Progesterone and the brain

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Stavia
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Progesterone and the brain

Post by Stavia »

Have we discussed this?
https://www.ncbi.nlm.nih.gov/pmc/articl ... po=2.24490

Roberta Brinton
Emerging data indicate that progesterone has multiple non-reproductive functions in the central nervous system to regulate cognition, mood, inflammation, mitochondrial function, neurogenesis and regeneration, myelination and recovery from traumatic brain injury. Progesterone-regulated neural responses are mediated by an array of progesterone receptors (PR) that include the classic nuclear PRA and PRB receptors and splice variants of each, the seven transmembrane domain 7TMPRβ and the membrane-associated 25-Dx PR (PGRMC1). These PRs induce classic regulation of gene expression while also transducing signaling cascades that originate at the cell membrane and ultimately activate transcription factors. Remarkably, PRs are broadly expressed throughout the brain and can be detected in every neural cell type. The distribution of PRs beyond hypothalamic borders, suggests a much broader role of progesterone in regulating neural function. Despite the large body of evidence regarding progesterone regulation of reproductive behaviors and estrogen-inducible responses as well as effects of progesterone metabolite neurosteroids, much remains to be discovered regarding the functional outcomes resulting from activation of the complex array of PRs in brain by gonadally and / or glial derived progesterone. Moreover, the impact of clinically used progestogens and developing selective PR modulators for targeted outcomes in brain is a critical avenue of investigation as the non-reproductive functions of PRs have far-reaching implications for hormone therapy to maintain neurological health and function throughout menopausal aging.
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Stavia
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Re: Progesterone and the brain

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And then there is the 2015 rat study by Barron et al, where the discontinuous P4 had a better neuroprotective effect than the continuous P4, both with E2


http://cloud.tapatalk.com/s/59db3753340 ... fbfabd.pdf
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Julie G
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Re: Progesterone and the brain

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Good stuff, Stavia. I'm sure we have previous threads discussing the importance of P4, but both of these papers are new to me. From the first one:
While E2 replacement is beneficial in regulation of Aβ metabolism, the interaction between E2 with P4 is more clinically relevant. That is, how are Aβ levels affected when P4 acts in concert with E2? Our group has recently addressed this question in the 3xTg-AD mouse model of AD. Our results suggest that continuous E2, but not P4 treatment attenuates the acceleration of Aβ accumulation and memory deficits observed in ovariectomized mice. More importantly, in animals receiving both hormones, P4 blocked the beneficial effect of E2 on Aβ accumulation
Perhaps I'm misunderstanding, but in terms of abeta accumulation, it appears that P4 blocks the beneficial effects of E2? This claim lead me to their reference:

Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice.
https://www.ncbi.nlm.nih.gov/pubmed/18045930/
Estrogen depletion in postmenopausal women is a significant risk factor for the development of Alzheimer's disease (AD), and estrogen-based hormone therapy may reduce this risk. However, the effects of progesterone both alone and in combination with estrogen on AD neuropathology remain unknown. In this study, we used the triple transgenic mouse model of AD (3xTg-AD) to investigate the individual and combined effects of estrogen and progesterone on beta-amyloid (Abeta) accumulation, tau hyperphosphorylation, and hippocampal-dependent behavioral impairments. In gonadally intact female 3xTg-AD mice, AD-like neuropathology was apparent by 3 months of age and progressively increased through age 12 months, a time course that was paralleled by behavioral impairment. Ovariectomy-induced depletion of sex steroid hormones in adult female 3xTg-AD mice significantly increased Abeta accumulation and worsened memory performance. Treatment of ovariectomized 3xTg-AD mice with estrogen, but not progesterone, prevented these effects. When estrogen and progesterone were administered in combination, progesterone blocked the beneficial effect of estrogen on Abeta accumulation but not on behavioral performance. Interestingly, progesterone significantly reduced tau hyperphosphorylation when administered both alone and in combination with estrogen. These results demonstrate that estrogen and progesterone independently and interactively regulate AD-like neuropathology and suggest that an optimized hormone therapy may be useful in reducing the risk of AD in postmenopausal women.
So, while P4 had a negative effect on abeta, :? it apparently significantly reduced tau, which according to the very recent work by Holtzman (et al.) may be more important for E4s. From your second paper:
Our results demonstrate the combined efficacy of E2 and P4 is dependent on the administration regimen. Importantly, the discontinuous-combined E2 P4 regimen had the greatest neuroprotective efficacy for both end points. These data extend a growing literature that indicates qualitative differences in the neuroprotective effects of E2 as a function of cotreatment with continuous versus discontinuous P4, the understanding of which has important implications for HT in postmenopausal women.
They suggest that the optimal regimen is P4 for only 10-12 days per month. I’m still using 100 mg of progesterone every night. This certainly makes me reconsider. How are you using P4, Stavia?
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Re: Progesterone and the brain

