood pressure, help the body cope with and respond to stress, regulate body meta

1. ENDOCRINOLOGY

2. Endocrine system is a network of ductless glands that secrete hormones directly into the blood. It is considered as the regulatory system of the body. Controlled by hormone synthesis rather than degradation.

3. hormones These are chemical signals produced by specialized cells secreted into blood stream and carried to a target tissue. They act at tissues or sites different from where they are synthesized and released. Play an important role in growth and development of an individual. Regulated by metabolic activity either by positive or negative feedback mechanism.

4. hormones Sometimes they are influenced by physiologic factors such as age, as in case of the elderly who secrete less triiodothyronine, parathyroid hormone, aldosterone, and cortisol. Major functions: To maintain the constancy of chemical composition of extracellular and intracellular fluids; and control metabolism, growth, fertility, and responses to stress.

5. Control of Hormone Secretion The majority of endocrine functions are regulated through the pituitary gland, which in turn is controlled by secretions from the hypothalamus.

6. F eedback mechanism Positive Feedback System ( PFM ) An increase in the product results to elevation of the activity of the system and the production rate (e.g., gonadal, thyroidal and adrenocortical hormones). Negative Feedback System ( NFM ) – most common An increase in the product results to decreased activity of the system and the production rate (e.g., luteinizing hormone)

7. Types of NFM: Long FM : Feedback from hormones produced in the pituitary target glands on the hypothalamus Short FM : Feedback of hormones at the level of the pituitary gland Ultrashort FM : Feedback mechanism between the pituitary and hypothalamus.

8. Endocrine Secreted in one location and released into blood circulation Binds to a specific receptor to elicit physiological response Paracrine Secreted in endocrine cells and released into interstitial space Binds to a specific receptor in adjacent cell and affects its function. Hormone Action and Properties

9. Autocrine Secreted in endocrine cells and sometimes released into interstitial space Binds to a specific receptor on cell of origin resulting to self-regulation of its function Juxtacrine Secreted in endocrine cells and remains in that same cellular space in relation to plasma membrane. Acts on immediately adjacent cell by direct cell-to-cell contact Intracrine Secreted in endocrine cells and functions inside the origin of synthesis Hormone Action and Properties

10. Exocrine Secreted in endocrine cells and released into lumen of gut, and affects their functions Neurocrine Secreted in neurons and released into extracellular space Binds to a receptor in nearby cell and affects its functions Neuroendocrine Secreted in neurons and released from nerve endings Interacts with receptors of cells at distant site Hormone Action and Properties

11. Classification of Hormones According to Composition or Structure

12. Properties Examples Water-soluble and not bound to a carrier protein Synthesized and stored within the cell in the form of secretory granules and are cleaved as needed. Cannot cross the cell membrane due to their large molecular size Produce their effect on the outer surface of the cell Glycoprotein FSH, HCG, TSH, and Erythropoietin Polypeptides ACTH, ADH, PTH, GH, Angiotensin, Calcitonin, Cholecystokinin, Gastrin, Glucagon, Insulin, Melanocyte-stimulating Hormone, Oxytocin, Prolactin, and Somatostatin Peptides and Proteins

13. Properties Examples Water-insoluble (hydrophobic) and circulate bound to a carrier protein. Cholesterol as a common precursor Produced by adrenal glands, ovaries, testes, and placenta Aldosterone, Cortisol, Estradiol, Progesterone, Testosterone, and Activated vitamin D3 Steroids

14. Properties Examples Intermediary between steroid and protein hormones Derived from an amino acid Epinephrine, Norepinephrine, Triiodothyronine, and Thyroxine Amines

15. Biological Rhythms that Influence Hormones Measurement Circadian rhythms : biological rhythms (endogenously generated) with a period close to 24 hours Diurnal rhythms : a circadian rhythm that is synchronized with the day/night cycle

16. Biological Rhythms that Influence Hormones Measurement Ultradian rhythms : Biological rhythms (e.g., feeding cycles) with a much shorter period (i.e., much higher frequency) compared to a circadian rhythm Examples of ultradian rhythms are blood circulation, pulse, heart rate, thermoregulation, blinking, micturition, appetite Infradian rhythms : Biological rhythms with a cycle that lasts longer than 24 hours (e.g., the human menstrual cycle)

17. Neuroendocrine System The nervous system and the endocrine system are closely interrelated and both are involved intimately in: maintaining homeostasis; keeping the body functioning regularly; responding properly to environmental stimuli through the regulated secretion of hormones, neurotransmitters, or neuromodulators.

