From Doisy's 1929 isolation of estrone to Tebbens 2022 finding that estrone is not associated with breast development in 212 trans women — every paper that built or undermined the "estrogen sulfate reservoir" framing, with verbatim quotes from primary literature, contestation noted, and a candid audit of community lore that overstates the evidence.
Yes, in two distinct forms. Plasma-level back-conversion was quantified by Ruder, Loriaux & Lipsett 1972 at ρ = 0.014 for E₁S → E₂ and ρ = 0.21 for E₁S → E₁. Tissue-level intracrine conversion via STS → HSD17B1 is documented in postmenopausal breast cancer tissue (Pasqualini 1996; Reed 2005) but is much weaker in normal adult breast (Lønning 2015) and has not been measured directly in trans-feminine breast tissue.
Yes — multiple times across 54 years. Ruder 1972 (IV + oral in 2 subjects), Longcope 1972 (IV in men), Schindler 1982 (pure oral E₁S vs E₁ vs E₂ vs Premarin head-to-head), Englund 1990 (piperazine E₁S vs oral E₂V head-to-head), the Bhavnani 1981–2000 Premarin program, and many Premarin / Ogen / Estropipate PK studies in postmenopausal women. What still does not exist: a modern LC-MS/MS PK study of pure oral E₁S in trans-feminine subjects. Doll 2022, the only modern trans LC-MS/MS PK study, deliberately did not measure E₁S.
The dispositive trans cohort data so far says no. Tebbens et al. 2022 (ENIGI, n=212): "Change in fat percentage and breast development in trans women were not associated with estrone concentrations nor with administration route." Oral users had ~8× the E₁ of transdermal users; breast volume changes were 62 vs 69 mL — statistically identical. E₁S itself was not measured in the cohort, but if its proximal product (E₁) does not predict outcomes, the strong-form reservoir argument loses most of its force.
Color band on the left maps to era. Every event card has a year, the primary paper or milestone, a verbatim quote where one was retrievable from the abstract or accessible text, and a "contemporary context" line noting what was contested or what the surrounding discussion looked like.
Allen E, Doisy EA. JAMA 81:819. [QUOTE UNAVAILABLE — JAMA archive paywall]
The "estrus-producing hormone" gets a quantitative bioassay (the Allen-Doisy test). Becomes the standard for hunting and purifying estrogens through the late 1930s.
Doisy EA, Veler CD, Thayer SA. Am J Physiol 90:329–330 (Aug). Butenandt A. Naturwissenschaften 17:879 (Nov–Dec).
Initially called "theelin" (Doisy) and "Progynon" (Butenandt). Doisy presented in Boston first; Butenandt printed first. The priority dispute is real and contemporaneous, not retroactive.
Butenandt later: "I was beaten to publicity, not to science." Butenandt receives the 1939 Nobel; Doisy receives the 1943 Nobel (for vitamin K).
Marrian GF. Biochem J 24:435. [QUOTE UNAVAILABLE — PMC image-only]
The third major natural estrogen is identified. Marrian becomes the dominant figure in conjugate chemistry through the 1930s–40s.
Cohen H, Marrian GF. Biochem J 28:1603 (1934); subsequent papers through 1936.
The acid-hydrolysis methodology that lets urinary estrogens be cracked open. The presence of glucuronide and sulfate conjugates is established. The dominant interpretation: conjugation is an inactivation step — the body's way of preparing estrogens for excretion.
This framing — conjugates as terminal end-products, not active reservoirs — will dominate clinical thinking for 30+ years.
MacCorquodale DW, Thayer SA, Doisy EA. J Biol Chem 115:435. [QUOTE UNAVAILABLE — JBC archive 403]
Earlier urinary work had suggested estrone was the primary estrogen. The sow-ovary work demonstrates that what the ovary actually secretes is estradiol, and estrone is a metabolite. Reframes the picture: E₂ is the source, E₁ is downstream.
