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2nd Year MBBS Pharmacology: Female Reproductive Pharmacology

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1. SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

Definition

Mechanism of Action (MOA)

Estrogen Receptor (ER-α / ER-β)
         ↓
SERM binds → ER conformation change
         ↓
    Tissue-specific
   co-activator/co-repressor recruitment
         ↙           ↘
  Agonist effect    Antagonist effect
  (bone, CV, uterus)  (breast, brain)

Classification & Names

Therapeutic Uses

• ER+ breast cancer (adjuvant therapy - premenopausal & postmenopausal)
• Chemoprevention of breast cancer in high-risk women
• Metastatic breast cancer
• Gynecomastia
• McCune-Albright syndrome (off-label)
• Dose: 20 mg/day orally

• Prevention & treatment of postmenopausal osteoporosis
• Breast cancer risk reduction in postmenopausal women
• Does NOT increase endometrial cancer risk (unlike tamoxifen)
• Dose: 60 mg/day

• Ovulation induction in anovulatory infertility (PCOS)
• Hypogonadism in males (increases LH/FSH)
• Dose: 50-100 mg/day for 5 days (day 2-6 of cycle)

Adverse Effects

• Endometrial hyperplasia/carcinoma (uterine agonism - most important)
• Thromboembolic events (DVT, PE) - 2-3x increased risk
• Hot flashes, vaginal discharge
• Cataracts
• Hepatotoxicity (rare)
• Hypercalcemia (in bone metastases initially)
• Teratogenic - contraindicated in pregnancy

• Hot flashes (common)
• DVT/PE (less than tamoxifen, but still elevated 3x vs placebo)
• Leg cramps
• No endometrial cancer risk (key advantage over tamoxifen)

• Ovarian hyperstimulation syndrome (OHSS)
• Multiple pregnancies (~8-10%)
• Anti-estrogenic effects on cervical mucus (↓ sperm penetration)
• Visual disturbances (reversible)
• Hot flashes

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2. PROGESTERONE - USES & ADVERSE EFFECTS

Natural Progesterone & Synthetic Progestins

• 17α-hydroxyprogesterone derivatives: Medroxyprogesterone acetate (MPA), Megestrol acetate
• 19-Nortestosterone derivatives: Norethindrone, Levonorgestrel, Desogestrel, Gestodene, Norgestimate
• Spirolactone derivative: Drospirenone

Therapeutic Uses of Progesterone/Progestins

PROGESTERONE USES
├── Gynecological
│   ├── Threatened/habitual abortion (luteal phase support)
│   ├── Luteal phase defect
│   ├── Endometriosis (suppress endometrial growth)
│   ├── Endometrial carcinoma (palliative)
│   ├── Dysfunctional uterine bleeding (DUB)
│   ├── Premenstrual syndrome
│   └── Amenorrhea (withdrawal bleed - "progesterone challenge test")
├── Contraception
│   ├── OCP (combined)
│   ├── Progestin-only pill (POP)
│   ├── Depot medroxyprogesterone acetate (DMPA)
│   ├── Implants (etonogestrel - Implanon/Nexplanon)
│   └── IUD (Mirena - levonorgestrel)
├── Obstetric
│   ├── Prevention of preterm labor (17α-hydroxyprogesterone caproate)
│   └── Cervical ripening (adjunct)
└── Other
    ├── HRT (combined with estrogen to prevent endometrial hyperplasia)
    ├── Benign prostatic hyperplasia (megestrol - off-label)
    └── Appetite stimulant in cachexia (megestrol acetate)

Adverse Effects of Progesterone/Progestins

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3. EMERGENCY CONTRACEPTION (EC)

Definition

Classification of EC Regimens

EMERGENCY CONTRACEPTION
├── Hormonal
│   ├── Levonorgestrel (LNG)
│   │   ├── 1.5 mg single dose within 72 hours
│   │   └── 0.75 mg × 2 doses, 12 hrs apart, within 72 hrs
│   ├── Ulipristal acetate (UPA) - Ella
│   │   └── 30 mg single dose within 120 hours (5 days)
│   └── Combined (Yuzpe regimen) - older
│       └── EE 100 mcg + LNG 0.5 mg × 2 doses, 12 hrs apart
├── Antiprogestins
│   └── Mifepristone 10 mg (low dose EC) - within 72-120 hrs
└── Non-hormonal
    └── Copper IUD (most effective EC, within 5 days, >99%)

EC Schedule Summary

Mechanism of Action of EC

• LNG: Primarily inhibits/delays ovulation. Also thickens cervical mucus. Does NOT prevent implantation (no evidence).
• Ulipristal: Progesterone receptor modulator - delays ovulation even when LH surge has begun (works later in cycle than LNG).
• Copper IUD: Toxic to sperm (Cu2+ ions), prevents fertilization; also prevents implantation.

