HORMONAL CONTRACEPTIVES — MASTER PHARM NOTE (LOGIC BASED)

1) BIG PICTURE

• Barrier methods → higher failure
• Hormonal methods → very effective, reversible, fertility returns (timing depends on method)
• Female contraception: near-100% confidence with correct use; fertility returns after stopping (except injectables slower)

A) COMBINED ORAL CONTRACEPTIVE PILL (COCP)

A1) CORE MECHANISM (EXAM LOGIC)

Main mechanism = ovulation suppression

1. Inhibits ovulation
2. Blocks estrogen-mediated positive feedback → no mid-cycle LH surge
3. Cervix: progestin → thick mucus → ↓ sperm penetration (“hostile mucus”)
4. Endometrium: ↓ receptivity to blastocyst (out-of-phase / atrophic / hypersecretory)
5. Tubal & uterine motility changes may contribute (less certain)

✅ Additional benefit: ↓ menstrual blood loss → ↑ iron stores / improves anemia

Hormone-specific roles

• Estrogen: mainly ↓ FSH (follicle fails to develop)
• Progestin: ↓ LH pulse frequency + supports cycle control + mucus effect
• Together: abolish LH surge

A2) FORMULATIONS (ORAL)

1) Monophasic COCP

• Fixed estrogen + progestin dose for all active pills
• “Second generation”: lower estrogen + progestin with same efficacy, fewer side effects
• “Third generation”: newer progestins (e.g., desogestrel) improved profile

Estrogen dose

• Ethinyl estradiol 30 µg/day often considered “threshold”
• Can be reduced to ~20 µg/day if progestin is potent anti-ovulatory

Progestins (19-nortestosterone derivatives; potent antiovulatory)

• Ovulation inhibitory doses listed (per day) in text:
• Levonorgestrel 60 µg
• Desogestrel 60 µg
• Norgestimate 200 µg
• Gestodene 40 µg
• Pill content may be 2–3× higher to reach near-100% certainty

2) Phased / Triphasic pills

• Aim: reduce total steroid exposure while maintaining efficacy by mimicking normal pattern
• Estrogen constant or slightly varied (30–40 µg)
• Progestin progressively increased across phases
• Used sometimes when:
• 35 years
• Breakthrough bleeding / no withdrawal bleed on monophasic
• Risk factors present

⚠️ Evidence of superiority over monophasic = insufficient

A3) DOSING SCHEDULE / STARTING

Standard cycle

• 1 tablet daily × 21 days
• 7-day gap → withdrawal bleeding
• Maintains 28-day cycle
• Calendar packs = most popular

When to start (as per your note)

• First day of menstruation (start day 1)
• Early miscarriage: can start same day
• Post-partum (non-lactating): can start day 21

(Clinical note: postpartum VTE risk is higher early; exam answers vary by guideline, but your line is kept as given.)

A4) PRACTICAL POINTS

• Stopping COCP → fertility returns in 1–2 months
• “Rebound fertility” (multiple pregnancy chance ↑) mentioned in your text for first 2–3 cycles

Missed pills

• Miss 1 pill → take 2 next day, continue
• Miss >2 pills → interrupt course, use alternative method, restart on 5th day of bleeding

A5) ADVERSE EFFECTS (STRUCTURED)

A. Common early (first 1–3 cycles; usually settle)

• Nausea/vomiting
• Mild headache (migraine may worsen)
• Breakthrough bleeding/spotting
• Breast discomfort

B. Later / metabolic & cosmetic

• Weight gain, acne, hirsutism (older androgenic progestins)
• Chloasma (face pigmentation like pregnancy)
• Pruritus vulvae (infrequent)
• Mood swings, depression
• Abdominal distension (esp progestin-only)

C. Serious complications (EXAM CORE)

1. VTE (DVT/PE)
• Higher with older pills; lower but still present with low-dose pills
• Risk ↑ in: >35, smokers, DM, HTN
• Mainly estrogen-related
2. Arterial thrombosis (MI / stroke)
• Risk small with low-dose in absence of risk factors, but ↑ after 35
• Both estrogen & progestin implicated

Mechanisms listed:

• ↑ clotting factors
• ↓ antithrombin III
• ↓ endothelial plasminogen activator
• ↑ platelet aggregation
3. ↑ BP
• Less common now
• Mechanism: ↑ angiotensinogen + renin → ↑ aldosterone → salt/water retention
4. Liver & biliary
• Hepatocellular adenoma (rare; may rupture/malignant)
• Cholestatic jaundice
• ↑ gallstones (↑ biliary cholesterol)
5. Eye
• Corneal damage in contact lens users
6. Cancers
• Overall: does not increase cancers in general population; risk ↑ in predisposed
• Slight ↑ breast cancer among current users (not past users) — stated as minor
• Protective: ↓ endometrial + ↓ ovarian malignancy

✅ “Iron levels increase” = via reduced menstrual loss.

