Starting to take it regularly, still zero feminization
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Molecular Mechanism of Binding between 17β-Estradiol and DNA
Although 17β-estradiol (E2) is a natural molecule involved in the endocrine system, its widespread use in various applications has resulted in its accumulation in the environment and its classification as an endocrine-disrupting molecule. These molecules can interfere with the hormonal system, and have been linked to various adverse effects such as the proliferation of breast cancer. It has been proposed that E2 could contribute to breast cancer by the induction of DNA damage. Mass spectrometryhas demonstrated that E2 can bind to DNA but the mechanism by which E2 interacts with DNA has yet to be elucidated. Using all-atom molecular dynamics simulations, we demonstrate that E2 intercalates (inserts between two successive DNA base pairs) in DNA at the location specific to estrogen receptor binding, known as the estrogen response element (ERE), and to other random sequences of DNA. Our results suggest that excess E2 has the potential to disrupt processes in the body which rely on binding to DNA, such as the binding of the estrogen receptor to the ERE and the activity of enzymes that bind DNA, and could lead to DNA damage.
https://www.sciencedirect.com/science/article/pii/S2001037016300800
Anything you notice subjectively or any differences in lab markers?
Idk, 2mg is nothing, I got it bumped to 4mg which I may or may not start soon
I really need to shrink the size of the gonads, they’re annoying, unnecessary, extremely uncomfortable, stupid, and traumatic.
Does taking exogenous estrogen not interfere with hormone production in a male? The same way that taking exogenous testosterone downregulatea the HPTA?
It does. There are doses where you can get away with it but 2mg daily will absolutely feminize you.
Probably a 5-AR inhibitor is a better, safer way for a male to reap the benefits of higher estrogen. Not to mention higher testosterone. My estrogen on finasteride always sat just barely higher than the reference range and I feel good with it there.
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Normal levels for estradiol are: 10 to 300 pg/mL for premenopausal women. <10 pg/mL for postmenopausal women. 20 to 50 pg/mL for men.
Well I tested 63.5 after taking some (at least over the past week)
I don’t notice any feminization either. At least this has a shot at lowering Glycanage…
| Link in the chain | Evidence | Take-away |
|---|---|---|
| a. Estradiol up-regulates key glycosyl-transferases (B4GALT1, ST6GAL1, etc.) in B-cells | In-vitro ERα/β stimulation and chromatin-IP studies show direct promoter binding Frontiers | Establishes mechanism. |
| b. Those enzymes increase IgG Fc galactosylation + α2,6-sialylation and decrease agalactosylated (G0) species | JCI Insight cohort of 1 502 adults: serum E2 was the strongest hormonal predictor of G1 + G2 glycans in both sexes after age/BMI adjustment PubMed Central | Effect is not sex-limited. |
| c. More galactosylated/sialylated IgG lowers inflammation and the GlycanAge clock | GlycanAge algorithm is a weighted ratio of G0 vs G2 + S1/S2 structures; shift of one SD equals ≈ one biological year PubMed | Defines the aging read-out. |
| d. Manipulating estradiol in humans moves GlycanAge | RCT in 36 young women: chemical castration ↑ GlycanAge by ≈9 y, transdermal E2 (100 µg/day) completely blocked the rise and nudged age ~0.2 y lower PubMed | Proof of principle in vivo. |
| e. Male data | Cross-sectional JCI study above; a case series of hypogonadal men on estradiol patches normalised IgG G0:G2 within 12 weeks (conference abstract, 2024) [not yet peer-reviewed]. | Same direction, but still low-N. |
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TL;DR
No human data yet show that giving standard 17β-estradiol to otherwise healthy men slows biological ageing or prolongs life.
- In rodents, the non-feminising stereoisomer 17α-estradiol (17α-E2) extends male lifespan by ≈ 10-20 %. (PubMed Central, PubMed Central)
- Human observational studies see a U-shaped relationship: both low and high circulating E2 predict higher mortality, with the nadir around 30-50 pg mL⁻¹. (PubMed, JAMA Network)
- Epigenetic-age work actually favours a higher testosterone : estradiol ratio, not higher estradiol per se. (PubMed Central, PubMed)
- Intervention studies in men are tiny; the best we have are prostate-cancer or transgender cohorts. Transdermal E2 can improve LDL and CRP, but even patch therapy raises venous-thrombo-embolism and stroke risk over time. (PubMed, PubMed Central)
Hence, “as long as you don’t see feminising changes” is not a sufficient safety screen—the vascular, metabolic and fertility risks arrive long before visible gynecomastia.
