1. Female Reproductive Diseases

A) Congenital (Developmental) Disorders

Embryological Basis

Classification of Uterine Anomalies

Key Clinical Points

• Septate uterus: women carry up to 60% risk of spontaneous miscarriage; embryos that implant on the poorly vascularized septum suffer abnormal placentation. Hysteroscopic metroplasty significantly reduces pregnancy loss.
• DES exposure in utero: diethylstilbestrol (banned 1971) causes T-shaped uterus, cervical abnormalities, vaginal adenosis, and associated obstetric complications. Women whose mothers took DES have higher malformation rates.
• Vaginal anomalies: imperforate hymen, transverse vaginal septum, and vaginal agenesis (in Müllerian agenesis) present with primary amenorrhea ± cyclical pain.
• Cervical anomalies: incompetent cervix associated with DES exposure and uterine hypoplasia → second-trimester loss and premature labor.

B) Inflammatory Diseases (Infections)

Vulvovaginal Infections

Pelvic Inflammatory Disease (PID)

• Neisseria gonorrhoeae — mucosal route of spread; acute suppurative salpingitis with intraluminal pus (pyosalpinx)
• Chlamydia trachomatis — causes cervicitis → salpingitis, endometritis; major cause of PID
• Post-abortion/postpartum polymicrobial: staphylococci, streptococci, coliforms, Clostridium perfringens — spread via lymphatics/veins → deeper tissue involvement

• Acute: peritonitis, bacteremia → endocarditis, meningitis, septic arthritis
• Chronic: infertility/tubal obstruction, ectopic pregnancy, chronic pelvic pain, intestinal adhesions

Bartholin Gland Infection

C) Hormonal / Functional Disorders

Polycystic Ovary Syndrome (PCOS)

• Most common endocrine disorder of reproductive-age women
• Features: anovulation/oligomenorrhea, hyperandrogenism, insulin resistance, ovarian radiologic appearance of multiple small follicles
• Elevated LH → premature oocyte aging and dyssynchronous endometrial maturation
• Linked to recurrent pregnancy loss (found in 40–80% of recurrent miscarriage patients)
• Insulin resistance and elevated androgens adversely affect uterine receptivity

Luteal Phase Insufficiency

• Inadequate progesterone production by the corpus luteum
• Impaired decidualization of the endometrium → natural selection of embryos → pregnancy loss
• Normal pregnancy depends on the corpus luteum from ovulation to 7–9 weeks, after which the trophoblast assumes progesterone production (luteal-placental shift)

Thyroid Disease

• Hypothyroidism associated with ovulatory dysfunction, luteal phase defects, and recurrent miscarriage
• Recommended TSH threshold during pregnancy: <2.5 mIU/mL
• Even euthyroid patients with anti-thyroid antibodies have elevated miscarriage rates; thyroid hormone supplementation reduces pregnancy loss in these patients undergoing IVF

Hyperprolactinemia

• Elevated prolactin → hypothalamic-pituitary-ovarian axis disruption → impaired folliculogenesis and luteal dysfunction → miscarriage
• Normalizing prolactin with dopamine agonists improves live birth rates in recurrent pregnancy loss patients

Diminished Ovarian Reserve (DOR)

• Associated with higher proportion of aneuploid embryos → increased first-trimester miscarriage
• Assessed by FSH, estradiol, and anti-Müllerian hormone (AMH) in early follicular phase

Endometriosis

• Ectopic endometrial glands and stroma outside the uterus (ovaries, peritoneum, fallopian tubes)
• Causes dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility
• Mechanism of infertility: altered uterine contractility, peritoneal inflammation, adhesions, impaired tubal function

2. Gestational and Placental Disorders

a) Implantation and Early Pregnancy Disorders

Spontaneous Abortion (Miscarriage)

• 60%: sporadic chromosomal aneuploidy (most common cause of 1st trimester loss)
• Remaining 40%: chronic maternal illness (diabetes, connective tissue disorders), uterine structural malformations, infections, inadequate progesterone, immunologic factors

Ectopic Pregnancy

• Implantation outside the uterine cavity, most commonly in the fallopian tube (especially ampullary region)
• Risk factors: prior PID/salpingitis (tubal scarring), prior ectopic, IUD use, assisted reproduction
• Presentation: amenorrhea, unilateral pelvic pain, vaginal bleeding; rising but subnormal hCG
• Diagnosis: transvaginal ultrasound (empty uterus + adnexal mass/ring)
• Life-threatening if tubal rupture occurs → hemoperitoneum
• Treatment: methotrexate (unruptured, stable) or surgical salpingostomy/salpingectomy

