Infertility — Overview & Causes (Male + Female)

Definition

• Primary infertility: Never achieved a pregnancy
• Secondary infertility: Infertility after at least one prior pregnancy
• ~85% of couples conceive within 12 months; ~95% within 24 months

Causes — Overview

A complete workup of both partners is always recommended since multiple causes are frequently identified simultaneously.

Female Causes

1. Ovulatory Dysfunction (~20–40% of female infertility)

• PCOS — most common cause of anovulation; hyperandrogenism, oligo/anovulation, polycystic-appearing ovaries
• Diminished ovarian reserve — age-related decline (fecundability drops 53% at age 40–41 vs. 30–31)
• Premature ovarian insufficiency (POI) — loss of ovarian function before age 40
• Endocrine causes: hypothyroidism, hyperprolactinemia

2. Tubal Factor (~14–35%)

• Pelvic inflammatory disease (PID) — most common cause of tubal damage; often Chlamydia or Gonorrhoea
• Endometriosis — can cause peritubal adhesions and obstruction
• Prior pelvic/tubal surgery
• Salpingitis isthmica nodosa

3. Uterine Factor

• Submucosal fibroids (leiomyomas)
• Congenital Müllerian anomalies (e.g., septate uterus)
• Intrauterine adhesions (Asherman's syndrome) — often post-D&C
• Endometrial polyps

4. Decreased Ovarian Reserve

• Assessed by day 2–3 serum FSH + estradiol, anti-Müllerian hormone (AMH), and antral follicle count (AFC) on ultrasound
• High FSH or low AMH signals reduced reserve

5. Pelvic/Peritoneal Factor

• Endometriosis causing periadnexal adhesions
• Other pelvic adhesive disease

Male Causes

1. Testicular/Spermatogenic Defects (~30–40% of male infertility)

• Klinefelter syndrome (47,XXY) — most common genetic cause; azoospermia or severe oligospermia
• Y chromosome microdeletions (AZF regions) — impair spermatogenesis
• Varicocele — most common reversible cause
• Prior orchitis (e.g., mumps orchitis)
• Cryptorchidism (undescended testes)
• Chemotherapy/radiation exposure

2. Anatomic/Obstructive

• Vasectomy
• Congenital bilateral absence of vas deferens (CBAVD) — associated with CFTR mutations (cystic fibrosis)
• Ejaculatory duct obstruction
• Prior inguinal/scrotal surgery

3. Endocrine

• Hypogonadotropic hypogonadism (low FSH/LH → low testosterone) — can be idiopathic (Kallmann syndrome) or secondary
• Hyperprolactinemia
• Hypothyroidism
• Morbid obesity (↑ estrogen from aromatization)
• Exogenous anabolic steroids/androgens (suppresses LH/FSH)

4. Sexual/Ejaculatory Dysfunction

• Erectile dysfunction
• Retrograde ejaculation (common in diabetes, post-prostatectomy)
• Anejaculation

5. Genetic

• Klinefelter's, Y-microdeletions (as above)

Key Investigations

Semen analysis (WHO reference values): Volume ≥1.4 mL; total sperm number ≥39 million per ejaculate; progressive motility ≥30%; normal morphology ≥4% (Tygerberg strict criteria). No single parameter predicts infertility — multiple abnormalities increase risk.

Age Effect on Female Fertility

High-Yield Exam Points

• Infertility = 12 months; >35 yrs → 6 months; >40 yrs → immediate
• Male factor is involved in up to 50% of cases (sole cause in ~20%)
• PCOS = most common cause of anovulatory infertility in women
• Varicocele = most common reversible cause in men
• Klinefelter (47,XXY) = most common genetic cause of male infertility
• CBAVD → always test for CFTR mutations
• Unexplained infertility = up to 30% after full workup
• Spontaneous conception less likely: age >42, infertility >4 years, severe endometriosis, severe tubal disease

General Pharmacology — Introduction, General Issues & Rational Pharmacotherapy

1. What is Pharmacology?

• Pharmacokinetics (PK) — what the body does to the drug: absorption, distribution, metabolism, excretion (ADME)
• Pharmacodynamics (PD) — what the drug does to the body: mechanisms of action, receptor interactions, dose-response relationships

"The chain of events between drug administration and its effects can be divided into pharmacokinetics and pharmacodynamics — both contribute to variability in drug action." — Harrison's Principles of Internal Medicine, 22e

