17-alpha-Estradiol May Work Through the Estrogen Receptor After All

Quoting @RapAdmin 's summary of Peter Attia’s podcast with Richard Miller:

Richard Miller tells Peter Attia that a pharmacologist named James Simpkins has studied estrogen receptors and suggested investigating 17α-Estradiol. He had tried to make a compound that was like estrogen—17β-estradiol—which is generically crudely referred to as estrogen. …

James Simpkins synthesized 17α-Estradiol—very much the same compound except for one of the bonds tilts up instead of tilting down. And in his studies mostly in tissue culture cells, he found that yes, it was tenfold less active compared to 17β-estradiol (the compound which most people refer to as the estrogen used in hormone replacement therapy).

When he gave it to mice, he found it was non-feminizing : So when you give it to male mice, it did not induce the secondary sexual characteristics that the stronger estrogens, like 17 beta- estradiol, estrogen would do. His idea was that giving estrogen to male mice might make them live as long as female mice (female mice live 5-10% longer than males) AND this compound called 17α-Estradiol will be good for males because “no man wants to look feminine” even if he lives as long as a women.

Big caveat: nearly all that follows was done in high fat-fed obese mice, which may not give insight on the mechanisms relevant to its effects in normal-for-one’s-age aging:

the signaling mechanism(s) and primary tissues through which 17α-E2 elicits these benefits remain unknown. Although 17α-E2 is a naturally occurring enantiomer to 17β-estradiol (17β-E2), it has been postulated that 17α-E2 signals through a novel uncharacterized receptor (Toran-Allerand, 2005; Toran-Allerand et al., 2002; Toran-Allerand et al., 2005; Green and Simpkins, 2000) as opposed to classical estrogen receptors α (ERα) and β (ERβ), which is due to 17α-E2 having significantly reduced binding affinity for ERα and ERβ as compared to 17β-E2 (Edwards and McGUIRE, 1980; Korenman, 1969; Littlefield et al., 1990; Anstead et al., 1997). For this reason, 17α-E2 is often referred to as a non-feminizing estrogen (Green and Simpkins, 2000; Engler-Chiurazzi et al., 2017; Kaur et al., 2015). A few studies have suggested that a novel but uncharacterized estrogen receptor, termed ER-X, may mediate 17α-E2 actions in the brain (Toran-Allerand, 2005; Toran-Allerand et al., 2002; Toran-Allerand et al., 2005; Green and Simpkins, 2000), although more recent studies supporting this hypothesis are lacking in the literature. Similarly, no reports to date have directly tested whether the doses of 17α-E2 shown to improve healthspan and lifespan in mice are mediated through ERα and/or ERβ.

There is a multitude of data in the diabetes and metabolism literature demonstrating that ERα is a regulator of systemic metabolic parameters. Although most of these studies have historically been performed in female mammals, more recent studies have demonstrated that ERα also plays a critical role in modulating metabolism in male mammals. For instance, Allard and colleagues recently demonstrated that genomic actions of ERα regulate systemic glucose homeostasis in mice of both sexes and insulin production and release in males (Allard et al., 2019). Other studies have also determined that hepatic steatosis and insulin sensitivity, and therefore the control of gluconeogenesis, are regulated through FOXO1 in an ERα-dependent manner in male mice (Yan et al., 2019). Furthermore, hepatocyte-specific deletion of ERα was sufficient to abrogate similar estrogen-mediated metabolic benefits (Guillaume et al., 2019; Qiu et al., 2017; Meda et al., 2020). Given that several reports have linked the administration of 17α-E2 to improvements in metabolic homeostasis, we hypothesized that 17α-E2 signals through ERα to modulate hepatic function and systemic metabolism, thereby potentially contributing to the lifespan-extending effects of 17α-E2.

Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. …

these findings strongly suggest that the liver is a primary site where 17α-E2 acts to improve metabolic homeostasis due to gluconeogenesis being tightly controlled by hormonal actions on hepatocytes (Zhang et al., 2018). However, it also well established that the hypothalamus can directly modulate gluconeogenesis in the liver through hepatic innervation … Interestingly, we found that [acute intracerebroventricular (ICV)] administration of 17α-E2 essentially phenocopied the effects of peripheral 17α-E2 infusion with regard to GIRs and suppression of hepatic gluconeogenesis (Figure 6G–I). These findings suggest that 17α-E2 likely acts through hypothalamic neurons to regulate hepatic gluconeogenesis. Indeed, agouti-related peptide/neuropeptide Y (AgRP/NPY) and pro-opiomelanocortin (Pomc) neurons are known to regulate hepatic glucose production (Könner et al., 2007; Ruud et al., 2017; Pocai et al., 2005a; Pocai et al., 2005b; Dodd et al., 2018) and both neuronal populations express ERα …

Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.

