ENDOCRINE

Endocrine Function

• Endocrinology is the study of glands and the hormones they secrete
• Hormones are broadly classified into two groups: water-soluble and lipid-soluble
• Water-soluble hormones travel through the bloodstream to target tissues, influencing their functions. They can also act on physically adjacent structures (paracrine function) or even on the cells that produced the hormone (autocrine function).
• Hormone levels are regulated by other hormones, negative feedback, and other homeostatic signals.
• Hormone secretion follows specific time patterns.
• Endocrine disorders often result from hormone excess or deficiency.

Water-Soluble Hormone Structures

• Norepinephrine: An amine hormone modified from the amino acid tyrosine. It is hydrophilic and polar, unable to passively cross cell membranes. It acts on G protein-coupled receptors.
• Oxytocin: A short peptide chain hormone consisting of nine amino acids. It is hydrophilic and water-soluble. It acts on G protein-coupled receptors.
• Growth hormone: A long protein chain hormone comprising 190 amino acids. It is hydrophilic and water-soluble. It acts on cytokine receptors and activates JAK-STAT signaling.

Lipid-Soluble Hormone Structures

• Steroid hormones: Derived from cholesterol, they are hydrophobic and lipid-soluble. They act on cytoplasmic and nuclear receptors.

Modes of Hormone Signaling

• Endocrine: Hormone is released into the bloodstream and travels to target cells.
• Autocrine: A cell has a receptor for its own hormone.
• Paracrine: A hormone diffuses to a neighboring cell with a receptor for that hormone.
• Neuroendocrine: A neuron synthesizes a hormone, and action potentials release it into blood vessels.

Cellular Mechanisms of Hormone Signaling: Hydrophilic Hormones

• Phospholipase C: Cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), serving as second messengers.
• Adenylyl cyclase: Catalyzes the conversion of ATP to 3',5'-cyclic AMP (cAMP), acting as a regulatory signal.

Cellular Mechanisms of Hormone Signaling: Hydrophobic Mechanisms

• Cytoplasmic and nuclear (intracellular) receptors: Hormone-response elements (HREs), messenger RNA (mRNA), and nuclear receptors are involved.

Hormone-Binding Proteins

• Hydrophobic hormones travel in the circulation bound to hormone-binding proteins (often produced by the liver), extending their half-life.
• Examples include corticosteroid-binding globulin, sex steroid-binding globulin, thyroxine-binding globulin, and albumin.
• Specific examples are listed in a table of hormones and their corresponding binding proteins.

Objectives for the Endocrine System Part 1: the Hypothalamus and Pituitary

• Learn the anatomy and pathophysiology of the hypothalamus and pituitary
• Understand relationships between the hypothalamus and pituitary
• Identify hormones secreted by the hypothalamus, anterior, and posterior pituitary
• Describe the function of specific cells (somatotrophs, gonadotrophs, lactotrophs, thyrotrophs, corticotrophs) and regulatory signals.

Major functions of the hypothalamus

• Controls food intake, body temperature, and sleep/wake cycles.
• Influences autonomic function through projections to the brainstem.
• Produces posterior pituitary hormones (arginine vasopressin (AVP), oxytocin (OT)).
• Produces releasing and inhibiting hormones that regulate anterior pituitary endocrine cells.

Hormones of the Hypothalamus

• Specific hypothalamic hormones (TRH, SST, GnRH, CRH, GHRH) are listed with corresponding functions related to stimulation of anterior pituitary hormones, etc.

Hormones of the Anterior Pituitary and Posterior Pituitary

• Specific anterior pituitary hormones (TSH, LH, FSH, GH, PRL, ACTH) and their functions are listed (stimulated by hypothalamic hormones and have specific targets)
• Specific posterior pituitary hormones (AVP/ADH and OT) and their functions are listed.
• The different sources of these hormones, including cell types are also listed.

other hormones from the pituitary: melanocyte stimulating hormones

• MSHs are a family of peptide hormones and neuropeptides (α-MSH, β-MSH, and γ-MSH) produced by cells in the pars intermedia of the anterior pituitary lobe.
• Melanocytes in skin produce and secrete MSH in response to ultraviolet light.

