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9. Anti-Androgens

• Steroidal: Cyproterone acetate (also a progestin; used in hirsutism, precocious puberty)
• Non-steroidal (pure): Flutamide, Bicalutamide, Enzalutamide (used in prostate cancer)
• Aldosterone antagonist with anti-androgen action: Spironolactone (used in PCOS, hirsutism)
• 5α-reductase inhibitors (indirect): Finasteride, Dutasteride

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10. ⭐⭐⭐⭐⭐ Tamoxifen vs Raloxifene

STAR trial: Raloxifene = Tamoxifen in breast cancer prevention but with fewer uterine cancers and thromboembolic events.

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11. ⭐⭐⭐⭐⭐ Ormeloxifene (Centchroman)

• Class: 3rd generation SERM (non-steroidal)
• MOA: Selective estrogen receptor modulator; causes asynchrony between ovulation and uterine endometrial maturation → prevents implantation
• Dose: 30 mg twice weekly for 3 months, then once weekly (oral)
• Uses:
  • Oral contraceptive (non-hormonal, no estrogen/progesterone)
  • Dysfunctional uterine bleeding (DUB)
• Advantages: No major hormonal side effects, not a hormone, taken weekly (good compliance)
• Side effects: Oligomenorrhea/amenorrhea, delayed periods, weight gain
• Contraindication: Pregnancy (teratogenic)

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12. Synthetic Progestins

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13. ⭐⭐⭐ Minipill (Progestogen-Only Pill)

• Contains only progestogen (norethisterone or levonorgestrel) in low dose
• Taken continuously, every day without a break
• MOA:
  1. Thickens cervical mucus → blocks sperm
  2. Renders endometrium atrophic → prevents implantation
  3. May inhibit ovulation (inconsistently)
• Advantages: Safe in breastfeeding mothers, women who cannot take estrogen (hypertension, DVT, smokers over 35)
• Disadvantages: Irregular bleeding, less effective than combined OCP, must be taken at same time daily
• Failure rate: ~1-3 per 100 women-years

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14. ⭐⭐⭐ Parenteral Contraceptive Measures

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15. ⭐⭐⭐ Rationale for Combining Estrogen + Progesterone in OCP

1. Better cycle control: Estrogen alone causes irregular bleeding; progesterone alone may cause breakthrough bleeding. Together they produce regular withdrawal bleeding.
2. Synergistic contraceptive effect: Estrogen suppresses FSH (prevents follicular development) + Progesterone suppresses LH (prevents ovulation) + thickens cervical mucus.
3. Lower dose possible: Combination allows lower individual doses of each hormone, reducing side effects.
4. Endometrial protection: Progesterone prevents estrogen-induced endometrial hyperplasia/cancer.
5. Reduced failure rate: Pearl index < 0.1 (nearly 100% effective).

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16. ⭐⭐⭐ Oxytocin vs Ergometrine

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17. ⭐⭐⭐⭐⭐ Tocolytics

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18. Uterine Stimulants (Oxytocics)

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19. Finasteride

• Class: 5α-reductase inhibitor (Type II isoenzyme)
• MOA: Inhibits conversion of testosterone → DHT (dihydrotestosterone); DHT is the active androgen in prostate and hair follicles
• Uses:
  • Benign prostatic hyperplasia (BPH) - reduces prostate size
  • Male pattern baldness (androgenic alopecia) - lower dose (1 mg)
• Effects: Reduces PSA by ~50%, reduces prostate volume by 20-30%
• Side effects: Decreased libido, erectile dysfunction, gynecomastia, decreased ejaculate volume
• Note: Dutasteride inhibits both Type I and II isoenzymes (more complete DHT suppression)

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20. Teriparatide

• What it is: Recombinant human PTH (1-34 fragment); anabolic bone agent
• MOA: Intermittent PTH stimulates osteoblast activity > osteoclast activity → net bone formation (paradoxical - continuous PTH causes bone resorption, but pulsatile stimulates formation)
• Dose: 20 mcg SC once daily
• Use: Severe osteoporosis (postmenopausal, glucocorticoid-induced); patients with multiple fractures; when bisphosphonates fail
• Side effects: Nausea, leg cramps, dizziness, transient hypercalcemia; risk of osteosarcoma (seen in rat studies - black box warning; avoid in Paget's disease, prior radiation)
• Duration: Max 2 years

