Endocrine Disorders - Comprehensive Overview

Endocrine disorders involve dysfunction of hormone-producing glands and their target tissues. The endocrine system regulates metabolism, growth, reproduction, and homeostasis. This article provides comprehensive coverage of major endocrine conditions, their pathophysiology, clinical presentations, diagnostic evaluation, and management.

Diabetes Mellitus

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

Classification of Diabetes

Type	Pathophysiology	Frequency	Key Features
Type 1 diabetes (T1DM)	Autoimmune destruction of pancreatic beta-cells; absolute insulin deficiency	5-10%	Onset usually <30 years; lean; ketosis-prone; autoantibodies (GAD65, IA-2, ZnT8, insulin); HLA association
Type 2 diabetes (T2DM)	Insulin resistance + relative insulin deficiency	90-95%	Onset usually >30 years (increasing in younger); obesity; no autoantibodies; strong genetic component
Gestational diabetes (GDM)	Insulin resistance due to placental hormones	6-9% of pregnancies	Onset in 2nd/3rd trimester; usually resolves after delivery; increased risk of future T2DM
Monogenic diabetes (MODY)	Single gene mutation affecting beta-cell function	1-2%	Early onset (<25), strong family history, no autoantibodies, not insulin-dependent initially; MODY types 1-14
Secondary diabetes	Pancreatic disease, endocrinopathies, drugs, genetic syndromes	<1%	Cystic fibrosis, hemochromatosis, Cushing, acromegaly, glucocorticoids, thiazides

Diagnostic Criteria for Diabetes

Test	Normal	Prediabetes	Diabetes
Fasting plasma glucose	<100 mg/dL (5.6 mmol/L)	100-125 mg/dL (5.6-6.9 mmol/L) - IFG	>=126 mg/dL (7.0 mmol/L), confirmed
2-hour OGTT (75g glucose)	<140 mg/dL (7.8 mmol/L)	140-199 mg/dL (7.8-11.0 mmol/L) - IGT	>=200 mg/dL (11.1 mmol/L)
HbA1c	<5.7%	5.7-6.4%	>=6.5%
Random glucose	<140 mg/dL	—	>=200 mg/dL with symptoms

HbA1c and Estimated Average Glucose (eAG)

HbA1c (%)	eAG (mg/dL)	eAG (mmol/L)
6	126	7.0
7	154	8.6
8	183	10.2
9	212	11.8
10	240	13.4
11	269	14.9
12	298	16.5

Type 1 Diabetes Management

Component	Details
Insulin therapy	Multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII/pump)
Basal insulin	Long-acting: glargine U-100/U-300, degludec U-100/U-200, detemir
Bolus insulin	Rapid-acting: lispro, aspart, glulisine; inhaled insulin; ultra-rapid lispro/aspart
Insulin-to-carbohydrate ratio	Typically 1 unit per 5-15g carbohydrate (individualized)
Insulin sensitivity factor	1 unit decreases glucose by 30-50 mg/dL (1800 rule for rapid-acting)
Continuous glucose monitoring (CGM)	Dexcom G7, FreeStyle Libre 3, Medtronic Guardian; provides real-time glucose data
Automated insulin delivery (AID)	Hybrid closed-loop systems: Medtronic 780G, Tandem Control-IQ, Omnipod 5
Goal HbA1c	<7% (individualized: <6.5% if low hypoglycemia risk; <8% for elderly or with complications)
Glucose targets	70-180 mg/dL 70%+ of time (time in range); <70 mg/dL <4% (time below range)

Type 2 Diabetes Management

Step	Intervention	HbA1c Reduction
1	Lifestyle modification (diet, exercise, weight loss)	1-2%
2	Metformin (first-line pharmacotherapy)	1-1.5%
3a	Add SGLT2 inhibitor or GLP-1 receptor agonist (if ASCVD, HF, CKD, or obesity)	0.5-1%
3b	Add sulfonylurea, TZD, DPP-4 inhibitor, or basal insulin	0.5-1.5%
4	Intensify insulin (basal-bolus or premixed)	1-3%