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4. MIFEPRISTONE (RU-486)

Mechanism of Action

Mifepristone
     ↓
Binds progesterone receptor (high affinity - 5× > progesterone)
     ↓
Competitive antagonism of progesterone
     ↓
    ┌─────────────────────────────────┐
    ↓                                 ↓
Decidua breakdown              Antigluco-corticoid
(↑ PGE2, PGF2α release)        (blocks cortisol at GR)
    ↓
Cervical softening + uterine contractions
    ↓
Endometrial shedding / expulsion of conceptus

Therapeutic Uses of Mifepristone

Adverse Effects of Mifepristone

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5. ORAL CONTRACEPTIVE PILLS (OCPs)

Classification

ORAL CONTRACEPTIVE PILLS
│
├── COMBINED OCPs (Estrogen + Progestin)
│   ├── Monophasic - constant dose throughout cycle
│   │   └── e.g., Mala-D, Mala-N, Loette (EE 20/30 mcg + LNG)
│   ├── Biphasic - 2 different doses
│   │   └── e.g., Binovum
│   └── Triphasic - 3 different doses (mimic natural cycle)
│       └── e.g., Triquilar, Trinordiol
│
└── PROGESTIN-ONLY PILLS (POP / "Mini-pill")
    ├── Traditional: Norethindrone 0.35 mg (Micronor)
    └── New: Desogestrel 75 mcg (Cerazette) - inhibits ovulation

Mechanism of Action (MOA)

COMBINED OCP MECHANISM
         ↓
Estrogen + Progestin
         ↓
↑ Negative feedback on hypothalamus/pituitary
         ↓
↓ GnRH → ↓ FSH → No follicular development
         ↓ LH  → No LH surge → No ovulation (PRIMARY mechanism)
         ↓
Additional mechanisms:
├── Progestin: ↑ cervical mucus viscosity → ↓ sperm penetration
├── Progestin: ↓ endometrial receptivity (atrophic endometrium)
└── Progestin: ↓ fallopian tube motility → ↓ sperm transport

• Primary: Cervical mucus thickening (main mechanism)
• Secondary: Endometrial atrophy
• Desogestrel POP: Also inhibits ovulation (like combined pill)

Dosage Schedule

• Take 1 pill daily for 21 days starting Day 1 or Day 5 of cycle
• Pill-free interval of 7 days (withdrawal bleed occurs)
• Restart next pack after 7 days
• Sunday start: Start on first Sunday after period begins

• 21 active + 7 placebo pills
• No pill-free interval; take continuously

• <12 hours late: Take immediately, no backup needed

• 12 hours (POP) or >24 hrs (combined): Take ASAP + condom for 7 days (48 hrs for POP)

• Two missed pills: Take 2 pills/day for 2 days + backup for 7 days

Adverse Effects of OCPs

OCP ADVERSE EFFECTS
├── Common/Minor
│   ├── Nausea, vomiting (take with food)
│   ├── Breast tenderness, enlargement
│   ├── Breakthrough bleeding/spotting
│   ├── Headache
│   ├── Weight gain (fluid retention)
│   ├── Mood changes, decreased libido
│   └── Chloasma (skin pigmentation)
│
├── Cardiovascular (SERIOUS)
│   ├── VTE (DVT/PE) - 3-4x risk increase
│   │   └── 3rd/4th generation progestins > LNG
│   ├── Stroke (especially with migraine + aura)
│   ├── Hypertension
│   └── Myocardial infarction (especially + smoking)
│
├── Metabolic
│   ├── ↑ TG, ↑ LDL (progestin-dependent)
│   ├── Glucose tolerance ↓ (mild)
│   └── ↑ SHBG (binding proteins)
│
├── Hepatic
│   ├── Cholestasis, jaundice
│   ├── Benign hepatic adenoma (rare, long-term use)
│   └── ↑ Gallstone risk
│
└── Other
    ├── Amenorrhea (post-pill amenorrhea)
    ├── Cervical ectropion (↑ risk of chlamydia)
    └── Contact lens intolerance

