Pharmacotherapeutics of the endocrine system
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Pharmacotherapeutics of the Endocrine System
Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics (14th Ed.) | Katzung's Basic and Clinical Pharmacology (16th Ed.)
Overview: The Hypothalamic-Pituitary-Endocrine Axis
The endocrine system operates through hierarchical feedback loops. The hypothalamus releases releasing/inhibiting factors that govern anterior pituitary hormone secretion, which in turn regulate peripheral endocrine glands. Most pharmacologic interventions either replace a deficient hormone, suppress excess hormone production, or block a hormone's receptor or peripheral action.
Key axes:
- Hypothalamus - Pituitary - Thyroid (HPT)
- Hypothalamus - Pituitary - Adrenal (HPA)
- Hypothalamus - Pituitary - Gonad (HPG)
- Endocrine pancreas (independent of pituitary)
1. THE PITUITARY AXIS - Drugs Targeting Growth Hormone & Prolactin
Growth Hormone (GH) Deficiency - Treatment
Recombinant Human GH (somatropin) is used for:
- GH deficiency in children (promotes linear growth, prevents dwarfism)
- Adult GH deficiency (body composition, bone density, lipid metabolism)
- Turner syndrome (higher doses, often with oxandrolone)
GH-Releasing Hormone (GHRH) analogs:
- Sermorelin, tesamorelin - stimulate endogenous GH secretion (tesamorelin indicated for HIV-associated lipodystrophy)
GH Excess (Acromegaly) - Treatment
| Drug Class | Agent | Mechanism |
|---|---|---|
| Somatostatin analogs | Octreotide, lanreotide, pasireotide | Bind SST receptors; suppress GH/IGF-1 |
| GH receptor antagonist | Pegvisomant | Blocks GH receptor; reduces IGF-1 |
| Dopamine agonists | Cabergoline, bromocriptine | Useful in mixed GH/PRL tumors |
Octreotide normalizes IGF-1 in ~65% of patients. GH secretion is regulated by GHRH (stimulatory), ghrelin (stimulatory), and somatostatin/IGF-1 (inhibitory).
Hyperprolactinemia - Treatment
Dopamine agonists are first-line (prolactin secretion is tonically inhibited by hypothalamic dopamine):
- Cabergoline - preferred; longer t1/2, better tolerability, once-to-twice weekly dosing
- Bromocriptine - older agent; effective but more GI side effects
- Both shrink prolactinomas and restore gonadal function
2. THYROID PHARMACOLOGY
Thyroid Hormone Pharmacokinetics
| Feature | T4 (Levothyroxine) | T3 (Liothyronine) |
|---|---|---|
| Oral bioavailability | 70-80% (tablets); higher with Tirosint gel caps | ~95% |
| Half-life | ~7 days | ~1 day |
| Protein binding | ~99.97% (mainly TBG) | ~99.7% |
| Conversion | Peripherally deiodinated → T3 (active) | Directly active |
| Potency | Prohormone | ~3-4x more potent than T4 |
Drugs that increase T4 clearance (CYP inducers): rifampin, phenobarbital, carbamazepine, phenytoin, tyrosine kinase inhibitors, HIV protease inhibitors. Patients on levothyroxine may need dose increases with these agents.
Drugs that increase TBG (increase total T4, not free T4): estrogens, tamoxifen, raloxifene, methadone.
Hypothyroidism Treatment
Levothyroxine (L-T4) is the standard of care:
- Absorbed in duodenum/ileum; take fasting 30-60 min before food
- Goal: normalize serum TSH
- Typical dose: 1.6 µg/kg/day in adults
- Myxedema coma: IV T4 ± T3; start with 200-400 µg IV T4
Liothyronine (T3) is occasionally used (myxedema coma, short-term thyroid cancer workup) but is not preferred for long-term therapy due to fluctuating T3 levels.
Hyperthyroidism Treatment
Thioamides (Antithyroid Drugs)
| Drug | Mechanism | Notes |
|---|---|---|
| Propylthiouracil (PTU) | Inhibits TPO-mediated oxidation/organification of iodide; also blocks peripheral T4→T3 conversion | Preferred in 1st trimester pregnancy, thyroid storm |
| Methimazole (MMI) | Inhibits TPO; does NOT block T4→T3 conversion | Preferred in most other situations; once-daily dosing; lower teratogenicity risk vs. PTU in 2nd/3rd trimester |
| Carbimazole | Prodrug of methimazole | Used in UK/Europe |
Adverse effects:
- Agranulocytosis (0.3-0.5%) - most dangerous; check WBC if fever/sore throat
- Rash, urticaria (3-5%)
- PTU: rare but severe hepatotoxicity (black box warning)
- MMI: aplasia cutis in neonates (teratogenic in 1st trimester)
Iodine and Iodides
- Lugol's solution / SSKI: High iodide concentrations acutely suppress thyroid hormone release (Wolff-Chaikoff effect). Used pre-operatively (reduces vascularity of thyroid), in thyroid storm.
