---

Complete Guide to Endocrine & Reproductive Pharmacology

---

PART 1: ENDOCRINE PHARMACOLOGY

---

SECTION 1: HYPOTHALAMIC & PITUITARY HORMONES

1.1 Growth Hormone (GH) System

What is GH and what does it do?

---

DRUGS THAT REPLACE/MIMIC GH

Somatropin (recombinant human GH)

• What it is: Lab-made copy of human GH
• How it works: Binds GH receptors → liver makes IGF-1 → bone and tissue growth
• Used for:
  • Children with GH deficiency (short stature)
  • Turner syndrome, Prader-Willi syndrome, chronic kidney disease
  • Adults with GH deficiency (improves muscle mass, bone density, body composition)
• Key side effects: Edema (fluid retention), joint/muscle pain, carpal tunnel syndrome, glucose intolerance (it raises blood sugar!), intracranial hypertension, slipped capital femoral epiphysis in children
• Contraindications: Active malignancy, Prader-Willi syndrome with obesity/sleep apnea, proliferative retinopathy
• Given: Subcutaneous injection daily

Mecasermin (recombinant IGF-1)

• What it is: Lab-made IGF-1 (the downstream worker, not GH itself)
• Why it's needed: Some children can't respond to GH (mutations in GH receptor, neutralizing antibodies to GH) - GH is present but the body can't hear it
• Two forms:
  • Mecasermin - rhIGF-1 alone
  • Mecasermin rinfabate - rhIGF-1 + binding protein (IGFBP-3), which prolongs its half-life
• Growth response: 8-9 cm/year (less impressive than somatropin which gives 9-14 cm/year)
• Most important side effect: Hypoglycemia - IGF-1 acts like insulin! Must eat a carb-containing meal within 20 minutes of giving the injection
• Other side effects: Intracranial hypertension, enlarged tonsils/adenoids (adenotonsillar hypertrophy), lipohypertrophy at injection site, elevated liver enzymes
• Given: Subcutaneous injection twice daily

---

DRUGS THAT BLOCK/SUPPRESS GH (for Acromegaly)

Somatostatin Analogs

Octreotide

• Mechanism: Binds somatostatin receptors (SST2, SST5) → inhibits GH secretion, also inhibits TSH, glucagon, insulin, gastrin, secretin, VIP
• Used for:
  • Acromegaly
  • Carcinoid tumors (reduces flushing, diarrhea from serotonin/substance P release)
  • VIPomas (reduces severe watery diarrhea)
  • Bleeding esophageal varices (reduces portal pressure)
  • Diarrhea in AIDS and chemotherapy patients
  • Short bowel syndrome
• Forms:
  • Immediate-release: IV or subcutaneous 3x/day
  • Octreotide LAR (long-acting release): Intramuscular once per month - much more convenient!
• Side effects: GI symptoms (nausea, cramps, diarrhea initially), gallstones (because it reduces gallbladder emptying - very important!), bradycardia, hyperglycemia or hypoglycemia (variable insulin suppression), vitamin B12 deficiency

Lanreotide

• Very similar to octreotide
• Available as a depot formulation (extended-release gel) - subcutaneous injection once every 4 weeks
• Also used for acromegaly and carcinoid syndrome

Pasireotide

• Newer, broader spectrum - binds SST1, SST2, SST3, and SST5 receptors
• More effective for Cushing's disease (it suppresses ACTH from pituitary corticotroph tumors, unlike octreotide)
• Major side effect: Hyperglycemia (more than other somatostatin analogs - very important side effect to know)

Dopamine Receptor Agonists (for GH tumors)

Cabergoline

• Mechanism: D2 receptor agonist
• Used for: Acromegaly (adjunct), prolactinomas (first-line - see below)
• Advantage: Oral twice weekly

Bromocriptine

• Mechanism: D2 receptor agonist (also partial D1 antagonist)
• Used for: Prolactinomas (older drug), acromegaly (less effective), Type 2 diabetes (Cycloset brand - unique use)
• Side effects: Nausea, orthostatic hypotension, headache, nasal congestion, Raynaud's phenomenon, psychiatric effects at high doses

GH Receptor Antagonist

Pegvisomant

• Unique mechanism: NOT a somatostatin analog. It is a modified GH molecule that binds GH receptors but does NOT activate them (it BLOCKS them)
• Result: GH cannot signal → IGF-1 levels fall → acromegaly improves
• Used for: Acromegaly when surgery + somatostatin analogs fail
• Monitor: Liver function tests (can cause liver injury), IGF-1 levels (not GH levels - because GH will actually rise as pituitary tries to compensate, but that doesn't matter since receptors are blocked)
• Given: Daily subcutaneous injection

---

1.2 Prolactin System

Prolactinomas

Cabergoline (preferred)

• D2 agonist, given orally twice weekly
• Normalizes prolactin in ~80% of patients, shrinks tumor
• Better tolerated than bromocriptine

Bromocriptine

• Older D2 agonist, given daily or multiple times/day
• Also used to suppress lactation postpartum if breastfeeding is not desired
• Drug of choice for pregnant women with prolactinoma (more safety data)

---

1.3 Vasopressin (ADH) System

• V1 receptors: Blood vessels (vasoconstriction)
• V2 receptors: Kidney collecting ducts (water reabsorption)

Desmopressin (DDAVP)

• Mechanism: Selective V2 receptor agonist (minimal V1 activity - so minimal vasoconstriction)
• Used for:
  • Central diabetes insipidus (pituitary doesn't make ADH)
  • Nocturnal enuresis (bedwetting in children)
  • Hemophilia A and von Willebrand disease (releases stored von Willebrand factor and factor VIII from endothelium - a completely different mechanism!)
  • Mild bleeding disorders before procedures
• Forms: Intranasal, oral, IV/subcutaneous
• Key side effect: Hyponatremia (water retention without salt = dilutional low sodium) - important in children!