• A - Abdominal pain (thrombosis, liver tumor)
• C - Chest pain (PE, MI)
• H - Headache severe (stroke, HTN)
• E - Eye problems (stroke, vascular occlusion)
• S - Severe leg pain (DVT)

Non-Contraceptive Health Benefits of OCPs

NON-CONTRACEPTIVE BENEFITS
├── Menstrual Benefits
│   ├── ↓ Dysmenorrhea (period pain)
│   ├── ↓ Menorrhagia (heavy periods)
│   ├── Regulated cycle (predictable withdrawal bleed)
│   └── ↓ Iron deficiency anemia
│
├── Cancer Prevention
│   ├── ↓ Endometrial cancer (50% risk reduction)
│   ├── ↓ Ovarian cancer (40-50% reduction with >5 yr use)
│   └── ↓ Colorectal cancer
│
├── Benign Conditions
│   ├── ↓ Ovarian cysts (functional cysts)
│   ├── ↓ Benign breast disease (fibroadenoma)
│   ├── ↓ Pelvic inflammatory disease (↑ cervical mucus barrier)
│   └── ↓ Ectopic pregnancy risk
│
├── Endocrine/Skin
│   ├── ↓ Acne (esp. EE + norgestimate/drospirenone)
│   ├── ↓ Hirsutism (drospirenone - anti-androgenic)
│   └── ↓ PCOS symptoms
│
└── Other
    ├── ↓ Endometriosis severity
    ├── ↓ Rheumatoid arthritis risk
    └── ↓ Uterine fibroids

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6. POSTCOITAL (EMERGENCY) CONTRACEPTION - MANAGEMENT & SCHEDULE

Clinical Management Outline

PATIENT PRESENTS AFTER UNPROTECTED INTERCOURSE
            ↓
HISTORY: Time since intercourse? LMP? Previous contraception?
            ↓
    ┌──────────────────────────────────┐
    ↓                                  ↓
< 120 hours (5 days)            > 5 days
    ↓                                  ↓
Offer EC                     Consider Copper IUD only
    ↓                          if within 5 days
Method Selection:
├── Within 72 hrs → LNG 1.5 mg (preferred, most accessible)
├── Within 120 hrs → Ulipristal 30 mg (superior beyond 72 hrs)
├── Within 5 days → Copper IUD (best efficacy)
└── Obesity (BMI >26) → Copper IUD or Ulipristal preferred
            ↓
ADMINISTER EC ASAP (efficacy ↓ with time)
            ↓
Counsel: EC is NOT 100% effective
- Next period may be early/late
- If period >1 week late → pregnancy test
- Start regular contraception
            ↓
FOLLOW-UP:
- 3-4 weeks: confirm menses / r/o pregnancy
- STI screening if indicated
- Long-term contraception counseling

Schedule

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7. HORMONAL CONTRACEPTIVES - COMPLETE OVERVIEW

Classification

HORMONAL CONTRACEPTIVES
│
├── ORAL
│   ├── Combined OCP (Estrogen + Progestin)
│   └── Progestin-only pill (POP/Mini-pill)
│
├── PARENTERAL
│   ├── Injectables
│   │   ├── DMPA (Depo-Provera) - Medroxyprogesterone acetate 150 mg IM q3months
│   │   ├── NET-EN (Noristerat) - Norethindrone enanthate 200 mg IM q2months
│   │   └── Combined monthly injectable (Cyclofem/Lunelle) - EE + MPA
│   ├── Implants (subdermal)
│   │   ├── Single rod: Etonogestrel (Implanon/Nexplanon) - 3 years
│   │   └── Two-rod: Levonorgestrel (Jadelle) - 5 years
│   └── IUS (Intrauterine System)
│       └── Levonorgestrel IUD (Mirena 52 mg/5 yrs, Kyleena 19.5 mg/5 yrs)
│
├── TRANSDERMAL
│   └── Patch (EE 20 mcg/day + norelgestromin 150 mcg/day - Ortho Evra)
│       └── Change weekly × 3, week off
│
└── VAGINAL
    └── Ring (NuvaRing - EE 15 mcg + etonogestrel 120 mcg/day)
        └── Insert 3 weeks, remove 1 week

Mechanisms

Benefits

• Highly effective (>99% with perfect use)
• Reversible (except permanent methods)
• Non-contraceptive benefits (as listed for OCPs)
• DMPA: Amenorrhea - beneficial in menorrhagia/endometriosis
• LNG-IUS: Highly effective for menorrhagia (Mirena licensed for this)

Adverse Effects (Hormonal Contraceptives General)