2. The Nature of Drugs

• Drugs can be agonists (activate receptors) or antagonists (block receptors)
• Some drugs act by inhibiting degradation of endogenous agonists (e.g., acetylcholinesterase inhibitors)
• Drugs may be synthesized in the body (e.g., hormones) or xenobiotics (foreign chemicals)
• "The dose makes the poison" (Paracelsus, 1493–1541) — any substance is harmful at the wrong dose

Drug Properties Required for Clinical Use

1. Appropriate size, shape, charge to fit receptor
2. Ability to be transported from administration site to site of action
3. Inactivated/excreted at a reasonable rate (appropriate duration of action)

Drug Size

• Most drugs: MW 100–1000 Da
• Too small (<100): insufficient selectivity
• Too large (>1000): poor membrane penetration; must be given directly at site of action (e.g., alteplase for thrombolysis)

3. Drug Receptors & Pharmacodynamics

Types of Drug-Receptor Interactions

Dose-Response Relationships

• Graded dose-response (continuous): effect increases with dose; used to determine EC50, Emax
• EC50 (effective concentration 50%) = concentration producing 50% of maximum effect → reflects potency
• Emax = maximum achievable effect → reflects efficacy
• Therapeutic index (TI) = TD50 / ED50 (or LD50 / ED50 in animals); higher TI = safer drug

Receptor Regulation

• Up-regulation: chronic antagonist use → receptor numbers increase (e.g., beta-blockers → ↑ beta receptors → rebound tachycardia if stopped abruptly)
• Down-regulation (desensitisation): chronic agonist use → receptor numbers decrease / reduced sensitivity (e.g., beta-agonists in asthma)
• Tachyphylaxis: rapid tolerance with repeated dosing

4. Pharmacokinetics (PK) — ADME

A. Absorption

• Bioavailability (F) = fraction of administered dose reaching systemic circulation unchanged
• Affected by: route of administration, first-pass metabolism, formulation
• First-pass effect: oral drugs absorbed from gut → portal vein → liver → metabolised before systemic circulation (e.g., morphine, lidocaine, glyceryl trinitrate — poor oral bioavailability)
• Routes: oral, sublingual (bypasses first-pass), IV (F=100%), IM, SC, transdermal, inhalation, rectal

B. Distribution

• Volume of Distribution (Vd) = apparent volume drug distributes into
  • Vd = Amount of drug / Plasma concentration
  • High Vd → drug distributes into tissues (lipophilic drugs, e.g., chloroquine Vd >200 L)
  • Low Vd → drug stays in plasma (e.g., warfarin, heparin)
• Factors affecting distribution: lipid solubility, plasma protein binding (mainly albumin), tissue binding, blood-brain barrier, placental transfer
• Loading dose: used when Vd is large and rapid effect needed: Loading dose = Vd × target plasma concentration / F

C. Metabolism (Biotransformation)

• Primarily in liver (also gut wall, lung, kidney, plasma)
• Two phases:
  • Phase I (functionalisation): oxidation, reduction, hydrolysis via CYP450 enzymes (CYP3A4, CYP2D6, CYP2C9 most important) → makes drug more polar
  • Phase II (conjugation): glucuronidation, sulfation, acetylation → water-soluble metabolites for excretion
• Prodrugs: inactive until metabolised (e.g., codeine → morphine via CYP2D6; enalapril → enalaprilat)
• CYP450 inducers (↑ metabolism → ↓ drug effect): rifampicin, carbamazepine, phenytoin, St John's Wort
• CYP450 inhibitors (↓ metabolism → ↑ drug effect / toxicity): erythromycin, ketoconazole, grapefruit juice, ciprofloxacin

D. Excretion

• Mainly renal (glomerular filtration, tubular secretion, passive reabsorption)
• Also: biliary/fecal, lungs (volatile drugs), breast milk, saliva, sweat
• Renal clearance reduced in renal failure → dose adjustment required

E. Half-Life (t½)

• Time for plasma concentration to fall by 50%
• t½ = 0.693 × Vd / Clearance
• Drug is near-eliminated after 4–5 half-lives
• Steady state achieved after 4–5 half-lives of regular dosing
• Steady-state concentration is directly proportional to dose — doubling dose doubles steady state

