Endocrine 4

Pathophysiology of Adrenal Cortex

• Addison’s Disease (hypofunction):

  • Definition: Hypofunction of the adrenal cortex leading to insufficient production of adrenocortical hormones (cortisol and aldosterone)

  • Causes:

    • Mainly due to autoimmune attacks on the adrenal glands.

    • Other causes include tuberculosis.

      • Majority of people don’t know they have it

  • Characteristics:

    • May involve total destruction of the adrenal gland.

    • Blood sugar drops, leading to a lack of energy

    • Loss of sodium and rise of potassium and protons, which can lead to acidosis of the blood

  • Treatment:

    • Administration of aldosterone or cortisol or synthetic glucocorticoids/mineralocorticoids

• Cushing’s Disease (hyperfunction):

  • Definition: Hyperfunction characterized by excessive production of glucocorticoids and increased mineralocorticoids.

  • Causes:

    • Can arise from increased circulating levels of ACTH due to pituitary or adrenal tumors.

  • Characteristics: Hyperplasia of the adrenal cortex seen in adrenal tumors or both types of tumors in the case of pituitary tumors.

    • Ion homeostasis is disrupted, leading to fluid retention and “moon face”

    • Increase in circulating blood glucose (can lead to diabetes mellitus and destruction of pancreatic cells)

    • Severe osteoporosis because of effect of protein synthesis

  • Treatment:

    • Removal of the affected area

Case Report: Cushing’s Disease

• Patient Profile: Female in her early 30s.

• Symptoms:

  • Diagnosed with hypertension unresponsive to medication.

  • Exhibited “moon face” and extremely high cortisol levels.

  • ACTH levels undetectable.

• Diagnosis:

  • Low levels of ACTH shows that the negative feedback loop of the pituitary gland is working, indicating a problem (tumor) with the adrenal

  • The other adrenal gland had atrophied because of the loss of circulating ACTH for months

• Treatment:

  • Surgery to remove a benign adrenal adenoma.

  • Post-surgery, experienced severe adrenal atrophy leading to Addison’s disease.

  • Prescribed synthetic glucocorticoids and mineralocorticoids post-surgery, but not needed for long as normal function is possible with only one adrenal.

The Pancreas as an Endocrine Organ

• Location: Situated behind the stomach.

• Functions:

  • 99% is exocrine, secreting digestive enzymes in the GI

  • Contains islets of Langerhans, which are endocrine structures.

• Cell Types:

  • Beta Cells: 60%, synthesize insulin.

  • Alpha Cells: 25%, synthesize glucagon.

• Hormones: Insulin and glucagon act to regulate blood glucose levels.

• Importance: Insulin is critical as it is the only hormone that lowers blood glucose, whereas the function of glucagon can be mimicked by glucocorticoids

Glucose Homeostasis: Actions of Insulin

• Function: Only hormone primarily functioning to lower blood glucose levels.

• Blood Glucose Levels: Fasting levels approximately 80 mg/100 ml (~5 mM).

• Mechanism:

  • Glucose is transported across cells rather than diffused directly as it is not soluble in lipids (the cell membrane), but rather water

  • Converted to glycogen (glucose polymer) in liver/muscle, fat in adipose tissue, or oxidized for energy in various cells.

• Insulin Receptors:

  • Membrane receptors that encourage the transport of glucose into cells via insertion of glucose transport proteins into the plasma membrane.

Insulin Deficiency and Diabetes Mellitus

• Causes: Resulting from the destruction of beta cells leading to inability to uptake glucose efficiently, causing accumulation in circulation.

• Consequences:

  • Elevated gluconeogenesis even without dietary glucose intake.

  • Free fatty acids (FFA) become primary energy source, leading to increased lipolysis.

    • However, fat is inefficiently used - incomplete oxidation of FFA and increased circulating waste products like acetoacetic acid and beta-hydroxybutyric acid and acetone (leading to foul smelling breath)

• Complications: Incomplete oxidation results in metabolic acidosis and ketosis, which can be life-threatening and result in a coma.

Other Symptoms of Diabetes Mellitus

• Symptoms:

  • Glycosuria occurs when glucose exceeds 180 mg%, resulting in polyuria, dehydration, and polydipsia as glucose is excreted in the urine.

• Management: Requires insulin administration and correction of acidosis and electrolyte imbalances in severe cases.

• Origins of the Terms:

  • "Diabetes": Greek for "running through" related to polyuria (excessive peeing).

  • "Mellitus": Latin for "sweet", identifying urine quality in diabetes.

• Types of Diabetes Mellitus:

  • Type 1: insulin deficiency (autoimmune).

  • Type 2: insulin resistance.

Type 1 Diabetes Mellitus

• Causes: Destruction of beta cells; requires insulin treatment.

• Potential Issues: Over-administration leads to hypoglycemic coma, requiring immediate glucose administration.

