Estrogen Receptors
Estrogen Receptor Alpha
Dominant in Reproductive Tissues & Liver
- Uterus, breast, liver, bone
- Hypothalamic-pituitary axis (negative feedback)
- Target for tamoxifen and raloxifene (SERMs)
- Mediates proliferative and feminizing effects
Estrogen Receptor Beta
Modulates Estrogen Receptor Alpha Activity
- Ovary (granulosa cells), colon, lung, central nervous system
- Generally opposes proliferative effects of estrogen receptor alpha
- Less targeted by available drugs
- Basis for tissue-selective SERM pharmacology
Estrogen Biosynthesis
Theca Cell
Luteinizing hormone → androgens (androstenedione, testosterone) from cholesterol
Granulosa Cell
Follicle-stimulating hormone → aromatase (CYP19A1) → converts androgens to estrogens
Products
Androstenedione → estrone | Testosterone → estradiol (most potent)
Postmenopause
Ovary stops; estrone from adipose aromatization of adrenal androstenedione becomes dominant → aromatase inhibitors work here
Estrogen Route — VTE Risk Comparison
| Property |
Oral Estradiol |
Ethinyl Estradiol |
Transdermal Estradiol |
| First-pass hepatic exposure |
Yes — high portal concentrations |
Yes — even higher hepatic stimulation |
No — bypasses portal circulation |
| Hepatic coagulation factors |
Increased |
Substantially increased |
Minimal increase |
| Sex hormone-binding globulin induction |
Moderate increase |
2–4x increase |
Minimal |
| VTE risk |
Increased |
~3–4x baseline |
Not increased |
| Preferred in VTE risk factors |
No |
No |
Yes |
Progestin Generations — Receptor Profiles
Natural
Micronized Progesterone
- Low oral bioavailability improved by micronization
- Selective for progesterone receptor
- Sedation (GABA-A metabolites)
- Vaginal use: luteal support
1st/2nd Gen 19-Nor
Norethindrone & Levonorgestrel
- Testosterone-derived → androgenic
- Levonorgestrel: highest androgenic index
- Reduces high-density lipoprotein, acne risk
- Depot: MPA 150 mg q12 wks; fertility delay 9–10 mo
3rd Gen 19-Nor
Desogestrel / Etonogestrel
- Reduced androgenic activity vs. levonorgestrel
- Etonogestrel: implant (3 yr), vaginal ring
- Better lipid profile
- Slightly higher VTE risk than levonorgestrel
4th Gen / Spiro-Derived
Drospirenone
- Anti-androgenic (AR blocker)
- Anti-mineralocorticoid → K+ retention
- Monitor K+ with ACE-I, ARBs, K+-sparing diuretics
- Use: polycystic ovary syndrome, PMDD
Key Drug Interactions
CYP3A4 Inducers → Contraceptive Failure
Rifampin & Enzyme-Inducing Antiepileptic Drugs
- Rifampin: most potent inducer; renders all hormonal OCs unreliable
- Induction persists 4 weeks after last rifampin dose
- Antiepileptic drugs that induce: carbamazepine, phenytoin, phenobarbital, oxcarbazepine
- Safe antiepileptic drugs: valproate, levetiracetam, gabapentin, pregabalin
- Backup: copper intrauterine device (non-hormonal)
Bidirectional Interaction
Ethinyl Estradiol + Lamotrigine
- Ethinyl estradiol induces lamotrigine metabolism (glucuronidation)
- Start combined oral contraceptive → lamotrigine levels fall 40–65% → seizure risk
- Stop combined oral contraceptive → lamotrigine levels rebound → toxicity (dizziness, diplopia)
- Progestin-only methods: no interaction (no ethinyl estradiol)
- Preferred: progestin-only or non-hormonal method in lamotrigine-treated epilepsy
Core Rule — Oral vs. Transdermal Estrogen
Oral estrogen (ethinyl estradiol, oral estradiol, conjugated equine estrogens) → portal first-pass → hepatic coagulation factors up → VTE risk up. Transdermal estradiol → bypasses portal → no VTE risk increase. In patients with VTE risk factors: transdermal route always preferred.