- Mechanism: Excess iodide transiently blocks its own organification (Wolff-Chaikoff), and inhibits thyroglobulin proteolysis, reducing T3/T4 release.
- Adverse effects (iodism): Acneiform rash, metallic taste, rhinorrhea, sialadenitis, conjunctivitis, anaphylactoid reactions.
Radioactive Iodine (¹³¹I)
- Orally administered sodium ¹³¹I; concentrated by thyroid follicular cells
- Beta emission (range 400-2000 µm) causes focal radiation necrosis of thyroid parenchyma - follicular disruption, epithelial necrosis, leukocyte infiltration within weeks
- Effective t1/2 = 5 days
- Contraindicated in pregnancy (crosses placenta, destroys fetal thyroid) and lactation
- Fears of genetic damage, leukemia, or neoplasia have NOT materialized after 50+ years of use
Beta-Blockers in Thyrotoxicosis
Propranolol (>160 mg/day) is most studied; also reduces T3 levels ~20% by inhibiting peripheral T4→T3 deiodination. Metoprolol, atenolol are alternatives. They relieve adrenergic symptoms (tremor, palpitations, anxiety) but do not alter thyroid hormone synthesis.
Amiodarone-Induced Thyroid Disease
- Type I (iodine-induced): occurs in pre-existing thyroid disease (Graves, MNG); treat with thioamides
- Type II (inflammatory thyroiditis): no pre-existing disease; treat with glucocorticoids
- Often co-administer both types since differentiation can be difficult; slow improvement due to amiodarone's very long t1/2
3. ADRENOCORTICAL PHARMACOLOGY
Glucocorticoids
Key agents ranked by relative potency:
| Drug | Anti-inflammatory Potency (relative) | Mineralocorticoid Activity | Duration |
|---|---|---|---|
| Hydrocortisone (cortisol) | 1 | 1 | Short (8-12 h) |
| Prednisone | 4 | 0.8 | Intermediate (12-36 h) |
| Methylprednisolone | 5 | 0.5 | Intermediate |
| Dexamethasone | 25-30 | ~0 | Long (36-54 h) |
| Betamethasone | 25-30 | ~0 | Long |
| Fludrocortisone | 10 | 125 | Mineralocorticoid only |
Mechanism of action:
- Bind intracellular glucocorticoid receptors (GR-α)
- GR-ligand complex translocates to nucleus → transactivation (anti-inflammatory proteins) and transrepression (blocks NF-κB, AP-1)
- Suppress phospholipase A2 (via lipocortin-1) → reduced arachidonic acid release → decreased prostaglandins and leukotrienes
Therapeutic uses:
- Adrenal insufficiency (primary/secondary) - hydrocortisone replacement
- Inflammatory/autoimmune diseases (asthma, RA, IBD, SLE, transplant rejection)
- Cerebral edema (dexamethasone)
- Accelerate fetal lung maturity (betamethasone IM, antenatal)
- Thyroid storm adjunct, amiodarone-induced thyroiditis type II
Adverse effects of chronic use:
- HPA axis suppression (do NOT abruptly stop)
- Cushing's syndrome (weight gain, buffalo hump, moon face, striae)
- Hyperglycemia, hypertension, osteoporosis, myopathy
- Immune suppression, cataracts, glaucoma
- Psychiatric effects (euphoria, psychosis)
- Peptic ulceration (especially with NSAIDs)
Mineralocorticoids
Fludrocortisone - synthetic; nearly pure mineralocorticoid activity; used for:
- Primary adrenal insufficiency (Addison's disease) - with hydrocortisone
- Orthostatic hypotension, salt-wasting disorders
Drugs Inhibiting Corticosteroid Synthesis
| Drug | Target | Use |
|---|---|---|
| Metyrapone | 11β-hydroxylase | Cushing's diagnosis; short-term treatment |
| Ketoconazole | Multiple CYP enzymes in steroidogenesis | Cushing's syndrome; adrenal carcinoma |
| Aminoglutethimide | Cholesterol side-chain cleavage (CYP11A1) | Cushing's; also inhibits thyroid hormone synthesis |
| Mitotane | Adrenolytic (destroys adrenal cortex cells) | Adrenocortical carcinoma |