• See OCP section; estrogen-containing methods carry VTE risk
• Progestin-only: irregular bleeding, mood changes, weight gain, ↓ libido
• DMPA specific: prolonged amenorrhea, ↓ BMD (reversible), delayed fertility return (up to 18 months)
• Implant: irregular bleeding most common reason for removal

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8. PARENTERAL CONTRACEPTIVES

Types, Advantages, Disadvantages

A. DMPA (Depo-Provera) - 150 mg IM every 12 weeks

• High efficacy (>99%), user-independent compliance
• Amenorrhea in 50-70% (beneficial)
• ↓ Sickle cell crises
• ↓ Endometrial cancer risk
• No estrogen - safe in DVT history, migraine with aura, smokers >35
• Useful in epilepsy (not affected by enzyme-inducing drugs like carbamazepine)
• Breastfeeding safe (progestin-only)

• Requires injection every 3 months
• Irregular/unpredictable bleeding (especially first 3-6 months)
• Weight gain (~2-3 kg)
• ↓ BMD (reversible after discontinuation)
• Delayed return of fertility (average 9-10 months post-last injection; can be up to 18 months)
• No protection against STIs
• Cannot be reversed once injected
• Mood changes, depression

B. NET-EN (Noristerat) - 200 mg IM every 8 weeks

• Similar to DMPA but shorter interval
• Used in short-term bridging (e.g., awaiting vasectomy to take effect)
• Less widely used

C. Monthly Combined Injectables (Cyclofem)

• EE 5 mg + MPA 25 mg IM monthly
• Regular withdrawal bleeds (advantage vs DMPA)
• More acceptable bleeding pattern
• Carries estrogen risks (VTE)

D. Subdermal Implants (Implanon/Nexplanon)

• Long-acting (3 years), highly effective (>99%)
• Rapid return of fertility after removal
• Progestin-only - safe in estrogen-sensitive conditions
• Convenient (no daily compliance)
• Cost-effective long-term

• Requires trained provider for insertion/removal
• Irregular bleeding (common; primary reason for discontinuation)
• Local reactions (bruising, infection at site)
• Not palpable occasionally → difficult removal

Adverse Effects of Parenteral Contraceptives

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9. UTERINE RELAXANTS (TOCOLYTICS)

Classification

UTERINE RELAXANTS / TOCOLYTICS
│
├── β2-ADRENERGIC AGONISTS (β2 stimulants)
│   ├── Ritodrine (first FDA-approved tocolytic - now withdrawn)
│   ├── Terbutaline (most widely used)
│   ├── Salbutamol (albuterol)
│   └── Isoxsuprine
│
├── CALCIUM CHANNEL BLOCKERS
│   └── Nifedipine (most commonly used now, 1st line in many guidelines)
│
├── OXYTOCIN ANTAGONIST
│   └── Atosiban (competitive antagonist at oxytocin receptor)
│
├── PROSTAGLANDIN SYNTHESIS INHIBITORS (NSAIDs)
│   └── Indomethacin (COX inhibitor → ↓ PG synthesis)
│
├── MAGNESIUM SULFATE
│   └── Competes with Ca2+ at motor end plate → ↓ uterine contractility
│       (also used for fetal neuroprotection, eclampsia)
│
├── NITRIC OXIDE DONORS
│   └── Glyceryl trinitrate (GTN) - nitroglycerin patch
│
└── PROGESTERONE
    └── Reduces myometrial excitability (used for preterm labor prevention)
        17α-hydroxyprogesterone caproate (17-OHPC) weekly IM

Uses of Uterine Relaxants

1. Administer corticosteroids (betamethasone) for fetal lung maturity
2. Transfer to higher-level NICU

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10. UTERINE STIMULANTS (UTEROTONICS)

Classification

UTERINE STIMULANTS / UTEROTONICS
│
├── OXYTOCIN (and analogues)
│   ├── Oxytocin (Syntocinon) - IV, IM
│   └── Carbetocin (long-acting oxytocin analogue)
│
├── ERGOT ALKALOIDS
│   ├── Ergometrine (Ergonovine) - PO, IM
│   └── Methylergometrine (Methergine) - PO, IM (preferred)
│
├── PROSTAGLANDINS
│   ├── PGE2: Dinoprostone (Cerviprime, Prostin E2) - vaginal/cervical gel
│   ├── PGE1: Misoprostol (Cytotec) - PO, sublingual, vaginal, rectal
│   ├── PGF2α: Dinoprost (Prostin F2α) - rarely used now
│   └── PGF2α analogue: Carboprost (15-methyl PGF2α, Hemabate) - IM
│
└── OTHERS
    └── Mifepristone (sensitizes myometrium to PGs, used with misoprostol)

