# Independent fact-check: estradiol pharmacokinetics and related claims

Reviewed 2026-05-14. I prioritized primary papers and PubMed-indexed reviews; when a number is mainly traceable to secondary compendia or older tracer studies, I mark it accordingly.

## Group 1 — Thermodynamics & enzyme kinetics

1. ⚠️ **Approximately right, but I could not verify a primary source for the exact E°' value.** The `-0.25 to -0.275 V` value is chemically plausible for the estrone/estradiol alcohol/ketone couple relative to NAD+/NADH, but I did not find a primary electrochemical paper giving a physiological formal potential for `E1 + 2H+ + 2e- <=> E2`. Treat it as an inferred/compiled biochemical value unless the original source is produced. The relevant comparator is NAD+/NADH at about `-0.320 V` under biochemical standard conditions, but that does not by itself prove the estrone value.

2. ✅ **Confirmed.** Williamson, Lund, and Krebs calculated the mean free cytoplasmic `[NAD+]/[NADH]` ratio in rat liver as `725` in fed rats, `528` in starved rats, and `208` in alloxan-diabetic rats. This is still repeatedly cited as a canonical estimate for free cytosolic redox state, although it is rat liver and inferred from metabolite indicator systems, not a direct human hepatocyte measurement. PMID: [4291787](https://pubmed.ncbi.nlm.nih.gov/4291787/).

3. ⚠️ **Approximately right, but fragile.** If `E°' E1/E2` is near `-0.26 V` and free cytosolic `[NAD+]/[NADH]` is about 700, the Nernst calculation gives an E1/E2 ratio in the rough single-digit to tens range; using `-0.260 V` gives about 6, while `-0.275 V` gives about 20. So `~11` is a plausible midpoint, not a measured cellular ratio, and it depends strongly on the unverified formal potential and pH/proton convention. Source anchor for NAD ratio: Williamson et al., 1967, PMID: [4291787](https://pubmed.ncbi.nlm.nih.gov/4291787/).

4. ⚠️ **Approximately right, but the exact range is shaky.** Human 17β-HSD type 2 is a microsomal oxidative enzyme, and in-vitro apparent Km values for estradiol are submicromolar-to-low-micromolar depending on preparation and assay. The original expression-cloning characterization is commonly summarized with estradiol Km around `0.2 uM`, while some tissue microsomal assays report values around `~2 uM`; therefore `1-5 uM` is plausible for some crude/tissue systems but too high as a blanket value for recombinant HSD17B2. Expression cloning: PMID [8099587](https://pubmed.ncbi.nlm.nih.gov/8099587/); kinetic summary: [LIPID MAPS HSD17B2](https://lipidmaps.org/databases/lmpd/LMP000023).

5. ✅ **Confirmed.** Human SULT1E1 is the high-affinity estrogen sulfotransferase, with low-nanomolar apparent Km values for estrogens; reviews and pharmacogenomic work explicitly describe it as having the lowest Km values among human SULTs for estrogens/catechol estrogens. Values near `5-20 nM` are repeatedly reported, much lower than typical UGT estrogen glucuronidation affinities. PMID: [12922923](https://pubmed.ncbi.nlm.nih.gov/12922923/); review: [PMC7923650](https://pmc.ncbi.nlm.nih.gov/articles/PMC7923650/).

6. ✅ **Confirmed.** SULT1E1 shows substrate inhibition by estradiol/estrone at higher substrate concentrations, with maximal activity reported around low-nanomolar to ~20 nM substrate in classic enzyme work. The exact "peak at 20 nM" is assay-dependent, but the qualitative substrate inhibition claim is real. Review summary: [PMC3866684](https://pmc.ncbi.nlm.nih.gov/articles/PMC3866684/); SULT1E1 mechanism paper DOI: [10.1021/bi902190r](https://doi.org/10.1021/bi902190r).