Vasopressin (AVP) / Terlipressin

• Mechanism: Activates both V1 (vasoconstriction) and V2 receptors
• Used for:
  • Bleeding esophageal varices (V1 constricts splanchnic vessels → reduces portal pressure)
  • Vasodilatory shock / septic shock (vasopressor)
  • Diabetes insipidus (less preferred than desmopressin due to V1 effects)
• Side effects: Myocardial ischemia (from coronary vasoconstriction), hypertension, abdominal cramping, pallor

Vasopressin Receptor Antagonists (Vaptans)

Conivaptan (IV) and Tolvaptan (oral)

• Used for: SIADH (syndrome of inappropriate ADH - hyponatremia due to too much ADH), heart failure with hyponatremia
• Tolvaptan also used in autosomal dominant polycystic kidney disease (ADPKD) - it slows cyst growth
• Side effect: Rapid correction of sodium → osmotic demyelination syndrome (rare but serious). Must correct sodium slowly.

---

1.4 Oxytocin

• Source: Posterior pituitary (hypothalamus actually makes it; stored + released from posterior pituitary)
• Mechanism: G protein-coupled receptor → phosphoinositide-calcium → contracts uterine smooth muscle + stimulates prostaglandin release → uterine contractions
• Also: Causes myoepithelial cells around breast alveoli to contract → milk letdown (ejection)
• Half-life: ~5 minutes (rapidly eliminated by kidney and liver)

1. Induction of labor: IV infusion, start 0.5-2 mU/min, increase every 30-60 min, max 20 mU/min
2. Augmentation of slow labor
3. Postpartum hemorrhage (uterine atony): 10-40 units in 1L D5W IV infusion, or 10 units IM
4. Oxytocin challenge test: Tests if placenta has enough reserve (late fetal heart rate decelerations = bad sign = possible immediate C-section needed)

• Water retention/hyponatremia at high doses (it has weak ADH-like activity at high concentrations - activates vasopressin receptors)
• Hypotension if given as rapid IV bolus (vasodilation)
• Uterine hyperstimulation → fetal distress

---

SECTION 2: THYROID PHARMACOLOGY

Normal Thyroid Physiology (Quick Review)

• Thyroid makes mainly T4 (thyroxine, 4 iodines) - the "storage" hormone
• T4 is converted in peripheral tissues to T3 (triiodothyronine, 3 iodines) - the active hormone
• T3 is 3-5x more potent than T4
• Iodine is essential - no iodine = no thyroid hormones

---

DRUGS FOR HYPOTHYROIDISM (Too Little Thyroid Hormone)

Levothyroxine (T4) - DRUG OF CHOICE

• What it is: Synthetic T4
• Why T4 and not T3? T4 has a long half-life (~7 days), giving steady hormone levels. The body converts it to T3 as needed (physiological regulation is maintained).
• Route: Oral (once daily, on empty stomach, 30-60 min before food)
• Interactions: Cholestyramine, calcium, iron, antacids - all reduce absorption; separate by 4 hours
• Narrow therapeutic index - must monitor TSH levels; TSH is the best marker (low TSH = too much T4, high TSH = too little T4)
• Side effects (= symptoms of hyperthyroidism if overdosed): Palpitations, tachycardia, anxiety, insomnia, heat intolerance, weight loss, osteoporosis (long-term)
• Special note: In hypothyroid patients with cardiac disease, start with very LOW doses (12.5-25 mcg/day) and increase slowly - sudden thyroid hormone can precipitate angina or arrhythmia

Liothyronine (T3 - Cytomel)

• Synthetic T3, short half-life (~1 day)
• Used rarely - mainly when rapid thyroid replacement is needed (e.g., myxedema coma where IV T3 is used)
• More fluctuating hormone levels than T4

Liotrix

• Fixed combination of T3:T4 in 1:4 ratio
• Rarely used today

---

DRUGS FOR HYPERTHYROIDISM (Too Much Thyroid Hormone)

Thioamides (Antithyroid Drugs)

Propylthiouracil (PTU)

• Mechanism - TWO important actions:
  1. Blocks thyroid peroxidase → prevents iodide oxidation and coupling → no T3/T4 synthesis
  2. Blocks peripheral conversion of T4 to T3 (inhibits deiodinase) - this is unique to PTU among thioamides!
• Used in: Hyperthyroidism, first trimester of pregnancy (methimazole causes birth defects in first trimester), thyroid storm (due to its rapid T4→T3 block)
• Side effects:
  • Agranulocytosis (rare but life-threatening - 0.2-0.5% risk; patients must stop the drug and seek emergency care if they develop fever/sore throat)
  • Hepatotoxicity (serious - can cause liver failure, especially in adults; monitor LFTs)
  • Rash, arthralgia, vasculitis (ANCA-positive)
  • Crosses placenta and breast milk

Methimazole (Tapazole) / Carbimazole

• Mechanism: Blocks thyroid peroxidase ONLY (no peripheral conversion block)
• Longer half-life than PTU - can be dosed once daily
• Preferred over PTU for most patients (except pregnancy first trimester and thyroid storm)
• Carbimazole: Prodrug converted to methimazole
• Side effects:
  • Agranulocytosis (same warning as PTU)
  • Teratogenic in first trimester - causes "methimazole embryopathy" (choanal atresia, aplasia cutis, esophageal atresia)
  • Rash, fever, arthralgias

Radioactive Iodine (RAI - I-131)

• Mechanism: Thyroid cells take up iodine avidly. I-131 emits beta rays that destroy the follicular cells from within. Takes 6-18 weeks for full effect.
• Used for: Graves' disease (most common treatment in USA), toxic multinodular goiter, toxic adenoma
• Contraindications: Pregnancy (absolutely contraindicated - destroys fetal thyroid), breastfeeding, children (controversial), severe ophthalmopathy (can worsen eye disease)
• Result: Most patients become hypothyroid eventually - need lifelong levothyroxine
• Advantage: Permanent cure, no surgery needed

Iodine / Iodide Solutions

Lugol's Solution (Strong Iodine Solution) and SSKI (Saturated Solution of Potassium Iodide)

• Mechanism: Wolff-Chaikoff effect - high iodide concentrations temporarily block thyroid hormone synthesis AND reduce vascularity of the thyroid gland
• Clinical use:
  • Preoperative preparation for thyroidectomy (given 10-14 days before surgery to firm up the gland and reduce bleeding)
  • Thyroid storm (rapid reduction of hormone release)
  • Emergency protection after radiation exposure (blocks radioactive iodine uptake)
• Important: Effect is TEMPORARY. The thyroid "escapes" from iodide block after 10-14 days ("escape phenomenon"). That's why it cannot be used long-term.

