# Ethinylestradiol (EE) Parameters for Pharmacokinetic Modeling Compiled 2026-05-14 for extension of an E2 PK model to handle ethinylestradiol. Sources are cited inline; key values flagged where literature disagrees. --- ## A. Core PK Parameters (drop-in values) ``` # ---- Absorption ---- F_oral_EE = 0.45 # fraction; consensus 38-48% (Wikipedia/Stanczyk 2013/PMC4285808) # PBPK (Lorbek 2018) used fa=0.948 with extensive first-pass ka_EE = 1.10 # 1/h (PBPK Lorbek 2018); pop-PK Klipping 2012 gave ka=0.295/h # Wide range across studies, IIV ~30% Tmax_EE_oral = 1.5 # h (range 0.5-3 h, peaks at ~1-2 h with 20-30 microg COCs) # ---- Distribution ---- Vd_EE_central = 24 # L (Klipping 2012 pop-PK V2/F = 23.9 L) Vd_EE_peripheral_deep = 1330 # L (Klipping 2012 V3/F; large depot compartment) Vd_EE_ss_per_kg = 4.06 # L/kg (PBPK Lorbek 2018; Vss) Vd_EE_apparent_total = 280 # L (rough whole-body Vd often cited; ~4 L/kg x 70 kg) # Flag: pop-PK three-compartment fits give wildly different # numbers depending on model; 4 L/kg is the cleanest summary. # ---- Elimination ---- CL_EE_oral_apparent = 25.3 # L/h (Klipping 2012 CL/F; ~600 L/day apparent oral) CL_EE_iv = 16.5 # L/h (Lorbek 2018 PBPK; ~395 L/day) MCR_EE = 400 # L/day (Wikipedia summary of MCR; range 250-500 L/day) # Flag: MCR poorly reported for EE vs E2. Compute as # CL_iv * 24 ~= 400 L/day or CL_oral*F ~= 270 L/day. t_half_EE = 18 # h (consensus 12-24 h; literature range 7-36 h) # Single dose vs steady state differs: ~12 h single, ~20 h SS # ---- Plasma protein binding ---- fu_EE = 0.02 # free fraction (PBPK Lorbek 2018 = 0.015; Wiki 2-3%) EE_pct_albumin = 0.97 # 97-98% bound, almost entirely to albumin EE_pct_SHBG = 0.00 # negligible; affinity ~2% of E2 (Wikipedia/Kuhl 2005) # Functionally EE does not bind SHBG. SHBG_Kd_EE_relative_to_E2 = 50 # i.e. ~50x weaker binding (2% affinity) ``` ### Notes on flagged values - **Bioavailability.** The "45% (38-48%)" range is from Stanczyk 2013 / Devineni 2007 and is the most-cited figure. Individual studies report values as low as 20% (high-CYP3A4 metabolizers) and as high as 65%. Use 0.45 as central, but **IIV is enormous (~40-60% CV)**; this is the single largest source of dose-response variance and is the same reason different women on the same pill can have 3x different EE levels (Stanczyk 2013, Goldzieher 1990). - **Volume of distribution** is route- and model-dependent. The PBPK Vss of ~4 L/kg is the most physiologically meaningful summary; the apparent V/F of ~25 L (central) + 1330 L (deep) reflects the multi-compartment kinetics. For a one-compartment model, use **Vd ~ 280-400 L** as a working value. - **Half-life.** Single-dose t1/2 ~10-16 h; **steady-state t1/2 ~ 17-24 h** because of slow release from the deep peripheral compartment. The 7-36 h range in Wikipedia covers all reported study means. - **MCR.** EE is not well-characterized by classical MCR experiments (unlike E2). The most defensible estimate comes from systemic clearance: ~16.5 L/h IV * 24 = **~400 L/day**, vs. E2's MCR of ~1500 L/day. EE is cleared **~3-4x more slowly** than E2. ### Metabolism / metabolites ``` # Fraction metabolized (Lorbek 2018 PBPK) fm_CYP3A4 = 0.22 # 2-hydroxylation, 4-hydroxylation fm_other_CYP = 0.18 # CYP2C9, CYP2C8, CYP1A2 (minor) fm_UGT = 0.05 # UGT1A1 primarily; also UGT1A3, UGT1A9 (forms 3-glucuronide) fm_SULT = 0.37 # SULT1E1 dominates (low-Km, Km ~4 