Schachter B, Marrian GF. J Biol Chem 126:663. [QUOTE UNAVAILABLE — JBC archive 403]
The foundational identification of estrone-3-sulfate as a distinct chemical entity. The mare's urine context is not accidental — the high concentration in pregnant-mare urine is what makes purification tractable. This paper enables Premarin four years later.
Ayerst (Canada 1941 → US 1942). Wyeth historical documentation.
An oral menopause-symptom drug, mostly E₁S by mass, with additional equilin sulfate, equilenin sulfate, and Δ⁸-E₁-sulfate. Clinically deployed in millions of women decades before the "E₁S as reservoir" framing is formalized.
Throughout the 1950s–60s, the dominant mental model in the menopause-medicine community is that Premarin works because some conjugates get hydrolyzed to active estrogens during/after absorption — but the kinetic picture is hand-waved until Bhavnani's 1980s program.
Szego CM, Roberts S. Recent Prog Horm Res 1948. Sandberg AA, Slaunwhite WR. J Clin Invest 36:1266 (1957). [QUOTE UNAVAILABLE — PMC image-only]
Szego/Roberts solidify the "liver inactivates estrogens via conjugation" view. Sandberg & Slaunwhite begin documenting enterohepatic recirculation of conjugates, which is the first hint that conjugates aren't strictly terminal.
Tait JF. JCEM 1963. Gurpide E, Mann J, Lieberman S. JCEM 23:1155 (1963).
The mathematical machinery — transfer constant ρ, blood production rate, metabolic clearance rate (MCR) — that all subsequent steroid kinetic studies use. The "no return" axiom (radiolabel doesn't recycle back to the pool it came from) makes the math tractable at the price of being slightly wrong at the tissue level.
Longcope C, Layne DS, Tait JF. J Clin Invest 47:93.
Free E₁ MCR ~1990 L/day/m²; free E₂ MCR ~1600 L/day/m². E₂ → E₁ transfer constant ~15%; E₁ → E₂ ~5%. The kinetics of unconjugated estrogen interconversion are pinned down.
Abbott Laboratories NDA. Marketed as Ogen.
A second oral E₁S product joins Premarin. Unlike CEE, Ogen is "clean" — just E₁S as a piperazine salt, no equine extras. Subsequent PK studies of estropipate become the cleanest data on what oral E₁S itself does to serum.
Hembree WC et al. JCEM 1969.
In tritiated-estrogen infusion studies, some radiolabel ends up in a slowly-equilibrating compartment that doesn't fit the free-E₁/E₂ kinetics. Hembree suspects but doesn't identify the responsible species. Ruder 1972 will demonstrate it's E₁S.
Ruder HJ, Loriaux DL, Lipsett MB. J Clin Invest 51:1020–1033. DOI 10.1172/JCI106862.
IV-infused radiolabeled E₁S in 5 men + 6 women; also orally administered to 2 subjects. Measures the three numbers that the entire modern conversation runs on.
MCRE1S = 157 L/day. About 1 in 70 plasma E₁S molecules makes it to plasma E₂; about 1 in 5 makes it to E₁. Oral and IV behave kinetically the same way.
This 1.4% number has never been re-measured by modern LC-MS/MS in the 54 years since. It is the single most-cited transfer factor in the entire estrogen-pharmacology literature.
Longcope C. J Clin Endocrinol Metab 34:113–122. DOI 10.1210/jcem-34-1-113.
Same year, independent cohort, slightly different numbers. ρE1S→E1 = 0.15 (95% CI 0.12–0.18); ρE1S→E2 = 0.022–0.044 in two subjects. MCR ~90 L/day/m².
Already in 1972, the "1.4% back-conversion" number has 1.5–3× scatter when measured in a different cohort. Modern reviews that cite "ρ = 0.014" as if it's a settled physical constant are doing the literature a small injustice.
Grodin JM, Siiteri PK, MacDonald PC. JCEM 36:207.
Establishes that postmenopausal estrogen comes substantially from peripheral aromatization of androstenedione, not just ovarian secretion. The systemic-pool model is supplemented with a tissue-source model.