We recently reported that estrogen receptor α is required for the majority of 17α-E2-mediated benefits in male mice, but that 17α-E2 also attenuates fibrogenesis in liver, which is regulated by estrogen receptor β (ERβ)-expressing hepatic stellate cells (HSC). The current studies sought to determine if 17α-E2-mediated benefits on systemic and hepatic metabolism are ERβ-dependent. We found that 17α-E2 treatment reversed obesity and related systemic metabolic sequela in both male and female mice, but this was partially blocked in female, but not male, ERβKO mice. ERβ ablation in male mice attenuated 17α-E2-mediated benefits on hepatic stearoyl-coenyzme A desaturase 1 (SCD1) and transforming growth factor β1 (TGF-β1) production, which play critical roles in HSC activation and liver fibrosis. We also found that 17α-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17α-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ERβ partially controls 17α-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17α-E2 likely signals through ERβ in HSCs to attenuate pro-fibrotic mechanisms.

Work from our lab found that 17α-E2 acts through pro-opiomelanocortin (POMC) appetite- regulating neurons in the hypothalamus, which respond to insulin and induce satiety. However, it is unclear whether 17α-E2 is acting directly on POMC neurons or indirectly through improvements in insulin sensitivity to induce reductions in food intake and adiposity. Discovering this mechanism of action could provide useful potential therapeutic targets for metabolic disorders in elderly obese people.

Purpose: The purpose of this study was to use an insulin-resistant model to determine whether 17α- estradiol (17α-E2) exerts its action via insulin signaling in POMC neurons in the hypothalamus.

Methods: Mice lacking the insulin receptors on POMC neurons (POMC-IR KO) and wild type (WT) mice, were pre-fattened via a 45% high-fat diet (HFD) for about 6 months. Baseline measures were taken, including body mass, daily calorie intake, body composition (lean and fat mass), fasting blood glucose, and fasting insulin, before randomizing the groups. The mice were then treated with either HFD or HFD+17α-E2 (14.4ppm).

Results: When compared to wild type mice with 17α-estradiol, POMC-IR KO mice treated with 17α-E2 demonstrated no significant differences in the percent change in the body mass (-5.91% ± 1.34; NS), fat mass (14.6g ± 1.41; NS), fasting glucose, fasting insulin, glucose tolerance, and insulin sensitivity. There were no significant improvements between Wild type and POMC-IR KO mice treated with high-fat diet.

Discussions/conclusions: The beneficial food intake, adiposity, and metabolic effects of 17α-E2 are not mediated via insulin signaling in POMC neurons. 17α-estradiol may be acting through some other mechanism, such as estrogen receptor α, on POMC neurons or multiple neuronal populations in the brain. However, determining molecular targets of 17α-E2 and their physiological role in curtailing disease conditions needs to be studied in detail.

Full PDF:

One important reason to watch this: estrogen improves the lipid profile and was long thought to be the reason why women enjoy lower ASCVD risks before hitting menopause. For this reason, the Coronary Drug Project back in the 70s had arms with low (2.5 mg) and high-dose conjugated estrogen for men. 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.

If these effects are mediated through estrogen’s hormone activity, and if 17-α-estradiol indeed has significant action through the estrogen receptor, it might be quite dangerous in men. Much of this might be obscured in mice because they don’t get atherosclerosis, though you would certainly think a cancer signal would be obvious.

I’ll have to relisten to the Peter Attia podcasts on this, because it was over a year ago and I remember the situation with regard to female HRT is much more nuanced than what the popular press covered and which drove some of the decisions regarding the large female HRT trial.

These episodes are about women given estrogen replacement therapy during and after menopause, which is indeed a very complex and difficult to parse set of therapeutic decisions — and in particular the Women’s Health Initiative, whose main results came out in 2002. I was discussing the Coronary Drug Project, which gave conjugated estrogen to men in the late 1960s and early 1970s and whose results were not ambiguous.

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Thanks - I will dig more deeply into all of this.

I can’t seem to get easy access to your first paper mentioned, only the second.



CoronaryDrugProject_jama.1973.03230060030009.pdf (2.1 MB)

No one (men or women) today should be using conjugated estrogen, which is basically horse estrogen, and a completely different molecule from human estrogen.

Human bioidentical (17beta-)estradiol has been available as patches or creams for over 20 years now. There are no studies showing any of the negative effects from Human bioidentical estrogen that are similar to the earlier studies based on conjugated estrogen.