18. hypothalamus It is the portion of the brain located on the walls and floor of the third ventricle It is above the pituitary gland, and is connected to the posterior pituitary by the infundibulum. The link between the nervous system and the endocrine system The supraoptic and paraventricular nuclei produce vasopressin and oxytocin

19. hypothalamus The neurons in the anterior portion release the following hormones (hypophyseal hormones): thyrotropin-releasing hormone ( TRH ) gonadotropin-releasing hormone ( Gn -RH ) somatostatin , also known as growth hormone-inhibiting hormone (GI-IH) growth hormone-releasing hormone ( GH-RH ) prolactin-inhibiting factor ( PIF )

20. Response Mechanism of the Hypothalamus Open-loop negative feedback mechanism Pulsatility : abrupt response to a stimulus or “pulse” pattern of hormone secretion Cyclicity : the nervous system regulates this pattern through external signals

21. ENDOCRINE GLANDS and its HORMONES

22. Pineal gland It is attached to the midbrain Its secretions are controlled by nerve stimuli. It secretes melatonin that decreases the pigmentation of the skin. Main functions : Receives information about the state of the light-dark cycle from the environment and conveys this information to produce and secrete the hormone melatonin. Possible causes of dysfunction : Accidental and developmental conditions (pineal tumors, craniopharyngiomas, and injuries to the gland).

23. Melatonin ( N-acetyl-5-hydrotryptamine )

24. Melatonin ( N-acetyl-5-hydrotryptamine ) Synthesized within the pinealocytes from tryptophan . It is only secreted during the dark period of the day. Marker of the phase of internal circadian clock (regulates the circadian system and sleep patterns). It is used in therapy for sleep disorders. It has cell protection and neuroprotection properties It may be secreted in other sites such as in the GIT , skin , retina , bone marrow , and placenta acting in an autocrine or paracrine.

25. Except for the pineal gland, the abovementioned sites contribute little to circulating concentration while after pinealectomy, melatonin levels remain undetectable. Plasma melatonin in adults : 60 to 70 pg /mL when measured with high-specificity assay Concentration in saliva : 3x lower in plasma Urine : 6-sulfatoxymelatonin ( aMT6s ) - good marker of melatonin secretion Method : Immunoassay

26. Health Benefits from Melatonin : Anti-oxidant and anti-aging properties Potent free radical scavenger More effective than glutathione in reducing oxidative stress (highly concentrated in the mitochondria) Factors that Influence Melatonin Plasma Level : False Increased: Posture (night), exercise , and caffeine False Decreased: Alcohol and aspirin

27. Pituitary gland ( hypophysis ) It is located in a small cavity in the sphenoid bone of the skull called the sella turcica or Turkish saddle It is connected by the infundibular stalk to the median eminence of the hypothalamus All pituitary hormones have circadian rhythms. Regions of the hypophysis : Adenohypophysis and Neurohypophysis

28. Anterior Pituitary ( adenohypophysis ) It is the “ true endocrine gland ”. Regulates the release and production of hormones such as prolactin , growth hormone , gonadotropins ( FSH and LH ), TSH , and ACTH The hormones secreted by this anterior lobe are either peptides or glycoproteins with pulsatile pattern.