Yen SSC, Martin PL, Burnier AM, Czekala NM, Greaney MO, Callantine MR. JCEM 40:518.
Peak E₂ 110 pg/mL at 5 h; peak E₁ 467 pg/mL at 6 h. E₁:E₂ ratio 3–6 (vs < 1 by IV). The textbook oral-vs-IV asymmetry — first-pass hepatic metabolism inflates E₁ — is empirically nailed down.
Webster D, France JT, Shapiro LJ, Weiss R. Lancet 1978.
A skin disease turns out to be a steroid-sulfatase enzyme defect on the X chromosome. The STS gene gets a chromosomal address. Sets up the 1987 cloning.
Bhavnani BR et al. JCEM 1981, 1983, 1989; J Soc Gynecol Investig 2000.
A 20-year program of CEE PK. 1981: oral vs IV Premarin; PO peak E₁ 1.4 ng/mL at 5 h (vs IV peak 11.2 ng/mL at 20 min). 1983–1989: dual-isotope ([³H]equilin-[³⁵S]sulfate) work demonstrates that some orally administered sulfate survives intact through the gut wall, while some is hydrolyzed first and re-sulfated post-absorption. "Oral E₁S" is two parallel kinetic routes, not one.
Schindler AE, Bolt HM, Zwirner M, Hochlehnert G, Göser R. Arzneim-Forsch 1982.
At equimolar doses (9.74 µmol of each), conjugated estrogens — including pure E₁S — produce a "much more protracted influx of oestrogens from the intestine into the plasma compartment," with a clear second-bump enterohepatic recirculation event at 10–12 hours. Free E₁ gives the highest serum E₁/E₂ ratio. This is the closest 1980s reference for "what does oral pure E₁S look like in serum" — and it shows the protracted, smoothed profile that the reservoir framing predicts.
Santner SJ et al. JCEM 1984.
The first quantitative demonstration that breast tumor tissue runs its own E₁S → E₂ chain locally. Sulfatase activity in tumor >> aromatase activity, suggesting most tumor E₂ comes from the conjugate pool, not from in-tumor androgen aromatization. The first crack in the "systemic pool only" model.
This breast-cancer-tissue finding will be heavily cited and over-generalized for the next 30 years.
Yen PH, Allen E, Marsh B, Mohandas T, Wang N, Taggart RT, Shapiro LJ. Cell 49:443–454. PMID 3471362.
Steroid sulfatase becomes a defined gene product, not just an enzyme activity. The molecular era of intracrine biology begins.
Labrie F. Mol Cell Endocrinol 78:C113–C118. PMID 1838014.
A new framework: in many tissues, local enzymes — not just plasma steroid concentration — set the active hormone concentration that the receptor sees. Endocrine (gland → blood → target) vs paracrine (cell → adjacent cell) vs intracrine (within-cell synthesis from circulating precursors).
Initially controversial; gradually adopted as the standard framing for postmenopausal estrogen biology, prostate androgen biology, and the breast-cancer sulfatase-inhibitor program.
Howarth NM, Purohit A, Reed MJ, Potter BVL. J Med Chem 1994.
Estrone 3-O-sulfamate — an irreversible STS inhibitor. The starting point of the Reed/Purohit Imperial College London STS-inhibitor program. The therapeutic logic: if breast tumor STS supplies most of tumor E₂ from the E₁S reservoir, disabling STS should be therapeutic.
Pasqualini JR, Chetrite G, Blacker C, et al. JCEM 1996.
Massive enzyme-activity ratio in tumor tissue. Becomes the quantitative anchor for the "the intracrine pathway dominates" framing in breast cancer.
Quantitative anchor for the strong-form reservoir argument. Will be cited (often without the "in tumor tissue" qualifier) for decades.
Tamai I, Nezu J, Uchino H, Sai Y, Oku A, Shimane M, Tsuji A. Biochem Biophys Res Commun 2001.