1. Why the idea is tempting
Fact What it really tells us Women live ≈ 5 years longer and have “younger” IgG glycans until menopause. Estrogen is one driver, but so are XX genetics, lower iron, immune dimorphism, etc. Estradiol up-regulates B4GALT1 & ST6GAL1 in B-cells, shifting the IgG glycome youthful. Good for GlycanAge, but that is a surrogate marker, not proven causal for survival. 17α-E2 rescues insulin sensitivity, lowers hypothalamic inflammation and extends lifespan in male mice without breast enlargement. Proof-of-concept that some ER-α/β agonism can be geroprotective in a male system. Caveat
17α-E2 binds ERs ~30-fold weaker than 17β-E2 and is metabolised differently, so mouse data do not guarantee that ordinary estradiol replacement in men will act the same. (eLife)
2. What the human evidence actually shows
Observational cohorts
- Seniors (≥ 65 y, Sweden): men in the lowest E2 quintile (< 21 pg mL⁻¹) had 1.6-fold higher all-cause mortality, but the highest quintile (> 43 pg mL⁻¹) was also bad (1.5-fold). Optimum ≈ 30-40 pg mL⁻¹. (PubMed)
- Systolic heart-failure clinic (JAMA 2009): identical U-shape; nadir 37-57 pg mL⁻¹. (JAMA Network)
- Framingham DNAm study: younger epigenetic age associated with higher testosterone and a higher T / E2 ratio; estradiol alone was neutral. (PubMed Central, PubMed)
Small male intervention studies
- Prostate-cancer ADT + 0.6 mg/day transdermal E2 (n = 18) – E2 ↑ 17-fold; LDL fell 16 %, CRP fell 25 % in 8 weeks, no change in carotid IMT. (PubMed)
- Hypogonadal men case-series (conference abstract, 2024) – topical E2 normalised IgG G0:G2 ratio in 12 weeks but no hard outcomes reported. Unpublished.
Sex-reassignment cohorts (thousands, ≥ 10 y follow-up)
- Trans-women on estradiol show ↑ venous thrombosis (HR 1.5-2.3) and ↑ ischaemic stroke versus cis-men, even after switching largely to patches. (PubMed Central)
- Cardiovascular excess appears within 2-3 years—well before any longevity signal could manifest.
3. Mechanistic pros & cons to weigh
Potential benefit Counter-risk / unknown ↑ HDL, ↓ LDL, ↓ CRP (via ERα in liver & endothelium). Oral delivery up-regulates hepatic clotting factors; even patches raise VTE risk in predisposed men. ↑ Bone-mineral density; ↓ fracture risk. ↓ Gonadotropins → testicular atrophy, reduced fertility and possibly ↓ endogenous T → sarcopenia. ↑ Nitric-oxide synthase, better endothelial reactivity. High estradiol can prolong QTc and facilitate atrial fibrillation. IgG glycome shifts younger (may dampen inflammaging). Long-term immune consequences unknown; ER agonism can unmask autoimmune tendencies. Possible hypothalamic AMPK modulation (seen with 17α-E2). Not demonstrated with 17β-E2; may require supra-physiologic dosing.
4. Pragmatic take-home for self-experimentation
- Stay in the physiologic male–low-female overlap (≈ 30-60 pg mL⁻¹). Going higher erodes the mortality U-curve advantage.
- Prefer transdermal gel/patch, titrated monthly; avoid oral ethinyl-estradiol entirely.
- Co-monitor: hematocrit, D-dimer, fasting lipids, liver enzymes, SHBG, estradiol (LC-MS/MS), testosterone, prolactin.
- Abort on: any thrombotic event, migraine-aura onset, hematocrit > 52 %, prolactin > 25 ng mL⁻¹, PSA jump, or unwanted breast growth.
- Don’t rely on “no boobs = no risk.” Endothelial and coagulation changes are silent until catastrophe.
5. Alternatives under investigation
Agent Status Rationale 17α-Estradiol Phase I planning; excellent male-mouse data, minimal feminisation. Partial ER agonist with sex-specific metabolism that spares breast tissue. (PubMed Central, PubMed Central) Selective ER-α agonists / G-protein ER modulators Pre-clinical. Aim to capture metabolic & anti-inflammatory effects without clotting. Aromatase tuning (low-dose anastrozole pulses) Small anti-aging clinics use it, no hard-outcome data. Seeks optimum T : E2 ratio suggested by epigenetic work. Lifestyle & known geroprotectors (fat loss, HIIT, metformin, rapamycin) Human data for mortality or epigenetic-age benefit already stronger than for estradiol. Lower risk profile.
Bottom line
- Rodent success with 17α-estradiol does not yet justify 17β-estradiol supplementation in men who are not hypogonadal.
- Human evidence points to a sweet spot, not “more is better.” Exceeding ~60 pg mL⁻¹ pushes you onto the wrong side of a U-curve for stroke and thromboembolism.
- If your goal is longevity, interventions with proven human outcome data (caloric moderation, exercise, blood-pressure control, statins where indicated, and emerging rapalog trials) remain the safer bet while we wait for selective, non-feminising ER agonists to reach the clinic.
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