## Group 2 — Estradiol PK

7. ✅ **Confirmed.** Modern reviews and drug references still give oral estradiol systemic bioavailability as low because of first-pass intestinal/hepatic metabolism, usually around `~5%` with a broad range around `2-10%` and occasional lower estimates. The exact `0.1-10%` range is wider than most clinical summaries, but the central `~5%` consensus is sound. Review: Kuhl 2005, Climacteric, PMID [16112947](https://pubmed.ncbi.nlm.nih.gov/16112947/); PubChem/drug-source summary: [PubChem estradiol](https://pubchem.ncbi.nlm.nih.gov/compound/Estradiol).

8. ⚠️ **Approximately right.** Unesterified estradiol has a short distribution/elimination half-life after non-oral administration, often cited as roughly `1-2 h` or even `10-70 min` depending on phase and method; estrone sulfate is much longer, about `10-12 h`. The direction and order of magnitude are correct, but "free E2 half-life" is not a single clean constant because protein binding, redistribution, enterohepatic recycling, and assay design matter. Estrone sulfate half-life summary: [NCBI/PubChem estradiol](https://pubchem.ncbi.nlm.nih.gov/compound/Estradiol); older E1S metabolism: Longcope/Williams literature summarized in [ScienceDirect topic](https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/estrone-sulfate).

9. ✅ **Confirmed.** Oral estradiol has a longer terminal/apparent half-life, commonly `~13-20 h`, because estrone/estrone sulfate and other conjugates form a circulating reservoir that can be hydrolyzed back to active estrogens. This is widely repeated in PK reviews and product summaries and is mechanistically consistent with enterohepatic recirculation. Review: Kuhl 2005, PMID [16112947](https://pubmed.ncbi.nlm.nih.gov/16112947/); drug-source summary: [PubChem estradiol](https://pubchem.ncbi.nlm.nih.gov/compound/Estradiol).

10. ⚠️ **Approximately right.** The often-cited 1 mg sublingual estradiol peak around `~144 pg/mL` at about `30 min` appears traceable to small older PK studies, and rapid decline is well supported. Absolute bioavailability around `~25%` is much shakier; some sources infer "about 5-fold oral" rather than directly measuring it in modern human trials. The peak/timing claim is plausible; the bioavailability number should be treated as approximate. See sublingual/buccal PK discussion in Kuhl 2005, PMID [16112947](https://pubmed.ncbi.nlm.nih.gov/16112947/), and transgender estradiol profile data: Cirrincione et al. 2021, DOI [10.1089/lgbt.2020.0249](https://doi.org/10.1089/lgbt.2020.0249).

11. ⚠️ **Approximately right.** Estradiol metabolic clearance rate near `~1,400 L/day` is a classic tracer-study value and is consistent with high hepatic/extrahapatic clearance; estrone sulfate clearance around `~150-170 L/day` is also in the right range. These are older isotope-derived values, not modern LC-MS/MS clinical PK constants, so I would not overfit the exact numbers. Estrone sulfate production/metabolism: Longcope and Williams 1974 summarized at [ScienceDirect](https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/estrone-sulfate); related classic estrogen production/clearance data in Endotext table: [NCBI Bookshelf](https://www.ncbi.nlm.nih.gov/books/NBK279054/table/female_the-normal-menstrual-cycle-and-the-control-of-ovulation.T/).

12. ⚠️ **Approximately right, but "80 ug/day" is too neat.** Postmenopausal estrone is mainly produced by peripheral aromatization of androstenedione in adipose and other tissues. However, sources give averages more like `~40-100 ug/day` and obesity changes the value, so `80 ug/day` is plausible but not a universal constant. NCBI Bookshelf/Holland-Frei states the pathway; note its text appears to contain a unit typo ("100 mg" where the physiology implies micrograms): [Biology of Aromatase](https://www.ncbi.nlm.nih.gov/books/NBK12904/). Older clinical summary gives `~55 ug/24 h`: [Current Diagnosis & Treatment OB/GYN excerpt](https://doctorlib.org/gynecology/current-diagnosis-treatment-obstetrics-gynecology/59.html).