Molar Pregnancy (Gestational Trophoblastic Disease)

b) Hypertensive Disorders of Pregnancy

Classification

1. Gestational hypertension: new-onset BP ≥140/90 mmHg after 20 weeks without proteinuria
2. Preeclampsia: hypertension + proteinuria (>0.3 g/24 hrs) after 20 weeks
3. Severe preeclampsia: BP >160/110 + significant proteinuria (>5 g/24 hrs) + end-organ damage
4. Eclampsia: preeclampsia + seizures (one or more convulsions)
5. Chronic hypertension with superimposed preeclampsia: accounts for 15–30% of hypertensive disease in pregnancy

Preeclampsia

• Soluble Flt-1 (VEGF receptor-1)
• Endoglin
• Decorin

• Mild: bed rest, close surveillance; delay delivery until fetal maturity or complications
• Severe: delivery within 24 hours
• Seizure prophylaxis: IV magnesium sulfate — loading dose 4 g over 15–20 min, then 2 g/hr infusion; continued 12–24 hours postpartum
• BP control: IV hydralazine if diastolic persistently >110 mmHg

HELLP Syndrome

• Hemolysis
• Elevated Liver enzymes
• Low Platelets

Eclampsia

• One or more generalized convulsions in a woman with preeclampsia
• Pathology: extensive placental infarcts reduce uteroplacental circulation → fetal malnutrition, FGR, fetal death
• Treatment: magnesium sulfate (prevention and treatment of seizures), urgent delivery

c) Metabolic / Systemic Gestational Disorders

Gestational Diabetes Mellitus (GDM)

• Glucose intolerance first recognized during pregnancy; results from insulin resistance amplified by placental hormones (hCS/human placental lactogen)
• Human chorionic somatomammotropin (hCS) causes decreased glucose utilization and increased free fatty acids in the mother, contributing to the diabetogenic state
• Screening: 50 g oral glucose challenge test (GCT) at 24–28 weeks; confirmed by 100 g OGTT
• Complications: macrosomia, shoulder dystocia, neonatal hypoglycemia, polyhydramnios, increased risk of C-section, future type 2 DM in mother
• Maternal hyperglycemia is directly linked to embryonic damage and increased risk of spontaneous pregnancy loss in overt insulin-dependent diabetes

Preterm Labor

• Betamethasone 12 mg IM × 2 doses (24–34 weeks) to accelerate fetal lung maturity
• GBS prophylaxis
• Tocolysis: magnesium sulfate, nifedipine; terbutaline limited to 48–72 hours only (FDA restriction)

Intrahepatic Cholestasis of Pregnancy

• Pruritus (especially palms/soles), elevated bile acids and liver enzymes in third trimester
• Associated with increased fetal risk (stillbirth); managed with ursodeoxycholic acid and early delivery

Thyroid Disease in Pregnancy

• Hypothyroidism: TSH should be kept <2.5 mIU/mL; associated with fetal neurodevelopmental impairment
• Hyperthyroidism (most commonly Graves'): propylthiouracil preferred in 1st trimester; methimazole after 1st trimester

d) Fetal Growth and Development Disorders

Fetal Growth Restriction (FGR) / Intrauterine Growth Restriction (IUGR)

• Estimated fetal weight <10th percentile for gestational age
• Causes:
  • Placental: preeclampsia (most important), placental infarction, abruption, poor spiral artery remodeling
  • Fetal: chromosomal anomalies (trisomy 18, 13), congenital infections (TORCH), structural malformations
  • Maternal: malnutrition, smoking, substance abuse, chronic disease (hypertension, renal disease, SLE)
• Pathophysiology in preeclampsia: anti-angiogenic molecules (sFlt-1, endoglin) impair uteroplacental perfusion → fetal malnutrition
• Consequences: increased perinatal mortality; long-term risk of cardiovascular disease and type 2 diabetes in adulthood (Barker hypothesis — "fetal programming")
  • Low birth weight followed by rapid catch-up growth further increases the risk of metabolic syndrome
  • Child obesity in epidemic proportions is partly traceable to placental dysfunction

Polyhydramnios

• Amniotic fluid index (AFI) >24 cm or deepest pocket >8 cm
• Associated with: fetal swallowing impairment (esophageal atresia, anencephaly), maternal GDM (fetal polyuria), preeclampsia
• Risk: preterm labor, cord prolapse, malpresentation