Beta-Blockers (Adjunct Therapy)

Propranolol (and Atenolol)

• Mechanism: Block sympathetic effects of excess thyroid hormone (tachycardia, tremor, anxiety, sweating)
• Propranolol also blocks peripheral T4→T3 conversion (like PTU) - useful in thyroid storm
• Does NOT reduce thyroid hormone levels - only treats symptoms
• Used as adjunct while waiting for thioamides or RAI to work

Thyroid Storm Treatment

1. PTU (blocks synthesis AND peripheral conversion)
2. Iodide (Lugol's) - given 1 hour AFTER PTU (so the new iodide isn't used to make more hormone first)
3. Propranolol (blocks sympathetic effects, also blocks T4→T3)
4. Glucocorticoids (dexamethasone - also blocks T4→T3 conversion, treats relative adrenal insufficiency)
5. Supportive care

---

SECTION 3: ADRENAL CORTEX PHARMACOLOGY

Three Zones, Three Hormones:

1. Zona Glomerulosa → Aldosterone (mineralocorticoid - controls sodium/potassium)
2. Zona Fasciculata → Cortisol (glucocorticoid - stress, metabolism, immunity)
3. Zona Reticularis → Androgens (DHEA, androstenedione - weak sex hormones)

---

GLUCOCORTICOIDS

• Anti-inflammatory (suppress cytokines, phospholipase A2, COX)
• Immunosuppressive (lymphopenia, reduced antibody production)
• Metabolic: raise blood glucose (gluconeogenesis), break down muscle protein, redistribute fat (central obesity, buffalo hump, moon face)
• Bone: reduce calcium absorption → osteoporosis
• CNS: mood changes, insomnia, psychosis at high doses

Short-Acting Glucocorticoids

Intermediate-Acting

Long-Acting

• Dexamethasone and betamethasone have negligible mineralocorticoid activity → preferred for pure anti-inflammatory/immunosuppressive use without fluid retention
• Hydrocortisone has significant mineralocorticoid activity → used for adrenal replacement therapy
• Prednisone is a prodrug → converted to prednisolone in liver (don't use prednisone in severe liver disease)

• Cushing's syndrome: Moon face, buffalo hump, central obesity, striae, easy bruising
• Osteoporosis (give calcium + vitamin D + bisphosphonate prophylaxis)
• Hyperglycemia/diabetes
• Hypertension, edema
• Cataracts, glaucoma
• Peptic ulcers (give proton pump inhibitor)
• Immunosuppression → infections (especially TB reactivation, fungal infections)
• Adrenal suppression (HPA axis suppression) → cannot stop drug abruptly! Must taper slowly to allow adrenal recovery
• Myopathy (proximal muscle weakness)
• Growth retardation in children
• Mood changes, psychosis

---

MINERALOCORTICOIDS

Fludrocortisone

• Mechanism: Potent mineralocorticoid (retains sodium, excretes potassium)
• Used for:
  • Primary adrenal insufficiency (Addison's disease) - given along with hydrocortisone
  • Congenital adrenal hyperplasia (especially 21-hydroxylase deficiency with salt-wasting)
  • Orthostatic hypotension (increases blood volume)
• Side effects: Hypertension, edema, hypokalemia, cardiac arrhythmias

---

DRUGS FOR ADRENAL EXCESS (Cushing's Syndrome)

Metyrapone

• Mechanism: Blocks 11-beta-hydroxylase → cannot convert 11-deoxycortisol to cortisol
• Used for: Cushing's syndrome, also used diagnostically (metyrapone test - tests ACTH reserve)

Ketoconazole

• Mechanism: Blocks multiple adrenal steroid synthesis enzymes (17-alpha-hydroxylase, C17-20 lyase)
• Used for: Cushing's syndrome, prostate cancer (reduces androgen synthesis)
• Also: Antifungal drug (its primary original indication)

Mitotane

• Mechanism: Destroys adrenocortical cells directly (adrenolytic) + inhibits steroid synthesis
• Used for: Adrenocortical carcinoma
• Side effects: GI toxicity, CNS effects, hepatotoxicity

Mifepristone (RU-486)

• Mechanism: Blocks glucocorticoid AND progesterone receptors
• For Cushing's: Approved for Cushing's syndrome-related hyperglycemia (cannot use in surgical candidates)
• Reproductive use: Abortifacient (see Section 5)

---

SECTION 4: DIABETES PHARMACOLOGY

• Type 1: No insulin at all (autoimmune destruction of beta cells) → must use insulin
• Type 2: Insulin resistance + relative insulin deficiency → start with oral drugs, add insulin as needed

---

INSULIN

Types of Insulin (by duration of action)

• U-500 Regular Insulin (5x concentration) - for severely insulin-resistant patients
• U-300 Glargine - lasts longer, less variability

Insulin Side Effects

1. Hypoglycemia - most common and most dangerous; symptoms: sweating, palpitations, tremor, confusion, seizures, coma
2. Weight gain (insulin promotes fat storage)
3. Lipohypertrophy at injection site (rotate sites!)
4. Lipodystrophy (older insulins)
5. Edema (sodium retention)
6. Somogyi effect: Nocturnal hypoglycemia → rebound morning hyperglycemia (counter-regulatory hormones); treat by reducing evening insulin
7. Dawn phenomenon: Early morning hyperglycemia without preceding hypoglycemia (growth hormone surge at dawn); treat by increasing basal insulin

Special Insulin Uses

• Diabetic Ketoacidosis (DKA): IV regular insulin infusion
• Hyperkalemia emergency: IV insulin + dextrose → drives K+ into cells (insulin activates Na/K ATPase)
• Gestational diabetes: Insulin is safe in pregnancy (large molecule, doesn't cross placenta well)