13. ⚠️ **Approximately right.** Estrone sulfate is well supported as the most abundant circulating estrogen in nonpregnant women, but the ratio varies by cycle phase and comparator. Hawkins/Oakey-type data report mid-cycle E1S about `5x` estradiol and `20x` estrone; other reviews say `5-10x` unconjugated estrogens or `~10x` estrone. So `10-25x total E1+E2` is likely too high as a general statement, though the "most abundant" part is correct. Review: [JNCI Monographs 2000](https://academic.oup.com/jncimono/article/2000/27/113/934445); topic summary citing Hawkins and Oakey 1974: [ScienceDirect](https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/estrone-sulfate).

14. ⚠️ **Approximately right, with mismatched labels.** Modern premenopausal data support follicular total estradiol around `~45-50 pg/mL`, estrone around `~40-50 pg/mL`, and estrone sulfate roughly `~650-1,000 pg/mL`; however, "free E2 ~50" is wrong if "free" means unbound, because measured free estradiol is about `~0.6 pg/mL`. Term pregnancy total estradiol in the tens of thousands pg/mL and estrone sulfate around `~50,000-100,000 pg/mL` are plausible, but exact values vary widely by gestational week and assay. Premenopausal LC/MS-type cohort: [PMC5718047](https://pmc.ncbi.nlm.nih.gov/articles/PMC5718047/). Pregnancy/endocrine overview: [Endotext](https://www.ncbi.nlm.nih.gov/books/NBK278962/).

15. ⚠️ **Approximately right, but not a directly established q5d average.** A single 5 mg IM estradiol valerate injection in oil peaks much higher than 200 pg/mL, roughly `400-650 pg/mL` around day 2 in classic PK work, then declines over about a week. Repeated 5 mg every 5 days could average around the low hundreds to several hundred pg/mL depending on absorption and assay, but `~200 pg/mL average` is a modeling/clinical-rule estimate, not something I found as a primary q5d trial result. Oriowo et al. 1980, PMID [7389356](https://pubmed.ncbi.nlm.nih.gov/7389356/); DailyMed label: [Delestrogen](https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e8f94df9-0692-4462-a7f0-fe019a0a3f07).

## Group 3 — Hepatic estrogen receptor & SHBG dynamics

16. ❌ **Wrong citation and overstated.** Yager & Williams 1989 Cancer Research does not appear to be the source of a hepatic ER-alpha Kd of exactly `0.25 nM`; the human liver ER papers I found report hepatic estrogen binding with Kd values around `10^-10 M` for DES or `4.7 x 10^-10 M` for estrogen binding in crude cytosol. Recombinant human ER-alpha does have E2 Kd around `0.2 nM`, so the number is plausible for ER-alpha generally, but the claimed paper/source is not verified. Human liver ER: PMID [6825981](https://pubmed.ncbi.nlm.nih.gov/6825981/) and PMID [2925054](https://pubmed.ncbi.nlm.nih.gov/2925054/). Recombinant ER-alpha comparative binding: PMID [19022364](https://pubmed.ncbi.nlm.nih.gov/19022364/).

17. ⚠️ **Approximately right.** Female SHBG is commonly in the tens of nmol/L, often `~40-120 nmol/L` depending on lab, age, hormones, and pregnancy status; estradiol binding affinity to SHBG is around low-nanomolar but weaker than testosterone/DHT. Pregnancy raises SHBG several-fold, oral estradiol raises SHBG strongly while transdermal estradiol often does not, and the `67-171%` increase is real but from Ropponen et al. 2005 JCEM, not Lindberg 2003. Ethinyl estradiol/combined OCs can raise SHBG by ~2.5- to 4-fold depending on formulation. Ropponen et al. DOI [10.1210/jc.2005-0352](https://doi.org/10.1210/jc.2005-0352); OC SHBG: PMID [3056190](https://pubmed.ncbi.nlm.nih.gov/3056190/); steroid-binding review: [PMC5064763](https://pmc.ncbi.nlm.nih.gov/articles/PMC5064763/).