nM); also SULT1A1 (which EE # paradoxically *inhibits* potently, contributing to EE-EE # drug-interaction effects on its own clearance and on co-meds) fm_other = 0.18 # gut conjugation, biliary excretion, enterohepatic recycling ``` Major metabolite is **ethinylestradiol-3-sulfate**, which accumulates to far higher plasma levels than parent EE and is partly hydrolyzed back to parent (deep-compartment behavior). Phase I oxidation gives **2-hydroxy-EE** (CYP3A4/2C9) and minor 4-OH-EE; Phase II conjugates are 3-sulfate (SULT1E1) and 3-glucuronide (UGT1A1, the bilirubin UGT). Excretion is **62% fecal / 38% urinary** as conjugates (Wikipedia, Stanczyk 2013). Enterohepatic recirculation is real but quantitatively modest in humans (much larger in rats; this confused early antibiotic-interaction concerns). **Does SULT matter for EE?** Yes — more than for E2. SULT1E1 has Km ~4 nM for EE and is a major contributor to gut/hepatic first-pass conjugation; this is one reason EE bioavailability is bimodal (high vs low SULT1E1 expressors). EE is also a potent inhibitor of SULT1A1, which modulates its own clearance and that of other SULT substrates. References for metabolism: Schrag 2004 (SULT1E1 Km); Ebner 1993 (sulfation/glucuronidation in human liver); Rodrigues 2022 (Clin Pharm Ther review on EE DDIs beyond CYP3A); Stanczyk 2013; Lorbek 2018 PBPK. --- ## B. SHBG Induction Potency This is the key pharmacodynamic difference vs. E2 and the reason EE is no longer used in trans HRT. ``` SHBG_relative_potency_EE_vs_E2_oral = 100 # per-mole; Kuhl 2005 / multiple sources # Range across hepatic proteins: 75-1000x SHBG_relative_potency_EE_vs_E2_systemic = 1.5 # rough ratio for systemic uterotrophic / # ER-binding effect; only ~50% more potent # at the receptor itself (Kuhl 2005) hepatic_disproportion_EE = SHBG_relative_potency_EE_vs_E2_oral / SHBG_relative_potency_EE_vs_E2_systemic # ~ 70x (this is the "hepatic disproportion" of EE) ``` ### Per-molar potency at hepatic SHBG induction (Kuhl 2005) Kuhl tabulates oral hepatic potency (SHBG, angiotensinogen, CBG, TBG) relative to **micronized oral E2 = 1**: | Estrogen | SHBG induction (per mg) | Per-mole vs E2 | |------------------------------|-------------------------|----------------| | Oral micronized E2 | 1 | 1 | | Oral estradiol valerate | 1 | ~1 | | Conjugated equine estrogens | 1.4-2.5 | 4-5 | | **Oral ethinylestradiol** | **~120** | **~100** | | Transdermal E2 | 0.05-0.1 | (route effect) | So 20 microg EE/day produces roughly the same hepatic SHBG response as **~2 mg of oral E2/day**. ### Typical SHBG rise on COCs (combined-OC studies) Different sources report somewhat different ranges; SHBG rise depends strongly on the **progestin** (androgenic progestins blunt it): | Dose / formulation | SHBG rise (% increase from baseline) | |---------------------------------------------|--------------------------------------| | EE 5 microg/day (postmenopausal) | +100% (Kuhl) | | EE 20 microg + LNG 100 microg (Alesse) | +80% to +150% (Stegeman 2013) | | EE 20 microg + dienogest 2 mg | +270% | | EE 30 microg + LNG 150 microg (Microgynon) | +100% to +150% | | EE 30 microg + desogestrel 150 microg | +200% | | EE 30 microg + drospirenone 3 mg (Yasmin) | +200% to +300% | | EE 30 microg + dienogest 2 mg | +320% | | EE 35 microg + cyproterone 2 mg (Diane-35) | +400% | | EE >50 microg (older COCs) | +500% to +1000% (5-10 fold) | Postmenopausal SHBG baseline is ~30-60 nmol/L; on a typical 30 microg EE COC it reaches ~150-200 nmol/L, similar to pregnancy. Source: Stegeman 2013 (JTH), Kuhl 2005, Wikipedia summary. ### Why is the hepatic effect of EE disproportionately high vs. E2? Three reinforcing mechanisms, all from the **17alpha-ethinyl group**: 1. **Resistance to 17beta-HSD oxidation.