This does raise a question : is the 17-alpha-Estradiol (in the German hair product, for example) actually based on the Human bioidentical 17-beta-Estradiol ? I would hope so, since it is synthesized, similar to the Human bioidentical 17-beta-Estradiol.

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Here is the CDP paper on higher-dose estrogen.
HighDoseEstrogenCoronaryDrugProject.pdf (1.4 MB)

That’s true — but there also haven’t been any studies as large and long on HRT using any form of HRT under any protocol in any patient population as the WHI.

It’s also important to note that nearly all the excess adverse outcomes reported in the WHI were from the conjugated estrogen plus medroxyprogesterone arm, not in women women receiving conjugated estrogen alone.

It is an isomer (in fact, an epimer) of 17-beta, as you suggest.


Do you think that the effects of 17alpha-estradiol can be attributed to 5AR inhibition / DHT reduction?

And I’m not quite sure what you mean by making testosterone “harmless” if not through stopping its conversion to DHT (which is exactly the effect I’m pointing out).

This would be consistent with the relevant mechanism being 5AR inhibition, because obviously you need testosterone for inhibition of T → DHT to have any point.

If the lifespan extension effect was due to DHT suppression, wouldn’t just taking finasteride or dutasteride (depending on which 5ar enzyme is most harmful for longevity and how much DHT suppression is needed) do the same? We already have extensive human research data on both drugs but not for longevity.

How does one get this 17 alpha-estradiol? Any recommendations?

Also, anyone w experience taking this? It may be nonfeminizing but reducing DHT is kinda in the same category isn’t it?

Lastly, what does it do for mood?

See these two earlier threads - there is oral (hard to get) and topical (order from europe):

Here: 17-Alpha Estradiol - Another Top Anti-Aging Drug

Here: 17 Alpha Estradiol: Use and Dosing Experiences

This can’t be it. Females have far lower levels of DHT than males, but males on 17aEstradiol live longer than control females or females on the drug.

“Furthermore, studies in male rodents (Livingstone et al., 2015; Dowman et al., 2013) and humans Wei et al., 2019 demonstrate that 5α-reductase inhibition or deficiency increases insulin resistance and hepatic steatosis and fibrosis, which are contradictory to the effects of 17α-E2 treatment in all of our studies utilizing male mice (Stout et al., 2017b; Steyn et al., 2018; Miller, 2020; Sidhom et al., 2020).”

In humans, the studies are inconclusive about finasteride increasing risk of insulin resistance but the effect is certainly seen with dutasteride.

Conclusions The risk of developing new onset type 2 diabetes appears to be higher in men with benign prostatic hyperplasia exposed to 5α-reductase inhibitors than in men receiving tamsulosin, but did not differ between men receiving dutasteride and those receiving finasteride. Additional monitoring might be required for men starting these drugs, particularly in those with other risk factors for type 2 diabetes.

Incidence of type 2 diabetes mellitus in men receiving steroid 5α-reductase inhibitors: population based cohort study | The BMJ

Results: Dutasteride and finasteride had similar effects on steroid profiles, with reduced urinary androgen and glucocorticoid metabolites and reduced circulating DHT but no change in plasma or salivary cortisol. Dutasteride, but not finasteride, reduced stimulation of glucose disposal by high-dose insulin (dutasteride by -5.7 [3.2] μmol/kg fat-free mass/min, versus finasteride +7.2 [3.0], and tamsulosin +7.0 [2.0]). Dutasteride also reduced suppression of nonesterified fatty acids by insulin and increased body fat (by 1.6% [0.6%]). Glucose production and glycerol turnover were unchanged. Consistent with metabolic effects of dutasteride being mediated in peripheral tissues, mRNA for 5αR1 but not 5αR2 was detected in human adipose tissue.

Conclusion: Dual inhibition of 5αRs, but not inhibition of 5αR2 alone, modulates insulin sensitivity in human peripheral tissues rather than liver. This may have important implications for patients prescribed dutasteride for prostatic disease.

5α-reductase type 1 modulates insulin sensitivity in men - PubMed (nih.gov)

As dutasteride is a more potent 5 alpha reductase type 1 blocker than finasteride, perhaps only inhibiting type 2 would bring the longevity effects without causing diabetes?

My personal hypothesis on that subject is that testosterone does seem to have a protective role from alzheimers disease and sarcopenia. Since 17a-estradiol does not affect testosterone, it’s role as a 5ar-2 inhibitor could mitigate the damaging aspects of testosterone (DHT) while preserving the benefical aspects.


Just look at nikolina lauc LinkedIn thread

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Would you please excerpt the relevant material, or if not, at least provide the permalink?

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