Pharmacological Actions

OXYTOCIN

Mechanism:
Oxytocin → Gq-coupled oxytocin receptor on myometrium
         → ↑ IP3 + DAG → ↑ intracellular Ca2+
         → Myosin light chain kinase activation
         → Uterine contraction

Physiological role:
- Released by posterior pituitary (Ferguson reflex)
- ↑ near term as oxytocin receptors increase 100-200x at term
- Half-life: 3-5 minutes IV

1. Uterus: Rhythmic contractions (low dose); sustained tetanic contractions (high dose)
2. Breast: Milk ejection (contracts myoepithelial cells)
3. Cardiovascular: ↓ BP (vasodilation), reflex tachycardia, water retention (ADH-like effect at high doses)

• Induction of labor (IOL) - IV infusion, titrated
• Augmentation of labor (oxytocin drip)
• Prevention of PPH (10 IU IM/IV after delivery of anterior shoulder or placenta)
• Active management of 3rd stage of labor
• Management of PPH (IV infusion)
• Missed abortion / incomplete abortion

ERGOT ALKALOIDS

Mechanism:
Ergometrine → α-adrenergic + serotonergic (5-HT2) receptors on uterus
           → Sustained tonic contraction (different from oxytocin rhythmic)
           → Vasoconstriction (peripheral + uterine)

1. Uterus: Powerful sustained (tonic) contraction - not suitable for IOL
2. Cardiovascular: Vasoconstriction → ↑ BP (important adverse effect)
3. CNS: Nausea, vomiting (dopamine receptor)

• Prevention and treatment of PPH (most important use)
• Active management of 3rd stage of labor (with oxytocin - "Syntocinon/Ergometrine" combination = Syntometrine)
• Subinvolution of uterus
• NOT used for induction of labor (causes sustained tetanic contraction → fetal distress)

PROSTAGLANDINS

Mechanism:
PGE2/PGF2α → Prostaglandin receptors (EP/FP) on myometrium
            → ↑ Ca2+ → Uterine contraction
            → Also: Cervical ripening (↑ collagenase → soften cervix)

PGE1 (misoprostol) → Very versatile:
- Gastric: ↓ acid, ↑ mucus (cytoprotective)
- Uterine: contraction + cervical ripening

• Uterine contraction (all trimesters, unlike oxytocin effective early in pregnancy)
• Cervical ripening/softening
• Smooth muscle effects (bronchospasm, GI motility)

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SUMMARY FLOWCHART: CONTRACEPTIVE PHARMACOLOGY

CONTRACEPTION CHOICE
        ↓
    ┌───────────────────────────────────────────────────┐
    │  Estrogen contraindicated?                        │
    │  (DVT Hx, migraine+aura, smoker>35, HTN, BF)    │
    └───────────────┬───────────────────────────────────┘
                    ↓
        YES                          NO
         ↓                            ↓
  Progestin-only options:      Combined options:
  - POP (mini-pill)            - Combined OCP
  - DMPA injection             - Patch, Ring
  - Implant                    - Monthly injectable
  - LNG-IUS (Mirena)
        ↓
  Desire LARC (>3 yrs)?
  YES → Implant or LNG-IUS
  NO → DMPA or POP

Emergency:
< 72 hrs → LNG 1.5 mg
72-120 hrs → Ulipristal 30 mg
Any time <5 days → Copper IUD

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QUICK REFERENCE TABLE: UTERINE DRUGS

SITUATION → DRUG OF CHOICE
──────────────────────────────────────────────────────
Induction of labor at term       → Oxytocin IV infusion
Cervical ripening                → Dinoprostone (PGE2 gel)
PPH prevention (3rd stage)       → Oxytocin 10 IU IM
PPH treatment (oxytocin failed)  → Ergometrine OR Carboprost
PPH in asthma                    → Ergometrine (NOT carboprost)
PPH in hypertension              → Carboprost (NOT ergometrine)
2nd trimester abortion           → Misoprostol ± Mifepristone
Medical abortion ≤9 wks          → Mifepristone + Misoprostol
Preterm labor tocolysis          → Nifedipine (1st line, oral)
Acute uterine relaxation         → GTN (nitroglycerin)
Fetal neuroprotection/eclampsia  → MgSO4

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