Antidiabetic Medications

Drug Class	Mechanism	Examples	HbA1c Reduction	Key Effects	Side Effects
Biguanides	Decrease hepatic glucose production	Metformin	1-1.5%	Weight neutral; CV benefit?	GI upset, lactic acidosis (rare), B12 deficiency
Sulfonylureas	Increase insulin secretion	Glipizide, glyburide, glimepiride	1-1.5%	Weight gain	Hypoglycemia
Meglitinides	Increase insulin secretion (short-acting)	Repaglinide, nateglinide	0.5-1%	Weight gain	Hypoglycemia
Thiazolidinediones (TZDs)	Increase insulin sensitivity	Pioglitazone	0.5-1.4%	Weight gain, edema	Fluid retention, fracture risk, bladder cancer (pioglitazone)
DPP-4 inhibitors	Increase incretin levels	Sitagliptin, saxagliptin, linagliptin, alogliptin	0.5-0.8%	Weight neutral	Pancreatitis, joint pain
GLP-1 receptor agonists	Enhance insulin secretion, slow gastric emptying, suppress glucagon	Semaglutide, dulaglutide, liraglutide, tirzepatide (dual GIP/GLP-1)	1-2.5%	Weight loss; CV benefit; renal benefit	GI (nausea, vomiting, diarrhea), pancreatitis
SGLT2 inhibitors	Block renal glucose reabsorption	Empagliflozin, dapagliflozin, canagliflozin, ertugliflozin	0.5-1%	Weight loss; CV benefit; HF benefit; renal benefit	UTI, genital mycotic infections, DKA (euglycemic), amputations (canagliflozin)
Alpha-glucosidase inhibitors	Delay carbohydrate absorption	Acarbose, miglitol	0.3-0.8%	Weight neutral	Flatulence, diarrhea
Bile acid sequestrants	Unknown	Colesevelam	0.3-0.5%	Decrease LDL	Constipation, triglycerides increase
Dopamine agonists	Dopamine receptor agonist	Bromocriptine	0.3-0.5%	Weight neutral	Nausea, dizziness
Amylin analogs	Slow gastric emptying, suppress glucagon	Pramlintide	0.3-0.5%	Weight loss	Nausea, vomiting (for T1DM)

Insulin Preparations

Type	Onset	Peak	Duration	Examples
Rapid-acting	10-30 min	30 min-3 h	3-5 h	Lispro (Humalog), aspart (NovoLog), glulisine (Apidra)
Short-acting (regular)	30-60 min	2-4 h	5-8 h	Regular insulin (Humulin R, Novolin R)
Intermediate-acting	1-3 h	4-8 h	12-16 h	NPH (Humulin N, Novolin N)
Long-acting	1-2 h	No peak	20-24 h	Glargine U-100 (Lantus), glargine U-300 (Toujeo), detemir (Levemir)
Ultra-long acting	1-2 h	No peak	>42 h	Degludec U-100/U-200 (Tresiba)
Inhaled insulin	5-15 min	30-60 min	2-3 h	Afrezza
Premixed	Varies	Varies	10-24 h	70/30 (NPH/regular), 75/25 (NPH/lispro), 50/50 (NPH/lispro)

Diabetic Ketoacidosis (DKA)

Parameter	Detail
Definition	Hyperglycemia + ketosis + metabolic acidosis (triad)
Precipitants	Infection, missed insulin, new-onset T1DM, stress (MI, stroke), drugs (cocaine, SGLT2 inhibitors)
Pathophysiology	Insulin deficiency + counterregulatory hormone excess (glucagon, catecholamines, cortisol) -> increased lipolysis -> fatty acids -> ketone bodies (acetoacetate, beta-hydroxybutyrate) -> metabolic acidosis
Key lab findings	Glucose >250 mg/dL, pH <7.3, HCO3 <15 mEq/L, anion gap >12, positive serum/urine ketones
Treatment	IV fluids (NS), insulin (IV bolus + infusion), potassium replacement, bicarbonate (pH <6.9 only), identify/treat precipitant
Transition to SC insulin	When glucose <200 mg/dL, bicarbonate >15, pH >7.3, anion gap normal

Hyperosmolar Hyperglycemic State (HHS)

