Estrogen drug 2nd year
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Estrogen Drugs - 2nd Year Pharmacology
1. Introduction
Estrogens are steroid hormones produced primarily by the ovarian granulosa cells (stimulated by FSH), corpus luteum, placenta (fetoplacental unit), and in small amounts by the adrenal cortex and adipose tissue. In males, they are produced by aromatization in peripheral tissues and the testes.
The three major endogenous estrogens are:
| Estrogen | Notes |
|---|---|
| Estradiol (E2) | Most potent; principal ovarian secretory product |
| Estrone (E1) | Less potent; formed from estradiol in liver and peripheral tissues |
| Estriol (E3) | Weakest; mainly a product of fetoplacental unit during pregnancy |
2. Mechanism of Action
Estrogens act primarily via nuclear estrogen receptors (ERs) - two subtypes:
- ERα - expressed in uterus, vagina, ovaries, mammary gland, hypothalamus, endothelial cells, vascular smooth muscle
- ERβ - expressed in prostate, ovaries, lung, brain, bone
Genomic pathway (classical):
- Estrogen diffuses into the cell and enters the nucleus
- Binds to ER monomer (previously bound to HSP-90, keeping it inactive)
- HSP-90 dissociates → receptor dimerization occurs
- ER dimer binds to Estrogen Response Elements (EREs) on DNA
- Recruits co-regulator proteins → regulates gene transcription (increases or decreases)
Non-genomic (rapid) effects: Mediated via membrane-associated ERα and GPER (G protein-coupled estrogen receptor / GPR30) - explains rapid effects like vasodilation.
(Goodman & Gilman's, pp. 978-988)
3. Pharmacological Preparations
A. Natural / Steroidal Estrogens
| Drug | Route | Notes |
|---|---|---|
| Estradiol (17β-estradiol) | Oral, transdermal patch, gel, IM injection | Most potent natural estrogen |
| Estradiol valerate | Oral, IM | Ester form; long-acting injection |
| Estradiol cypionate | IM | Long-acting depot |
| Conjugated equine estrogens (CEE / Premarin) | Oral | Mixture from pregnant mare urine; contains equilin, equilenin + estrone sulfate |
| Estrone | Oral, vaginal | Less potent |
| Estriol | Vaginal cream | For local (vaginal atrophy) effects |
B. Synthetic Steroidal Estrogens
| Drug | Notes |
|---|---|
| Ethinyl estradiol | Most widely used synthetic; highly potent orally; component of almost all combined oral contraceptives |
| Mestranol | Prodrug - converted to ethinyl estradiol in the liver |
C. Synthetic Non-Steroidal Estrogens (historical)
| Drug | Notes |
|---|---|
| Diethylstilbestrol (DES) | Potent synthetic; NOT used now due to teratogenicity (vaginal clear cell carcinoma in daughters) |
| Chlorotrianisene | Long-acting; stored in fat |
(Katzung's Basic & Clinical Pharmacology, 16e, p. 1127)
4. Physiological Actions
Reproductive Tract
- Uterus: Endometrial proliferation, increase myometrial contractility
- Vagina: Cornification of epithelium, increased glycogen (Doderlein's bacilli → acidic pH)
- Cervix: Thin, watery, ferning mucus (promotes sperm entry at ovulation)
- Fallopian tubes: Increases motility and secretion
- Breast: Ductal growth and development, fat deposition
Neuroendocrine (Hypothalamus-Pituitary)
- Low levels (follicular phase): Negative feedback → suppresses GnRH, FSH, LH
- High levels (pre-ovulatory): Positive feedback → triggers LH surge → ovulation
Metabolic Effects
| System | Effect |
|---|---|
| Bone | Inhibits osteoclasts → maintains bone density (prevents osteoporosis) |
| Lipids | ↑ HDL, ↓ LDL, ↑ triglycerides |
| Coagulation | ↑ clotting factors (I, II, VII, X), ↑ fibrinogen → pro-thrombotic |
| Liver | ↑ SHBG, angiotensinogen, clotting factors |
| Cardiovascular | Vasodilation (↑ NO production), cardioprotective in premenopausal women |
| Skin/hair | Feminizing effects, reduced sebum production |
| CNS | Neuroprotective, mood regulation, hot flash prevention |
5. Therapeutic Uses
A. Hormonal Contraception (most common use)
- Combined oral contraceptives (COCs): ethinyl estradiol + progestin
- Mechanism: inhibit LH surge (block ovulation), alter cervical mucus, alter endometrium
- Postcoital / emergency: high-dose estrogen-progestin within 72 hours
B. Menopausal Hormone Therapy (MHT / HRT)
- Indications: hot flashes (vasomotor symptoms), vaginal atrophy, dyspareunia, urinary symptoms
