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[Tc]

I was diagnosed in my 20's. It's a genetic disorder where the faulty gene causes bilirubin to not passed into bile at the normal rate and it builds up in the blood.
  I was told although It can cause jaundice most people have few other symptoms And it's a relatively harmless condition.  So as a result I have given it very ittle thought in the last 30 years. I always have high readings but normal liver function which Is a feature of it. My Gp was going through my bloods today and said "high bilirubin, but we know that's because you've got Gilberts". Not unusual, but today it set me thinking.

So I looked it up on the NHS site. Something I've never done before and it said
Symptoms inchude
Tummy pain, fatigue, dizziness, nausea, IBS, brain fog and generaly feeling unwell.

more importantly there was a list of possible triggers associated with the condition:

Dehydration, fasting, lack of sleep, infection, surgery, stress and,... wait for it ....MENSTRUATION.

A link to hormones!!

I wonder if this so called "harmless disease" which I have dismissed  over the years because I wrongly thought it's only symptom was jaundice could be causing me problems now especially all my issues with HRT and particularly oral utrogestan.

I'd be interested if anyone has the condition how or if meno and HRT has affected it and vice versa. But I'd also be interested on any thoughts/ideas of you ladies who dont have it as well.

Thanks in anticipation. Xxxx






.

[bear]

Hello Tc,
I thought you might be interested in this https://www.ncbi.nlm.nih.gov/books/NBK470200/ particularly the Toxicokinetics.
I used to teach Genetics at Uni, many so called 'normal' enzyme deficiencies and variations are still poorly understood, because there are so many possible interactions with new chemicals (meds and xenobiotics).
On the bright side, read 'Pearls and Other Issues' 
BeaR.

[Tinkerbell]

Three of my sons and their father have been diagnosed with Gilbert's disease, two youngest are affected more severely, my youngest son can go quite a nice shade of yellow!

[Tc]

Thank you bear. Just had a look. It's so interesting about the toxicokinetiks. I do wonder whether because its metabolized in the liver that could be why I'm having such severe reaction to utrogestan.
It seems to build up in my system very quickly.

. Good to see there is something actually positive to having it as well.

That mustve been such an interesting subject to teach genetics, though extremely complicated!!
Thanks for taking the time to send me the linkx

[Tc]

Tinkerbell. I dont get the jaundice severe. But my dad does. Like you say it's a definite yellow and the whites of the eyes  as well.
X

[Tc]

I've been reading more about it. I read that studies have shown Gilbert's syndrome can affect how a drug is processed or metabolised by the body. In some cases increasing toxicity. Theres quite a lot about it online. But I cant find any mention of utrogestan. It could explain why as it accumulates in my system my symptoms get steadily worse but then suddenly it seems to get to "overload" point and I then I feel very ill  very quickly.
 I stopped it on Monday night after 12 days but at 10 days i felt exhausted  nauseas pounding head. and by yesterday started shaking, sweating profousely and felt faint. I still felt the same this morning and at the docs she gave me diazepam cos I was shaking and sweating so much but it wasnt anxiety driven. this happens every time I take it. It's a definite pattern.
Maybe taking it orally just increases all the bad side effects for me because of the GS.
Its realy got me thinking.

[Ladybt28]

There are going to be ladies who don't like what I am going to write now because it is a somewhat controversial subject and some have voiced their opinions that it is "irresponsible".  I am not sure why because it is something which can be clearly read of Professor John Studd's website regarding progesterone intolerance. He uses a 7 day regime only for utrogestan on a cycle with gel.  Nick Panay (Studd's student) at Chelsea and Westminster has also used this for some of his ladies and there are those who have written about it on this website - have a look to see if you can find the posts.

Having made a bit of progress, the progesterone is obviously a problem for you in either the length of time or the dose.  You should play with these before changing to Provera.  Check out Studd's website, there is loads written there.

[Tc]

Lady. The last gynae I saw has referred me to panay. She suggested 7 days to me. And put on my letter to doc that I can take it for 7 days  until I see him. So she put it in writing. My gp.read it today and said its o.k with her as it's what my consultant has said. This consultant is in the process of heading her own meno clinic at the hospital by 2021. She knew all about panay and studd. And she recommended 7 days.