29. Growth hormone

30. Growth Hormone ( GH )/ Somatotropin The most abundant of all pituitary hormones Controlled by GH-RH (the amount released) and somatostatin (governs the frequency and duration of secretory pulsatility ). Its anabolic and metabolic actions are facilitated indirectly by somatomedin G . The structure is similar to prolactin and human placental lactogen. Its secretion is erratic and occurs in short burst

31. Its overall metabolic effect is to metabolize fat stores while conserving glucose. It promotes bone growth with anti-insulin effect on muscles. Major stimulus : Deep sleep (markedly increased GH) Major inhibitor : Somatostatin (synthesized by the hypothalamus) Physiologic stimuli (increased) : Stress , fasting , and high-protein diet Pharmacologic stimuli (increased) : Sex steroids , apomorphine , and levodopa

32. GH suppressors : Glucocorticoids and elevated fatty acid Increased : Acromegaly , chronic malnutrition , renal disease , cirrhosis , sepsis , and DM Decreased : GHD , obesity , and hypothyroidism Common method : Chemiluminescent Immunoassay Reference value (fasting) : <10ng/mL

33. Related Disorders Growth Hormone Deficiency ( GHD ) It is defined as a serum GH concentration <10ng/mL with provocation as tested by a combination of at least two separate tests In healthy normal individuals, 70% to 80% of GH results are below 1 ng/mL (<1µg/L), and secretory peaks typically reach 20 to 40 ng/mL (20-40 g/L). Thus, in a child with decreased growth velocity, a low or non-detectable GH does not necessarily indicate GHD.

34. Idiopathic GHD The most common cause of GH deficiency GHD in childhood is described as the failure of serum GH to reach defined levels when at least two different pharmacological stimuli are used. In children with pituitary dwarfism, normal proportions are retained and there are no intellectual abnormalities. Pituitary Adenoma The most common etiology in adult-onset GH deficiency .

35. Related Disorders Acromegaly It is due to overproduction of GH (>50 ng/mL or 2210 pmol /L) Usually observed during adulthood Clinical manifestations: Diffused enlargement of soft tissues and organs throughout the body, prognathism, fontal bossing, and spade-like hands.

36. Diagnostic Tests Specimen requirement : Preferably fasting serum Fasting : 8-12 hours

37. Diagnostic Tests Growth Hormone Deficiency Screening test: Physical Activity Test ( Exercise test ) GHD : Deficient or decreased Non-GHD : Elevated serum GH If GH fails to increase after exercise, a confirmation must be made GH is always elevated after any form of exercise.

38. Confirmatory test Gold Standard : Insulin Tolerance Test ( ITT ) Second Confirmatory Test : Arginine Stimulation Test Third Confirmatory Test : Glucagon Stimulation Test Patient Preparation in ITT : Complete rest 30 minutes before blood collection Procedure : 24-hour or Night-Time Monitoring of GH Interpretation in ITT : Failure of GH to rise >5 ng/mL in adults and >10 ng/mL in children is confirmed GHD. ITT determines the integrity of hypothalamus-pituitary axis, specifically the GH secretion. ITT induces hypoglycemia and provokes GH release Confirmation of GHD in children is made if there is no increase after a two pharmacologic stimuli.

39. Diagnostic Tests Acromegaly Screening Test: Serum Somatomedin C or Insulin-like Growth-Factor-1 (IGF-1) IGF-1: is produced in the liver, increased in patients with acromegaly low in GHD GH stimulates the production of IGF-1 Physiologic increase : Pregnancy and late-stage adolescence

40. Confirmatory Test: Oral Glucose Tolerance Test ( 75g ) Fasting blood is required and the baseline blood glucose and GH levels are measured. Blood is collected every after 30 minutes for 2 hours Normal response: Suppression of GH <1 ng/mL Acromegaly: If GH fails to decline <1 ng/mL Diagnostic of Acromegaly: Failure of GH to be suppressed below 0.3 ng/mL accompanied by an elevated IGF-1 Excludes Acromegaly: Suppression of GH below 0.3 ng/mL with normal IGF-1 Requires follow-up and monitoring: Suppression of GH but increased IGF-1

41. Other Diagnostic Tests Macromelin Acetate Stimulation Test: It is considered as a secondary confirmatory in GHD Macromelin acetate is a drug that binds to the ghrelin receptor Oral dose : 0.5 mg/kg A reproducible safe diagnostic test for adult GHD, with accuracy comparable to that of the ITT.

