#148

17α-estradiol Alleviates High-Fat Diet-Induced Inflammatory and Metabolic Dysfunction in Skeletal Muscle of Male and Female Mice

We hypothesized that male, but not female, mice, would benefit from 17α-E2 treatment during a HFD with changes in the mitochondrial proteome to support lipid oxidation and subsequent reductions in DAG and ceramide content. To test this hypothesis, we used a multi-omics approach to determine changes in lipotoxic lipid intermediates, metabolites, and proteins related to metabolic homeostasis. Unexpectedly, we found that 17α-E2 had marked but different beneficial effects within each sex. In male mice, we show that 17α-E2 alleviates HFD-induced metabolic detriments of skeletal muscle by reducing the accumulation of diacylglycerol (DAGs) and ceramides, inflammatory cytokine levels, and altered the abundance of most of the proteins related to lipolysis and beta-oxidation. Similar to male mice, 17α-E2 treatment reduced fat mass while protecting muscle mass in female mice but had little muscle inflammatory cytokine levels. While female mice were resistant to HFD induced changes in DAGs, 17α-E2 treatment induced the upregulation six DAG species. In female mice, 17α-E2 treatment changed the relative abundance of proteins involved in lipolysis, beta-oxidation, as well as structural and contractile proteins but to a smaller extent than male mice. These data demonstrate metabolic benefits of 17α-E2 in skeletal muscle of male and female mice and contribute to the growing literature of the use of 17α-E2 for multi-tissue healthspan benefits.

Paywalled Paper: https://journals.physiology.org/doi/abs/10.1152/ajpendo.00215.2023

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#149

Perhaps not many people have seen the patent application from Longevica Therapeutics, since I’ve only seen it mentioned once on this forum.

United States Patent Application Publication — METHODS AND COMPOSITIONS FOR EXTENDING LIFESPAN

They tested a bunch of compounds in female B6C3F1hybrid mice, which is a long-lived strain. The compound which reduced mean lifespan most was 17beta-E2 (-21%). I couldn’t find the exact doses used.

They tested 1033 different compounds, and when the compounds were grouped by pharmacology, the only class which significanlty reduced lifespan was the estrogen agonists. In contrast, SERMs (which act as estrogen antagonists in tissues like breast and uterus, while acting as estrogen agonists in many other tissues) as a group extended lifespan.

17beta-E2 may damage DNA independent of its ER-binding activity, which might partially explain the above results.

We have demonstrated that E2 can bind to DNA directly and that binding not only occurs at the centre of the ERE half site but can also bind to random DNA sequences. E2 is shown to intercalate between base pairs, forming aromatic interactions with these base pairs…We predict that this intercalation will alter the structure of the DNA duplex, and therefore have the potential to affect the biological functions of DNA including the inhibition of transcription, replication, and DNA repair processes [40]. Therefore, excess E2 has the potential to exert some serious side effects such as disruption of ER-DNA binding, DNA damage and possibly the initiation of cancer. Molecular Mechanism of Binding between 17β-Estradiol and DNA

Mendelian randomization suggests that estrogen is causal for ER-positive breast cancer and endometrial cancer, so this could also be contributing to the above results. Obviously this would be an issue specific to female mice.

Another MR study suggests 17beta-E2 supports kidney function in men:

Our two-sample MR analysis based on the instruments assessing estradiol levels below vs. above the detection limit revealed a significant causal effect in males with a positive effect direction, implying that higher levels of estradiol could lead to higher eGFRs. This association was validated in the one-sample MR using continuous levels of estradiol above the detection limit.
Mendelian randomization indicates causal effects of estradiol levels on kidney function in males

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#150

Now as for why the female mice don’t benefit in ITP, I think due to higher levels of endogenous estrogen, they already possess the ERalpha and ERbeta-mediated benefits (as studies suggest male benefits occur through these receptors).

We can estimate in women the amount of bound ERalpha using equation: %bound receptor=1/(Kd/[L])+1. Using 17beta-E2’s 115pM Kd @ ERalpha, we can see that going from 200pg/mL to 300pg/mL only increases bound receptor by about 4%. In contrast, going from 10pg/mL to 100pg/mL leads to 314% increase in bound receptor!