Parameter	Detail
Definition	Extreme hyperglycemia + hyperosmolality without significant ketosis
Precipitants	Infection, non-adherence, new-onset T2DM, drugs (glucocorticoids, thiazides), acute illness
Key lab findings	Glucose >600 mg/dL (often >1000), pH >7.3, HCO3 >15, normal/low ketones, serum osmolality >320 mOsm/kg, severe dehydration
Treatment	Aggressive IV fluids (NS then 0.45% NS), insulin (lower dose than DKA), electrolyte replacement, thromboprophylaxis (high risk of thrombosis)
Complications	Thrombosis, cerebral edema (rare), rhabdomyolysis

DKA vs HHS

Feature	DKA	HHS
Typical patient	T1DM (can occur in T2DM)	T2DM
Onset	Rapid (hours to 1-2 days)	Subacute (days to weeks)
Blood glucose	250-800 mg/dL	>600 mg/dL (often >1000)
pH	<7.3	>7.3
Bicarbonate	<15 mEq/L	>15 mEq/L
Serum osmolality	Variable	>320 mOsm/kg
Ketones	Positive (strong)	Negative or trace
Anion gap	Elevated	Normal or slightly elevated
Fluid deficit	6-9 L	8-12 L
Mortality	<1% (young), 5-20% (elderly)	10-50%

Chronic Diabetes Complications

Complication	Type	Pathophysiology	Screening	Management
Diabetic retinopathy	Microvascular	Capillary damage -> hemorrhage, exudates, neovascularization	Annual dilated eye exam	Glucose/BP control, laser photocoagulation, anti-VEGF (ranibizumab, aflibercept)
Diabetic nephropathy	Microvascular	Glomerular basement membrane thickening, mesangial expansion, glomerulosclerosis	Annual UACR, eGFR	ACEi/ARB, glucose control, BP control, SGLT2i, GLP-1 RA
Diabetic neuropathy	Microvascular	Axonal degeneration, demyelination; distal symmetric polyneuropathy	Annual monofilament test	Glucose control, duloxetine, pregabalin, gabapentin, amitriptyline
Diabetic foot ulcers	Microvascular + macrovascular	Neuropathy + vascular insufficiency + infection	Annual foot exam	Debridement, offloading, infection control, revascularization
Cardiovascular disease	Macrovascular	Accelerated atherosclerosis	BP, lipids, symptom assessment	Statin, SBP <130, antiplatelet (secondary prevention)
Cerebrovascular disease	Macrovascular	Stroke risk 2-4x higher	BP, lipids, AFib screening	Statin, BP control, antiplatelet

Thyroid Disorders

Hypothyroidism

Parameter	Detail
Definition	Reduced thyroid hormone production
Prevalence	5-10% of population; female > male (5:1)
Most common cause	Hashimoto thyroiditis (autoimmune)
Other causes	Iodine deficiency (worldwide), post-surgical, post-radioactive iodine, medications (amiodarone, lithium), subacute thyroiditis, pituitary dysfunction (central hypothyroidism)

Hypothyroidism Lab Patterns

Condition	TSH	Free T4	Free T3
Primary hypothyroidism	Elevated	Low	Low (may be normal early)
Subclinical hypothyroidism	Elevated	Normal	Normal
Central (secondary) hypothyroidism	Low, normal, or mildly elevated	Low	Low
Euthyroid sick syndrome	Normal	Normal or low	Low (reverse T3 elevated)

Hyperthyroidism

Parameter	Detail
Definition	Excess thyroid hormone production
Most common cause	Graves disease (autoimmune, 60-80%)
Other causes	Toxic multinodular goiter, toxic adenoma, subacute (De Quervain) thyroiditis, painless (silent) thyroiditis, postpartum thyroiditis, factitious, amiodarone-induced

Graves Disease Features

Feature	Description
Pathophysiology	TSH receptor autoantibodies (TSI) stimulate thyroid hormone production
Thyroid exam	Diffuse goiter, bruit
Ophthalmopathy	Proptosis, lid retraction, lid lag, periorbital edema, extraocular muscle dysfunction (limited upgaze), optic neuropathy (rare)
Dermopathy	Pretibial myxedema (localized, thickened, erythematous skin)
Acropachy	Digital clubbing (rare)
Thyroid scan (I-123)	Diffuse increased uptake