---

ORAL & INJECTABLE ANTIDIABETIC DRUGS (for Type 2 Diabetes)

CLASS 1: BIGUANIDES

Metformin - THE FIRST-LINE DRUG FOR TYPE 2 DIABETES

• Mechanism (complex):
  • Activates AMPK (AMP-activated protein kinase) - the "fuel gauge" of the cell
  • Primarily reduces hepatic glucose production (gluconeogenesis) - does NOT stimulate insulin secretion
  • Also improves insulin sensitivity in muscle
  • May also work through gut microbiome effects
• Why it's first-line:
  • Does NOT cause hypoglycemia (doesn't stimulate insulin)
  • Weight neutral or causes slight weight loss
  • Cardiovascular benefit (reduces cardiovascular events in Type 2 DM)
  • Very cheap, generic, available worldwide
• Route: Oral, with meals
• Side effects:
  • GI side effects (nausea, diarrhea, cramping) - very common, especially when starting; take with food, start low
  • Lactic acidosis (rare but serious) - mainly a risk when metformin accumulates in conditions where it can't be cleared (see contraindications)
  • Vitamin B12 deficiency (long-term use impairs B12 absorption in ileum - check B12 annually)
• Contraindications:
  • Renal impairment (eGFR < 30 - absolute; caution 30-45) - kidneys can't clear metformin → accumulates → lactic acidosis
  • Liver failure (impairs lactate clearance)
  • Heart failure (older guidance was more restrictive; now only severe decompensated HF)
  • Iodinated contrast media - hold metformin on day of procedure and 48 hrs after (contrast can cause AKI → metformin accumulation)
  • Acute illness, major surgery - hold temporarily

---

CLASS 2: SULFONYLUREAS

• Chlorpropamide, tolbutamide, tolazamide

• Side effects:
  • Hypoglycemia (most important - especially glyburide in elderly!)
  • Weight gain (stimulating insulin → fat storage)
  • Hyponatremia (especially chlorpropamide - SIADH-like effect)
  • Disulfiram-like reaction with alcohol (chlorpropamide)

---

CLASS 3: MEGLITINIDES (Glinides)

Repaglinide and Nateglinide

• Mechanism: Also block KATP channels like sulfonylureas, but at a DIFFERENT binding site
• Key difference: Very short-acting → taken with each meal (and skipped if meal is skipped) → less hypoglycemia between meals
• Repaglinide: Metabolized by liver → can be used in renal impairment
• Nateglinide: Weaker, more rapid - purely meal-related coverage

---

CLASS 4: THIAZOLIDINEDIONES (TZDs / Glitazones)

Pioglitazone and Rosiglitazone

• Mechanism: Activate PPAR-gamma nuclear receptor → increases transcription of genes that improve insulin sensitivity in fat, muscle, liver → enhances glucose uptake
• They don't stimulate insulin → no hypoglycemia alone
• Pioglitazone: Also improves lipid profile (raises HDL, lowers triglycerides)
• Rosiglitazone: Controversial - associated with increased cardiovascular risk (still available in USA but restricted)
• Side effects:
  • Weight gain (fluid retention + fat redistribution)
  • Edema - contraindicated in heart failure (NYHA Class III-IV)
  • Osteoporosis/fractures (especially in postmenopausal women)
  • Bladder cancer risk (pioglitazone - long-term use; avoid in patients with bladder cancer history)
  • Takes 4-12 weeks for full effect (gene transcription changes are slow)

---

CLASS 5: GLP-1 RECEPTOR AGONISTS (Incretin Mimetics)

• Stimulate insulin secretion in a glucose-dependent manner (only when glucose is high → lower hypoglycemia risk)
• Suppress glucagon (opposite hormone to insulin)
• Slow gastric emptying (food digested slower → glucose rise is slower)
• Suppress appetite / promote satiety (act on hypothalamus) → weight loss!

• Significant weight loss (2-15 kg depending on drug)
• Cardiovascular benefit - liraglutide and semaglutide reduce cardiovascular events (LEADER trial, SUSTAIN trials)
• Kidney protection (emerging data)

• Nausea, vomiting (most common, especially at start - due to slowed gastric emptying; improves with time)
• Pancreatitis (rare but warned - stop if pancreatitis suspected)
• Thyroid C-cell tumors (in rodents - avoid in patients with personal/family history of MTC or MEN2)
• Gallstones (rapid weight loss)
• Injection site reactions

---

CLASS 6: DPP-4 INHIBITORS (Gliptins)

• No hypoglycemia (glucose-dependent insulin stimulation)
• Weight neutral
• Well tolerated
• Side effects: Nasopharyngitis, UTI, joint pain, rare pancreatitis, rare severe bullous pemphigoid (skin blistering - especially alogliptin and others)

---

CLASS 7: SGLT2 INHIBITORS (Gliflozins)

• Cardiovascular protection: Empagliflozin reduced cardiovascular death in EMPA-REG outcome trial; dapagliflozin in DECLARE trial
• Heart failure benefit: Dramatically reduce HF hospitalization (now approved for HF even without diabetes!)
• Kidney protection: Slow progression of diabetic nephropathy; dapagliflozin approved for CKD
• Weight loss (glucose + calories lost in urine)
• Blood pressure lowering (osmotic diuresis)

• Genital mycotic infections (candida in genitalia - because glucose in urine feeds yeast; more common in women) - very common!
• UTIs (increased glucose in urinary tract)
• Diabetic ketoacidosis (DKA) - euglycemic DKA - rare but dangerous; blood sugar may be only mildly elevated, but patient is in ketoacidosis. Risk especially during starvation, illness, surgery. Hold SGLT2 inhibitors before major surgery/procedure.
• Fournier's gangrene (necrotizing fasciitis of genitalia) - rare but serious
• Volume depletion, hypotension (osmotic diuresis)
• Amputations: Canagliflozin specifically associated with lower limb amputations (FDA black box)
• Fractures: Canagliflozin associated with bone fractures