E₁S doesn't passively cross cell membranes — it needs an organic-anion transporter. OATP1B1, OATP2B1 (OATP-B), OATP4A1 get characterized as the main carriers. A third rate-limiting step in the reservoir → E₂ chain (after STS hydrolysis and HSD17B1 reduction): the steroid has to get into the cell first.
Reed MJ, Purohit A, Woo LWL, Newman SP, Potter BVL. Endocr Rev 26:171–202. DOI 10.1210/er.2004-0003.
The standard reference for the molecular biology of STS, its regulation, its tissue distribution, and the rationale for STS inhibitors. 200+ pages, extensively cited.
Kuhl H. Climacteric 8 Suppl 1:3–63. PMID 16112947.
Becomes the standard reference for oral / sublingual / transdermal / injectable PK comparison. Among other things, states that on oral 2 mg E₂V at steady state, "E₁ is 4–6× E₂; E₁S is about 200× E₂."
Stanway SJ et al. Clin Cancer Res 12:1585.
Reed/Purohit's lead compound reaches a phase I trial in advanced breast cancer. 98–99% tumor STS inhibition achieved. The strong-form intracrine model predicts substantial clinical benefit.
Peltoketo H, Isomaa V, Mäentausta O, Vihko R. FEBS Lett 239:73–77.
First cloning of an HSD17B from human placenta. 327-aa cytosolic protein. Prefers the reductive direction (E₁ → E₂). Concentrated in placenta and ovary. The "estrogen-activating" isoform.
Until this paper, "17β-HSD" was treated as a single enzyme. Now the field starts to grasp that it's a family.
Wu L, Einstein M, Geissler WM, Chan HK, Elliston KO, Andersson S. J Biol Chem 268:12964.
A distinct enzyme. Microsomal. Broader substrate range. Prefers oxidation (E₂ → E₁), the opposite direction. Expressed in liver, gut, secretory endometrium. The "estrogen-inactivating" isoform.
Miettinen MM, Mustonen MVJ, Poutanen MH, Isomaa VV, Vihko RK. Biochem J 314:839.
Whether a tissue runs E₁ → E₂ or E₂ → E₁ is set by which HSD17B isoform it expresses. Estrogen-target tissues (ER+ breast, ovary, endometrium) tend toward HSD17B1/7/12 (reductive); estrogen-inactivating tissues (liver, GI, placenta-fetal interface) tend toward HSD17B2/4/8 (oxidative). This is the fact that determines whether a high circulating E₁S pool actually produces local E₂ in any given tissue.
Geissler WM 1994 (HSD17B3); Adamski J 1995, 2001 (HSD17B4); Penning TM (AKR1C3 = HSD17B5); Luu-The 2006 (HSD17B12).
The "17β-HSD" field bifurcates by structural family — most are SDRs (short-chain dehydrogenase/reductase, NAD-preferring); HSD17B5 is an AKR (aldo-keto reductase, NADPH-preferring, cytosolic). The field is messy through ~2000.
Englund DE, Johansson EDB. Maturitas 1990.
8 postmenopausal women, crossover, 2.5 mg/day piperazine E₁S vs 2.0 mg/day estradiol valerate, 21-day arms.
Dose-for-dose, oral E₁S raises serum E₁ and E₁S more than oral E₂. The 21-day arm accumulated E₁S without saturation. Translation: if you actually want a big E₁S pool, oral E₁S is more efficient at building one than oral E₂ is.
Lobo RA, Cassidenti DL. J Reprod Med 37:77–84.
Crystallized the framing for menopause medicine. Premenopausal E₂:E₁ ~1:1; transdermal ~1:1; oral E₂ ~1:5, sometimes 1:20. Oral E₂ raises E₁S by 8–20× over premenopausal baseline. Oral E₂, oral E₂V, and oral E₁S/PE₁S/estropipate all converge on a similar first-pass-dominated serum fingerprint.