This is my own fault. I felt good at day 7 so I pushed  to 12 days. Big mistake.
Xxx

[bear]

Tc, your case is very interesting (sorry, I know you're struggling) because progesterone has been shown to bind to the region (promoter) that regulates the expression of the UGT1A1 gene, enhancing its activity in a concentration dependent way. A mutation (actually several different variations) in the UGT1A1 gene is responsible for Gilbert's Syndrome.

Considering that your UGT1A1 gene is defective, an increase in activity induced by high levels of progesterone may be causing the production of intermediate metabolites (produced by a defective enzyme) that your body is not used to handle. This is only conjectural, but it's very interesting regarding progesterone intolerance.

[Tc]

Bear. That is so interesting. Thank you so much for that info.  I've struggled so much since ovary removal and with HRT. I was told I "dont fit into the box". In the way my body is reacting.
I've been referred to Chelsea and Westminster as they deal with eastrogen absorption and progesterone intolerance problems. I am on very high dose eastrogen and my blood seum level has actually dropped as though I'm not on any eastrogen at all. My own gynae had to admit I need more specialized help. Something unusual is happening  and it so far has them stumped.
Thanks for taking the time to reply. I've learned a lot about GS today that I didnt know. Including that menopause can trigger GS symptoms!!
I was also  amazed to read that

"billirubin is involved in the metabolism of eastrogen and other drugs , therefore individuals with GS may be susceptible to toxicities from these substances which require glucoronidation for metabolism "

Im not sure if that applies  transdermal eastrogen although I dont seem to be metabolizing that properly either but  if it applies to oral eastrogen then why not oral progesterone.
I'm intrigued.
X

[bear]

Tc, please read 'Hepatic processing of bilirubin' in this article https://www.tandfonline.com/doi/pdf/10.1080/10408363.2018.1428526

Estrogen and testosterone are inhibitors of UGT1A1. Progesterone isn't.

[NorthArm]

Hi Tc

Have you tried the Utrogestan vaginally?

[Tc]

Bear. I've read it again and seen that bit. It's a bit complicated for my little brain but does that mean that E and T can cause billirubin to rise? It doesnt mention P. I'm not sure if it only applies to oral exogenous E and T but the fact that the bodies own E and T can cause fluctuations might suggest not. I'm on E patches but I also use Testosterone gel. Thanks bear.

Northern, hiya. I tried once and it kept falling out!! I think it's the way to go. Next round I will use it vaginally and see if it makes a difference.

Xx

[bear]

Tc,

Estradiol metabolism is the same, once it reaches the bloodstream, no matter if it comes from endogenous or exogenous sources. Of course transdermal delivery bypasses first liver metabolism.

According to this estradiol patch (Estraderm) leaflet: 

Metabolism

Transdermally applied oestradiol is metabolised in the same way as the endogenous hormone. Oestradiol is metabolised to oestrone, then later – primarily in the liver – to oestriol, epioestriol and catechol oestrogens, which are then conjugated to sulphates and glucoronides. Cytochrome 450 isoforms CYP1A2 and CYP3A4 catalyse the hydroxylation of oestradiol forming oestriol. Oestriol is glucuronidated by UGT1A1 and UGT2B7 in humans. Metabolic plasma clearance ranges from 650 to 900 L/(day x m²). Oestradiol metabolites are also subject to enterohepatic circulation. Oestradiol metabolites are far less active than oestradiol.

https://www.medicines.org.uk/emc/product/5838/smpc

As you can see, estriol is glucuronidated by UGT1A1, so in theory, your estriol levels are higher than expected, but that of course is not the entire picture, because the other enzyme might be doing the job.

Regarding progesterone, there is not much data. It's known that it increases UGT1A1 levels, but it's not metabolised by this enzyme.

I'm very interested in the subject of pharmacogenomics, so I'm more than glad to further investigate this. It also helps me forget my persistent depressive disorder.

I think taking Utrogestan vaginally would be a good option to bypass hepatic metabolism. It is known that both oestrogen and progesterone levels are on average 3 times higher in the liver than in the bloodstream, so usual blood tests don't show the bigger picture.

BeaR.

[CLKD]

We R a mine of info. 

R U getting support for the depression?