Endocrine Disorders of the Hypothalamus and Pituitary

• Common and specific disorders are listed.

Hypothalamic-Pituitary-Target Gland Axes

• Hypothalamic neuroendocrine cells control pituitary hormone release.
• Anterior pituitary cells control target gland hormone release.
• Target gland hormones provide negative feedback to pituitary and hypothalamus.

The Structure of the Hypothalamus

• The hypothalamus is found at the base of the brain, surrounding the third ventricle above the pituitary gland.
• Hypothalamic nuclei interact by synaptic connections, producing peptide neurotransmitters.
• It regulates sleep/wake, food, thirst and temperature/autonomic function
• Neuroendocrine cells in the nuclei have axons traveling in the pituitary stalk, releasing pituitary-controlling hormones to/via blood vessels.

Relationship of Hypothalamus With Pituitary

• The hypothalamus lies below the thalamus, connected to the pituitary gland by the infundibulum (pituitary stalk).
• Blood vessels in the infundibulum receive hypothalamic hormones.
• Axons of AVP and OT neurons.
• The posterior pituitary gland is the site of AVP and OT secretion.
• Anterior pituitary contains endocrine cells secreting ACTH, TSH, LH, FSH, GH, and PRL.

Hypothalamic/Posterior Pituitary Hormones

• Neuroendocrine cells in specific nuclei produce AVP and OT.
• AVP secretion is stimulated by higher blood osmolality or hypotension.
• Angiotensin II receptors in the hypothalamus stimulate AVP secretion and cause thirst.
• Oxytocin secretion is stimulated during labor and milk let-down.

Hypothalamic Regulation of Energy Intake and Expenditure

• Arcuate and paraventricular nuclei regulate food intake and energy expenditure, integrating central and peripheral signals.
• ARC NPY/AgRP/GABA neurons promote food intake via projections to the PVN, acting on Y1 and Y5 receptors.
• ARC POMC neurons synthesize α-MSH, inhibiting food intake

Hypothalamus and Pituitary Development

• Oral ectoderm folds to form Rathke's pouch.
• Neural endoderm folds downward, below the third ventricle.
• Rathke's pouch-derived tissue creates the anterior pituitary.
• Neural endoderm forms the pituitary stalk and posterior pituitary.

Hypothalamus and Anterior Pituitary Regulation

• Hypothalamic neuroendocrine cells project to pituitary stalk capillary portal system.
• Anterior pituitary cells receive releasing and inhibiting hormones via portal veins and pituitary capillaries.
• Anterior pituitary cells secrete hormones into a secondary capillary bed within the pituitary to travel to the systemic circulation.

Targets of Anterior Pituitary Hormones

• Specific hormones (GH, ACTH, LH, FSH, PRL, TSH) are listed with their corresponding cell type and targets.
• Percentage of pituitary population for each cell type is included.

Anterior Pituitary Somatotrophs

• Function: synthesize and secrete growth hormone
• Regulation of Growth Hormone secretion (stimulated and inhibited by specific hormones and factors)
• Circadian pulsatile rhythm with increased secretion at night.
• Highest levels in growing children and adolescents.

Growth Hormone Secretion

• GH secretion is stimulated by hypothalamic GHRH, ghrelin, etc.
• Growth hormone acts to stimulate secretion of IFG-1 by liver.
• IGF-1 inhibits hypothalamic somatostatin secretion to suppress pituitary GH secretion.
• Relevant hormones/factors (GH, GHRH, IGF-1, SS)

Growth Hormone Mechanism of Action

• Growth hormone receptors are cytokine-type, linked to JAK-STAT signaling; some have direct effects on target tissues.
• Promotes liver synthesis of IGF-1, which elicits wide-ranging growth-promoting effects via insulin-type receptors.
• Actions include: bone growth, muscle growth, organ growth & maintenance (brain, heart, kidneys, etc.) antagonism of insulin's action on glucose regulation.

Growth Hormone Mechanism of Action (Part 2)

• Prenatal growth depends on GH; marked effects on bone and muscle in childhood.
• GH deficiency leads to short stature, whereas excess leads to extreme height.
• GH effects are mediated by IGF-1.
• Importance of GH, GHRH, and IGF-1 in regulating growth.