- Prevents osteoporosis
- Given with progestin if uterus intact (to prevent endometrial carcinoma)
- Conjugated equine estrogens (0.625 mg/day) is the standard oral regimen
- WHI trial raised concerns about breast cancer and CVD with long-term combined therapy
C. Primary Amenorrhea / Hypogonadism
- Induction of sexual maturation in girls with gonadal dysgenesis (e.g., Turner syndrome)
- Low-dose estrogen to mimic pubertal development
D. Dysmenorrhea / Endometriosis
- Combined OCP suppresses ovarian function and reduces endometrial proliferation
E. Hirsutism
- Combined OCP + androgen suppression
F. Osteoporosis Prevention
- Prevent post-menopausal bone loss
G. Prostate Cancer (palliative)
- High-dose estrogen (diethylstilbestrol) suppresses LH → reduces testosterone → used in metastatic prostate cancer
H. Gender-Affirming Care
- Feminizing therapy in transgender women
I. Atrophic Vaginitis
- Local vaginal estrogen cream (estriol)
6. Adverse Effects
| Adverse Effect | Details |
|---|---|
| Uterine bleeding | Postmenopausal bleeding - most common; can mask endometrial cancer |
| Endometrial carcinoma | Unopposed estrogen increases risk 2-10x; prevented by adding progestin |
| Breast cancer | Risk ↑ with long-term combined HRT (WHI data); 5-10 years use ≈ slight increase |
| Thromboembolic disease | DVT, PE - due to ↑ clotting factors; especially oral estrogens (first-pass liver effect) |
| Nausea, vomiting | Common, especially early in therapy |
| Fluid retention / edema | |
| Migraine | Can worsen or trigger migraines |
| Hypertension | Due to ↑ angiotensinogen (renin substrate) |
| Cholestasis | Impaired bile secretion, especially in susceptible women |
| DES teratogenicity | Clear cell adenocarcinoma of vagina/cervix in daughters exposed in utero |
7. Contraindications
- Estrogen-dependent cancers (breast, endometrial)
- History of DVT / PE / thromboembolic events
- Undiagnosed uterine bleeding
- Active liver disease
- Pregnancy
- Stroke / CAD (caution)
- Migraine with aura
8. Selective Estrogen Receptor Modulators (SERMs)
These are drugs that act as estrogen agonists in some tissues and antagonists in others:
| Drug | Agonist Actions | Antagonist Actions | Use |
|---|---|---|---|
| Tamoxifen | Uterus, bone | Breast | Breast cancer (ER+); reduces recurrence by 50% over 5 years |
| Raloxifene | Bone, lipids | Breast, uterus | Osteoporosis; does NOT increase endometrial cancer risk |
| Clomiphene | Peripheral tissues | Hypothalamus/pituitary | Ovulation induction in PCOS (blocks negative feedback → ↑ FSH) |
| Fulvestrant | - | Breast (pure antagonist) | Advanced ER+ breast cancer, tamoxifen-resistant |
| Toremifene | Similar to tamoxifen | Breast | Metastatic breast cancer |
9. Estrogen Synthesis Inhibitors (Aromatase Inhibitors)
These block the enzyme aromatase (CYP19) which converts androgens to estrogens:
| Drug | Type | Use |
|---|---|---|
| Anastrozole | Non-steroidal (reversible) | Postmenopausal breast cancer |
| Letrozole | Non-steroidal (reversible) | Postmenopausal breast cancer; ovulation induction |
| Exemestane | Steroidal (irreversible) | Postmenopausal breast cancer |
10. Key High-Yield Points for Exams
- Estradiol > Estrone > Estriol in potency
- Ethinyl estradiol is the synthetic estrogen in most oral contraceptive pills
- Estrogens → positive feedback at high levels only (pre-ovulatory LH surge); negative feedback at low/moderate levels
- Unopposed estrogen → endometrial hyperplasia and carcinoma → always add progestin if uterus is intact
- Tamoxifen → used in breast cancer but increases endometrial cancer risk (uterine agonist)
- Raloxifene → NO endometrial cancer risk (uterine antagonist)
- Clomiphene → blocks hypothalamic feedback → ↑ FSH → used in anovulatory infertility
- DES → causes vaginal clear cell adenocarcinoma in daughters (in utero exposure) - no longer used
- Oral estrogens have first-pass liver effect → more hepatic effects, higher DVT risk than transdermal
- Post-menopausal estrogen source = adipose tissue (aromatization of androstenedione)
Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 48; Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 40
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