** The ethinyl group sterically blocks the 17beta-hydroxysteroid dehydrogenase that converts E2 to estrone (E1) and effectively inactivates E2 in liver and uterus on first pass. EE survives intact through hepatocytes. 2. **Resistance to phase II conjugation** at the 17-OH (only the 3-OH remains accessible), slowing first-pass clearance. 3. **Long residence time in hepatocytes.** Because hepatic clearance is the *route* by which oral estrogens reach the hepatocyte ER, and because EE is concentrated there relative to systemic plasma, the **hepatic-to-systemic potency ratio is ~50-100x that of E2**. The peripheral receptor sees only 1-2x more EE than equimolar E2 (Kuhl 2005: "approximately equipotent for uterotrophic activity"); the hepatic receptor sees ~100x more. This is the central pharmacology lesson: EE is **not** "100x more estrogenic" — it is "100x more *hepatically* estrogenic per mole." Drives VTE, gallstones, lipid effects, and the SHBG signature people sometimes still mistake for "high estrogen." --- ## C. Specific dosing scenarios — expected steady-state plasma EE concentration Population-average values; individual variability is enormous (CV 30-50% on every parameter). Sources: Devineni 2007 (PMC4285808), Klipping 2012 (PMC3632974), Schramm/Heinemann (Yasmin label, NDA 21098), Stanczyk 2013, Goldzieher 1990, Vinerean 2014. ### 1. 20 microg/day EE in modern COC (Loestrin, Alesse, Yaz) ``` EE_20_Cmax_total = 60 # pg/mL (range 38-85; Klipping 2012, Devineni 2007 = 59.6 pg/mL) EE_20_Cmin_total = 13 # pg/mL (range 10-22; Klipping = 10.5, Devineni = 12.9) EE_20_Cavg_total = 25 # pg/mL (Devineni = 25.5; AUC0-24 ~600 pg*h/mL) EE_20_Tmax = 1.5 # h EE_20_AUC_ss = 600 # pg*h/mL/day (Klipping median 808; Devineni 611) ``` For reference: this Cavg of ~25 pg/mL is **similar to physiologic E2 mid-follicular**, but binds essentially zero SHBG, so total estrogenic stimulus of peripheral receptors is modest while hepatic stimulus is ~5x larger than a 4 mg oral E2 dose would give. ### 2. 30 microg/day EE in COC (Yasmin, Microgynon, Marvelon) ``` EE_30_Cmax_total = 95 # pg/mL (range 60-140; Yasmin label ~95, Microgynon ~77, # Marvelon (desogestrel) reports 136) EE_30_Cmin_total = 20 # pg/mL (range 13-25; Yasmin label ~20) EE_30_Cavg_total = 40 # pg/mL (AUC0-24 ~900-1000 pg*h/mL) EE_30_Tmax = 1.5 # h EE_30_AUC_ss = 950 # pg*h/mL/day (population mean, Yasmin label) ``` Steady-state Cmax is **~1.5x first-dose Cmax** due to accumulation (Yasmin label: 1.5-2x AUC accumulation factor; this is the deep-compartment / SHBG-rise / SHBG-binds-EE-weakly feedback). ### 3. 