Price TM, Blauer KL, Hansen M, Stanczyk F, Lobo R, Bates GW. Obstet Gynecol 89:340. DOI 10.1016/S0029-7844(96)00513-3.
6 postmenopausal women, multiple doses of micronized E₂ given orally or sublingually, E₂ / E₁ / E₁S measured.
SL gave a 13× higher peak E₂ (451 vs 34 pg/mL for 1 mg). SL E₁:E₂ ratio was lower over 24 h. BUT E₁S correlated with dose, not route: at 4 hours, mean E₁S was 11.8 ng/mL after 1 mg SL. Sublingual administration did NOT avoid the E₁S pool.
This is the single most important fact for the "sublingual is just better" community claim. The Cmax narrative is right; the "avoids first-pass" narrative is partial — swallowed saliva delivers a substantial fraction through the gut anyway.
Bhavnani BR. Proc Soc Exp Biol Med 217:6–16.
The clearest published summary of what "oral E₁S as a drug" actually does in the body.
Slater CC, Hodis HN, Mack WJ, Shoupe D, Paulson RJ, Stanczyk FZ. Menopause 8:200–203. PMID 11355042.
Postmenopausal women, oral 1 mg E₂ daily for 16 months vs transdermal patches. Oral E₂ → serum E₁S 38.8 ng/mL at 15 months (RIA). Transdermal → 1.8–3.2 ng/mL. A ~10–20× difference at matched serum E₂.
This 38.8 ng/mL is the single most-cited "E₁S elevates a lot on oral E₂" number in the literature. Note: it is RIA. The Zumenon SmPC (LC-MS/MS-based) gives Cavg 5.28 ng/mL for the same 1 mg oral dose — a 7× discrepancy that has never been fully reconciled, and is almost certainly assay methodology.
Stanczyk FZ, Clarke NJ. J Steroid Biochem Mol Biol 2010; Rosner W et al., Endocrine Society position 2007 / 2013.
A wave of methodology critiques. Direct E₂ immunoassays are unreliable below ~50 pg/mL — useless at transdermal serum ranges. Median postmenopausal E₂ reference values differ by 6× across assays (Stanczyk 2007). Older RIA conjugate values, especially E₁S, are systematically biased high due to cross-reactivity.
Implication for everything before ~2010: numbers should be treated as approximations whose absolute calibration is uncertain. The Slater 2001 vs Zumenon SmPC discrepancy is the textbook example.
Wierckx K, Van Caenegem E, Schreiner T, et al. J Sex Med 11:1999.
The European Network for the Investigation of Gender Incongruence cohort begins publishing. For the first time, large trans-feminine HRT outcome data exists, with multiple routes (oral, transdermal, injectable), modern assays, and rigorous outcome tracking.
Lønning PE, Helle H, Duong NK, Ekse D, Aas T, Geisler J. PMID 25721699.
LC-MS/MS measurement of E₂ in normal breast tissue and matched serum in cycling women. Median tissue E₂ ≈ median serum E₂ (~30 pg/g vs ~30 pg/mL).
The strong-form intracrine framing inherited from breast-cancer-tissue literature does not generalize to healthy adult breast. Tissue does not concentrate E₂ above serum levels in normal physiology. The "tissue is 5–50× serum" community claim is a misapplied tumor-tissue number.
Palmieri C et al. — IRIS phase II trial of irosustat (STX-64) added to aromatase inhibitor.
Phase II in advanced postmenopausal breast cancer. STS inhibitor added to AI gives a clinical benefit rate of only 18.5%. The strong-form prediction — that disabling the E₁S reservoir would substantially augment AI therapy — is largely not borne out.
If the E₁S reservoir were as load-bearing in tumor biology as the 1980s–90s in-vitro work suggested, IRIS should have shown a much larger effect. The 2017 clinical signal is the strongest empirical pushback on the strong-form reservoir argument.
Tebbens M, Heijboer AC, T'Sjoen G, Bisschop PH, den Heijer M. J Clin Endocrinol Metab 107:e458. DOI 10.1210/clinem/dgab638. PMID 34632510.