18. ❌ **Wrong / not defensible as a clean rule.** Hepatic estrogen effects are not governed by a binary plasma threshold at one ER-alpha Kd; receptor occupancy is graded, liver exposure differs by portal vs systemic route, metabolites matter, and ER transcriptional effects depend on time, dose, route, and hepatic extraction. Transdermal estradiol can have hepatic effects at sufficient systemic levels, while oral estradiol can have disproportionate hepatic effects at modest systemic E2 because of first pass. The Kd value is useful for intuition, not a clinical rule for "genuinely avoid hepatic estrogen effects." Route-dependent hepatic effects and SHBG/CRP examples: Ropponen et al. DOI [10.1210/jc.2005-0352](https://doi.org/10.1210/jc.2005-0352); transdermal vs oral VTE/hepatic biomarker literature summarized in Olie/Canonico/Scarabin, PMID [20601871](https://pubmed.ncbi.nlm.nih.gov/20601871/).

## Group 4 — VTE / clinical

19. ⚠️ **Approximately right, but oral risk was understated.** ESTHER found adjusted OR for VTE of `4.2` for current oral estrogen users and `0.9` for transdermal estrogen users versus nonusers. Later pooled observational estimates often put oral menopausal estrogen around `~2-4x` and transdermal near null (`~1.0-1.2`), so "transdermal essentially baseline" is supported, but "oral E2 HRT ~2x" is lower than ESTHER's own estimate. Canonico et al. 2007 Circulation, PMID [17309934](https://pubmed.ncbi.nlm.nih.gov/17309934/).

20. ✅ **Confirmed.** Combined oral contraceptives increase VTE risk by about `3-4x` overall, with variation by estrogen dose and progestin type. A BMJ network meta-analysis found RR `3.5` with 95% CI `2.9-4.3`. BMJ 2013: [PMC3771677](https://pmc.ncbi.nlm.nih.gov/articles/PMC3771677/); PMID [24030561](https://pubmed.ncbi.nlm.nih.gov/24030561/).

21. ⚠️ **Approximately right.** Pregnancy and postpartum VTE risks are clearly increased, with the postpartum period much higher than antepartum; CDC currently summarizes pregnancy as about `5-fold` overall. Literature estimates differ by reference population and time window, with postpartum risk often cited as `~20-fold` or higher in the first 6 weeks and highest immediately after delivery. The exact `3x antepartum, 9x third trimester, 20-25x postpartum` set is plausible but not a single universal estimate. CDC: [Pregnancy and blood clots](https://www.cdc.gov/blood-clots/risk-factors/pregnancy.html); review/example: Sultan et al., Blood 2014, DOI [10.1182/blood-2014-05-572834](https://doi.org/10.1182/blood-2014-05-572834).

22. ⚠️ **Real finding, overinterpreted if stated as equivalent VTE risk.** Bar On et al. 2024 reported interim pilot data that low-dose sublingual estradiol in treatment-naive trans women decreased free protein S, creating a "potentially pro-thrombotic profile." That supports concern that sublingual is not automatically benign for coagulation, but it does not prove clinical VTE risk is similar to oral estradiol; it is an abstract-level biomarker study, not an outcomes study. Journal of the Endocrine Society abstract DOI [10.1210/jendso/bvae163.1629](https://doi.org/10.1210/jendso/bvae163.1629); related ECE pilot abstract: [Endocrine Abstracts ECE2023 P182](https://www.endocrine-abstracts.org/ea/0090/ea0090p182).

## Bottom line

The strongest confirmed claims are the Williamson cytosolic NAD ratio, low-nanomolar SULT1E1 affinity/substrate inhibition, low oral estradiol bioavailability, estrone sulfate reservoir/longer apparent oral half-life, transdermal-vs-oral VTE distinction in ESTHER, and combined-OC VTE risk. The weakest claims are the exact estrone/estradiol formal potential, the derived `E1/E2 = 11` precision, the exact hepatic ER-alpha `0.25 nM` citation, and the "below hepatic ER Kd avoids hepatic effects" rule. Several round numbers (`80 ug/day`, `150 pg/mL threshold`, `5 mg q5d = 200 pg/mL`) are best treated as rough heuristics rather than primary facts.