50 microg/day EE in older COC (Ovral, original Enovid era) ``` EE_50_Cmax_total = 180 # pg/mL (Goldzieher 1990: ~201 pg/mL peak after 50 microg EE # + norgestrel single dose; multi-dose ~150-200) EE_50_Cmin_total = 35 # pg/mL (scaled from 30 microg data, not always reported) EE_50_Cavg_total = 70 # pg/mL EE_50_AUC_ss = 1675 # pg*h/mL/day (Lorbek 2018 PBPK simulation) ``` Note: dose-proportionality of EE is approximately linear in the 20-50 microg range (Stanczyk 2013, Goldzieher 1990). ### 4. Free EE concentration vs total With ~98% albumin binding and ~0% SHBG binding: ``` EE_free_fraction = 0.02 # 2% EE_20_Cavg_free ~ 0.5 pg/mL EE_30_Cavg_free ~ 0.8 pg/mL EE_50_Cavg_free ~ 1.4 pg/mL ``` Critically, **unlike E2, the free fraction of EE does not change when SHBG rises**, because EE doesn't bind SHBG. So as a COC drives SHBG up 2-4x, the free E2 endogenous (or exogenous-E2) fraction crashes, but free EE stays the same. This is why EE retains biological activity even while suppressing endogenous E2 to near-castrate levels. --- ## D. Other things to know ### Why is EE clinically out of favor for trans HRT? 1. **VTE risk.** Oral EE roughly **doubles VTE risk vs. oral E2** at equivalent uterotrophic doses (and is far worse than transdermal E2). In trans-women cohorts the older EE-based regimens drove the high VTE rates seen in van Kesteren 1997 (Amsterdam cohort). 2. **No way to bypass first pass.** No commercially available transdermal or injectable EE in HRT formulations (only as a contraceptive patch, see below) — so the disproportionate hepatic estrogen exposure is intrinsic to its use. 3. **Unresponsive to monitoring.** Standard E2 immunoassays don't measure EE. Clinicians cannot use the usual E2 levels to titrate, and EE-specific assays are rarely available outside research. 4. **No fertility/feminization advantage.** EE is not more "feminizing" than E2 at the ER; the receptor sees essentially the same potency. The hepatic over-stimulation is purely downside. 5. **Drug interactions.** EE is a strong inhibitor of SULT1A1 and CYP3A4 substrates; inducers (carbamazepine, rifampicin, St John's wort) dramatically reduce levels. WPATH SOC8 and Endocrine Society 2017 guidelines explicitly recommend against EE in trans HRT and recommend transdermal or oral 17beta-estradiol instead. ### VTE risk: COC vs. HRT Approximate per-10,000-woman-year absolute VTE rates (Stegeman 2013, ASH 2024): ``` no exposure ~ 1-5 oral E2 HRT (menopause) ~ 9-15 (RR ~1.5-2 vs none) transdermal E2 HRT ~ 5 (RR ~1, ~ baseline) COC: EE + LNG (Microgynon) ~ 5-7 (lowest among EE COCs; RR ~2.3) COC: EE + desogestrel/gestodene ~ 9-12 (RR ~4) COC: EE + drospirenone (Yasmin) ~ 10-12 (RR ~4) COC: E2-valerate + dienogest (Qlaira) ~ 4-6 (closer to natural-E2 HRT) old high-dose EE (>50 microg) COC ~ 15-20+ (historical) ``` So a "standard" 30 microg EE pill carries ~**3x the VTE risk of oral E2 HRT** and ~**5-10x the risk of transdermal E2**. The progestin matters (LNG safest, drospirenone worst), but the estrogen choice (EE vs E2-valerate) is at least as important. ### Sublingual / transdermal EE — does it exist? - **Sublingual EE:** Exists pharmacologically (Englund/Hellman 1983 used a sublingual paper disc 12.5 microg in ovariectomized women, and got higher peak FSH suppression and cervical mucus effects than the same oral dose — implying ~2-5x effective bioavailability). However, **no commercial sublingual EE product is marketed**. Compounded sublingual EE is rare. - **Transdermal EE:** Yes — only in combined contraceptive patches: - **Ortho Evra / Xulane** (EE + norelgestromin; ~20 microg/day EE systemic) - **Twirla** (EE + levonorgestrel; ~30 microg/day EE systemic) - **EE + gestodene** patches (Europe; ~13-21 microg/day) Transdermal EE patches reduce Cmax but produce **comparable or higher AUC** than oral COCs