Prospective 1-year ENIGI cohort, n=212 trans women, two arms: oral vs transdermal E₂.
Oral users had ~8× the E₁ of transdermal users. Breast development was 62 vs 69 mL volume change — statistically not different. E₁S itself was not measured. This is the dispositive trans-cohort paper for the "reservoir → feminization" claim.
The strong-form community claim — that high E₁S pools drive more breast growth or more feminization — is contradicted by the best trans data we have.
Doll EE, Shoger KE, Hooper MJ, Patel R, Tangpricha V, Sarvaideo JL. Endocr Pract 28:237. PMID 34781041.
10 trans women, 1 mg oral vs 1 mg SL E₂, LC-MS/MS. SL Cmax 144 vs PO 35 pg/mL; AUC₀-₈ ratio 1.8×; E₂:E₁ ratio 1.1 ± 1.0 (SL) vs 0.7 ± 0.4 (PO).
E₁S was not measured. The single biggest missed opportunity for the reservoir question in the modern era.
Cirrincione LR, Smith K, McAuley J, et al. PMC8859944.
The Beckman Access Sensitive Estradiol direct immunoassay under-reports E₂ by ~40% specifically in patients on oral E₂, almost certainly via estrone cross-reactivity. Pre-2022 "oral E₂ trough is low" clinical reports are systematically biased.
This is the explicit answer to "has E₁S been put into humans?" Compiled from era-05's deep dive. Multiple studies across 54 years — but no modern LC-MS/MS pure-oral-E₁S PK in trans-feminine subjects exists.
| Year | Authors / journal | Product | Route, dose | n | Key result |
|---|---|---|---|---|---|
| 1972 | Ruder, Loriaux, Lipsett / J Clin Invest | Radiolabeled E₁S | IV infusion + PO in 2 subjects | 11 + 2 | ρ E₁S→E₁ = 0.21; ρ E₁S→E₂ = 0.014; MCR 157 L/d; "essentially similar" oral vs IV |
| 1972 | Longcope / JCEM | Radiolabeled E₁S | IV infusion | males | ρ E₁S→E₁ = 0.15; ρ E₁S→E₂ = 0.022–0.044; MCR ~90 L/d/m² |
| 1975 | Yen et al. / JCEM | Oral micronized E₂ | PO 2 mg | 9 postmenopausal | Peak E₂ 110, E₁ 467 pg/mL; E₁:E₂ ratio 3–6 |
| 1981 | Bhavnani / JCEM | Premarin | IV 10 mg + PO 10 mg | postmenopausal | PO peak E₁ 1.4 ng/mL at 5 h vs IV peak 11.2 ng/mL at 20 min |
| 1982 | Schindler et al. / Arzneim-Forsch | Pure oral E₁S vs E₁ vs E₂ vs Premarin | PO 9.74 µmol each | women, small n | "Protracted influx" + 10–12 h enterohepatic bump for conjugates |
| 1989 | Bhavnani et al. / JCEM | [³H]equilin-[³⁵S]sulfate | PO + IV (dual-isotope) | postmenopausal | Some oral sulfate absorbs intact; some hydrolyzed and re-sulfated post-absorption |
| 1990 | Englund, Johansson / Maturitas | Piperazine E₁S vs E₂V | PO 2.5 vs 2.0 mg | 8 postmenopausal | PE₁S → higher AUC for E₁ and E₁S than E₂V; 21-day E₁S accumulation |
| 1992 | Lobo & Cassidenti / J Reprod Med | Oral E₂ (review) | PO 1 mg | review | Oral E₂ raises E₁S 8–20× over baseline |
| 1997 | Price et al. / Obstet Gynecol | Micronized E₂ SL vs PO | SL 1, 0.5, 0.25 mg; PO 1, 0.5 mg | 6 postmenopausal | SL Cmax 13× PO; E₁S correlated with dose not route |
| 2000 | Bhavnani et al. / J Soc Gynecol Investig | Premarin vs synthetic CES | PO single dose | 41 | Not bioequivalent; total estrone AUC >> unconjugated |
| 2001 | Slater et al. / Menopause | Oral E₂ vs transdermal E₂ | PO 1 mg vs patch | 33 | E₁S 38.8 ng/mL (oral) vs 1.8–3.2 ng/mL (transdermal) at 15 months |
| 2022 | Doll et al. / Endocr Pract | Oral vs SL E₂ | PO 1 mg vs SL 1 mg | 10 trans women | SL Cmax 144 vs PO 35 pg/mL; E₂:E₁ different; E₁S NOT measured |
What r/TransDIY, r/Estrogel, Discord servers, and DIY-HRT compendia say vs what the primary literature actually supports. Note: Aly's writeups at Transfeminine Science are usually careful and do NOT make the strong-form claims; those are folk extrapolations from Wikipedia's PK page and selective Reddit reading.
