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[dangermouse]

Yes, this isn't really a scientific discussion, for the reasons that Crispy explains, there just isn't enough research into it.

Whether progesterone physically pushes excess oestrogen into the bowels or whether (and I suspect this) it's a more complex mechanism, the result is that progesterone can put a lid on oestrogen spikes. I'm using pedestrian language because the specific mechanism is not clear, only the result.

[dangermouse]

Crispy - The lozenges were in 25mg squares and I tried between 25mg and 150mg, all with good results for the first few hours but it seemed to trail off before the next dose was due causing a rush of anxiety, even when taking every 12 hours. I felt like I needed to do every 6 hours so that is why I went back to the cream.

It may build up and then this isn't an issue but I didn't give it that long.

[CrispyChick]

Thanks Dangermouse. Appreciate you taking time to reply 👍😁

How's the DIM going?

[Mary G]

I agree dangermouse, this is not a scientific discussion.   I'm not interested in studies either which very often conflict with each other anyway.   

Remember the two disastrous HRT studies that were badly conducted and deeply flawed?  Those studies are responsible for making millions of womens' lives utterly miserable because they were (wrongly) terrified of taking HRT.  How ironic that one of those destructive studies was called million women study.

[Marchlove]

Hi Guys
I’ve just bought yet another book called A Practitioner’s Guide to Physiologic Bioidentical Hormone Balance by Jim Paoletti who is a compounding pharmacist in the States.
It’s got a whole section in chapter 2 regarding down regulation of hormone receptors. It’s all a bit complicated so I’ll have to keep reading it until it sinks in.
 What is a bit easier though on page 26 is he says that sublingual or buccal administration return to baseline in approx 6 hours, so you should theoretically dose three times a day. But he says many patients do well on less frequent dosing, but thus may require a slightly larger total daily dosing. A slightly higher dose is needed to maintain threshold levels until the next dose.
Eg a patient using progesterone 25mg sublingually twice a day (50mg total daily dose) would probably do as well clinically on 12.5 mg sublingually three times a day (37.5mg) total daily dose).
He then goes on to say that any increased amount of supplemented estrogen will increase the amount of potentially carcinogenic metabolites, therefore estrogen sublingual or buccal should be administered at least three times a day!!
I’ve been doing it all wrong!
Another very very long section on transdermal use which I can’t even begin to put in this post!
I think you guys very into the technical side of all this would find this book very useful.
That’s my bedtime reading sorted for the next six months! xx

[CrispyChick]

Great Marchlove.

Problem is, there are books and articles everywhere. I just never know what to believe.

Does it say anything about up regulating estrogen receptors when you first start micronised prog???

[Marchlove]

The book is a bible really, no fluffy stuff, just technical.
So the bit I’ve found so far says-
When a women is given estrogen, even estrogen that she does not need, or in excess of what she needs, the first reaction is an increase in the number and sensitivity of estrogen receptors, and symptom management may be achieved. After a period of time, usually one or two months the receptors are down regulated.
Down regulation of estrogen receptors also leads to symptoms of progesterone deficiency. One of the effects of estrogen is the production of progesterone receptors. Excessive estrogen may down regulate estrogen receptors, leading to a deficiency in progesterone receptors.
Progesterone normally down regulates estrogen receptors, a mechanism for controlling estrogen activity. Excessive progesterone can down regulate estrogen receptors to the degree that estrogen deficiency symptoms occur.
Excessive progesterone down regulates receptors typically in a period of one to twelve months after initiation of therapy.

Sorry, it goes on and on.....

I think it might become clearer at the end of the book where there is a whole section on dosing for peri, post and surgical. He talks about hormone holidays to overcome the down regulation problem.
For instance in post (either natural or surgical) he says women using topical progesterone should take a hormone holiday of one day a week.

Peri ladies, lots of dosage suggestions  for progesterone depending on if you have pms, cyclically days 14-26.
Estrogen for peri ladies it says for topical start low and increase slowly,
0.05 - 0.20 mg daily, take on days 1-25.

It’s too complicated I’m afraid to give you a definitive answer!