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Forgive my lack of time to peruse the material here ... just throwing in an off the cuff thought ... If progesterone preserves Aβ but blocks tau that sounds like a win-win ... preserves the antimicrobial function of Aβ while preventing the next step in AD progress of tau? I'm thinking I recall that it's that transition that leads to clinical manifestations? Maybe if women had enough P4 (gotta look up the different Ps now!) they wouldn't have to go to other lengths to modulate Aβ. Maybe P4 is the body's own way of doing so up to the end of reproduction and irrelevance of our lives to DNA survival? Really don't know what I'm talking about.
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: Progesterone and the brain

Post by Julie G »

Interesting thought, Circ. We still have the problem of cycling... Yes or no? Which days do I want to block tau? Perhaps shorter periods without for us? :roll:
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Re: Progesterone and the brain

Post by circular »

Yes, sounds like another quandry! Julie do you notice your hypermobility getting worse with progesterone? I have to limit how much I use which throws my estrogen:progesterone ratio off. I'd be happy to not use it part of the time because of the its laxity promoting effects in me, but I think we'd be left wondering about the implications of not having a better estrogen:progesterone ratio on those days?
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: Progesterone and the brain

Post by SusanJ »

I've gone to 15 days on and 15 days off. But have considered going down to 12 days, because that's what is recommended in the patient insert for the generic I use.

I felt that my brain function was worse (especially word recall), and my mood (anger and depressive thoughts) were much worse when taking P4 (100 mg) continuously. Felt better within a week of dropping P4. Now I don't have any brain scans to show what was going on, but I know that I feel better with this approach.

Hathaway's slides are what got me to the conclusion to cycle longer. And it does seem to match more closely what our premenopausal bodies were doing normally. Will be getting another lab at the end of the year and will see where my ratios end up. Hathaway says test at the end of the progesterone-taking period to know if you are getting enough.
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Re: Progesterone and the brain

Post by circular »

Wow, somehow I glossed over that part of Dr. Hathaway's slides/video. Here's a link to download the slides and here's a link to the video.

'Progesterone-P4 -- Basics of BHRT' (slide 47)
All women on Estradiol need to be on Progesterone to protect the uterine lining from hyperplasia. Hyperplasia can develop into endometrial cancer.
  • P4 is often cycled, part of month on, part off--mimics premenopausal physiology and increases P4 receptor sensitivity. Not always cycled.

    P4 is more tissue and fat soluble so can build up in tissue and an excess total body burden can be present than is reflected in the blood level when taken continuously.

    Best to take P4 at bedtime, sleep enhancing, 15 to 26 days per month, depending on patient preference, and days needed to get to adequate peak levels to protect uterine lining.
Here are her 'Recommended Safe E2 to P4 Levels' (slide 48):
Adequate Minimum Progesterone Levels by Ann Hathaway MD
provide adequate protection of the endometrium from excess proliferation, hyperplasia and increased cancer risk. This is remarkably uncharted territory as far as hard science is concerned. I have found the saliva levels unreliable. These recommendations are based on my 20 years BHRT experience plus my interpretation of the literature:

[Took a few formatting liberties for readability]

Estradiol pg/ml ..... Safe Peak P4 ng/ml ..... Suggested Max P4

E2=25-30 ..... P4=1.5 ..... 3
E2=30-40 ..... P4=1.5-2.5 ..... 4
E2=40-50 ..... P4=2.5-3.5 ..... 6
E2=50-60 ..... P4=3.5-4.5 ..... 7
E2=60-80 ..... P4=4.5-6.5 ..... 8
E2=80-100 ..... P4=6.5-7.5 ..... 10
Timing for Testing E1, E2 and P4 (slide 49)
Optimal time to check serum levels:
  • On the middle day of the estradiol patch
    8 to 12 hours after the last dose of topical estradiol
    The morning after the last night of progesterone to get peak
This will help to get more useful and consistent results.
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: Progesterone and the brain

Post by Stavia »

Julie, I have just started 25mg at night. I'm trying a lower dose because of the sedation. I plan to cycle 21/rest of the month.

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Re: Progesterone and the brain

Post by SusanJ »

circ, you're not the only one. My last labs sent me back to her slides to see what was going on. I never associated the brain stuff with P4 until I reread the slides. The other thing that got my attention was that point about building up in tissues and fat, and labs not being representative of total burden. My P4 labs were actually lower than I've ever been on a seemingly higher dose. Next test will be interesting for sure.
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