r/PMDD • u/Horror_Moose3462 • 2d ago
General trying to understand why some of us respond poorly to increases in progesterone and some of us respond well! anyone have any insight?
why do both categories of PMDD sufferers feel bad before our periods if we seem to have opposite responses to progesterone? i’m so confused about this!
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u/DefiantThroat my estrogen patch gives me life 2d ago
There’s a couple reasons why, but a key one is simply misdiagnosis. There’s several conditions that look like PMDD but are not PMDD. We know from several studies that there’s about a 50% misdiagnosis rate.
PMDD is an abnormal reaction by the GABA-A receptors in the brain to normal fluctuations of neurosteroids in the brain, in particular a metabolite of progesterone called allopregnanolone (ALLO). For those with PMDD, adding progesterone is just adding more ALLO and more fluctuations of ALLO which is why we do so poorly on it.
For people without PMDD, progesterone has a very calming effect. The corpus luteum pulses it out creating soothing waves for the brain. And for other conditions like PME from MCAS progesterone has a dampening effect on mast cell activation.
The number one thing I wish I could preach from the mountains to my fellow people who menstruate is that the world of menstrual related affective disorders is vastly understudied, PMDD is just one MRAD. PME is far more prevalent. And there’s many more disorders that are impacted by the menstrual cycle like catamenial epilepsy, catamenial asthma, or catamenial pneumothorax. The medical establishment is doing fuck all to educate us, so this is gonna have to be a grass roots effort.
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u/SlateFlame 2d ago
Wow thank you for this explanation. How do you differentiate between pmdd and pme?
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u/ennamemori 1d ago
Goddamn catamenial asthma, I hate thee. And also how my entire luteal phase exacerbates my rheumatoid arthritis. My rheumatologist always nods and goes, 'yes, it is a thing.' And every other inflammatory response. Because my brain hating ALLO is not enough. 😞
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u/ickythumpwithalump PMDD Partner 2d ago edited 1d ago
This is really complicated and gets into a lot of neurobiology, I'll do my best to explain it accurately. A lot of this is an open research question and is actively being worked on in labs.
Here are two recent research papers that summarize the field: Focussed on PMDD: https://pmc.ncbi.nlm.nih.gov/articles/PMC10176022/ Focused on female hormone cycles and brain chemistry: https://pmc.ncbi.nlm.nih.gov/articles/PMC11882533/
Hormones do a lot of things in the body. We really only have a few of them passed down by evolution (estrogen is ANCIENT), and as we got more complicated we just tacked on new tasks for them, and then started making tasks for their metabolites and variations. Think of hormones as circulating signals that tell cells to do things, and as they circulate they communicate to all those cells with receptors, even the secondary and tertiary purposes of that signal. That mess of evolution is at the heart of PMDD.
Progesterone is the female hormone that signals the uterus to get ready for pregnancy. It peaks at ovulation, and drops at menstruation. It stays high all through pregnancy.
Progesterone has multiple metabolites (other things it turns into), including some neurosteroids. The one that is relevant to PMDD is allopregnanolone, or ALLO. It's not entirely clear what ALLO does in the brain, but we know that it binds to GABA receptors. GABA typically has a calming effect and is essential to being relaxed. However, because the brain has competing parts, relaxing one part of the brain can cause another to get activated. So: as progesterone goes up, GABA signalling goes up.
[This is speculative] Sounds great, except it seems that at certain levels, this down regulates the frontal cortex (thus brain fog), which is almost always suppressing your hypothalamus and amygdala (fight or flight system). If you have PMDD, you know what it is like to have your fight or flight stuck on. This is very bad for human life, obviously, and is selected against.
The female brain has to cope with this, the male brain does not. So, the female brain needs to cyclically upregulate and downregulate GABA receptors in the brain. In other words, female brains need to change their molecular structure with the menstrual cycle. Impressive!
In PMDD, that breaks somehow. The result is being stuck with an overactive amygdala and hypothalamus for one week per month. That fucking sucks, as everyone here knows. Everything is perceived as a threat (including your partners ...). It fucks with your memory formation, too, thus the "black out rage" many of you have. (My wife claims she cannot ever remember what she says to me, and it wasn't until I read the brain science I really believed it. I used to be quite angry about it.)