I do hope you’ll buy it though as I don’t think I’ve got the brain to understand it all 
xx

[Uptick]

Hi ladies, just a word on the science behind it all (still in its infancy, I'm afraid)

The influence (modulation) of progesterone on ERα (ESR1) or ERβ (ESR2) (estrogen receptors found in the membrane, nucleus and cytoplasm of the cell) and G-protein–coupled estrogen receptor, GPER (found only in the membrane of the cell), dependends on many factors: specific tissue (breast, uterus, ovaries, vagina, brain areas, thyroid, colon, bone, etc), because ER’s regulation is modulated by tissue-specific coactivators and corepressors; status of current and previous hormonal stimulation (oophorectomised or intact ovaries, exposure to HRT), because depending on previous estrogen priming or cotreatment or during postpartum phase when estrogen level sharply rises, progesterone can either increase or decrease the experession of ERα in the hypothalamus https://www.hindawi.com/journals/ije/2015/949085/; the relative levels of ERα and ERβ and the corepressors and coactivators can change with sex, age, disease, and tissue thereby altering the response to estrogen; and, last but not least, the type of organism studied, because most of the studies have been carried out in animals or in human breast cancer cells in vitro, and their results might not always correlate with what happens in women using HRT.

‘progesterone and vitamin D negatively regulate ER levels’

https://www.ahajournals.org/doi/10.1161/circresaha.115.305376

‘PR (progesterone receptor) is an upregulated target gene of ER, its expression is dependent on estrogen, and PR can modulate ER action.’

https://www.dovepress.com/the-role-of-progesterone-receptors-in-breast-cancer-peer-reviewed-fulltext-article-DDDT#cit0008

‘Progesterone inhibited oestrogen-mediated growth of ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist.’

https://pubmed.ncbi.nlm.nih.gov/26153859/

Progesterone modulation of D5 receptor expression in hypothalamic ANP neurons, the role of estrogen

https://www.nature.com/articles/4000781

Crosstalk between progesterone receptor membrane component 1 and estrogen receptor α promotes breast cancer cell proliferation

https://www.nature.com/articles/s41374-021-00594-6

[CrispyChick]

Wow. A lot of worthy effort there ladies.

That's all a bit much for me though - I just want to know if, as described anecdotally in the States, my low level application of progesterone cream, can indeed make my high estrogen symptoms worse.  thereby demonstrating the need for a higher dose.

Uptick - are you confirming that in any of that information??? I'm not clear.

Maybe this bit? -

'progesterone can either increase or decrease the experession of ERα in the hypothalamus'

[Marchlove]

https://www.amazon.co.uk/exec/obidos/ASIN/B088GJF6QK/menopausema0e-21

[Gnatty]

So if we supplement with Vitamin D, are we lowering our oestrogen levels? So complicated!

[Marchlove]

Hi Guys,
My last post with the Amazon link wasn’t the link I sent by the way, I think it got changed. Never seen that book before! X

[Uptick]

That's all a bit much for me though - I just want to know if, as described anecdotally in the States, my low level application of progesterone cream, can indeed make my high estrogen symptoms worse.  thereby demonstrating the need for a higher dose.

Uptick - are you confirming that in any of that information??? I'm not clear.

Maybe this bit? -

'progesterone can either increase or decrease the experession of ERα in the hypothalamus'

Hi CrispyChick,

What do you mean by 'my high estrogen symptoms'?

What are your current symptoms? Sorry if you have already mentioned them, but it's useful to have them all listed in one place to get a better picture of what's happening with you.

[CrispyChick]

Sorry Uptick. I must have misunderstood.

I thought the scientific articles you posted were in relation to Hurdity's request to see the science in relation to a discussion on how progesterone affects estrogen receptors, with points Hurdity queried from myself and another member?

It's a long saga I'm afraid. It's all in this thread as some of us are using 'alternatives' in an attempt to feel better.

In short. I'm 45. Estrogen levels are good. Been suffering horrifically for years from dizziness, nausea, brain fog, aches etc NHS meno clinic only offered pill - no joy after trying them all. Then tried HRT. The estrogen part alone made me feel poisoned. Now seeing bhrt clinic. Found progesterone to be very low. Now supplementing with progesterone.

It's early days. I'm on a low dose of progesterone. There is a huge amount of anecdotal evidence to suggest that low doses antagonise the estrogen receptors and make symptoms worse. Simply, I'm wondering if that is what I'm experiencing.

[Hurdity]

Hi Hurdity

I found this article very good for explaining where I am at in terms of perimenopause, and why progesterone supplementation alone may be beneficial - and much more appropriate than the contraceptive pill for managing my symptoms.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987489/

As you'll have seen from the thread, I have started low dose progesterone treatment via a compounded pharmacy - as progesterone treatment alone has never been explored with me through my GP or NHS meno clinic.