Oligohydramnios

• AFI <5 cm
• Causes: renal agenesis/urinary tract obstruction (Potter sequence), PPROM, severe FGR with placental insufficiency, post-term pregnancy
• Risk: pulmonary hypoplasia, limb deformities (positional), umbilical cord compression

Rh Incompatibility / Hemolytic Disease of the Fetus and Newborn (HDFN)

• Rh(D)-negative mother sensitized by Rh(D)-positive fetal blood → anti-D IgG crosses placenta → fetal hemolysis
• Prevention: anti-D immunoglobulin (RhoGAM) at 28 weeks, at delivery, and after any sensitizing event
• Severe cases: hydrops fetalis, fetal death
• Management: intrauterine transfusion; neonatal phototherapy or exchange transfusion

The Barker Hypothesis (Developmental Origins of Health and Disease — DOHaD)

• Cardiovascular disease
• Type 2 diabetes
• Hypertension
• Obesity (especially with rapid postnatal catch-up growth)

• Berek & Novak's Gynecology
• Robbins, Cotran & Kumar — Pathologic Basis of Disease
• Textbook of Family Medicine, 9th Edition
• The Developing Human: Clinically Oriented Embryology

Part 1 — Diuretics

Physiology Background: Why Diuretics Work

Classes of Diuretics

1. Carbonic Anhydrase Inhibitors

• Glaucoma (reduces aqueous humor formation)
• Altitude sickness (accelerates respiratory compensation)
• Alkaline diuresis in some overdoses
• Epilepsy (metabolic acidosis raises seizure threshold)

2. Loop Diuretics

• Furosemide induces COX-2 → prostaglandin synthesis (PGE₂) → renal vasodilation and increased renal blood flow
• Both furosemide and ethacrynic acid reduce pulmonary congestion and left ventricular filling pressure before measurable diuresis occurs (important in acute pulmonary edema)
• NSAIDs blunt the action of loop diuretics by reducing prostaglandin synthesis

3. Thiazide Diuretics

• Hypertension (first-line, especially in low-renin or volume-expanded hypertension; chlorthalidone preferred for CV outcomes)
• Mild heart failure / edema
• Nephrogenic diabetes insipidus (paradoxically reduces urine volume by inducing mild volume contraction → enhanced PCT water reabsorption)
• Hypercalciuria / calcium oxalate nephrolithiasis (reduces urinary Ca²⁺)
• Osteoporosis (reduces renal Ca²⁺ wasting)

4. Potassium-Sparing Diuretics

A. Aldosterone Receptor Antagonists (Mineralocorticoid Receptor Antagonists)

• Spironolactone: also blocks androgen receptors → used for acne and female-pattern hair loss; anti-fibrotic effects
• Eplerenone: selective MR antagonist; reduces myocardial perfusion defects post-MI; reduces mortality by 15% vs. placebo in mild-to-moderate heart failure post-MI; may reduce atrial fibrillation recurrence; also slows diabetic albuminuria progression at low doses (25–50 mg/d)
• Finerenone: non-steroidal MR antagonist; reduces risk of atrial fibrillation in CKD + T2DM

B. ENaC Blockers

5. Osmotic Diuretics

6. SGLT2 Inhibitors (Glucosuric Diuretics)

Summary: Urinary Electrolyte Effects and Clinical Use

Part 2 — Agents Affecting the Uterine Musculature

Physiology of Myometrial Contraction

1. Action potentials arrive at pacemaker cells → voltage-sensitive Ca²⁺ channels open → Ca²⁺ influx
2. Ca²⁺ binds calmodulin → activates MLCK → phosphorylates myosin → actin-myosin cross-bridge cycling → contraction
3. Relaxation is mediated by elevated cAMP or cGMP → protein kinase A or G → phosphorylation and inactivation of MLCK

• Oxytocin receptor upregulation: increases 50- to 100-fold in 1st trimester, and an additional 200- to 300-fold during pregnancy, maximal in early labor; driven by estrogen (upregulates) and progesterone (suppresses)
• Prostaglandins (PGE₂, PGF₂α): promote contractions and cervical ripening
• Inflammatory cascade at term labor: proinflammatory cytokines (IL-1β, IL-6, TNF-α) → neutrophil/macrophage infiltration into myometrium → contraction-associated proteins (CAPs)

I. Uterotonic Agents (Stimulants of Uterine Contraction)

A. Oxytocin

• Uterine hyperstimulation: >5 contractions/10 min → fetal distress, uterine rupture, maternal/fetal trauma. Discontinue infusion immediately (short t½ → effects resolve in ~12–15 min); restart at half the hyperstimulatory dose
• Water intoxication: Oxytocin at high doses activates vasopressin V2 receptor → antidiuretic effect → hyponatremia → convulsions, coma, death (especially if hypotonic fluids given liberally)
• Hypotension + reflex tachycardia: from vasodilatory effects at high doses; exacerbated by deep anesthesia