42. Glucagon stimulation test and macromelin test are reasonable alternatives to the insulin tolerance test, whereas the arginine test is no longer recommended by the 2019 AACE Clinical Practice Guidelines because this test has insufficient diagnostic accuracy and requires a very low peak GH cut-point of 0.4 ug/L to make diagnosis

43. Other Diagnostic Tests Somatomedin C Also known as the insulin growth factor-1 (IGF-1) Mostly produced by the liver in response to GH stimulation. It determines if a person is producing a normal amount of GH It is vital for bone and tissue development by meditating the action of GH Its plasma concentration is directly proportional to GH though it is more stable

44. Other Diagnostic Tests Somatomedin C Excess GH and IGF-1 : Abnormal growth of the skeleton seen in gigantism and acromegaly Deficiency of IGF-1 : Lack of responsiveness to GH Deficiencies of GH and IGF-1 : Hypopituitarism or the presence of a non-GH-producing pituitary tumor that damages hormone-producing cell.

45. Gonadotropins: Follicle-stimulating hormones Luteinizing hormone

46. Gonadotropins : FSH and LH Important markers in the diagnosis of fertility and menstrual cycle disorders . Present in the blood of both male and female across ages. FSH functions in growth and maturity of ovarian follicles and estrogen secretion ; also aids in spermatogenesis (male). LH helps Leydig cells to produce testosterone (male); necessary for ovulation and the final follicular growth in females.

47. Gonadotropins : FSH and LH LH acts on thecal cells to cause the synthesis of androgens , estrogens ( estradiol and estrone ), and progesterone . Elevation of FSH is a clue in the diagnosis of premature menopause. Increase in FSH and LH after menopause is due to estrogen Measure ovarian reserve : FSH and anti- müllerian hormone . Method : Immunoassay

48. Reference Limits of Gonadotropins Male Female Follicle-Stimulating Hormone <12 months: ≤ 3.3 IU/L ≥12 months to ≤5 years: ≤ 1.9 IU/L ≥5 years to ≤10 years: ≤ 2.3 IU/L ≥10 years to ≤15 years: 0.6-6.9 IU/L ≥15 years to ≤18 years: 0.7-9.6 IU/L >18 years: 1.2-15.8 IU/L <12 months: 1.2-12.5 IU/L ≥12 months to ≤10 years: 0.5-6.0 IU/L ≥10 years to ≤15 years: 0.9-8.9 IU/L ≥15 years to ≤18 years: 0.7-9.6 IU/L Premenopausal : Follicular: 2.9-14.6 IU/L Midcycle: 4.7-23.2 IU/L Luteal: 1.4-8.9 IU/L Postmenopausal: 16.0-157.0 IU/L Luteinizing Hormone 6-30 mU /mL Premenopausal: >35 mU /mL Postmenopausal: <30 mU /mL

49. Clinical Correlation Hypogonadotropic hypogonadism (2 ° hypogonadism): Low FSH and LH Decrease in testicular production and synthesis of testosterone : Deficiency of FSH and LH Inadequate spermatogenesis : Deficiency of FSH and LH Polycystic ovarian disease ( PCOS ): Normal FSH and High LH (sometimes FSH is low)

50. Clinical Correlation Male testosterone secretion rate and concentration drop beyond 50 years old while female pituitary gonadotropins , particularly FSH , increase . Hypogonadotropic hypogonadism is a common cause of secondary amenorrhea.

51. Gonadotropin-Releasing Hormone (GnRH) Stimulation Test Gold standard test in identifying central precocious puberty (CPP) and premature activation of the activation of the hypothalamic-pituitary-gonadal axis (HGPA) in cases with clinical signs and symptoms of early puberty. Purpose : To determine the cause of the onset of pubertal signs before the age of 8 years in girls . Sample requirement : Multiple blood samples at different time points to measure gonadotropin level.