I have been quite shocked to find my original symptoms ramp up during this progesterone trial. I have therefore highly researched and discovered a phenonomon which I would describe as 'progesterone in low doses, or when starting out, can antagonise the estrogen receptors'. In fact, some say this is why many women on cyclical hrt suffer as the stop/start approach induces this - although I wouldn't like to comment on that.

Although not a scientific paper, I found this, which explains much better than I can, and will allow you to research further, should you be interested.

https://doc.vortala.com/childsites/uploads/88/files/Why-Some-Women-Feel-Worse-When-Starting-Natural-Progesterone.pdf

Not sure there are any scientific papers on this in the UK. Perhaps it's not been studied. However, there is a huge amount of anecdotal evidevce about this, particularly from America - where they often use progesterone therapy.

I personally find other people's experiences much more valuable than any scientific paper. As I do feel this area of pre menopause is lacking in research and advice in the UK.

Only time will tell if this is what I am experiencing. I currently believe the progesterone cream is not strong enough for me and is antognising my estrogen rather than increasing my progesterone sufficiently enough to bring balance.

Hi Crispychick

Thanks for taking the trouble to reply to my questions.

I understand you are trying to work out the best way to feel better, having tried lots of different regimes and the reasons you are not feeling so good.

In terms of other people's experiences - these are of course very valuable and can be reassuring but the underlying treatments and the rationale behind them must be based on sound science - as I know you appreciate.

There are lots of "theories" out there and anecdotal accounts whihc may or may not have any basis to them or may not be universally applicable.

If you don't mind my saying I think you're making it too complicated by focussing on receptors and trying to work out precisely what is happening. Our endocrine system is extremely complex and yes there are feedback mechanisms going on, and different scenarios at different stages in our reproductive lives.

I can't remember off-hand what stage of menopause you're at in terms of cycles - before you started HRT - whether you are early or late peri and how long this has been going on?

Aside from that, the way I see it as I remember - your oestrogen levels are average and not deficient, maybe you're not experiencing flushes and sweats? It all depends on your natural cycles. You are supplementing with progesterone (cream.lozenges) and not feeling any better and increasing the dose makes you feel worse. To me this suggests you don't need to supplement with progesterone.

I had a look at the reference (the first one - the paper). The guy who wrote it there is using progesterone to treat peri-menopausal symptoms in a pharmaceutical way rather than physiological - ie as a drug rather than replacing what is missing. This is a well known phenomenon and is actually reported on this website - and works with artificial progestins as well as progesterone.

"HIGH DOSE PROGESTOGENS (MPA) Medroxyprogesterone Acetate and Megestrol Acetate (Megace) are synthetic forms of progesterone which sometimes reduce hot flushes and sweats. They also offer a degree of bone protection. They have been prescribed to women who cannot take estrogen after breast cancer treatment but concern currently exists about the possible effect of progestogen on the breast and so are now used less often. The side effects of these drugs can sometimes outweigh the benefits. In particular there is known to be an increased risk of clotting with higher doses of progestogens. "

https://www.menopausematters.co.uk/prescribed.php

So you don't actually need extra progesterone as such unless you are still having cycles but some are anovulatory so you could be getting erratic high spikes of oestrogen - in which case taking it will help regulate your cycles, and maybe help prevent the spikes?

In addition the dose the guy recommended is indeed a pharmaceutical dose - he recommends 300 mg taken daily. This is very high - and women only take this for endometrial protection on higher doses of oestrogen as HRT, if the endometrium is not protected.

If you want to use it in this way - eg to prevent flushes and sweats - then you might as well use Utrogestan which is the cheapest and safest way to take "natural" progesterone at such high doses. If you wnated to space it out to prevent spikes then perhaps take it 3 times per day though the guy in the paper I think recommended to take it in one dose at night.

I haven't gone into the receptor issue and if you're not taking oestrogen in any case I don't think it is especially relevant to your situation?

I know this is obvious but I presume you've had other things ruled out for your symptoms if they've been going on for that long?

Also have you tired any of the pills like Zoely or Qlaira which regulate your cycles and also give progestogens - OK not natural ones - but may also be beneficial?

Just a few thoughts off the top of my head but really concerned that yuo are spending lots of money going down this route (your choice obivousdly!) when it's not doing any good and I'm not sure the theory (the receptor issue) has any proper scientific basis.

In yur position I would see if I could stand back and say - try this or that - if that makes me feel worse then try something else. Each regime needs to be tried for a reasonable length of time....

Hope this helps a little and that you get some answers and the right treatment

Hurdity x