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.
https://sci-hub.wf/10.1001/jama.1973.03230060030009#
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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.
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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.
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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):
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).”
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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.
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.
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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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The TF with the best score was ESRRA (estrogen-related receptor alpha). This TF regulates expression of multiple metabolism-related genes, including those of mitochondrial function, biogenesis and turnover, as well as lipid catabolism (Tripathi et al., 2020). It is also linked to autophagy and NF-kB inflammatory response via Sirt1 signaling (Cantó et al., 2009; Yuk et al., 2015; Kim et al., 2018; Suresh et al., 2018). Mitochondrial dysfunction and autophagy impairments are consistently among the hallmarks of aging (López-Otín et al., 2013, 2023; Mattson and Arumugam, 2018; Amorim et al., 2022). Notably, ESRRA expression is downregulated in aging according to various studies (Schaum et al., 2020; Tripathi et al., 2020). Altogether, ESRRA acts as a regulatory hub of multiple aging-associated pathways as outlined in Supplementary Fig. 19. The other transcription factors that we identified are also validated by literature reports on TFs implicated in aging and neurodegeneration (see Supplementary Information).
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What kind of animal did they use here? 30 day lifespan is worm territory.
C elegans worm
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Do those things even produce hormones?
Probably some kind of hormones I just thought it was an interesting lifespan effect. I wonder what finasteride would do.
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According to my AI c elegans don’t seem to be producing 5ar enzymes or DHT. I wonder what makes dutasteride cause thís negative lifespan effect in c elegans then?