A6) CONTRAINDICATIONS

Absolute

1. Thromboembolic / coronary / cerebrovascular disease (or history)
2. Moderate–severe HTN; hyperlipidemia
3. Active liver disease, hepatoma, or jaundice in past pregnancy
4. Suspected/overt genital or breast malignancy
5. Porphyria
6. Impending major surgery (stop estrogen pills 4 weeks before)

Relative (avoid/caution)

• Diabetes
• Obesity
• Smoking
• Undiagnosed vaginal bleeding
• Fibroid (leiomyoma) — may enlarge (progestin-only may be used)
• Mentally ill (adherence)
• Age >35
• Mild HTN
• Migraine
• Gallbladder disease

A7) DRUG INTERACTIONS → CONTRACEPTIVE FAILURE

Enzyme inducers (↑ metabolism)

• Phenytoin, phenobarbital, primidone, carbamazepine
• Rifampin
• Ritonavir

Reduced gut flora → ↓ enterohepatic circulation

• Tetracyclines
• Ampicillin

Advice in your text

• Consider 50 µg EE pill or alternative method
• Rifampin: usually long duration + potent → advise alternative contraception

A8) OTHER HEALTH BENEFITS

• ↓ Endometrial + ovarian (probably colorectal) cancer
• ↓ Menstrual blood loss → ↓ anemia
• Regular cycles
• Improves PMS, dysmenorrhea, menorrhagia
• Endometriosis and PID tend to subside
• ↓ fibrocystic breast disease symptoms
• ↓ ovarian cysts

B) PROGESTIN-ONLY PILL (POP / MINIPILL)

B1) WHEN USED

• Alternative when estrogen contraindicated
• Taken daily continuously (no gap)

B2) MECHANISM

• Ovulation occurs in 20–30% (so inhibition is inconsistent)
• Contraception via:
• hostile cervical mucus
• endometrial effect (implantation interference)

B3) EFFICACY

• Lower than COCP:
• POP: 96–98%
• COCP: 98–99.9%

B4) CLINICAL NOTE

• Cycles irregular
• Suspect pregnancy if amenorrhea > 2 months
• Not popular

C) EMERGENCY (POSTCOITAL) CONTRACEPTION

C1) LEVONORGESTREL (STANDARD)

• 0.75 mg × 2 doses 12h apart OR 1.5 mg single dose
• As soon as possible, before 72 hours

Compared to Yuzpe method

• 2–3× more effective + better tolerated
• Yuzpe: LNG 0.5 mg + EE 0.1 mg ×2 within 72h

Side effects

• Nausea/vomiting: ~6% (progestin-only) vs 20–50% (Yuzpe)
• Headache milder
• Next period may be delayed/disrupted

C2) ULIPRISTAL (SPRM) — approved 2010 (as per your text)

• 30 mg single dose
• Within 120 hours (5 days)
• Failure rate 1–3% vs LNG 2–4% (as stated)

C3) MIFEPRISTONE (antiprogestin)

• 600 mg single dose within 72 hours
• Used particularly in parts of Europe/China (as per your text)

C4) CLINICAL RULE

• Reserve for unexpected exposure (rape, condom rupture)
• Higher failure + side effects than regular low-dose COCP

(Note: some modern guidelines use lower mifepristone doses, but I’m keeping your book figures.)

D) INJECTABLE PROGESTINS (LONG-ACTING)

D1) GENERAL

• Given IM as oily solution
• Highly effective
• Major limitations:
• Menstrual irregularities / amenorrhea common
• Return of fertility delayed 6–30 months
• Weight gain + headache >5%
• ↓ BMD after 2–3 years esp DMPA (low estrogen via Gn suppression)
• Menopause-like symptoms: hot flashes, vaginal dryness, ↓ libido

Cancer concerns (your text)

• Animal carcinogenic potential
• WHO study: no proof but noted ↑ overall risk of cervical/ovarian/hepatic; breast cancer risk slightly ↑ in <35

D2) TYPES

(a) DMPA (Depot medroxyprogesterone acetate)

• 150 mg IM every 3 months
• Peak blood level in 3 weeks
• t½ ~ 50 days
• Inject during first 5 days of menstrual cycle

(b) Norethisterone enanthate (NEE)

• 200 mg every 2 months
• Shorter acting, higher failure than DMPA

Key drawback: menstrual disruption / total amenorrhea (more with DMPA)

Not suitable (as per your note): adolescent girls, lactating mothers

Used when unlikely to use other methods effectively.

E) IMPLANTS / PROGESTIN IUS

E1) Subdermal implants

• Steroid released slowly 1–5 years
• Types:
• Biodegradable (no removal)
• Non-biodegradable (must remove)

Norplant (example)

• 6 capsules × 36 mg LNG (total 216 mg)
• Works up to 5 years
• Discontinued in USA

E2) Progestin IUD / intrauterine insert

• Contains 52 mg levonorgestrel
• Acts mainly locally on endometrium
• Effective 5 years
• Efficacy rated lower (as per your text)

F) TRANSDERMAL PATCH

• Patch with norelgestromin + ethinyl estradiol
• Apply once weekly × 3 weeks, then 1 week gap

G) MALE CONTRACEPTION (WHY NO GOOD DRUG YET)

Core exam reasons (from your text)

1. Hard to suppress sperm completely without toxicity
2. Huge sperm output vs 1 ovum/month
3. Spermatogenesis 64 days → long latency + slow recovery
4. Gonadotropin suppression ↓ testosterone → libido loss/impotence (unacceptable)
5. Adverse effects risk
6. Motivation factor: men don’t get pregnant

Approaches tried

1. Antiandrogens → ↓ spermatogenesis but ↑ Gn; libido loss
2. Estrogens/progestins → suppress Gns but feminization
3. Continuous GnRH analogues → suppress Gn; ↓ testosterone → impotence
4. Cytotoxics (cadmium, nitrofurans, indoles) → toxic
5. Gossypol ✅ (you asked to add)

GOSSYPOL (Nonsteroidal; cottonseed derivative) — exam add-on

• Mechanism: suppresses spermatogenesis (functional/structural sperm impairment)
• Problems: toxicity + hypokalemia risk + incomplete reversibility in some → limited/abandoned in many settings
• Bottom line: effective but safety/reversibility concerns prevented adoption

HORMONAL CONTRACEPTION — COMPLETE PHARMACOLOGY MASTER TABLE (ZERO-OMISSION)