F. Zero-Order vs. First-Order Kinetics

5. Pharmacogenomics & Variability in Drug Response

1. Genetic factors — polymorphisms in CYP enzymes (CYP2D6: poor vs. ultrarapid metabolisers), drug transporters, receptor genes
2. Age — neonates (immature hepatic enzymes), elderly (↓ renal/hepatic function, ↓ albumin)
3. Sex — differences in Vd, CYP activity
4. Disease — hepatic failure (↓ metabolism), renal failure (↓ excretion), hypoalbuminaemia (↑ free drug)
5. Drug interactions — CYP induction/inhibition, protein binding displacement, additive/synergistic toxicity
6. Adherence — preferred term over "compliance"; non-adherence is a major cause of treatment failure

6. Adverse Drug Reactions (ADRs)

Classification (Rawlins & Thompson — Type A/B)

7. Fundamentals of Rational Pharmacotherapy

Core Principles (Harrison's framework):

• Benefits: symptom relief, disease modification, prevention, improved survival
• Risks: ADRs, drug interactions, cost, adherence burden

• Empirical therapy: initiated before a definitive diagnosis (e.g., broad-spectrum antibiotics in sepsis)
• Definitive therapy: based on specific diagnosis and targeted drug selection

• Start low, titrate up ("start low, go slow" — especially in elderly)
• Use pharmacokinetic principles: loading dose for rapid effect; maintenance dose = clearance × target concentration
• Adjust for renal/hepatic impairment

• Narrow therapeutic index drugs: digoxin, lithium, phenytoin, aminoglycosides, vancomycin, cyclosporin, warfarin
• Timing of sampling: trough levels (just before next dose) most commonly used

• Pharmacokinetic (ADME-level): CYP interactions, protein binding displacement, altered absorption (e.g., antacids + ciprofloxacin)
• Pharmacodynamic (additive/synergistic/antagonistic): e.g., two CNS depressants → excessive sedation; beta-blocker + verapamil → heart block
• Pharmaceutical (in-vitro incompatibility): precipitation in IV lines

• All drug trials must account for the placebo effect
• Therapy should ideally be evidence-based (RCT data > observational)
• "Number needed to treat" (NNT) and "number needed to harm" (NNH) quantify benefit-risk in populations

8. Summary — High-Yield Exam Points

Important Clarification First

Warfarin + Antacids: Mechanisms & Management

1. Warfarin's Physicochemical Properties

Unionised fraction predominates when pH < pKa Ionised fraction predominates when pH > pKa

2. Normal Absorption in Acidic Gastric Environment

pH << pKa → warfarin exists predominantly in unionised form
→ lipid-soluble → crosses gastric mucosa readily
→ excellent absorption (bioavailability ≈ 93–100%)

3. How Antacids Reduce Bioavailability — Mechanisms

Mechanism 1: pH Elevation → Increased Ionisation (Ion Trapping)

pH ↑ toward/above pKa → greater proportion of warfarin becomes ionised (R-COO⁻)
→ ionised drug cannot cross lipid membranes
→ reduced passive diffusion across gastric/intestinal epithelium
→ ↓ absorption rate and potentially ↓ overall bioavailability

Mechanism 2: Adsorption / Chelation

• Reduces free drug concentration available for absorption
• May accelerate transit of bound drug to the colon, where absorption is minimal

Mechanism 3: Accelerated Gastric Emptying

4. Warfarin's Pharmacokinetics in Brief

5. Broader Context: More Important Warfarin Interactions

6. Dosing Schedule Recommendations

Primary Recommendation: Temporal Separation

• Take warfarin 2 hours before antacid intake (ensures absorption in low gastric pH environment)
• Or take antacid ≥2 hours after warfarin

Additional Practical Recommendations

INR Monitoring Target

• Standard indications (AF, DVT/PE, mechanical heart valves — bileaflet aortic): INR 2.0–3.0
• Mechanical mitral valve or high-risk: INR 2.5–3.5
• If INR falls below therapeutic range after starting antacid: cautious dose increase after verifying consistent pattern over ≥2 readings

7. Summary

Antacid → ↑ gastric pH → warfarin (weak acid, pKa ~5) 
  → ↑ ionised fraction → ↓ membrane permeability 
  → ↓ passive diffusion → ↓ absorption
  → ↓ plasma levels → ↓ anticoagulant effect → ↑ thrombosis risk

MANAGEMENT: Separate doses by ≥2 h; monitor INR; 
            maintain consistent dosing time; increase monitoring 
            frequency during any change in antacid use

The interaction is a textbook example of pH-dependent absorption of a weak acid drug, governed by the Henderson-Hasselbalch equation. In practice, warfarin's absorption is robust enough that this is a moderate (not severe) interaction — but given its narrow therapeutic index, any reduction in bioavailability carries real clinical consequence.