#37

Definitely. Before TRT was one of the times my estradiol was way too low.

The other was when I still needed an AI and got the dose wrong.

Now I can sense when it’s just a little too high or low, almost intuitively. It’s very subtle.

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#38

This was tried back in the 1970s by the Coronary Drug Project. The high-dose estrogen arm was terminated iafter a mean follow-up of 1.5 years because of a significant increase in nonfatal MI and a trend toward increased total mortality. The low-dose estrogen arm was terminated after a mean follow-up of 4.7 years because of an increase in cancer deaths and a trend toward increased total mortality.

ERT even seems to be harmful to women if started long after menopause (seems largely beneficial if started early in the process).

The estrogens in CEE are neither 17-alpha nor largely estradiol, but it’s a pretty strong signal not to mess with this.

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#39

"The treatment groups included: low-dose estrogen (2.5 mg/day), high-dose estrogen (5.0 mg/day), clofibrate (1.8 g/day), DT4-dextrothyroxine (6.0 mg/day), niacin (3.0 g/day), and placebo (3.8 mg lactose/day)

“Our skin has various oestrogen receptors that help induce the production of collagen and hyaluronic acid which hold water in the skin. So the drop in the level of sex hormones in the menopause pushes a foot down hard on the ageing accelerator in women.”

This says they can suppress appetite, improve insulin sensitivity,

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#40

I haven’t read this whole chapter, but it appears to be about the role of endogenous estrogen in males, not pharmacological estrogen treatment. Endogenous estrogen is also important for bone mineral accretion in response to exercise and for mood in males. That’s not a reason to take more of it.

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#41

Starting to take it regularly, still zero feminization

4 Likes
#42

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

#43

Anything you notice subjectively or any differences in lab markers?

#44

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.

#45

Does taking exogenous estrogen not interfere with hormone production in a male? The same way that taking exogenous testosterone downregulatea the HPTA?

#46

It does. There are doses where you can get away with it but 2mg daily will absolutely feminize you.

#47

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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#48

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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#49

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

  1. 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 )

  2. 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.

  3. 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

  1. Stay in the physiologic male–low-female overlap (≈ 30-60 pg mL⁻¹). Going higher erodes the mortality U-curve advantage.
  2. Prefer transdermal gel/patch, titrated monthly; avoid oral ethinyl-estradiol entirely.
  3. Co-monitor: hematocrit, D-dimer, fasting lipids, liver enzymes, SHBG, estradiol (LC-MS/MS), testosterone, prolactin.
  4. Abort on: any thrombotic event, migraine-aura onset, hematocrit > 52 %, prolactin > 25 ng mL⁻¹, PSA jump, or unwanted breast growth.
  5. 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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#50
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#51

Below is a mechanics‑first overview of the ways 17β‑estradiol (E2) has been shown to blunt homocysteine (Hcy) toxicity, organized from the earliest “up‑stream” steps (lowering the Hcy burden itself) to the “down‑stream” cell‑stress pathways that Hcy normally triggers.

1. Lowering the dose of Hcy that cells ever see

Route What estrogen does Net effect
Trans‑sulfuration Via ERα/ERβ–dependent transcription, E2 up‑regulates cystathionine‑β‑synthase (CBS) and cystathionine‑γ‑lyase (CSE). More CBS/CSE → faster conversion of Hcy → cystathionine → cysteine/H₂S. (ResearchGate)
Remethylation Estrogen increases hepatic methionine synthase activity and improves folate/B‑12 turnover, shifting Hcy → methionine and raising the SAM/SAH ratio (better global methylation). (Older liver and vascular studies—mechanism confirmed in human hormone‑replacement cohorts.)
Plasma clearance Clinical data show 10‑20 % lower fasting Hcy in pre‑menopausal vs. age‑matched men; surgical menopause or aromatase inhibition reverses this. Replacement therapy brings Hcy back down, supporting a systemic, not merely local, effect.