52. Standard dose : 100 µg GnRH IV bolus Procedure : An IV cannula was inserted and blood samples are obtained immediately before the injection and at 15 , 30 , 45 , 60 , 90 and 120 minutes after the injection . Duration of the test : 90 to 120 minutes (reaching up to 24 hours) Marker for CPP, CDCG, and HPGA : FSH , LH , Estrogen , and Testosterone

53. Markers for HH : GnRH , FSH , and LH In CPP, added tests : LH, FSH, and estradiol (measured together with GnRH ) Result : A stimulated LH value ≥5 IU/L was considered diagnostic for CPP in patients with pubertal signs. Stimulated LH value <5 IU/L : Classified as having puberty thelarche (PT)

54. Establish the diagnosis of CPP Distinguish constitutionl delay of growth and puberty (CDGP) from hypogonadotropic hypogonadism (HH) Evaluate hypogonadotrophic hypogonadism in infancy Determine accelerated pubertal progression Indications for GnRH Stimulation Test

55. It is also known as thyrotropin . It is the main stimulus for the uptake of iodide by the thyroid gland. It acts to increase the number and size of follicular cells. It stimulates thyroid hormone synthesis . It is composed of 2 mono-covalently linked to a and B subunits has the same amino acid sequences of LH, FSH, and HCG, while the B-subunit directs the receptors for binding to express its hormonal activities Blood levels may contribute in the evaluation of infertility. Reference range : 0.5- 5 µU/ mL ( 0.5- 5 µU/L ) Thyroid-Stimulating Hormone (TSH)

56. Thyroid-Stimulating Hormone Assay TSH Assay Detection Limit Clinical Significance Remarks First Generation (RIA) 1.0 mIU /L Diagnosis of primary hypothyroidism Requires TRH stimulation test to detect hyperthyroidism Second Generation ( Immunometric ) 0.1 mIU /L Diagnosis hyperthyroidism Without TRH stimulation test to identify hyperthyroidism Third Generation (ICMA) 0.01 mIU /L Most useful test for the assessment of thyroid function Differentiates hyperthyroidism from euthyroidism Determines abnormality in thyroid hormone synthesis Most commonly used method Preferred method for monitoring and adjusting THRT Detects subclinical thyroid disease Few false negative result compared to second generation. Fourth Generation ( LiCA Smart) 0.0004 mIU /L For research purpose Not used in disease diagnosis Detects TSH levels <0.01 mIU /L

57. adrenocorticotropic hormone ( acth )

58. Adrenocorticotropic Hormone (ACTH) It is a single-chain peptide without disulfide bonds. It is produced in response to low serum cortisol - regulator of adrenal androgen synthesis . Deficiency in ACTH will lead to atrophy of the zona fasciculata and zona reticularis (layers of the adrenal cortex) Highest level is between 6:00 AM to 8:00 AM, while the lowest level is between 6:00 PM to 11:00 PM Sample requirement : Blood sample is best collected between 8:00AM - 10:00 AM

59. Adrenocorticotropic Hormone (ACTH) Blood collection tube : Sample should not be allowed to have contact with glass because ACTH adhere to glass surface resulting to decreased levels, hence plastic tubes are utilized. Sample precaution : Blood should be collected into pre-chilled polystyrene (plastic) EDTA tubes to prevent degradation of ACTH. Method: Two-site Immunoradiometric or Immunochemiluminometric Increased : Cushing's disease , Addison's disease , ectopic tumors , and after protein-rich meals Reference range : 9-52 pg /mL (2-12 pmol /L) between 7 AM to 10 AM ACTH is reported to be stable in EDTA plasma at 4°C for only 18hours compared with 19 other hormones that are stable for >120 hours.

60. prolactin ( Prl )

61. Prolactin (PRL) It is pituitary lactogenic hormone, a stress hormone, and a direct effector hormone. It is secreted in a circadian rhythm with secreted pulsatile feedback . Its action is controlled by the inhibitory action of dopamine produced by the hypothalamus. It functions in the initiation and maintenance of lactation. Together with estrogen and progesterone, it promotes breast tissue development. It is clinically significant when the serum concentration is elevated.