| Mifepristone (RU-486) | GR antagonist | Cushing's with hyperglycemia; also antiprogestin |
| Etomidate | 11β-hydroxylase (at low doses) | Acute severe Cushing's (IV) |
4. ENDOCRINE PANCREAS - DIABETES PHARMACOTHERAPY
Insulin Preparations
Insulin is the cornerstone of Type 1 DM and advanced Type 2 DM management. Classified by onset/duration:
| Type | Examples | Onset | Peak | Duration |
|---|---|---|---|---|
| Rapid-acting analog | Lispro, Aspart, Glulisine | 10-15 min | 1-2 h | 3-5 h |
| Short-acting (Regular) | Regular (soluble) insulin | 30-60 min | 2-4 h | 6-8 h |
| Intermediate-acting | NPH (isophane) | 1-3 h | 4-10 h | 12-18 h |
| Long-acting analog | Glargine (U-100, U-300), Detemir | 1-2 h | Peakless | 20-24 h / ~24 h |
| Ultra-long-acting | Degludec | ~1 h | Peakless | >42 h |
| Premixed | 70/30 NPH-Regular, BiAsp | Variable | Variable | Variable |
Mechanism: Insulin binds tyrosine kinase receptors (IR) → IRS-1/2 phosphorylation → PI3K/Akt → GLUT4 translocation (muscle, adipose); suppresses hepatic gluconeogenesis; promotes glycogen/protein/lipid synthesis; inhibits lipolysis and ketogenesis.
Adverse effects: Hypoglycemia (most important), weight gain, lipohypertrophy at injection sites, hypokalemia (insulin drives K+ into cells).
Oral and Injectable Antidiabetic Drugs
Biguanides
Metformin - first-line for Type 2 DM
- Mechanism: activates AMPK → reduces hepatic gluconeogenesis (primary); improves peripheral insulin sensitivity
- Advantages: weight-neutral/mild weight loss, no hypoglycemia, cardiovascular benefit (UKPDS)
- Adverse effects: GI (nausea, diarrhea); lactic acidosis (rare, risk with renal impairment - hold if eGFR <30); B12 deficiency
- Contraindicated: eGFR <30, iodinated contrast (hold peri-procedure), severe hepatic disease
Sulfonylureas (SU)
- 1st gen: Tolbutamide, chlorpropamide (mostly obsolete)
- 2nd gen: Glibenclamide (glyburide), glipizide, glimepiride
- Mechanism: Close ATP-sensitive K+ channels (SUR1) on beta cells → depolarization → Ca2+ influx → insulin secretion (glucose-independent)
- Adverse effects: Hypoglycemia (major risk, especially glyburide in elderly/renal insufficiency), weight gain
- Contraindicated: severe renal/hepatic disease
Meglitinides (Glinides)
- Repaglinide, Nateglinide
- Same mechanism as SU (K+ channel closure) but shorter-acting, taken with meals
- Less hypoglycemia than SU; useful in irregular meal patterns
Thiazolidinediones (TZDs / Glitazones)
- Pioglitazone, Rosiglitazone
- Mechanism: Agonists of PPARγ nuclear receptors → improve insulin sensitivity in adipose, muscle, liver; promote adiponectin secretion
- Adverse effects: Weight gain, fluid retention, heart failure risk (contraindicated in NYHA III-IV), bladder cancer (pioglitazone - long-term use), bone fractures in women, macular edema
Alpha-Glucosidase Inhibitors
- Acarbose, Miglitol, Voglibose
- Mechanism: Inhibit intestinal alpha-glucosidases → delay carbohydrate digestion/absorption → blunts postprandial glucose spike
- Adverse effects: Flatulence, diarrhea, abdominal cramps (fermentation of undigested carbohydrates)
- No hypoglycemia when used alone
DPP-4 Inhibitors ("Gliptins")
- Sitagliptin, Saxagliptin, Alogliptin, Linagliptin, Vildagliptin
- Mechanism: Inhibit dipeptidyl peptidase-4 → prevent degradation of endogenous GLP-1 and GIP → enhanced glucose-dependent insulin secretion + suppressed glucagon
- Advantages: Weight-neutral, no hypoglycemia alone, well tolerated, oral
- Adverse effects: Nasopharyngitis, possible pancreatitis; saxagliptin associated with increased heart failure hospitalization
GLP-1 Receptor Agonists ("Incretin mimetics")