---

CLASS 8: ALPHA-GLUCOSIDASE INHIBITORS

Acarbose and Miglitol

• Mechanism: Block alpha-glucosidases in the intestinal brush border → slow breakdown of complex carbohydrates/starches → slower glucose absorption → reduces postprandial glucose spikes
• Must be taken with first bite of each meal
• No hypoglycemia (no insulin stimulation)
• Weight neutral
• Side effects: Severe GI effects - flatulence, bloating, diarrhea (due to undigested carbohydrates reaching colon where bacteria ferment them) → poor compliance!
• If hypoglycemia occurs while on acarbose + another drug, must treat with glucose (dextrose), NOT sucrose/table sugar (acarbose blocks sucrose digestion too)

---

CLASS 9: AMYLIN ANALOGS

Pramlintide

• What is amylin? A hormone co-secreted with insulin from beta cells. It reduces postprandial glucose by slowing gastric emptying and suppressing glucagon.
• Who lacks amylin? Type 1 diabetics (whose beta cells are destroyed) and advanced Type 2 diabetics
• Mechanism: Synthetic amylin analog → slows gastric emptying, suppresses glucagon, promotes satiety
• Used as: Adjunct to insulin in Type 1 and Type 2 DM
• Side effects: Nausea, vomiting, hypoglycemia (when combined with insulin - must reduce insulin dose when starting pramlintide)
• Given: Subcutaneous injection before major meals (in a DIFFERENT syringe/site than insulin - incompatible with insulin)

---

Insulin Strategy Summary for Type 2 DM (from Katzung Figure 41-6)

---

SECTION 5: BONE MINERAL PHARMACOLOGY (Brief)

Vitamin D

• Cholecalciferol (D3): From sunlight/diet → converted in liver to 25-OH-D3 → converted in kidney to 1,25-(OH)2-D3 (calcitriol) = active form
• Calcitriol: Active vitamin D, promotes calcium absorption in gut
• Used for: Vitamin D deficiency, hypoparathyroidism, osteoporosis, renal osteodystrophy

Bisphosphonates (for Osteoporosis)

• Mechanism: Bind hydroxyapatite in bone → inhibit osteoclast activity (cells that break down bone) → bone density increases
• Must be taken: Oral forms - with FULL glass of water, sitting upright, 30 min before any food/medication - otherwise esophagitis
• Side effects: Esophagitis (oral), atypical femur fractures (long-term), osteonecrosis of jaw (especially with cancer/high-dose IV use)

---

PART 2: REPRODUCTIVE PHARMACOLOGY

---

SECTION 6: HYPOTHALAMIC-PITUITARY-GONADAL AXIS

---

GnRH AGONISTS (Paradoxically Used as SUPPRESSORS)

1. Prostate cancer (most common use) - reduces testosterone → slows prostate cancer growth. Must add antiandrogen during first 2 weeks to block "flare" (see below)
2. Endometriosis - suppresses estrogen → reduces ectopic endometrium; limited to 6 months (add "add-back" estrogen/progestin if longer)
3. Uterine fibroids (leiomyomata) - shrinks fibroid size preoperatively
4. Precocious puberty - suppresses premature sexual development
5. IVF/controlled ovarian stimulation - suppresses endogenous LH surge to control timing
6. Breast cancer (premenopausal) - medical oophorectomy

• Hot flashes (most common)
• Osteoporosis/decreased bone density (estrogen/testosterone deficiency)
• Erectile dysfunction, decreased libido (in men)
• Mood changes, depression
• Vaginal dryness (in women)

---

GnRH ANTAGONISTS (Immediate Suppression - No Flare)

---

SECTION 7: SEX HORMONES & THEIR DRUGS

ESTROGENS

• Development of female secondary sex characteristics
• Breast development and uterine growth
• Maintain bone density (prevents osteoclast activity)
• Cardiovascular protective effects (premenopausal women have lower CVD risk than men)
• Negative feedback on pituitary → suppresses FSH/LH (basis of contraception)
• Increase HDL, lower LDL
• Promote clotting (increase synthesis of factors VII, IX, X, fibrinogen)

Types of Estrogens

• 17-beta Estradiol (E2): Most potent natural estrogen; patch, gel, spray, vaginal ring
• Estrone (E1): Weaker, mainly postmenopausal
• Estriol (E3): Very weak, mainly during pregnancy (made by placenta)

• Ethinyl estradiol (EE): Most widely used synthetic estrogen - in nearly all combined oral contraceptives (highly potent, good oral bioavailability)
• Diethylstilbestrol (DES): Non-steroidal estrogen, now mainly historical - given to pregnant women in 1950s-70s, caused vaginal clear cell adenocarcinoma in daughters (major pharmacology tragedy)
• Mestranol: Prodrug → converted to ethinyl estradiol

1. Hormone replacement therapy (HRT) / menopausal symptoms - hot flashes, vaginal atrophy, sleep disruption
2. Oral contraceptives (combined with progestin)
3. Primary hypogonadism (Turner syndrome, premature ovarian failure)
4. Osteoporosis prevention (post-menopause)
5. Dysfunctional uterine bleeding (estrogen withdrawal bleeding)
6. Prostate cancer (high-dose estrogen suppresses LH → reduces testosterone)

• Thromboembolism (DVT, PE) - estrogen raises clotting factors (especially with oral synthetic estrogens - transdermal is safer)
• Breast cancer risk - increases with long-term use
• Endometrial cancer - unopposed estrogen (without progestin) in women with uterus!
• Nausea, breast tenderness, headache
• Hypertension (via renin-angiotensin activation)
• Gallstones (increases cholesterol saturation in bile)

---

PROGESTINS

• Transforms proliferative endometrium → secretory endometrium (prepares for implantation)
• Maintains pregnancy (prevents uterine contractions)
• Opposes estrogen on endometrium (protects against endometrial cancer)
• Negative feedback on pituitary → suppresses LH (basis of contraception)
• Raises basal body temperature (ovulation thermometry)