Hyperthyroidism Lab Patterns

Condition	TSH	Free T4	Free T3	Radioiodine Uptake
Graves disease	Suppressed	Elevated	Elevated	Diffusely increased
Toxic nodular goiter	Suppressed	Elevated	Elevated (T3 may be more elevated)	Nodular increased uptake
Subacute thyroiditis	Suppressed	Elevated	Elevated	Very low (destructive)
Factitious	Suppressed	Elevated	Elevated	Very low

Thyroid Hormone Replacement (Hypothyroidism)

Medication	Dosing	Half-life	Notes
Levothyroxine (T4)	1.6 mcg/kg/day (typical start: 50-100 mcg; elderly or CVD: 25 mcg)	7 days	Standard of care; take on empty stomach, wait 30-60 min before food; monitor Ca/Fe supplements timing
Liothyronine (T3)	5-25 mcg 2-3x/day	1 day	Rarely used alone (short half-life, fluctuation); second-line
Desiccated thyroid (Armour Thyroid)	30-180 mg/day	Variable	Contains T4 + T3; not recommended as first-line

Antithyroid Drug Therapy (Hyperthyroidism)

Drug	Mechanism	Dosing	Side Effects
Methimazole	Inhibits thyroid peroxidase	Initial: 10-40 mg/day; maintenance: 5-15 mg/day	Rash, arthralgia, cholestatic jaundice; agranulocytosis (rare, 0.3-0.5%)
Propylthiouracil (PTU)	Inhibits TPO + inhibits T4 to T3 conversion	Initial: 300-600 mg/day; maintenance: 50-150 mg/day	Hepatotoxicity (can be severe), agranulocytosis; avoid in children (hepatotoxicity risk)

Definite Therapy for Hyperthyroidism

Modality	Indications	Side Effects/Outcomes
Radioactive iodine (I-131)	First-line for most adults, failing medications, toxic nodular disease	Induces hypothyroidism in 80-90% within 6-12 months; contraindicated in pregnancy, active ophthalmopathy
Thyroidectomy (subtotal/total)	Large goiter with obstructive symptoms, suspicious nodules, active ophthalmopathy, pregnancy (2nd trimester), failed RAI	Surgical risk: hypoparathyroidism, recurrent laryngeal nerve injury; lifelong levothyroxine

Thyroid Nodules

Feature	Benign	Malignant
Frequency	90-95%	5-10%
Ultrasound characteristics	Spongiform, simple cyst, isoechogenic, well-defined margins	Hypoechogenic, microcalcifications, irregular margins, taller than wide, central vascularity
TI-RADS classification	TR1-TR3 (low to moderate suspicion)	TR4-TR5 (suspicious)
Nodules requiring FNA	>=2.5 cm (low suspicion), >=1.5 cm (intermediate), >=1.0 cm (high suspicion)	—

Thyroid Cancer Types

Type	Frequency	Prognosis (10-year survival)	Treatment
Papillary	80-85%	>95%	Thyroidectomy +/- RAI; thyroglobulin monitoring
Follicular	10-15%	>90%	Thyroidectomy + RAI
Medullary	3-5%	50-80%	Thyroidectomy + lymph node dissection; RET inhibitors (selpercatinib) for advanced
Anaplastic	<2%	<10% (median survival 6 months)	Multimodality: surgery (if resectable), radiation, chemo, targeted (BRAF/MEK if BRAF mutant)

Cushing Syndrome

Parameter	Detail
Definition	Chronic exposure to excess glucocorticoids
Endogenous causes	ACTH-dependent: Cushing disease (pituitary adenoma, 70%), ectopic ACTH (SCLC, carcinoid, 10%); ACTH-independent: adrenal adenoma (10-15%), adrenal carcinoma (5%), micronodular/macronodular hyperplasia
Exogenous causes	Glucocorticoid therapy (most common overall)