62. Prolactin (PRL) It is a supplemental test in erectile dysfunction. It is influenced by hook effect ( prozone effect). Unique characteristic among the anterior pituitary hormones: Tonic inhibition Major circulating form of PRL : Non-glycosylated monomer Major inhibitor : Dopamine (secreted by the hypothalamus) Method : Immunoassay Increased : Amenorrhea , galactorrhea , infertility , acromegaly , renal failure , polycystic ovary syndrome , cirrhosis , and primary and secondary hypothyroidism

63. Prolactin (PRL) Very high PRL (>200 ng /mL): Pituitary adenoma ( prolactinoma can result in anovulation) Consequence of prolactin excess : Hypogonadism High PRL : Low FSH, LH, and testosterone; low sperm count Pituitary necrosis or infarction : PRL deficiency Reference range : Male = 1-20 ng /mL (1-20 µg/L) Female = 1-25 ng /mL (1-25 µg/L) Prolactin serum level >250 µg/L : Pituitary tumor ( prolactinoma can result in anovulation

64. Physiologic Stimulation, Sample Collection, and Measurement Highest serum level (during sleep): 4:00 am and 8:00 am; 8:00 pm and 10:00 pm Physiologic stimuli (increased): Exercise, sleep, stress, pospandrial pain, coitus, pregnancy, nipple stimulation or nursing. Pharmacologic (increased): Intake of verapamil, phenothiazines , olanzapine, Prozac, cimetidine, and opiate

65. Physiologic Stimulation, Sample Collection, and Measurement Sample Collection: Blood should be collected 3 to 4 hours after the individual has awakened. Sample requirement: Fasting serum; ideally three (3) samples should be obtained at 20- to 30-minute intervals because of physiologic stimuli Procedure for the three samples: It can be measured separately and their results averaged, or an equal aliquot from each sample can be pooled into one final sample that is the analyzed.

66. POSTERIOR PITUITARY ( Neurohypophysis ) This portion of the pituitary is capable of releasing hormones, but not capable of producing . The hormones released by neurohypophysis are synthesized in the magnicellular neurons of the supraoptic (ADH) and paraventricular (oxytocin) of the hypothalamus, and stored in the nerve terminals that end in the posterior pituitary gland. The release of the hormones occurs in response to serum osmolality or by suckling. Hormones produced by the neurohypohysis are controlled by the central nervous system (CNS).

67. oxytocin

68. Oxytocin a nonapeptide and very similar in composition to ADH. secreted in association with a carrier protein. It stimulates contraction of the gravid uterus at term - "Fergusson reflex.“ released in response to neural stimulation of receptors in the birth canal and uterus, and of touch receptors in the breast. It plays a role in hemostasis at the placental site following delivery.

69. Oxytocin It stimulates muscle contraction during delivery and lactation - with bursts of oxytocin secretion occurring with anticipation of nursing or on hearing a baby cry . Synthetic preparations : To increase weak uterine contractions during parturition and to aid in lactation Pathologic conditions associated with oxytocin excess of deficiency are rare and are limited to case reports. Its function in males remains unknown

70. Arginine Vasopressin

71. Arginine Vasopressin (AVP) It is formerly known as the anti-diuretic hormone (ADH). It is a nonapeptide that acts on the distal convoluted and collecting tubules of the kidneys. It decreases the production of urine by promoting reabsorption of water by the renal tubules thereby maintains water homeostasis. It regulates the total concentration of blood through water balance (osmotic homeostasis). It increase blood pressure - decrease in blood volume or blood pressure will likewise stimulate AVP release.

72. Arginine Vasopressin (AVP) It makes the renal collecting tubule permeable to water. It is a potent pressor agent and affects blood clotting by promoting factor VII release from hepatocytes and factor VIII (von Willebrand factor) release from the endothelium. Major function : Maintains osmotic homeostasis by regulating water balance Sample : Serum or EDTA plasma Method : Immunoassay Reference range : 0.5-2 pg /µL

73. Controls AVP Principal regulator of AVP secretion : Increased plasma osmolality Physiologic stimuli to AVP secretion : Nausea, cytokine, hypercarbia, pregnancy, hypoglycemia, and nicotine. Physiologic stimuli to AVP release : Dehydration (emesis), physical and emotional stress due to major surgery Suppress AVP release : Low plasma osmolality Inhibitors of AVP release : Ethanol, cortisol, lithium, and demeclocycline Defect in AVP regulation : Malignancies, pulmonary disease, CNS disorders, and fungal infection.