Types of Progestins

• Medroxyprogesterone acetate (MPA/Depo-Provera): Injectable contraceptive
• Norethindrone/norethisterone: In many oral contraceptives
• Levonorgestrel (LNG): Potent, in many OCs, IUD (Mirena), emergency contraception
• Etonogestrel: Implant (Nexplanon), combined vaginal ring (NuvaRing)
• Drospirenone: In some OCs; has anti-mineralocorticoid activity (reduces water retention) - good for PMS/PMDD
• Desogestrel, gestodene: "Third generation" progestins - minimal androgenic effect

1. Oral contraceptives (with estrogen)
2. Progestin-only pills (mini-pill)
3. Injectable contraceptive (Depo-Provera)
4. IUD (Mirena, Kyleena - local progestin)
5. Endometriosis treatment
6. Protect endometrium in HRT (women with uterus must have progestin added to prevent endometrial cancer from unopposed estrogen)
7. Threatened/habitual abortion (progesterone)
8. Luteal phase support in IVF

---

SECTION 8: CONTRACEPTIVES

Combined Oral Contraceptives (COCs) - "The Pill"

1. Primary: Suppresses LH surge → prevents ovulation (most important)
2. Thickens cervical mucus → blocks sperm penetration
3. Thins endometrium → hostile to implantation
4. Slows fallopian tube motility

• Monophasic: Same dose every day (e.g., Yasmin = EE + drospirenone)
• Biphasic: Two different dose levels across the cycle
• Triphasic: Three different dose levels (mimic natural cycle)
• Continuous/extended cycle: 84 active + 7 placebo pills (Seasonale) - only 4 periods/year
• 24/4 pills: 24 active + 4 placebo (less breakthrough bleeding)

• Reduces dysmenorrhea (painful periods)
• Reduces menorrhagia (heavy periods) → less anemia
• Reduces PMS/PMDD symptoms
• Reduces acne (antiandrogenic progestins like drospirenone)
• Reduces ovarian and endometrial cancer risk
• Reduces ovarian cysts
• Reduces endometriosis pain
• Reduces benign breast disease

• Thromboembolism (DVT, PE, stroke) - MAJOR risk; estrogen raises clotting factors
• Hypertension
• Nausea, breast tenderness (especially early)
• Spotting/breakthrough bleeding (especially first months)
• Reduced libido (especially with androgenic progestins)
• Mood changes
• Drug interactions: Rifampin, carbamazepine, phenytoin - induce liver enzymes → reduce OC levels → contraceptive failure!

• History of DVT/PE or clotting disorders
• Smoking + age >35
• Migraine with aura (increased stroke risk)
• Breast cancer
• Uncontrolled hypertension
• Active liver disease
• Pregnancy

---

Progestin-Only Contraceptives

Progestin-Only Pills (Mini-Pill)

• Norethindrone or norgestrel; taken daily at the same time every day (no pill-free interval)
• Primary mechanism: Thickens cervical mucus (not primarily ovulation suppression)
• Used when estrogen is contraindicated: Breastfeeding women, smokers >35, history of DVT, hypertension, migraine
• Side effect: Irregular bleeding (most common reason for discontinuation)

Depo-Provera (Medroxyprogesterone Acetate 150mg IM every 3 months)

• Highly effective (>99%)
• Primary mechanism: Suppresses ovulation
• Side effects: Irregular bleeding (then amenorrhea after several months), bone density loss (monitor in long-term users), weight gain, delayed return to fertility (can take 9-18 months after stopping)

Subdermal Implant (Nexplanon - Etonogestrel)

• Single rod implanted in upper arm - lasts 3 years
• Most effective contraceptive available (>99.9%)
• Works mainly by suppressing ovulation
• Side effects: Irregular bleeding, headache

Intrauterine Devices (IUDs)

• Levonorgestrel released locally into uterus
• Thickens cervical mucus, thins endometrium, may suppress ovulation
• Lasts 3-8 years depending on device
• Reduces menstrual bleeding dramatically (often amenorrhea) - benefit for heavy periods
• Non-contraceptive use: Menorrhagia treatment, endometriosis

• No hormones - copper ions are spermicidal
• Lasts up to 10 years
• Also used as emergency contraception (most effective emergency method - if inserted within 5 days)
• Side effect: Heavier, more painful periods (especially first few months)

---

Emergency Contraception

Levonorgestrel (Plan B, Morning-After Pill)

• 1.5 mg orally as soon as possible after unprotected sex (within 72 hours, can be used up to 120 hrs with reduced efficacy)
• Mechanism: Primarily delays or inhibits ovulation; does NOT prevent implantation of fertilized egg (important: it is NOT an abortifacient)
• No effect if already pregnant
• Side effects: Nausea, headache, breast tenderness, irregular bleeding
• Effectiveness: ~89% if taken within 72 hours; less effective in heavier women (BMI >26-30)

Ulipristal Acetate (ella)

• Selective progesterone receptor modulator (SPRM)
• Effective up to 120 hours after unprotected sex
• More effective than levonorgestrel (especially if taken later or in heavier women)
• Works by delaying/inhibiting ovulation

Mifepristone (low dose) + Levonorgestrel

• More effective combination for emergency contraception

---

SECTION 9: DRUGS AFFECTING UTERINE MOTILITY

OXYTOCIN (Covered in Section 1.4)

---

PROSTAGLANDINS (Uterine Stimulants)

Dinoprostone (PGE2)

• Used for: Cervical ripening before induction of labor (vaginal insert/gel)
• Mechanism: Softens (ripens) the cervix; also stimulates uterine contractions

Misoprostol (PGE1 analog)

• Primary indication: Gastric ulcer prevention (with NSAIDs)
• Reproductive uses:
  • Medical abortion (with mifepristone - see below)
  • Cervical ripening and labor induction
  • Postpartum hemorrhage (sublingual or rectal - especially in low-resource settings where oxytocin refrigeration unavailable)
  • IUD insertion (soften cervix)
• Routes: Oral, sublingual, vaginal, rectal
• Side effects: Uterine hyperstimulation, nausea, diarrhea, fever, chills