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21. Pramlintide

• What it is: Synthetic amylin analog (amylin is co-secreted with insulin by pancreatic β-cells)
• MOA:
  1. Slows gastric emptying → reduces postprandial glucose spike
  2. Suppresses glucagon secretion (postprandial)
  3. Promotes satiety (acts on hindbrain amylin receptors) → weight loss
• Route: SC injection before each meal
• Use: Adjunct to mealtime insulin in Type 1 and Type 2 DM (not used alone)
• Side effects: Nausea (most common), vomiting, hypoglycemia (when combined with insulin - reduce insulin dose at initiation)
• Advantage: Weight loss (unlike insulin which causes weight gain)

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1. ⭐⭐⭐ Oestrogen Preparations

Classification

• Estradiol (E2) - most potent natural estrogen
• Estrone (E1)
• Estriol (E3) - weakest; used in vaginal atrophy

• Steroidal: Ethinyl estradiol (EE) - highly potent; used in OCPs; highest VTE risk
• Non-steroidal: Diethylstilbestrol (DES) - synthetic; now obsolete due to teratogenicity

• Mixture of equine estrogens (equilin + estrone sulfate); used in HRT

Routes of Administration & Preparations

Uses

• Hormone replacement therapy (postmenopausal symptoms - hot flushes, vaginal atrophy)
• Oral contraceptives (combined with progestin)
• Dysfunctional uterine bleeding
• Primary amenorrhea, hypogonadism
• Prostate cancer (high-dose DES - anti-androgenic)
• Osteoporosis prevention

Important Pharmacokinetics

• Ethinyl estradiol is far more potent orally than estradiol because the 17α-ethinyl group prevents first-pass metabolism
• Transdermal route avoids first-pass metabolism → lower DVT risk than oral
• All estrogens bind to estrogen receptors (ERα, ERβ) in target tissues

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2. ⭐⭐⭐⭐⭐ SERMs (Selective Estrogen Receptor Modulators)

Definition

Mechanism

• Bind to ERα and ERβ receptors
• Tissue-specific conformational change in ER determines agonist vs antagonist effect
• Differ from pure estrogen agonists and pure antagonists (like fulvestrant)

Classification & Tissue Effects

Key Clinical Points

• Tamoxifen → endometrial cancer risk (uterine agonism)
• Raloxifene → no endometrial cancer (uterine neutral)
• All SERMs → increased DVT/PE risk
• All SERMs → hot flushes as side effect
• STAR trial: Raloxifene = Tamoxifen for breast cancer prevention, but safer uterine profile

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3. ⭐⭐⭐⭐⭐ Clomiphene Citrate

Drug Profile

• Class: SERM (non-steroidal); triphenylethylene derivative
• Available as: Mixture of two geometric isomers - enclomiphene (active, trans) + zuclomiphene (less active, cis)

Mechanism of Action

1. Binds to hypothalamic ER → blocks normal inhibitory feedback of estrogen on hypothalamus
2. Hypothalamus "perceives" low estrogen → increases GnRH pulse frequency and amplitude
3. ↑GnRH → ↑FSH and ↑LH secretion from pituitary
4. ↑FSH → follicular development and maturation → ovulation

Acts primarily at pituitary level - increases LH and FSH pulse amplitude without changing frequency

Pharmacokinetics

• Oral, well absorbed
• Long half-life (~5-7 days); stored in fat
• Zuclomiphene persists for weeks (accounts for anti-estrogenic side effects)

Dose & Regimen

• 50 mg/day × 5 days, starting on Day 2-5 of menstrual cycle
• If no response: increase to 100 mg/day × 5 days (max 150 mg)
• Ovulation expected 5-10 days after last dose

Uses

• Ovulation induction in anovulatory infertility (PCOS is commonest indication)
• Unexplained infertility
• WHO Group II anovulation