2. Raising protective co‑factors generated from Hcy

The same CBS/CSE induction that drains Hcy also boosts endogenous H₂S, a gaseous transmitter with direct antioxidant and vasodilatory actions (activates K_ATP channels, sulfhydrates Keap1 to release Nrf2, etc.). (ResearchGate)

3. Blocking the canonical stress pathways that make Hcy harmful

Hcy toxicity pathway What E2 does Experimental evidence
Oxidative & nitrosative stress • Phenolic A‑ring scavenges ROO• directly.
• ER‑PI3K/Akt signaling up‑regulates SOD1/2, catalase, GPx.
• Restores eNOS expression & phosphorylation that Hcy normally suppresses, rescuing NO bioavailability so superoxide is not diverted to peroxynitrite.		 Ex‑vivo porcine coronary arteries: 1 µM E2 prevented the Hcy‑induced drop in endothelium‑dependent relaxation, restored eNOS protein, and cut O₂•⁻ production by ~60 %. (PubMed )
Inflammatory signaling Membrane ER→ PI3K/Akt → phosphorylation of IκB keeps NF‑κB in the cytosol, so Hcy fails to raise ICAM‑1/VCAM‑1, MCP‑1, and IL‑6. HUVECs: 50 nM E2 before 500 µM Hcy cut ICAM‑1 mRNA by >70 % and blocked monocyte adhesion.
Autophagy & proteostasis New 2025 work shows E2 activates protective autophagy (PI3K/Akt → mild mTOR inhibition) and clears the mis‑folded proteins & damaged mitochondria accumulated under Hcy stress. Sci Rep 15:24270 (2025) – autophagy flux markers (LC3‑II/I ratio, p62 turnover) restored; endothelial IL‑1β, IL‑18 fell 40‑60 %. (PubMed )
Apoptosis E2 raises Bcl‑2/Bax ratio, inhibits caspase‑3 cleavage, and prevents Hcy‑triggered cytochrome‑c release. Net: fewer dying endothelial & neuronal cells in vitro and in rodent hyper‑Hcy models.
Endoplasmic‑reticulum stress Through the same Akt–mTOR axis and H₂S signaling, E2 suppresses PERK/eIF2α and CHOP, blunting ER‑stress‑induced apoptosis that is otherwise prominent with high Hcy.

4. System‑level consequences

Vascular: Preservation of flow‑mediated dilation, reduced arterial stiffness, slower atheroma growth in animal HHcy models receiving E2.
Neural: In hippocampal and cortical cultures, E2 blocks Hcy‑evoked NMDA‑dependent Ca²⁺ overload and maintains mitochondrial membrane potential, translating to better cognitive and seizure thresholds in HHcy rodents.
Bone & connective tissue: By lowering Hcy and oxidative stress, E2 indirectly protects collagen cross‑linking and bone matrix integrity (important in post‑menopausal osteoporosis context).

5. Practical implications & open questions

  1. Sex differences in cardiovascular risk before menopause are now thought to be mediated partly by this Hcy‑detox pathway.
  2. Hormone‑replacement therapy: standard oral doses (~1 mg estradiol/day) lower plasma Hcy 2‑4 µmol/L in most trials; transdermal patches show a similar effect without first‑pass metabolism.
  3. Selective ER modulators (SERMs) differ: raloxifene lowers Hcy modestly, while tamoxifen can raise it—indicating receptor‑isoform and tissue‑specific cofactor requirements.
  4. Outstanding: How much of E2’s benefit is indirect (via H₂S & NO) versus direct genomic protection? Multi‑omics in ER‑knockout endothelium and CBS/CSE‑null mice are underway.

Bottom line: Estrogen attenuates homocysteine toxicity through a multi‑layered defence—draining Hcy at its source (CBS/CSE induction and remethylation), recycling part of it into protective H₂S, and armouring the endothelium and neurons against the oxidative, inflammatory, and proteostatic stress that residual Hcy still provokes.

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#52

There is some breast growth if you take enough estradiol. Small amounts.

There is a chance it might not be reversible.
Spironolactone also induces small (and reversible) amounts of it.

#53

Isn’t SERM’s available to be used to reverse gynecomastia as long as the breast growth hasn’t solidified?

#54

Please keep us posted on your estradiol experiment. I’m curious how it goes and I’m glad you’re getting lab tests.

#55

i’m developing some nipple tenderness so I’m gonna stop for a while and mostly just use spironolactone for now

#56

but I KNOW that while some trans people encourage me to go all the way, I really do not feel it’s worth the social risk, it’s too much. Mostly just enough to give some glycan benefits, not enough to actually transition…

well, AT LEAST FOR NOW, maulik sells estriol for super-cheap

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