Carboprost (15-methyl-PGF2-alpha)

• Used for: Refractory postpartum hemorrhage (uterine atony not responding to oxytocin)
• IM injection
• Contraindicated in asthma (PGF2-alpha causes bronchospasm)
• Side effects: Nausea, vomiting, diarrhea, bronchospasm, hypertension

---

TOCOLYTICS (Uterine Relaxants - Stop Preterm Labor)

Beta-2 Agonists

Ritodrine and Terbutaline

• Mechanism: Beta-2 adrenergic agonists → relax uterine smooth muscle
• Ritodrine was the only FDA-approved tocolytic (now discontinued)
• Terbutaline still used short-term
• FDA warning: Terbutaline injectable should NOT be used for tocolysis for >48-72 hours or outside hospital (cardiac risks in mother)
• Side effects: Maternal and fetal tachycardia, hypotension, hypokalemia, hyperglycemia, pulmonary edema (serious)

Magnesium Sulfate

• Mechanism: Competes with calcium in uterine smooth muscle → reduces contractions
• Used for: Tocolysis (especially <32 weeks), eclampsia prevention/treatment (anticonvulsant)
• Fetal neuroprotection: IV MgSO4 given before delivery <32 weeks reduces risk of cerebral palsy in infant
• Toxicity (at increasing serum levels):
  • Loss of deep tendon reflexes (first sign)
  • Respiratory depression
  • Cardiac arrest
• Antidote: Calcium gluconate IV - calcium reverses magnesium toxicity

Nifedipine (Calcium Channel Blocker)

• Mechanism: Blocks L-type calcium channels → uterine smooth muscle relaxation
• Widely used for tocolysis, well tolerated
• Side effects: Headache, flushing, hypotension

Indomethacin (COX Inhibitor)

• Mechanism: Inhibits prostaglandin synthesis → reduces uterine contractions (prostaglandins trigger labor)
• Effective but limited use - use only <32 weeks gestation because:
  • Premature closure of ductus arteriosus (very serious!)
  • Oligohydramnios (reduced amniotic fluid)
  • Neonatal renal dysfunction

Atosiban

• Oxytocin receptor antagonist - blocks oxytocin from stimulating uterine contractions
• Used in Europe (not FDA-approved in USA)
• Side effects: Nausea, headache, dizziness

---

SECTION 10: ANDROGENS & ANTIANDROGENS

ANDROGENS

• Development of male secondary sex characteristics (puberty)
• Spermatogenesis (with FSH)
• Muscle protein synthesis, bone density
• Red blood cell production (EPO stimulation)
• Sebum production (acne)

Testosterone and Derivatives

1. Male hypogonadism (primary - testicular failure, or secondary - pituitary/hypothalamic failure)
2. Delayed puberty in boys (short-term low-dose)
3. Anemia (stimulates erythropoietin)
4. Gender-affirming hormone therapy (trans men)
5. Wasting syndromes (HIV, cancer cachexia)

• Polycythemia (elevated hematocrit - raises DVT/stroke risk; monitor hematocrit)
• Suppression of spermatogenesis (exogenous testosterone suppresses FSH → less sperm production; may cause infertility)
• Acne, oily skin
• Male pattern baldness (androgenetic alopecia)
• Prostatic hypertrophy (exacerbates BPH)
• Prostate cancer stimulation (contraindicated in known/suspected prostate cancer)
• Liver toxicity (especially 17-alpha-alkylated oral androgens like methyltestosterone, stanozolol, oxandrolone)
• Cardiovascular risks (polycythemia, lipid changes)
• In women: Virilization (deepening voice, clitoromegaly, facial hair)
• Gynecomastia (testosterone is aromatized to estradiol in peripheral fat)

Anabolic Steroids (Abuse)

• Modified testosterone derivatives (nandrolone, stanozolol, oxandrolone)
• Used illicitly for athletic performance - causes all testosterone side effects plus: HDL reduction, testicular atrophy, psychiatric effects ("roid rage")

---

ANTIANDROGENS

5-Alpha Reductase Inhibitors

Finasteride (5mg - Proscar; 1mg - Propecia)

• Mechanism: Blocks Type 2 5-alpha reductase → reduces DHT in prostate and scalp
• Used for:
  • BPH (benign prostatic hyperplasia) - 5mg dose - reduces prostate volume, improves urine flow (takes 6-12 months for full effect)
  • Male pattern baldness - 1mg dose - reduces scalp DHT → hair growth
• Side effects: Decreased libido, erectile dysfunction, gynecomastia (due to reduced androgen effect - can persist after stopping = "post-finasteride syndrome")
• Important: Lowers PSA levels by ~50% (adjust PSA interpretation in screening!)

Dutasteride (Avodart)

• Mechanism: Blocks BOTH Type 1 AND Type 2 5-alpha reductase → more complete DHT suppression
• More effective for BPH than finasteride
• Also used for hair loss

Androgen Receptor Blockers (Competitive Antagonists)

Spironolactone

• Primarily a mineralocorticoid (aldosterone) receptor antagonist
• But also blocks androgen receptors - used for:
  • Hirsutism in women (excess facial/body hair)
  • PCOS (polycystic ovary syndrome)
  • Acne (androgen-driven)
  • Gender-affirming therapy in trans women (anti-androgen)
• Side effects: Hyperkalemia, gynecomastia, menstrual irregularities, teratogenic (avoid in pregnancy)

Bicalutamide, Flutamide, Enzalutamide

• Pure androgen receptor antagonists (no other hormonal activity)
• Used for: Prostate cancer (combined with GnRH agonist = complete androgen blockade, OR as monotherapy)
• Flutamide: Added during first 2 weeks of GnRH agonist therapy to block the testosterone "flare"
• Enzalutamide: Newer, more potent; also blocks androgen receptor nuclear translocation; for castration-resistant prostate cancer
• Side effects: Hot flashes, gynecomastia, hepatotoxicity (flutamide especially), loss of libido

Cyproterone Acetate

• Androgen receptor blocker + progestin; used for prostate cancer, hirsutism, severe acne