Cushing Syndrome Clinical Features

Feature	Frequency	Notes
Central obesity	>90%	Truncal obesity, dorsocervical fat pad (buffalo hump), supraclavicular fat pads
Moon facies	>90%	Rounded, plethoric face
Easy bruising	>70%	Skin thinning, capillary fragility
Purple striae	>60%	Wide (>1 cm), purple, on abdomen, flanks, breasts, thighs
Proximal myopathy	>60%	Difficulty climbing stairs, rising from chair
Hypertension	70-85%	Glucocorticoid-induced
Osteoporosis	50-80%	Increased fracture risk
Glucose intolerance / diabetes	40-60%	Insulin resistance
Hirsutism / menstrual irregularity	70-80%	Women
Psychiatric symptoms	50-70%	Depression, anxiety, insomnia, psychosis
Immunosuppression	Increased infections	Neutrophilia, lymphopenia

Cushing Syndrome Diagnostic Algorithm

Step	Test	Result Indicating Cushing
1 (Screening)	1 mg overnight dexamethasone suppression test	Morning cortisol >1.8 mcg/dL (50 nmol/L)
1 (Screening)	24-h urinary free cortisol (UFC)	Elevated (3x ULN or more)
1 (Screening)	Late-night salivary cortisol (11 PM)	Elevated (>145 ng/dL or assay-specific)
2 (Confirm)	Repeat abnormal test or do 2-mg low-dose DST	Failure to suppress
3 (Differentiate ACTH-dependent vs independent)	Plasma ACTH	ACTH >20 pg/mL (Cushing disease/ectopic), <10 (adrenal), 10-20 (indeterminate)
4 (Localize)	Pituitary MRI, CRH stimulation test, BIPSS (if needed)	Tumor localization
5 (Localize ACTH-independent)	Adrenal CT/MRI	Adrenal mass

Cushing Syndrome Treatment

Cause	Treatment
Pituitary adenoma	Transsphenoidal adenomectomy (first-line); radiation (if surgery fails); medical therapy: pasireotide, cabergoline
Ectopic ACTH	Surgery of primary tumor; medical therapy: ketoconazole, metyrapone, osilodrostat, mifepristone
Adrenal adenoma	Unilateral adrenalectomy (laparoscopic)
Adrenal carcinoma	Surgery (curative if localized); mitotane + chemotherapy (advanced)
Exogenous	Taper glucocorticoids to lowest effective dose; if possible, switch to alternate-day dosing

Addison Disease (Primary Adrenal Insufficiency)

Parameter	Detail
Definition	Destruction of adrenal cortex leading to deficiency of glucocorticoids, mineralocorticoids, and adrenal androgens
Most common cause (developed)	Autoimmune (70%): isolated or part of APS-1/APS-2
Most common cause (world)	Tuberculosis

Addison Disease Clinical Features

Symptom/Sign	Frequency	Notes
Hyperpigmentation	>90%	Buccal mucosa, palmar creases, scars, extensor surfaces; due to high ACTH
Fatigue, weakness	>95%	Most common symptom
Weight loss, anorexia	>80%
Hypotension / orthostasis	80-90%	Mineralocorticoid deficiency
Salt craving	60-70%	Aldosterone deficiency
Abdominal pain, nausea, vomiting	50-60%	May mimic acute abdomen
Hyponatremia	70-80%
Hyperkalemia	50-60%	Aldosterone deficiency
Hypoglycemia	20-40%	Glucocorticoid deficiency (children especially)

Adrenal Crisis

Parameter	Detail
Precipitants	Infection, trauma, surgery, stress, abrupt steroid withdrawal
Presentation	Hypotension/shock, severe abdominal pain, vomiting, hyponatremia, hyperkalemia, hypoglycemia, fever
Treatment	IV hydrocortisone (100 mg bolus, then 50-100 mg q6h), fluid resuscitation (NS/D5NS), electrolyte correction, treat precipitant

Polycystic Ovary Syndrome (PCOS)

Parameter	Detail
Definition	Heterogeneous disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology
Prevalence	6-20% of reproductive-age women
Diagnostic criteria (Rotterdam)	2 of 3: oligo-/anovulation, clinical/biochemical hyperandrogenism, polycystic ovaries on ultrasound; exclude other causes