Type 2 Diabetes Mellitus

• Characteristics: Normal or high insulin levels, but target cells show hyporesponsiveness (insulin resistance).

• Contributing Factors: Commonly associated with obesity, poor diets leading to downregulation of receptors.

• Management: Focus on diet, exercise, and weight control can upregulate insulin receptors.

• Juvenile Diabetes: Identified in childhood, treated with insulin.

Glucose Tolerance Test

• Overview: Assesses glucose metabolism.

• Procedure:

  • After fasting, glucose administered; blood glucose measured before and after handling over 3-4 hours.

• Results in Normal vs. Diabetic: Diabetics show greater glucose levels that return to normal more slowly.

Control of Insulin Secretion

• Mechanisms: Insulin release is primarily controlled by blood glucose levels. Low levels trigger reduced insulin secretion, while high levels increase secretion.

• Additional Stimuli: Gastrin release and vagal impulses also induce insulin secretion.

Glucagon

• Function: Synthesized by alpha cells, opposite effect of insulin.

• Mechanism: Raises blood glucose by promoting glycogenolysis and gluconeogenesis in the liver and increasing lipolysis in adipose tissue.

• Eligibility: Release is dependent on blood glucose levels; low levels stimulate glucagon release.

Glucagon-like peptide-1 (GLP-1)

• Summary: Derived from same precursor as glucagon, produced by enteroendocrine L cells in the intestine.

• Properties: Short half-life; synthetic GLP-1 receptor agonists mimic effects and are more stable, stimulating insulin release only in the presence of glucose.

  • In adipose tissue and muscle, it increases glucose uptake, storage, and/or oxidation, reducing blood glucose levels

  • Also cardioprotective

• Weight loss:

  • GLP-1 also promotes satiety, leading to decreased appetite and caloric intake, which contributes to its effectiveness in aiding weight management.

  • Also slows down digestion

Growth Hormone (GH)

• Definition: Produced by the anterior pituitary, promotes growth known as somatotropin (STH).

• Mechanisms:

  • Increases protein synthesis in tissues: bones, muscles, kidneys, liver.

  • Increases lipolysis and use of free fatty acids for energy.

• Somatomedins (IGF-I, IGF-II): Produced in the liver under GH influence; structurally similar to insulin and aid in growth stimulation.

Control of GH Release

• Somatostatin inhibits the release of growth hormone (GH) from the anterior pituitary gland

  • Somatostatin increases with exercise, sleep, stress, and low blood sugar

    • In exercise, carbon is to be used for energy, not growth

• Feedback Mechanisms: Mediated by growth hormone releasing hormone (GRH) and somatostatin, tightly regulated to ensure balanced levels.

Pathophysiology of Growth Hormone

• Deficiency: Leads to decreased growth in youth.

• Excess: Causes gigantism in youth and acromegaly in adults.

Reproductive System Overview

• Structures: Gonads: testes in males, ovaries in females.

  • Functions: Gametogenesis (production of gametes) and hormone secretion (testosterone, estrogen, and progesterone).

• Hormonal Differences: Quantitative differences in hormone production between sexes.

Estrogen in Males

• Production: Local conversion of testosterone to estrogen estradiol by aromatase.

• Deficiency Consequences: Increased body fat, decreased sexual function.

Gonadotropin Regulation

• Process:

  1. GnRH secreted by the hypothalamus enters the anterior pituitary.

  2. Stimulates release of gonadotropins (follicle-stimulating hormone (FSH), luteinizing hormone (LH)) regulating development of gametes (spermatozoa and ova) and secretion of sex steroids.

  3. Gonads also produce inhibin which blocks the release of FSH

Testes Functionality

• Functions:

  • Producing sperm (spermatogenesis) and steroid hormones (steroidogenesis) to maintain a relatively constant supply throughout life

• Spermatogenesis Timeline: Approximately 60 days required for maturation from spermatogonia to spermatozoon.

• Cell Types:

  1. Leydig Cells: Outside seminiferous tubules in the ISF, synthesize androgens upon LH stimulation.

     • Leydig cells are responsive to luteinizing hormone

       • Synthesize androgens

  2. Sertoli Cells: Inside seminiferous tubules, support sperm development and produce ABP and inhibin upon FSH stimulation.

     • Sertoli cells are responsive to FSH

       • Synthesize androgen binding protein (ABP) and inhibin

Testicular Androgen Synthesis Control

• ABP keeps local (seminiferous tubules) androgen levels high, promoting spermatogenesis

• Feedback Mechanisms:

  • GnRH from the hypothalamus stimulates release of LH and FSH from the anterior pituitary gland, stimulating Leydig cells and Sertoli cells. Leydig cells produce androgen, which inhibit the release of GnRH, LH, and FSH.

  • Non-steroidal inhibin secreted by the Sertoli cells inhibits FSH release only