- Exenatide, Liraglutide, Semaglutide, Dulaglutide, Albiglutide
- Mechanism: Mimic GLP-1 → glucose-dependent insulin secretion, glucagon suppression, delay gastric emptying, hypothalamic satiety signals
- Advantages: Weight loss (significant), cardioprotective (liraglutide, semaglutide - LEADER, SUSTAIN trials - reduce MACE), no hypoglycemia alone
- Adverse effects: Nausea/vomiting (most common, transient), pancreatitis risk, C-cell thyroid tumors (rodent data - contraindicated in MEN2/family hx medullary thyroid cancer), injection site reactions
- Semaglutide available orally (Rybelsus)
SGLT-2 Inhibitors ("Flozins" / Gliflozins)
- Empagliflozin, Dapagliflozin, Canagliflozin, Ertugliflozin
- Mechanism: Inhibit sodium-glucose co-transporter 2 in the proximal tubule → prevent renal glucose reabsorption → glycosuria (~70 g glucose excreted/day)
- Advantages: Weight loss, BP reduction, strong cardiorenal protection (empagliflozin - EMPA-REG; dapagliflozin - DAPA-HF; indicated in heart failure and CKD regardless of diabetes)
- Adverse effects: Genital mycotic infections, UTIs, diabetic ketoacidosis (euglycemic DKA - important in T1DM), Fournier's gangrene (rare), volume depletion, fracture risk (canagliflozin)
Amylin Analog
- Pramlintide - synthetic amylin; adjunct to insulin in T1DM/T2DM; suppresses glucagon, slows gastric emptying, promotes satiety; risk of hypoglycemia with insulin
5. REPRODUCTIVE ENDOCRINE PHARMACOLOGY
Estrogens
Natural/bioidentical: 17β-Estradiol (most potent endogenous), estrone, estriol
Synthetic: Ethinyl estradiol (most potent oral), conjugated equine estrogens (Premarin), mestranol
Synthetic: Ethinyl estradiol (most potent oral), conjugated equine estrogens (Premarin), mestranol
Mechanisms:
- Bind nuclear ERα/ERβ → gene transcription (genomic)
- Rapid, non-genomic effects via membrane ERs
Uses:
- Menopausal hormone therapy (vasomotor symptoms, osteoporosis prevention)
- Contraception (combined OCP)
- Turner syndrome induction of puberty
- Ovulation induction (clomiphene, aromatase inhibitors, gonadotropins)
Anti-estrogens:
| Drug | Type | Uses |
|---|---|---|
| Clomiphene | SERM (ER antagonist in hypothalamus) | Ovulation induction |
| Tamoxifen | SERM (antagonist in breast, agonist in uterus/bone) | Breast cancer treatment/prevention |
| Raloxifene | SERM (agonist in bone, antagonist in breast/uterus) | Osteoporosis; breast cancer prevention |
| Fulvestrant | Pure ER antagonist (SERD) | Advanced ER+ breast cancer |
| Aromatase inhibitors (letrozole, anastrozole, exemestane) | Block CYP19 (aromatase) - estrogen synthesis | Postmenopausal ER+ breast cancer; ovulation induction |
Progestins
Endogenous: Progesterone
Synthetic: Medroxyprogesterone acetate (MPA), norethindrone, levonorgestrel, desogestrel, drospirenone
Synthetic: Medroxyprogesterone acetate (MPA), norethindrone, levonorgestrel, desogestrel, drospirenone
Uses: Contraception, hormone therapy (endometrial protection), endometriosis, threatened abortion, luteal phase support in ART
Antiprogestins:
- Mifepristone (RU-486): Competitive PR + GR antagonist; used for medical termination of pregnancy (with misoprostol), Cushing's syndrome
Androgens
- Testosterone (IM, transdermal, topical gel, SC pellet) - male hypogonadism, constitutional delay of puberty
- Anabolic steroids (nandrolone, oxandrolone, stanozolol) - muscle wasting, aplastic anemia
- 5α-Reductase inhibitors: Finasteride (5AR type II), dutasteride (5AR type I+II) - BPH, androgenic alopecia; block conversion of testosterone → DHT
- Anti-androgens:
- Spironolactone (blocks AR, also inhibits androgen synthesis)