Somatotroph Dysfunction

• Hyposomatotrophism: congenital GH deficiency resulting in growth retardation.
• Hypersomatotropism: due to GH-secreting tumors, presenting as gigantism or acromegaly in childhood or adulthood, respectively resulting in various symptoms and difficulties.

Gonadotrophs

• LH and FSH secretion is stimulated by hypothalamic GnRH.
• GnRH stimulates LH and FSH during fetal development, though levels normally decrease after birth.
• GnRH neurons are activated at puberty by hypothalamic kisspeptin.
• Hypo- and hyper-functioning are rare.

Anterior Pituitary Lactotrophs

• Function: synthesis and secretion of prolactin.
• Prolactin is secreted as a monomer, dimer, etc.
• Regulation of prolactin secretion via dopamine and estrogen stimulation.
• Important for lactotroph proliferation during pregnancy for lactation.

Lactotroph Dysfunction

• Hypoprolactinemia: rare, related to pituitary damage or another adenoma.
• Hyperprolactinemia: common, often due to microprolactinomas, presenting with symptoms like amenorrhea, infertility, etc.

Thyrotrophs

• Secrete TSH, a water-soluble glycoprotein hormone.
• Stimulated by hypothalamic TRH, inhibited by triiodothyronine (T3) negative feedback.
• TSH deficiency can result from pituitary damage, while TSH excess is rare.

Posterior Pituitary: Vasopressin

• Vasopressin (AVP/ADH) is a small peptide hormone that acts on G protein-coupled receptors.
• Promotes renal water conservation.
• Secretion is stimulated by increased blood osmolality or hypotension
• Hypofunction (Diabetes insipidus) presents as excessive urine production, while hyperfunction (SIADH) results in fluid retention.

Anterior Pituitary Corticotrophs

• Function: synthesize ACTH from precursor POMC.
• Hypothalamo-pituitary-adrenal (HPA) axis: Hypothalamic CRH stimulates ACTH synthesis and release.
• Adrenal cortisol inhibits hypothalamic CRH and pituitary ACTH release.
• ACTH is a growth factor for the adrenal gland and directly stimulates adrenal cortisol synthesis and secretion.

Production of ACTH

• POMC gene expression in anterior pituitary corticotrophs, hypothalamic intermediate lobe cells, etc.
• Differential splicing produces different final products, including ACTH and β-endorphin, for secretion.

Corticotroph and Adrenal Hypofunction

• Causes of decreased cortisol levels include pituitary damage, autoimmune destruction, and exogenous steroid treatment.

Corticotroph Hyperfunction

• Cushing disease is a result of an ACTH-secreting pituitary adenoma that causes excessive cortisol secretion.
• Negative effects of prolonged cortisol excess include various symptoms e.g. weight gain, immune response, etc

Endocrine System Part 2: The Adrenal Glands

• Major functions of adrenal glands include secretion of different hormones (aldosterone, cortisol, sex steroids, epinephrine) which influence various bodily functions such as blood pressure regulation, stress response, etc.

Adrenal Gland Hormone Production

• Steroid hormone production occurs in the cortical zone.
• The medulla produces epinephrine and norepinephrine.

Hormones of the Adrenal Glands

• Specific adrenal hormones (cortisol, aldosterone, androgens, epinephrine, norepinephrine).
• Actions and targets of each hormone are elaborated.

Pediatric Genetic Disorder: Congenital Adrenal Hyperplasia

• Most common deficiency of enzyme 21-hydroxylase.
• This impairs the paths of cortisol and aldosterone synthesis.
• The resulting effects cause the body to utilize alternative pathways (e.g., producing sex steroids).
• Symptoms/effects vary greatly, possibly including ambiguous genitalia, sexual development differences or significant health issues.
• Other causes of CAH include defects in other enzymes.

Congenital Adrenal Hyperplasia

• Different enzymes in the pathway can be affected, resulting in variable expressivity and severity.
• This often leads to prenatal development issues, particularly in females with masculinized genitalia, and often salt-losing issues.