In essence, due to the nonlinear nature of the occupancy equation, raising a woman’s estrogen levels will produce a relatively small increase in ERalpha signaling, whereas an equivalent increase in a man’s estrogen levels will produce a much greater increase in ERalpha signaling.

If adding more 17beta-E2 has a relatively small effect in women, then this will especially be the case with 17alpha-E2—due to it’s much weaker affinity at ERalpha. On the other hand, since men would be expected to see a much greater effect from an equivalent increase in 17beta-E2, similar reasoning suggests they would see a much greater effect from an increase in 17alpha-E2.

You can do similar analysis with ERbeta (where 17beta-E2 has a similar Kd), just keep in mind that this is an approximation. Serum levels don’t necessarily reflect tissue or intracellular levels, where the relevant signaling is taking place. Additionally, I used human 17alpha-E2 Kd and serum levels, so this relationship would need to also hold with mouse values.

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#151

Very interesting. I am using topical Pantostin Alfatradiol (with DMSO). Do you happen to know what strain of 17-Aplha Estradiol this contains?

#152

OK - so what exactly is your point? Nobody here is planning to use 17 beta estradiol, we’re only talking about 17 alpha estradiol.

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#153

You’re fine - you’re using the 17 alpha estradiol version, thats not what he’s talking about. I’m not sure why he’s bring up the 17 beta estradiol test results, they are different molecules.

With the Pantostin you want to watch for changes in your other hormones and IGF1 though. See this thread: 17 Alpha Estradiol: Use and Dosing Experiences

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#154

17beta-E2 reducing female mouse lifespan is something you should be aware of if you plan on taking 17alpha-E2, as they are both estrogen agonists.

#155

Yes - but the ITP tested 17-alpha E2 on mice and while the female mice did not see any lifespan increase (and no decrease), we saw very good lifespan increase in the male mice. Given the very different effects of 17-alpha E2 on male mice and male humans, I don’t think the effect of the feminizing hormone (17 beta-E2) in a mouse study is of much concern.

That said, there are things people need to be concerned about, and track, when using 17-alpha E2, such as IGF1 and sex hormone levels, as covered in the the Rhesus monkey study here: 17 Alpha Estradiol: Use and Dosing Experiences - #123 by RapAdmin

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#156

The non-feminizing claim I’m extremely skeptical of, and actually the study in post you linked even suggests that 17alpha-E2 (or one of its metabolites) is feminizing in macaques. Mouse studies have shown basically identical transcriptional profiles for both 17alpha-E2 and 17beta-E2 in liver, which further suggests that 17beta-E2 would be feminizing at high doses.

Like I said, if you plan on taking an estrogen agonist, you should be aware that estrogen agonists decrease lifespan in female mice. Obviously 17alpha-E2 increased male mice lifespan, which suggests the effects of estrogen agonists are biphasic, so you should be aware so you don’t overshoot the dose. If anyone knows any RCTs or MR studies relating to ER signaling please link them.

My 17alpha-E2 just came in actually, but I’m not sure on dose or ROA yet.

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#157

This video convinced me that 17-alfa estradiol is a substance that I should add to my health extending efforts. As well as keep taking sildenafil or other PDE5 inhibitors.

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#158

I used to take a German hair product. but now take 0.5ml of pomegranate seed oil daily. Not sure how much 17-alpha estradiol is in it.

#159

So you are not using Pantostin any more?

I wonder how well the 17eA in pantostin is absorbed through the skin and if some amounts of 17aE will reach systemic circulation.

I consider using 17aE in the form of (Pantostin) on my face. There are indications that topical 17aE might be beneficial to skin health, and since I don’t focus on my scalp, it might be an attractive ingredient to use topically on my face.

And since some products on the market already contain estriol and methyl estradiolpropanoate (MEP) etc, I think it is reasonable to think that it might be beneficial to my face as well as possibly being a tiny bit beneficial to the rest of my body.

This is what I will do till I find a way to get my hands on 17aE for oral ingestion.