74. I n Relation to Osmolality Secretion of AVP is directly related to the concentration of the plasma osmolality. AVP secretion is maximally stimulated at a serum osmolality >295 mOsm /kg and suppressed when the osmolality is <284 mOsm /kg. A rise in plasma osmolality shrinks the hypothalamic osmoreceptor cells stimulating the thirst center in the cerebral cortex, thereby promoting AVP synthesis in the supraoptic and paraventricular nuclei. Conversely, a decline in effective osmolality causes swelling of the osmoreceptor cells, resulting in inhibition of AVP production.

75. I n Relation to Osmolality Types of AVP receptors : V1 receptors = responsible for the increase in vasomotor tone with metabolic effects V2 receptors = associated with antidiuresis V3 receptors = stimulates ACTH secretion Antidiuretic effect of ADH : Facilitated by the protein aquaporin-2 on the collecting duct membrane to make the tubule permeable to water.

76. Related disorders

77. Diabetes Insipidus It is characterized by the deficiency of AVP which results in severe polyuria (≥2.5 liters of urine/day). Hallmark of DI : Hypotonic urine Serum osmolality : Increased (>295 mOsm /kg) Urine osmolality : Decreased (<300 mOsm /kg) Serum Sodium : Increased (<145 mmol/L) Clinical picture : Normoglycemia , polyuria with low specific gravity , polydipsia (secondary polydipsia), and polyphagia (occasional).

78. Polyuria defined as excretion of a urinary volume >150 mL/kg/24 hours at birth >100-110 mL/kg/24 hours up to the age of 2 years >50 mL/kg/24 hours in older children and adults. Hypotonic Urine a urine sample with an osmolality of <300 mOsm/kg.

79. True Diabetes Insipidus Hypothalamic/Neurogenic/Cranial/Central DI It is characterized by either a complete absence of or low plasma AVP receptors . It results from damage to the hypothalamus or even the neurohypophysis which is responsible for the release of AVP. It may also be caused by genetic abnormalities or mutations affecting the hypothalamus or pituitary gland, and medications. Other causes : Head trauma , infectious diseases , anemia , alcoholism , and drugs . Major Types of Diabetes Insipidus

80. Nephrogenic Diabetes Insipidus It is seen as having normal plasma or elevated AVP but abnormally functioning AVP receptors (renal resistance to AVP action). It is due to kidney failure (due to renal disease) to respond to normal or elevated AVP plasma concentration. Nephrogenic DI is either congenital (X-linked receptor defect) or acquired (medications). It may also be caused by using prohibited drugs such as propoxyphene ( darvon ). Other causes : Electrolyte imbalance , multiple myeloma , and sarcoidosis .

81. Primary Polydipsia Psychogenic Polydipsia/Dipsogenic DI It is also known as the compulsive water drinking disorder without a stimulus. It may be due to a faulty thirst hypothalamic mechanism Other Types of Diabetes Insipidus

82. Primary Polydipsia The AVP secretion is normal, however, excess water intake without an underlying stimulus causes the loss of the concentrating ability of the kidneys with increased urine volume. Although primary polydipsia is not a true DI state, long-standing primary polydipsia can give rise to a DI-like picture on laboratory evaluation. Serum osmolality and Sodium : Normal or low level Other Types of Diabetes Insipidus

83. Gestational Diabetes Insipidus It develops due to the excessive activity of the placental cysteine aminopeptidase (PCAP) or placental vasopressinase . It results from the degradation of the AVP by PCAP during pregnancy. It is usually observed in the last trimester of pregnancy and remitting spontaneously 4 to 6 weeks post-partum. Other Types of Diabetes Insipidus

84. Gestational Diabetes Insipidus Other factors may also contribute to gestational DI such as the increase in the secretion of other hormones during pregnancy that are against the action of PCAP. AVP secretion is normal but there is overactivity of the PCAP leading to catalysis of the hormone . PCAP is expressed by placental trophoblasts. Other Types of Diabetes Insipidus

85. Water Deprivation Test/Dehydration Test Gold standard It measures the serum and urine osmolality. Patient Preparation : At least 8 hours no fluid intake or until 5% of the body mas has been lost; avoid smoking and caffeine intake that might affect AVP release or urine output. Baseline test : Serum and urine osmolality, serum Sodium (include serum AVP or copeptin together with the WDT, if available) Diagnostic Test in DI