Gerontological Considerations

• Endocrine alterations with aging include decreased growth hormone/IGF-1 (somatopause), Decreased DHEA and DHEAS, Increased cortisol, with potential correlations with cognitive decline and depression.

Hormones Made by the Pancreas and Their Functions

• The specific hormones from the pancreas-- insulin and glucagon and somatostatin are listed, including their molecular type and molecular weight.
• Their activities/functions are described.

Metabolism and the Pancreas

• The liver, muscles, and adipose tissue are major metabolic tissues.
• Glucose, fatty acids, and amino acids are important metabolic biomolecules, especially related to energy/fuel usage in the fed and fasting states.
• Specific metabolic pathways and processes are detailed during the fed and fasting states for each tissue (e.g. glycogenolysis, gluconeogenesis), especially in response to different hormones.

Metabolism and the Pancreas (Part 2)

• Insulin is the major anabolic hormone in the fed state, while glucagon is the major catabolic one in the fasting state.
• Other hormones (cortisol, epinephrine, growth hormone, and chorionic somatomammotropin) also affect glucose/insulin/lipid homeostasis via antagonistic activities.

Metabolism and the Pancreas (Part 3)

• Diabetes mellitus (DM) is a disorder of insulin metabolism, often resulting in chronic hyperglycemia.
• Type 1 DM results from autoimmune destruction of β cells, leading to absolute insulin lack.
• Type 2 DM results from insulin resistance, plus dysfunction of beta cells, leading to declining insulin production.
• Diagnosis (e.g., fasting blood glucose, oral glucose tolerance test, hemoglobin A1c) to identify altered glucose homeostasis.

Disorders Associated with the Pancreas and DM

• Various disorders related to the pancreas and DM (e.g., diabetic ketoacidosis, hypoglycemia), and complications (e.g., diabetic microangiopathy, retinopathy).

Metabolic Processes in the Fed State-Liver, Muscle, Adipose

• Processes like glucose use, glycogen formation, fatty acid production in response to insulin.
• How different organs/tissues (liver, muscle, adipose) respond to insulin, metabolize glucose, and store/release fuels during the fed state.

Metabolic Processes in the Fasting State-Liver, Muscle, Adipose

• Specific processes (gluconeogenesis, glycogenolysis, lipolysis) in different organs are detailed.
• This section explains how organs can release glucose or fatty acids to meet the body's needs during fasting.

Liver Ketone Production

• Elevated fatty acid metabolism in the liver can lead to ketone body production.
• How liver uses fatty acids for energy, especially in prolonged fasting and/or stress states.
• Ketone bodies are a secondary energy source for the body, but especially the brain.

Insulin

• Insulin is a protein hormone that promotes anabolic activity, lowering blood glucose, and promoting growth/development.
• It is secreted from clusters of endocrine cells from pancreatic exocrine structures.

Insulin Structure and Synthesis, Mechanisms of Action 1/2

• Insulin is initially made as a precursor (preproinsulin), which is processed into proinsulin and cleaved to insulin and C-peptide.
• Details of how insulin binds to its receptor and triggers intracellular signaling to promote glucose transport into tissues (muscle, fat) are described for both parts.
• Different steps and pathways are involved.

Insulin Causes GLUT4 Translocation in Muscle and Fat

• Insulin triggers movement of GLUT4 transporters to the membrane, promoting glucose uptake into muscle and fat cells.
• The process is a response to changes in insulin and glucose levels.

Effect of Insulin on the Liver

• Insulin promotes various anabolic processes, like glycogen synthesis, synthesis of fatty acids, cholesterol, etc.
• Insulin inhibits catabolic processes like glycogenolysis and glucose production (gluconeogenesis).

Insulin Actions in Fat Cells

• Insulin promotes glucose uptake, glycerol formation, and triglyceride synthesis (lipogenesis) in fat cells.
• Inhibits lipolysis (breakdown of triglycerides) through inhibition of hormone-sensitive lipase.

Control of Insulin Secretion

• Glucose enters beta cells, generating ATP, closing potassium channels, depolarizing the membrane, opening calcium channels, triggering insulin secretion.
• Additional stimuli (e.g., amino acids, gut hormones GLP-1 and GIP) enhance insulin secretion.