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#160

Correct, I’m trying the switch to 17AE in pomegranate seed oil. Just check re: dangers of getting in your eyes :flushed:

#161

Could you elaborate on how you formulate it with DMSO ?

I am using it with transcutol a 10:7 ratio.

#162

As DSMO is more potent, I am using a 10:2 ratio. Essentially, I add about 20% of DSMO directly in the bottle and I use the bottle to dispense substance. I use it on my inner thigh.

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#163

I prefer Transcutol. IMO: It is much more pleasant. It smells and feels better on the skin it penetrates the dermal layer enough to be effective but does not get into the bloodstream as DMSO does.
DMSO is a slightly better solvent for some things than Transcutol
Everything, such as rapamycin, melatonin, and doxycycline that I use dissolves nicely in Transcutol.

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#164

Excellent video. One of the most informative ever, and a very strong case for 17a-estradiol. Already taking a PDE5 inhibitor, and keeping my eye on the SGL2 inhibitors.

#165

New paper:

The effects of 17α-estradiol treatment on endocrine system revealed by single-nucleus transcriptomic sequencing of hypothalamus

In this study, we investigated the role of 17α-estradiol in lifespan extension and its potential side effects for long-term administration. Pooled hypothalami from aged male Norway brown rats treated with 17α-estradiol (O.T), aged male controls (O), and young male controls (Y) were subjected to single-nucleus transcriptomic sequencing (snRNA-seq). To evaluate the effects of 17α-estradiol in anti-aging in neurons, supervised clustering on neurons by neuropeptides and their receptors were used to evaluate the responses of each neuron subtype during aging and after 17α-estradiol treatment. The elevated cellular metabolism, stresses and decreased synaptic activity in neurons initiated by aging were remarkably attenuated by 17α-estradiol. Assessment of changes in neuron populations showed that neurons related to food intake, reproduction, blood pressure, stress response and electrolyte balance were sensitive to 17α-estradiol treatment. 17α-estradiol treatment not only increased Oxytocin (Oxt), but also increased the activity of hypothalamic-pituitary-gonadal (HPG) axis, evidenced by significantly elevated levels of plasma Gnrh, bioavailable testosterone, and decreased estradiol. Elevated Gnrh1 was verified to be one of the causal effects mediating the role of 17α-estradiol in energy homeostasis, neural synapse, and stress response. Notably, Crh neurons displayed most prominently senescent phenotype among all checked neuron subtypes in O.T, which may be a potential side effect of 17α-estradiol treatment. Therefore, HPG axis and energy metabolism may be key targets of 17α-estradiol in male lifespan extension. Additionally, supervised clustering of neurons was shown to be a useful method to assess the responses to treatment among different neuron subtypes in the hypothalamus.

https://www.biorxiv.org/content/10.1101/2024.06.14.599053v1#:~:text=17α-estradiol%20treatment%20not%20only,bioavailable%20testosterone%2C%20and%20decreased%20estradiol.

PDF:

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#166

I bought a small amount of pomegranate seed oil and started taking maybe 1cc per day. Maybe 4 days in a row. My skin has never been so smooth. I really didn’t expect anything to happen and have several questions since I have no knowledge on this subject at all.

How much do I absorb through the gut? I expected it to be digested and not survive the stomach. Since I’m taking estrogen with the 17 alpha, is that good too as long as the side effects aren’t annoying? My last checkup my estriol was 17 I think, which is low but not too low.

I welcome any input, thanks.

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#167

I can find no studies that taking pomegranate seed oil raises estradiol in men.

In one study it reduced menopausal symptoms in women without raising serum estradiol levels. In another study it only mildly increased levels in women.

Several studies say that it increases collagen production and improves skin.

I don’t know for sure, but I don’t think it is going to significantly raise estradiol serum levels in men.

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As for cognitive benefits: A study ([4]) investigated a nasal delivery system for pomegranate seed oil and found that nasal administration in a phospholipid oily gel formulation significantly improved memory and locomotor activity in animal models compared to oral administration, suggesting that nasal delivery may enhance the potential cognitive benefits of pomegranate seed oil."

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