PCOS Diagnostic Criteria

Criterion	Assessment	Definition
Oligo-/anovulation	Menstrual history	<8 cycles/year or cycle length >35 days
Hyperandrogenism (clinical)	Modified Ferriman-Gallwey score	Hirsutism (score >4-8 depending on ethnicity); acne, alopecia
Hyperandrogenism (biochemical)	Lab testing	Elevated testosterone (total or free), DHEA-S, androstenedione
Polycystic ovarian morphology	Ultrasound	>=20 follicles per ovary (2-9 mm) and/or ovarian volume >=10 mL (transvaginal)
Exclusion of other causes	Lab testing	TSH, prolactin, 17-OHP (to exclude NCAH), ACTH, cortisol

PCOS Management

Issue	First-Line	Second-Line	Third-Line
Anovulation/infertility	Lifestyle modification (weight loss 5-10%)	Clomiphene, letrozole, metformin	Gonadotropins, ovarian drilling, IVF
Hirsutism/acne	OCP (anti-androgenic progestin: drospirenone, cyproterone)	Spironolactone, finasteride, eflornithine cream	Laser hair removal, electrolysis
Metabolic (IR, obesity)	Lifestyle modification, metformin	GLP-1 receptor agonists	Bariatric surgery (if BMI >35)
Menstrual regulation	OCP (cyclic or continuous)	Cyclical progestins	LNG-IUS (Mirena)

Osteoporosis

Parameter	Detail
Definition	Systemic skeletal disease characterized by low bone mass and microarchitectural deterioration leading to increased fracture risk
Diagnosis	T-score <= -2.5 at hip, spine, or forearm by DXA
Primary osteoporosis	Postmenopausal (type 1): age-related bone loss in trabecular bone; Senile (type 2): age-related bone loss in cortical and trabecular
Secondary osteoporosis	Glucocorticoids (most common), hyperparathyroidism, hyperthyroidism, hypogonadism, GI malabsorption, CKD, medications (SSRIs, PPIs, thiazolidinediones, anticoagulants)

Bone Density Classification (WHO)

Category	T-score	Fracture Risk
Normal	>= -1.0	Low
Osteopenia (low bone mass)	-1.0 to -2.5	Intermediate
Osteoporosis	<= -2.5	High
Severe (established) osteoporosis	<= -2.5 + fragility fracture	Very high

Fracture Risk Assessment (FRAX)

Risk Factor for FRAX	Weight
Age	Major
Sex	Major
BMI	Moderate
Prior fragility fracture	Major (doubles risk)
Parental hip fracture	Major
Current smoking	Moderate
Glucocorticoid use (>=5 mg prednisone/day for >3 months)	Major
Rheumatoid arthritis	Moderate
Secondary osteoporosis	Moderate
Alcohol >=3 units/day	Moderate
Femoral neck BMD	Optional (improves accuracy)

Osteoporosis Treatment

Drug Class	Examples	Mechanism	Efficacy (vertebral fracture reduction)	Key Side Effects
Bisphosphonates	Alendronate, risedronate, zoledronic acid, ibandronate	Inhibit osteoclast activity (farnesyl pyrophosphate synthase)	40-70%	GI intolerance (oral), acute phase reaction (IV), hypocalcemia, ONJ (rare), atypical femur fractures (rare, long-term)
RANKL inhibitor	Denosumab	Inhibit osteoclast maturation (RANKL antibody)	60-70%	Hypocalcemia, infection risk; rebound fractures if stopped without transitioning
PTH analog	Teriparatide, abaloparatide	Stimulate bone formation (intermittent PTH)	65-90%	Hypercalcemia, nausea, dizziness; avoid in Paget disease, bone metastases
Sclerostin inhibitor	Romosozumab	Dual: stimulates formation + inhibits resorption	70-75%	Cardiovascular risk (consider before starting), injection site reactions
SERMs	Raloxifene, bazedoxifene	Estrogen receptor agonist (bone), antagonist (breast)	30-50%	VTE risk, hot flashes; reduce breast cancer risk
Estrogen therapy	Various	Osteoclast inhibition	30-50%	VTE, breast cancer (long-term), stroke; limited to menopausal symptom management
Calcium + Vitamin D	Supplementation	Essential for bone mineralization	10-20% (with vitamin D)	Renal stones (excess calcium)