Mechanisms of Insulin Secretion

• Detailed mechanisms, beginning with meal consumption, explaining how increased glucose and amino acids stimulate insulin release.

Phases of Insulin Secretion

• The first phase of insulin secretion is rapid, involving readily available insulin stores.
• The second phase is slower, involving the synthesis and release of newly produced insulin.

Hormones of Fasting and Catabolic States 1/2/3/4/5

• Listing of anti-insulin hormones (glucagon, cortisol, epinephrine, growth hormone, and chorionic somatomammotropin) and their actions to release stored fuels during fasting/stress. This section describes various hormones involved during the fasting/stress states—their sources, effects/actions on different organs and tissues, and the reasons behind their production in specific situations.

Diabetes Mellitus

• Definition and types of diabetes mellitus (DM): type 1, type 2, gestational.
• Pathogenesis of each type, risk factors, and possible causes are detailed.

Diabetes Mellitus (Diagnosis)

• Diagnosis of DM focuses on glucose measurements (fasting blood glucose, oral glucose tolerance test, Hemoglobin A1c).
• Glucose homeostasis and various ways to assess blood glucose are explored.

Type 1 DM

• Autoimmune disorder, with genetic influence and concordance among twins.
• Antibodies to islet proteins (GAD, ICA512, insulin).
• Details of type 1 DM's severe presentation, characteristic symptoms (polyuria, polydipsia, polyphagia), and metabolic disturbances (DKA, proteolysis, lipolysis).

Type 1 DM (Diabetic Ketoacidosis)

• Detailed explanation of diabetic ketoacidosis (DKA), including metabolic processes, like lipolysis, proteolysis, and the specific role of ketones/glucose.

Hypoglycemia

• Results from imbalance of insulin dose and foods/exercise, with sleep reducing counterregulation responses.
• Common acute complication of type 1 diabetes mellitus, detailed causes.

Type 2 DM

• Type 2 diabetes encompasses 95% of all DM cases.
• Pathogenesis, including insulin resistance and beta-cell vulnerability, is explained.
• Risk factors, and screening methods for identifying patients with diabetes/prediabetes are provided.

Trajectory of T2DM

• Insulin resistance increases progressively in prediabetic patients.
• Endogenous insulin secretion increases to compensate, but it can cause postprandial hyperglycemia and eventually lead to beta-cell failure as the disease progresses.

The “Ominous Octet" of T2DM Pathophysiology

• Pathophysiology of T2DM encompasses eight factors related to impaired glucose metabolism; describing the factors driving the development of T2DM. A key concept for identifying the complex nature of type 2 diabetes

Obesity and T2DM

• Obesity is highly correlated to T2DM, although all obese individuals do not get T2DM.
• Visceral obesity releases fatty acids and cytokines, promoting liver insulin resistance and hyperglycemia.
• Fatty acid metabolism reduction of glucose utilization, contributing to hyperglycemia.

Hyperosmolar Hyperglycemic Syndrome

• A critical acute complication of T2DM, often triggered by infections, resulting in decreased fluid intake and increased stress hormones, causing a severe hyperosmotic state that is challenging to treat.

Chronic Diabetes Complications

• Macrovascular complications (e.g., stroke, myocardial infarction).
• Factors like inflammation, smoking, and hypertension contribute to the development of macrovascular issues in individuals with diabetes.
• Microvascular complications and chronic hyperglycemia's impact on the small blood vessels in the retina, causing retinopathy and nephropathy.
• Microvascular disease combined with axonal injury can contribute to the development of diabetic neuropathy.

Chronic Microvascular Diabetes Complications

• Key factors contributing to diabetic microangiopathy such as advanced glycation end products (AGEs) and reactive oxygen species (due to excessive glucose metabolism and oxidative stress.)

Gestational Diabetes Mellitus

• Pathogenesis, characterized by insulin resistance in pregnancy, often correlating with the placenta’s degrading insulin, stressing beta cells, and increasing hepatic glucose production.
• A history of gestational diabetes mellitus is a risk factor for later development of Type 2 diabetes.