Endocrine Axes, Metabolism, and Diabetes

Endocrine Reasoning Map

Endocrine physiology is organized around hypothalamic releasing hormones, anterior pituitary trophic hormones, peripheral gland output, and negative feedback. Primary gland failure means the gland cannot produce the final hormone, so the pituitary signal rises: primary hypothyroidism has high TSH, primary adrenal insufficiency has high ACTH, and primary hypogonadism has high LH and FSH. Secondary or tertiary disease means pituitary or hypothalamic drive is low or inappropriately normal.

Autonomous hormone secretion suppresses upstream drive, as in a toxic thyroid adenoma with low TSH or an adrenal cortisol-producing tumor with low ACTH. Step 1 questions often give a mixed lab panel and ask which level of the axis is defective.

Hormone receptor location predicts speed and mechanism. Peptide hormones such as insulin, glucagon, ACTH, TSH, LH, FSH, PTH, ADH, and oxytocin are made as proteins, stored in secretory granules, and act at cell-surface receptors. Many use G protein pathways: Gs raises cAMP for ACTH, TSH, FSH, LH, glucagon, PTH, calcitonin, and V2 ADH; Gi lowers cAMP for somatostatin and alpha2 adrenergic signaling; Gq raises IP3 and intracellular calcium for GnRH, TRH, oxytocin, V1 ADH, and alpha1 adrenergic signaling.

Steroid hormones diffuse through membranes, bind cytosolic or nuclear receptors, and alter transcription; examples include cortisol, aldosterone, estrogen, progesterone, testosterone, and vitamin D. Thyroid hormone is synthesized in follicles but acts like a steroid at nuclear receptors.

The hypothalamic-pituitary-thyroid axis begins with TRH, which stimulates TSH and prolactin. TSH activates follicular thyroid cells through Gs, promoting iodide trapping by the sodium-iodide symporter, oxidation and organification by thyroid peroxidase, coupling of iodotyrosines, endocytosis of thyroglobulin, and release of T4 and T3. T4 is the major secreted product and is peripherally converted to active T3 by 5 prime deiodinase; reverse T3 rises in severe illness.

Thyroid hormone increases basal metabolic rate, oxygen consumption, beta adrenergic receptor expression, bone turnover, lipolysis, and carbohydrate absorption. Graves disease is due to IgG stimulation of the TSH receptor, causing diffuse hyperplasia, hyperthyroidism, ophthalmopathy from fibroblast glycosaminoglycan deposition, and pretibial myxedema. Hashimoto thyroiditis is autoimmune follicular destruction with antithyroid peroxidase or antithyroglobulin antibodies, lymphoid aggregates with germinal centers, and risk of thyroid lymphoma.

Subacute granulomatous thyroiditis follows viral illness and has painful thyroid enlargement with transient hormone leak.

Adrenal cortex zones make different steroid classes. Zona glomerulosa produces aldosterone under angiotensin II and potassium control; zona fasciculata produces cortisol under ACTH control; zona reticularis produces androgens under ACTH influence. Cortisol supports vascular responsiveness to catecholamines, increases gluconeogenesis, mobilizes amino acids, redistributes fat, suppresses phospholipase A2 through lipocortin, and decreases cytokine and T cell activity.

Cushing syndrome causes central obesity, facial rounding, thin skin, easy bruising, proximal weakness, osteoporosis, hypertension, hyperglycemia, and infection risk. Dexamethasone suppression logic depends on whether ACTH remains suppressible. Aldosterone increases sodium reabsorption and potassium and hydrogen secretion in principal and alpha intercalated cells of the cortical collecting duct, producing hypertension, hypokalemia, and metabolic alkalosis when excessive.

Primary adrenal insufficiency destroys all cortical zones, so patients have hypotension, hyperkalemia, hyponatremia, hypoglycemia, high ACTH, and hyperpigmentation from POMC-derived melanocyte stimulation. Secondary adrenal insufficiency preserves aldosterone because the renin-angiotensin system remains intact.

Congenital adrenal hyperplasia is best solved by tracking blocked steroid enzymes. 21-hydroxylase deficiency lowers cortisol and often aldosterone, raising ACTH and shunting precursors to androgens. It causes virilization in genetic females, salt wasting, hypotension, hyperkalemia, and increased 17-hydroxyprogesterone. 11beta-hydroxylase deficiency also increases androgens, but 11-deoxycorticosterone has mineralocorticoid activity, causing hypertension and hypokalemia.