| Claim | Verdict | Evidence |
|---|---|---|
| "Sublingual is just better." | refined | SL gives higher Cmax and modestly higher early-window AUC (Doll 2022, 1.8×), but no breast-development advantage in any modern cohort. SL does not avoid the E₁S pool (Price 1997). |
| "E₁S is a reservoir that drives extra feminization." | refuted | Tebbens 2022 (n=212): "breast development in trans women were not associated with estrone concentrations nor with administration route." E₁S unmeasured but its proximal product E₁ is null. |
| "Premarin is a slow-release E₁S reservoir." | refined | Pharmacokinetically true that CEE is ~50–70% E₁S by mass and has a slow-release profile (Bhavnani 1981–2000). But CEE contains equilin sulfate, equilenin sulfate, Δ⁸-E₁-sulfate which are not pharmacologically equivalent to micronized E₁S. "Premarin = pure oral E₁S" is wrong. |
| "Sublingual generates less E₁S." | refined | Price 1997 found E₁S correlated with dose, not route. SL still delivers a substantial dose through the swallowed-saliva GI route, and recycled E₁/E₂ still get sulfated. Cirrincione 2021 found SL still drives high E₁. |
| "Tissue E₂ is 5–50× serum E₂ in target tissues." | overstated | The 5–50× figure is from postmenopausal breast cancer tissue (Pasqualini, Geisler). In normal breast tissue (Lønning 2015 LC-MS/MS), tissue E₂ ≈ serum E₂ in cycling women. |
| "Oral E₂ is 'really' 15–25% bioavailable when you count E₁S." | refuted | Not a published PK metric. Bioavailability is a plasma metric for intact drug. Tissue activation via reservoir doesn't compress to one percent. |
| "Anastrozole + oral E₂ proves the STS bypass." | overstated | STS bypasses aromatase mechanistically. But the IRIS phase-II trial showed STS inhibition added to AI gives only 18.5% clinical benefit rate in postmenopausal breast cancer — much less than the strong-form intracrine model predicts. No trans oral-E₂ + AI study supports the clinical claim. |
| "E₁S half-life is up to 30 hours." | refined | Kuhl 2005 and Lobo & Cassidenti 1992 both give 10–12 h. The 30 h anchor wasn't located in any primary source. |
The full evidence map sits at darkarts.wiki/research/oral-vs-sublingual-e2/historical/:
brief.md — research scopeera-01-discovery-1920s-1960s.md — 36 KBera-02-tracer-studies-1960s-1980s.md — 33 KBera-03-sts-pathway-1990s-2000s.md — 29 KBera-04-hsd17b-isoforms.md — 31 KBera-05-direct-e1s-administration.md — 20 KBera-06-modern-reframing-trans-community.md — 32 KBtimeline.md — chronological synthesisquotes/ — 91 individual verbatim-quote files, one per paperEach era file cites primary papers with PMID/DOI and links to a verbatim quote file in quotes/. The full era-by-era research output runs to about 180 KB of structured analysis, plus the quote library.