Side Effects

• Ovarian hyperstimulation syndrome (OHSS) - most serious
• Multiple pregnancy (twins ~8%, higher-order rare)
• Vasomotor symptoms (hot flushes)
• Visual disturbances (blurring, scotoma) → stop drug immediately
• Cervical mucus hostility (anti-estrogenic on endometrium/cervix)
• Ovarian cyst formation
• Abdominal bloating

Contraindications

• Liver disease
• Abnormal uterine bleeding (undiagnosed)
• Ovarian cysts (other than PCOS)
• Pregnancy
• Hormone-dependent tumors

Success Rate

• Ovulation in ~70-80%; pregnancy in ~30-40% (discordance due to anti-estrogenic effect on endometrium/cervical mucus)
• If no ovulation after 3 cycles at 150 mg → clomiphene resistant → use letrozole or gonadotropins

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4. Aromatase Inhibitors (AIs)

Mechanism

• Aromatase (CYP19A1) is the enzyme that converts androgens (androstenedione, testosterone) → estrogens (estrone, estradiol) in peripheral tissues (fat, liver, muscle)
• AIs block aromatase → ↓estrogen synthesis (mainly in postmenopausal women where ovarian estrogen is absent and peripheral aromatization is the main source)

Classification

Uses

1. Breast cancer - adjuvant therapy in postmenopausal ER+ breast cancer (now first-line over tamoxifen in postmenopausal women)
2. Ovulation induction - Letrozole (off-label but now preferred over clomiphene in PCOS; better endometrial receptivity, no anti-estrogenic effect on uterus, less OHSS)
3. Endometriosis (letrozole)
4. Gynecomastia (anastrozole)

Side Effects

• Musculoskeletal pain/arthralgia (most common)
• Osteoporosis (significant - estrogen deprivation → bone loss; bisphosphonates often co-prescribed)
• Hot flushes
• Vaginal dryness
• Hypercholesterolemia
• Not for premenopausal women (ovarian aromatase not fully suppressed; can cause ovarian stimulation)

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5. ⭐⭐⭐⭐⭐ Mifepristone (RU-486)

Drug Profile

• Class: Synthetic 19-norsteroid; analog of norethindrone
• Primary action: Competitive antagonist at progesterone receptors (high affinity - 5× greater than progesterone itself)
• Additional action: Anti-glucocorticoid (also antagonizes glucocorticoid receptors) and weak anti-androgenic

Mechanism of Action

1. Blocks progesterone receptors in decidua → decidual breakdown → detachment of conceptus
2. Increases uterine sensitivity to prostaglandins
3. Softens and dilates cervix
4. Combined with misoprostol (PGE1): prostaglandin causes uterine contractions → expulsion of products of conception

• Ripens cervix and sensitizes uterus to oxytocin

Dose Regimens

Efficacy

• Mifepristone alone: ~60-80% complete abortion
• Mifepristone + Misoprostol: >95% effective in first trimester

Uses

1. Medical termination of pregnancy (MTP) - up to 9 weeks
2. Emergency contraception
3. Cervical priming before surgical MTP or induction
4. Cushing's syndrome (hyperglycemia due to hypercortisolism)
5. Uterine leiomyomas (investigational)
6. Endometriosis (investigational)
7. Postcoital contraception

Side Effects

• Nausea, vomiting, diarrhea
• Abdominal cramping
• Heavy bleeding (expected; may need surgical intervention if incomplete)
• Prolonged bleeding
• Serious (rare): Fatal sepsis reported with Clostridium sordellii (rare, associated with vaginal misoprostol route)

Contraindications

• IUD in situ (remove first)
• Adrenal insufficiency (blocks glucocorticoid receptors)
• Long-term corticosteroid therapy
• Coagulopathy / anticoagulant use
• Ectopic pregnancy
• Unreliable for follow-up

Key Points to Remember

• Half-life: ~18 hours
• Progesterone maintains pregnancy - mifepristone blocks this → withdrawal of progesterone support
• The combination with misoprostol (a PGE1 analog that contracts uterus) is the gold standard for medical abortion
• Progesterone is the "hormone of pregnancy maintenance" - blocking it is the rationale