17alpha-hydroxylase deficiency lowers cortisol and sex steroids while increasing mineralocorticoid precursors, causing hypertension, hypokalemia, and sexual infantilism or undervirilization.

Calcium homeostasis connects parathyroid, bone, kidney, gut, and vitamin D. Low ionized calcium stimulates PTH release. PTH increases osteoblast RANKL expression, which activates osteoclasts indirectly and releases calcium and phosphate from bone. In the kidney, PTH increases distal calcium reabsorption, decreases proximal phosphate reabsorption, and stimulates 1alpha-hydroxylase to convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Vitamin D increases intestinal absorption of calcium and phosphate.

Primary hyperparathyroidism usually causes high calcium, low phosphate, high PTH, kidney stones, bone pain, abdominal symptoms, and psychiatric changes. Secondary hyperparathyroidism in chronic kidney disease occurs because phosphate retention and low vitamin D activation reduce ionized calcium. Pseudohypoparathyroidism is end-organ resistance to PTH, so PTH is high but calcium remains low and phosphate high.

Diabetes mellitus reflects impaired insulin action. In type 1 diabetes, autoimmune T cell destruction of pancreatic beta cells causes absolute insulin deficiency, often with anti-GAD65, anti-insulin, or islet cell antibodies. Lack of insulin decreases GLUT4-mediated glucose uptake in muscle and adipose tissue, removes inhibition of hormone-sensitive lipase, increases hepatic gluconeogenesis and ketogenesis, and predisposes to diabetic ketoacidosis.

DKA has hyperglycemia, anion gap metabolic acidosis, ketonemia, dehydration, Kussmaul respirations, and total body potassium depletion even if serum potassium is initially high. In type 2 diabetes, insulin resistance in muscle, liver, and adipose tissue initially causes compensatory hyperinsulinemia. Amylin deposition in islets and glucotoxicity eventually impair beta cell secretion. Hyperosmolar hyperglycemic state usually retains enough insulin to suppress lipolysis and ketogenesis but not enough to control hyperglycemia, causing severe dehydration and altered mental status.

Diabetes drugs are tested by mechanism and adverse effects. Metformin activates AMP-activated protein kinase, decreases hepatic gluconeogenesis, improves insulin sensitivity, does not cause weight gain, and can cause lactic acidosis risk in severe renal or tissue hypoxia states. Sulfonylureas close beta cell ATP-sensitive potassium channels and increase insulin release, so they can cause hypoglycemia and weight gain. GLP-1 receptor agonists increase glucose-dependent insulin secretion, decrease glucagon, slow gastric emptying, promote satiety, and may cause gastrointestinal symptoms.

DPP-4 inhibitors prolong endogenous incretins. SGLT2 inhibitors reduce proximal tubular glucose reabsorption, causing glucosuria, osmotic diuresis, genital mycotic infections, and rare euglycemic ketoacidosis. Thiazolidinediones activate PPAR-gamma to increase insulin sensitivity but can cause edema, weight gain, heart failure worsening, and fracture risk. Insulin drives potassium into cells and is essential for DKA treatment with fluids and potassium monitoring.

Endocrine neoplasia patterns are high-yield because they reflect cell lineage and receptor signaling. MEN 1 is due to MEN1 mutation and includes parathyroid hyperplasia, pancreatic endocrine tumors such as gastrinoma or insulinoma, and pituitary adenomas. MEN 2 is due to activating RET mutation. MEN 2A includes medullary thyroid carcinoma from parafollicular C cells, pheochromocytoma, and parathyroid hyperplasia; MEN 2B includes medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, and marfanoid habitus.

Medullary thyroid carcinoma secretes calcitonin and may show amyloid stroma. Pheochromocytoma produces episodic catecholamine excess with headaches, sweating, palpitations, and paroxysmal hypertension; alpha blockade must precede beta blockade to avoid unopposed alpha vasoconstriction. Prolactinomas suppress GnRH and cause infertility, amenorrhea, and galactorrhea; dopamine agonists reduce prolactin. Acromegaly from a GH-secreting pituitary adenoma raises IGF-1 and causes soft tissue growth, insulin resistance, cardiomyopathy, and colon polyp risk.