- Flutamide, bicalutamide, enzalutamide (AR antagonists - prostate cancer)
- Cyproterone acetate (prostate cancer, hirsutism, PCOS)
6. CALCIUM & BONE PHARMACOLOGY
Agents for Osteoporosis and Bone Disorders
| Drug Class | Examples | Mechanism | Use |
|---|---|---|---|
| Bisphosphonates | Alendronate, risedronate, zoledronic acid, ibandronate | Inhibit osteoclast farnesyl pyrophosphate synthase → osteoclast apoptosis | Osteoporosis, Paget's, hypercalcemia, bone metastases |
| Rank-L inhibitor | Denosumab | Monoclonal antibody vs RANKL → inhibits osteoclastogenesis | Osteoporosis, bone metastases |
| PTH analogs | Teriparatide (PTH 1-34), Abaloparatide | Anabolic - stimulate bone formation via intermittent PTH receptor activation | Severe osteoporosis |
| Anti-sclerostin | Romosozumab | Blocks sclerostin → dual anabolic + anti-resorptive | Postmenopausal osteoporosis (high fracture risk) |
| Calcitonin | Salmon calcitonin (nasal, SC) | Inhibits osteoclasts, analgesic in vertebral fracture | Second-line osteoporosis; Paget's |
| SERMs | Raloxifene | ERβ agonist in bone | Postmenopausal osteoporosis |
Vitamin D and PTH
- Vitamin D analogs: Cholecalciferol (D3), ergocalciferol (D2) - converted to active calcitriol [1,25-(OH)2 D3] by renal 1α-hydroxylase
- Active analogs: Calcitriol, alfacalcidol, paricalcitol - bypass renal activation; used in CKD
- Mechanism: VDR nuclear receptor → intestinal Ca2+/phosphate absorption; bone remodeling
- Cinacalcet (calcimimetic) - activates CaSR on chief cells of parathyroid → suppresses PTH secretion; used in secondary hyperparathyroidism (dialysis patients) and parathyroid carcinoma
Key Drug Interactions and Clinical Pearls
| Situation | Key Point |
|---|---|
| Levothyroxine + CYP inducers | Increased T4 clearance → need higher LT4 dose |
| Levothyroxine absorption | Calcium, iron, antacids, sucralfate reduce absorption (separate by 4 h) |
| Iodinated contrast + thyroid | Can precipitate iodide-induced hyperthyroidism (Jod-Basedow) in nodular goiter |
| Metformin + contrast | Hold at time of and 48 h post-contrast (renal risk of lactic acidosis) |
| SU + alcohol | Disulfiram-like reaction (especially chlorpropamide) |
| GLP-1 agonist + insulin/SU | Increase hypoglycemia risk |
| SGLT2 inhibitors + insulin | Risk of euglycemic DKA - educate patient to maintain hydration |
| Corticosteroids + NSAIDs | Greatly increased peptic ulcer risk |
| HPA suppression | Taper steroids after >3 weeks of use; do not abruptly discontinue |
Summary Table - Major Drug Classes by Endocrine Organ
| Endocrine Axis | Hormone Deficiency Tx | Hormone Excess Tx |
|---|---|---|
| Pituitary GH | Somatropin (recombinant GH) | Octreotide/lanreotide; pegvisomant |
| Pituitary PRL | - | Cabergoline, bromocriptine |
| Thyroid | Levothyroxine (T4) | PTU/methimazole; ¹³¹I; surgery |
| Adrenal cortex (gluco) | Hydrocortisone/prednisone | Metyrapone, ketoconazole, mitotane |
| Adrenal cortex (mineralo) | Fludrocortisone | Spironolactone, eplerenone |
| Endocrine pancreas | Insulin preparations | Diazoxide (insulinoma); octreotide |
| Gonads (estrogen) | Estradiol/CEE | Tamoxifen, aromatase inhibitors |
| Gonads (androgens) | Testosterone | Flutamide, enzalutamide, 5-ARi |
| Parathyroid/Bone | Calcitriol, teriparatide | Cinacalcet, bisphosphonates |
Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th Ed. (Chapters 46-52) | Katzung's Basic and Clinical Pharmacology, 16th Ed. (Chapter 38 - Thyroid; Chapter 39 - Pancreatic hormones and antidiabetic drugs; Chapter 40 - Adrenocorticosteroids)
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