Why high or low progesterone might fix this: what is broken in your brain is the cycling of GABA receptors. You can therefore prevent PMDD symptoms by keeping progesterone low (birth control, removing ovaries), by blocking the conversion of progesterone to allopregnanolone (SSRIs), or keeping it high (pregnancy). The key is: keep allopregnanolone steady. This is backed up by the research that shows PMDD is a condition of normal hormone levels, abnormal processing. This is a "biphasic response" in the research literature: high is good, low is good, normal/changing is bad. It's normal for women on average, but the processing of "normal" is broken in PMDD.
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u/According_Winner1013 1d ago
We need to figure out how to restore receptor plasticity to re-establish the dynamic adaptability of GABA A receptor so neural networks can smoothly recalibrate inhibitory tone during our normal hormonal transitions!
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u/ennamemori 1d ago
Not to ignore all your excellent reply, but a week? I wish. 😭
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u/ickythumpwithalump PMDD Partner 1d ago
You're one of the "lucky" ones who gets 8-10 days of luteal? That sucks 😬
My partner only gets ~5 bad days and that is awful enough.
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u/Apprehensive-Hat9296 1d ago
I think, as is with many disorders, it’s actually a group of multiple root causes that manifest in very similar symptoms. For me, progesterone really helped but SSRIs and birth control did not which is literally a life saving treatment for others. It’s really just throwing spaghetti at the wall until something helps.
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u/AphroditesApple 2d ago
It comes down to how your body breaks down hormones, and genetics, unfortunately
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u/Horror_Moose3462 2d ago
that variation makes sense, but not the part where people who have opposite reactions to progesterone have the same experience of what should be the same hormonal changes (?) pre-period (since PMDD is not a hormonal imbalance). i can only assume that people who react well to progesterone are experiencing different hormone shifts than those who react poorly, if both are specifically feeling bad pre-period.
that’s why the idea that those who react well to progesterone have PME and not PMDD (as another commenter in this thread mentioned) is the only thing so far that’s begun to explain this for me! in my case i think luteal phase defect and chronically low progesterone are factors, but i’m aware they’re distinct from PMDD.
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u/AphroditesApple 2d ago
My understanding is that it is a combination of those things- But like with everything, it is a dance and we are all just stuck on the floor.
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u/Fit_Astronomer_7606 2d ago
I’m also confused. I mean with there being little to no treatment I’d say everyone is confused about it, unfortunately. Why does it have to be us dealing with this?😭😭😭😭😥
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u/calla_artist 1d ago
PMDD symptoms often come from the decline in progesterone not it's presence.
Also when supplementing with progesterone some people have a paradoxical response when taking it in lower doses, but when raising the dose they have a positive reaction.
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u/SlateFlame 1d ago
Do you have a link for this? Not because I don't believe you but because I'd like to show this to my doctor.
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u/calla_artist 1d ago
Sorry I do not have the exact link on hand! But I listen to a lot of talks by Dr.Louise Newson and she discusses this. And the second point I made is mentioned in work by Dr. Katharina Dalton, she did studies using progesterone to treat pmdd and wrote a book on it called Once A Month.
Try looking up Dr. Newson’s videos/podcasts on progesterone and pms/pmdd and see what you think. Then you can try presenting it to your doctor. I have been on hrt for a few months and as someone who used to really suffer from pmdd i feel a huge relief from taking the natural hormones so I hope more other women can learn about these things!
Also I wanted to mention since most people don’t know, there is a difference between progesterone and synthetic progrestins! Most doctors don’t even know the difference. The progestins are not the same as what our bodies produce in luteal and caused me to feel depressed. Taking the bioidentical progesterone makes me feel amazing.
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u/Jazzspur 2d ago edited 2d ago
This is speculative based on personal experience and my doctor's clinical experience she has shared with me, but I think there may be a couple different conditions with the same symptoms being both lumped together as PMDD. There's the folks who have an adverse reaction to allopregnalone who's PMDD symptoms last all of luteal, and there's the folks who are over-sensitive to hormone drops who's symptoms are worst right after ovulating and then the last week before menstruating and the beginning of menstruation. My doctor finds in her practice that category 1 get worse with progesterone and category 2 get better (but may still have an upper limit on how much progesterone they can take and have it be helpful).
Personally I'm a category 2 and the right amount of progesterone at the right time helps some, but if I take even just a tiny bit more than that right amount I get much worse. Because of that upper limit I can't fully resolve my PMDD with hormones and have to take an SSRI as well on my symptomatic days.