---

SECTION 11: DRUGS FOR INFERTILITY & OVARIAN STIMULATION

Clomiphene Citrate (Clomid)

• Mechanism: Selective Estrogen Receptor Modulator (SERM) - blocks estrogen receptors in the hypothalamus and pituitary → pituitary thinks estrogen levels are low → increases FSH and LH release → stimulates follicle development and ovulation
• Used for:
  • Anovulatory infertility (first-line - especially PCOS)
  • Ovulation induction
• Oral drug (convenient compared to injectables)
• Effectiveness: ~80% ovulate, ~50% conceive
• Side effects:
  • Multiple pregnancies (~10% twins, rare triplets)
  • Hot flashes (anti-estrogen effect)
  • Ovarian hyperstimulation (mild-moderate)
  • Visual disturbances (blurring, spots) - stop drug if this occurs
  • Cervical mucus thickening (anti-estrogenic effect on cervix - paradoxically makes it harder for sperm)

Letrozole (Femara)

• Mechanism: Aromatase inhibitor - blocks conversion of androgens to estrogens → lower estrogen → feedback → more FSH → follicle development
• Off-label but widely used for ovulation induction, especially in PCOS (actually shown superior to clomiphene in PCOS)
• Advantage over clomiphene: Does not thicken cervical mucus (no anti-estrogenic effect on uterus/cervix)
• Side effects: Hot flashes, headache, lower multiple pregnancy rate than clomiphene

Gonadotropins (Injectable)

• Too many follicles develop → massive release of VEGF → fluid shifts from vessels to abdomen/chest
• Mild: Bloating, mild discomfort
• Severe: Ascites, pleural effusion, respiratory distress, thrombosis, renal failure
• hCG (used to trigger ovulation) worsens OHSS - can substitute GnRH agonist trigger in high-risk cases
• Treatment: Supportive, IV fluids, cabergoline (reduces VEGF)

Progesterone Support (Luteal Phase)

• After IVF egg retrieval, corpus luteum is disrupted → progesterone levels fall
• Vaginal progesterone (Crinone, Endometrin) or IM progesterone supplemented to maintain pregnancy

---

SECTION 12: DRUGS FOR ABORTION

Mifepristone (RU-486) - Medical Abortion Protocol

• Mechanism: Competitive progesterone receptor antagonist - blocks progesterone → decidual breakdown → endometrium sheds (progesterone is required to maintain pregnancy)
• Also: Antiglucocorticoid (blocks cortisol receptors)
• Protocol: Mifepristone 200mg orally Day 1 → Misoprostol (PGE1) vaginally/buccally 24-48 hours later
  • This combination is ~95-97% effective for abortion up to 10 weeks gestation
• Side effects: Heavy bleeding, cramping, nausea
• Contraindications: IUD in place, ectopic pregnancy, bleeding disorders, chronic adrenocorticoid therapy

---

SECTION 13: DRUGS FOR POLYCYSTIC OVARY SYNDROME (PCOS)

1. Metformin - improves insulin resistance → reduces androgen production → restores menstrual cycles; first-line for PCOS metabolic aspects
2. Clomiphene/Letrozole - ovulation induction
3. Combined OCs - regulate menstrual cycles, reduce androgens (suppress LH → less ovarian androgen production + SHBG increases → less free testosterone)
4. Spironolactone - reduces hirsutism and acne (androgen receptor blockade)
5. GnRH agonists - for severe ovarian hypersecretion of androgens
6. Inositol (D-chiro-inositol / myo-inositol) - supplements shown to improve insulin sensitivity in PCOS

---

SECTION 14: SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

Tamoxifen

• Estrogen ANTAGONIST at breast → used to treat estrogen receptor-positive (ER+) breast cancer
• Estrogen AGONIST at uterus → increases risk of endometrial cancer (important!)
• Estrogen AGONIST at bone → maintains bone density (good)
• Used for:
  • Adjuvant treatment of ER+ breast cancer (reduces recurrence and mortality)
  • Prevention of breast cancer in high-risk women
  • Gynecomastia in men
• Side effects:
  • Hot flashes (anti-estrogenic)
  • Endometrial cancer risk (agonist at uterus)
  • DVT/PE (clotting effect)
  • Vaginal discharge/bleeding
  • Cataracts
• Duration: Usually given for 5-10 years
• Drug interaction: CYP2D6 inhibitors (fluoxetine, paroxetine) reduce conversion of tamoxifen to active metabolite endoxifen → reduce efficacy

Raloxifene (Evista)

• Antagonist at both breast AND uterus (safer profile than tamoxifen)
• Agonist at bone → treats/prevents osteoporosis
• No uterine cancer risk (unlike tamoxifen)
• Used for:
  • Postmenopausal osteoporosis
  • Breast cancer prevention in high-risk postmenopausal women
• Side effects: Hot flashes, leg cramps, DVT/PE risk

Fulvestrant (Faslodex)

• "Pure estrogen antagonist" / Selective Estrogen Receptor Downregulator (SERD)
• Blocks AND DEGRADES estrogen receptors (unlike tamoxifen which partially acts as agonist)
• Used for: Metastatic ER+ breast cancer (especially after tamoxifen failure or resistance)
• Given: IM injection once monthly
• No agonist effects anywhere

---

SECTION 15: AROMATASE INHIBITORS (AIs)

1. Postmenopausal ER+ breast cancer (first-line, superior to tamoxifen in many settings)
2. Ovulation induction (letrozole - off-label but widely used, especially PCOS)
3. Gynecomastia (in men - reduce estrogen from testosterone aromatization)
4. Endometriosis (reduce estrogen)

• Joint pain and stiffness (arthralgia - very common, major cause of stopping treatment)
• Osteoporosis (major - no estrogen = bone loss; must monitor bone density and give bisphosphonates/vitamin D)
• Hot flashes, vaginal dryness
• Menopausal symptoms (because they eliminate estrogen entirely)

---

SUMMARY TABLE: Key Drug-Disease Associations to Remember

---

---