because they bypass first-pass entirely — and notably **they do not reduce VTE risk** vs. oral COCs (Ortho Evra had a higher-VTE black-box warning). This is consistent with the EE hepatic-disproportion mechanism being driven by EE's **intrinsic resistance to hepatic inactivation**, not by first-pass concentration: once EE reaches the liver via portal or systemic blood, it persists. There is **no transdermal EE marketed for menopausal HRT** anywhere I can find. --- ## Sources used (primary) 1. Stanczyk FZ, Archer DF, Bhavnani BR (2013). *Ethinyl estradiol and 17beta-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment.* Contraception 87(6):706-727. PMID 23375353. 2. Kuhl H (2005). *Pharmacology of estrogens and progestogens: influence of different routes of administration.* Climacteric 8(Suppl 1):3-63. PMID 16112947. 3. Lorbek G et al. (2018). *Risk-benefit assessment of ethinylestradiol using a physiologically based pharmacokinetic modeling approach.* PMC6282492. 4. Klipping C et al. (2012). *Characterisation of the pharmacokinetics of ethinylestradiol and drospirenone in extended-cycle regimens: population pharmacokinetic analysis.* PMC3632974. 5. Devineni D et al. (2007 / Vinerean 2014). *Pharmacokinetic overview of ethinyl estradiol dose and bioavailability using two transdermal contraceptive systems and a standard combined oral contraceptive.* PMC4285808. 6. Goldzieher JW (1990). *Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinical implications.* Am J Obstet Gynecol 163(1 Pt 2):318-22. PMID 2196804. 7. Stegeman BH et al. (2013). *Effect of ethinylestradiol dose and progestagen in combined oral contraceptives on plasma SHBG levels.* J Thromb Haemost 11(1):203-205. 8. Rodrigues AD et al. (2022). *Drug interactions involving 17alpha-ethinylestradiol: considerations beyond CYP3A induction and inhibition.* Clin Pharmacol Ther 112(1):69-90. 9. Schrag ML et al. (2004). *Sulfotransferase 1E1 is a low-Km isoform mediating the 3-O-sulfation of ethinyl estradiol.* Drug Metab Dispos. 10. Wikipedia: *Pharmacokinetics of estradiol*, *Ethinylestradiol*, *Feminizing hormone therapy* (well-referenced summary articles, used as index into primary sources). 11. FDA labels: Yasmin (NDA 021098), Yaz (NDA 021676), Alesse (NDA 020683), Microgynon (DailyMed levonorgestrel/EE tablets). 12. ASH 2024 Hematology Education Program: *Estrogen, progestin, and beyond: thrombotic risk and contraceptive choices.* 13. Aly Hormones / Transfeminine Science writeups (used for trans-HRT context and route discussion, not for primary PK numbers). ## Where sources disagree (flags for the modeler) - **Bioavailability**: 38-48% (most common) vs. as low as 20% in high-CYP3A4 metabolizers; use 45% mean but model IIV at >= 30% CV. - **Volume of distribution**: 24 L (central, pop-PK) vs. 280 L (apparent total) vs. 4 L/kg (PBPK Vss). Choose based on compartment count in your model. - **Half-life**: 7-36 h reported in literature; central tendency for steady state is ~17-20 h. - **MCR**: poorly characterized; CL_iv * 24 = ~400 L/day is the best estimate, vs. E2's ~1500. - **SHBG induction potency relative to E2**: 75 to 1000x in the Kuhl table depending on which hepatic protein you measure; ~100x is the median value cited. - **30 microg EE Cmax**: studies report 60-140 pg/mL; the progestin and the assay matter (RIA vs. LC-MS gives ~30% differences). Use ~95 pg/mL central.