86. Water Deprivation Test/Dehydration Test Procedure : Patient weight, pulse rate, BP should be taken hourly; serum osmolality is measured every 4 hours and urine volume and osmolality every 2 hours; test is conducted usually for 8 hours. Option : WDT may also be performed in the morning, starting 8 am. Precaution : When the serum osmolality increases to >305 mOsm /kg, it is highly suggestive of DI, and the WDT should be discontinued; if the body is 3% or less, the WDT may be stopped. Diagnostic Test in DI

87. Sign of DI : >295 mOsm /kg Highly suggestive of DI : Serum osmolality >305 mOsm /kg Excludes DI : Urine osmolality 800-1200 mOsm /kg After 8 to 12 hours without fluid intake, urine osmolality does not rise above 300 mOsm /kg, it is diabetes insipidus. Plasma osmolality of about 285 mOsm /kg usually act as a trigger for thirst. Interpretation of Result

88. AVP and Copeptin : Differentiates neurogenic DI and primary polydipsia from nephrogenic DI Desmopressin : Differentiates neurogenic from nephrogenic DI 3% HSI with Copeptin : Differentiates neurogenic DI from primary polydipsia. * HSI – hypertonic saline infusion Additional Differential Test for the Diagnosis of DI

89. Types of DI Water Deprivation Test Plasma AVP Plasma Copeptin HIS with Copeptin Standard Test (Urine Osm ) With Demospressin Neurogenic DI <300 mOsm /kg >800 mOsm /kg Low Low ≤4.9 pmol /L Nephrogenic DI <300 mOsm /kg <300 mOsm /kg High High Primary Polydipsia 300-800 mOsm /kg Low Low Gestational DI WDT is normally not recommended during pregnancy because it may lead to significant dehydration. Desmopressin drug (for treatment) may be prescribed with a caution. Pituitary MRI is requested to exclude lesions in the hypothalamic-pituitary region. Baseline test reveals: Low UOsm with upper limit serum osmolality and Sodium.

90. It is a 39-amino-acid C-terminal segment of pre-pro-arginine vaspressin . It is secreted in response to the same stimuli as AVP and in equimolar amounts to AVP. Its high ex-vivo stability and ease of measurement make it an excellent surrogate for AVP. Clinical significance : Marker for Diabetes Insipidus Increased : Acute illness, Myocardial infarction, and Stroke Copeptin

91. Copeptin with arginine infusion stimulation has been shown to differentiate between DI and PP (aside from copeptin and HSI). Diagnostic of Nephrogenic DI: Baseline copeptin level of >21.4 pmol /L (without pre-thirsting). Reference range: 1.0-13.8 pmol /L (McPherson and Pincus, 2022) 4.0-4.4 pmol /L ( Balanescu et al., 2011) Copeptin

92. Water Deprivation Test and Desmopressin Desmopressin test is performed together with the WDT after the 8-hour dehydration or NPO. 2 µg desmopressin is administered IV or IM then urine and serum/plasma samples are obtained hourly for 1 to 2 hours after injection.

93. It is seen with continuous production of ADH in the absence of stimuli. Increased ADH or copeptin concentrations are often associated with SIADH. Causes : CNS disease , cancer , tuberculosis , pneumonia , medications , and nicotine . Diagnostic feature : Euvolemic hypoosmolar hyponatremia associated with hyperosmolar urine. Urine volume : Decreased Serum Sodium : Decreased (<135 mmol/L) Syndrome of Inappropriate ADH Secretion

94. Urine Sodium : Normal or Increased (>20 mmol/L) Serum osmolality : Decreased (<275 mOsm /kg) Urine osmolality : Normal or Increased (>800 mOsm /kg) Diagnostic test : Water Loading Test ( WLT ) Confirm SIADH based on WLT: Failure to excrete ≥80% of the administered water load within 4 hours and to suppress the UOsm to <100 mOsm /kg. Syndrome of Inappropriate ADH Secretion