B. Prostaglandins

Dinoprostone (PGE₂)

• FDA-approved for cervical ripening
• Available as:
  • Intracervical gel: 0.5 mg via syringe; max 3 doses/24 h
  • Vaginal insert (pessary): 10 mg; releases PGE₂ at 0.3 mg/h for up to 12 h; removed at labor onset or after 12 h (advantage: quickly removable if hyperstimulation occurs)
• Contraindications: history of asthma, glaucoma, or MI
• Adverse effect: uterine hyperstimulation

Misoprostol (PGE₁ synthetic analogue)

• Off-label use for cervical ripening and labor induction
• Much cheaper than dinoprostone — key advantage
• Doses: 100 µg orally or 25 µg vaginally
• Adverse effects: uterine hyperstimulation, rarely uterine rupture
• Must be discontinued ≥3 hours before initiating oxytocin

PGF₂α analogues (carboprost, dinoprost)

• Potent stimulants of myometrial contraction
• Used primarily for refractory postpartum hemorrhage and second-trimester pregnancy termination

C. Ergot Alkaloids

II. Tocolytic Agents (Inhibitors of Uterine Contraction)

• Administer corticosteroids (betamethasone 12 mg IM × 2 doses, 24 h apart) → accelerate fetal lung maturity
• Transfer to a tertiary care center

• Maternal: severe preeclampsia/eclampsia, antepartum hemorrhage, placental abruption, chorioamnionitis, significant cardiac disease
• Fetal: gestational age >37 weeks, fetal demise/lethal anomaly, severe fetal distress

A. β₂-Adrenergic Receptor Agonists (β-Mimetics)

• Cardiovascular: tachycardia, hypotension (5–10 mmHg fall in diastolic BP), palpitations, chest pain, arrhythmias (premature ventricular/nodal contractions, atrial fibrillation), pulmonary edema, rare MI and death
• Metabolic: transient hyperglycemia and hypokalemia (measure glucose and K⁺ at baseline and during first 24 h; increased risk with concurrent corticosteroids)
• Neonatal: hypoglycemia, hypocalcemia, ileus if infusion not discontinued ≥2 h before delivery
• Tachyphylaxis: receptor desensitization with prolonged use → increasing doses needed; continuous subcutaneous infusion does not reduce preterm birth rate
• FDA restriction: terbutaline not to be used for >48–72 hours; prohibited for outpatient/long-term maintenance tocolysis

B. Calcium Channel Blockers

C. NSAIDs / COX Inhibitors

• Ductus arteriosus: COX inhibitors → premature closure of ductus arteriosus in utero → pulmonary hypertension in neonate → do not use beyond 32 weeks gestation or at term
• Inhibit platelet function → bleeding risk

D. Magnesium Sulfate (MgSO₄)

1. Tocolysis: although used clinically, Cochrane review concluded MgSO₄ is ineffective as a tocolytic (does not delay delivery or improve fetal outcomes)
2. Neuroprotection of the preterm fetus: reduces risk of cerebral palsy in preterm infants (<32 weeks)
3. Seizure prophylaxis in preeclampsia/eclampsia: loading dose 4 g IV over 15–20 min → maintenance 2 g/hr; continue 12–24 h postpartum

E. Oxytocin Receptor Antagonists

F. Nitric Oxide Donors

Summary: Sites of Tocolytic Action

Uterine Contraction Pathway:
Oxytocin/PGF₂α → GPCR → PLC → IP₃ → ↑Ca²⁺
Depolarization → Voltage-gated Ca²⁺ channels → ↑Ca²⁺

Ca²⁺ + Calmodulin → MLCK activation → Contraction

Tocolytic targets:
├─ Reduce Ca²⁺ entry: Ca²⁺ channel blockers (nifedipine), MgSO₄
├─ Block receptor → PLC cascade: OTR antagonists (atosiban), FPr (COX inhibitors)
├─ ↑ cAMP → inactivate MLCK: β₂-agonists (terbutaline)
└─ ↑ cGMP → inactivate MLCK: NO donors (nitroglycerin)

Comparative Summary: Tocolytic Agents

• Katzung's Basic and Clinical Pharmacology, 16th Edition
• Goodman & Gilman's The Pharmacological Basis of Therapeutics
• Creasy & Resnik's Maternal-Fetal Medicine: Principles and Practice