Thyroid Hormone Transporters in a Human Placental Cell Model

[helvella]

There has long been the received wisdom that T3 does not cross the placenta. I am not aware this has been proved in any level of detail.

This paper appears to make that look wrong.

Indeed, it appears to identify specific pharmaceutical agents which directly and significantly affect T3 transport.

Silychristin is a constituent of Milk Thistle extract and its impact suggests that it should be avoided in pregnancy - and possibly other circumstances.

ThyroidVol. 32, No. 9 Thyroid Economy: Regulation, Cell Biology, and Thyroid Hormone Metabolism and ActionOpen AccessCreative Commons license

Thyroid Hormone Transporters in a Human Placental Cell Model

Zhongli Chen,

A.S. Elise van der Sman,

Stefan Groeneweg,

Linda Johanna de Rooij,

W. Edward Visser,

Robin P. Peeters, and

Marcel E. Meima

Published Online:14 Sep 2022 doi.org/10.1089/thy.2021.0503

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Abstract

Background: Fetal brain development in the first half of pregnancy is dependent on maternal thyroid hormone (TH), highlighting the importance of trans-placental TH transport. It is yet unclear which transporters are involved in this process. We aimed to identify the major TH transporters in a human placental cell model (BeWo cells).

Methods: Messenger RNA expression of the known TH transporters (the monocarboxylate transporter [MCT]8, MCT10, the L-type amino acid transporter [LAT]1, LAT2, the organic anion transporting peptide [OATP]1A2 and OATP4A1) in BeWo cells and human placenta were determined by quantitative PCR. To determine the specificity and efficacy of transporter inhibitors, we first determined TH uptake at different inhibitor concentrations in African green monkey kidney fibroblast-like cells (COS1 cells) overexpressing TH transporters. We then tested TH uptake in BeWo cells in the presence or absence of the optimal inhibitor concentrations.

Results: All tested TH transporters were expressed in human term placentas, whereas MCT8 was absent in BeWo cells. Both 2-amino-2-norbornanecarboxylic acid (BCH) and L-tryptophan at 1 mM inhibited LATs, whereas at the highest concentration (10 mM) L-tryptophan also inhibited MCT10. Verapamil inhibited OATP1A2 and less efficiently both MCTs, but not LATs. Both rifampicin and naringin reduced OATP1A2 activity. Finally, silychristin inhibited MCT8 at submicromolar concentrations and OATP1A2 partially only at the highest concentration tested (10 μM). In BeWo cells, verapamil reduced triiodothyronine (T3) uptake by 24%, BCH by 31%, and 1 mM L-tryptophan by 41%. The combination of BCH and verapamil additively decreased T3 uptake by 53% and the combination of BCH and 10 mM L-tryptophan by 60%, suggesting a major role for MCT10 and LATs in placental T3 uptake. Indeed, transfection of BeWo cells with MCT10-specific small interfering RNA significantly reduced T3 uptake. Only the combination of BCH and verapamil significantly reduced thyroxine (T4) uptake in BeWo cells, by 32%.

Conclusions: Using pharmacological inhibitors, we show that MCT10 and LATs play a major role in T3 uptake in BeWo cells. T4 uptake appears independent of known TH transporters, suggesting the presence of, currently unknown, alternative transporter(s).

Full paper accessible here:

liebertpub.com/doi/10.1089/...

[jimh111]

I've seen studies showing T3 doesn't cross the placenta (long time ago). However, there have been millions of successful deliveries from mothers on NDT over the past centuary and some from Dr Lowe's patients on liothyronine monotherapy. Hence there is a missing factor we don't know about. Good evidence that T3 doesn't cross the placenta and good evidence it does.

[greygoose in reply to jimh111]

This is like the brain, isn't it. It is said that only T4 crosses the blood/brain barrier, and yet those of us on T3 monotherapy still have functioning brains. Could it be with both of them that the prefered hormone is T4, but if there's no T4 - or less T4 than T3 - the T3 will cross the barrier just as well?

[helvella Administrator Thyroid UK in reply to greygoose]

That is, as you point out, another canard! (What is French for a canard? )

I'm not sure that T4 is even preferred! My guess is that, like for T3 from the thyroid, its quantity may be (relatively) modest, but it is important. And it will be transported in all of us.

But the science required to identify small quantities of T3 being transported, and to investigate their importance, has yet to be done. (Some has been - but not enough to make the textbooks.)

[greygoose in reply to helvella]

I think the French for 'canard' is 'duck', isn't it?

Anyway, that makes sense, yes: quantity rather than quality.

[TSH110 in reply to helvella]

what is canard full stop? A word I have never come across until now. Rumour or a bit of an aeroplane….

[helvella Administrator Thyroid UK in reply to TSH110]

canard

noun [ C ]

literary

uk

/ˈkæn.ɑːd/ us

/kəˈnɑːrd/

a false report or piece of information that is intended to deceive people

dictionary.cambridge.org/di...

Sometimes pronounced with a French/fake French accent to emphasise a degree of jocularity.

I think it might translate as un bobard.

[TSH110 in reply to helvella]

don’t know bobard either! Inconsequential lie

[JGBH in reply to helvella]

🤣…. excellent!

[helvella Administrator Thyroid UK in reply to TSH110]

Sorry - missed - it is standard French for a duck - as in a bird that quacks.

[jimh111 in reply to greygoose]

The brain gets 80% of its T3 from T4 and 20% from T3, at least in rats it does they haven't got around to chopping up human brains to find out.

There's good evidence that TSH promotes type 2 deiodinase (D2) and the brain uses D2 to convert T4 to T3. My view is that when people have low levels of TSH (or TSH with low bioactivity) they have impaired T4 to T3 conversion in the brain. (by low TSH I mean TSH that is lower than you would expect for their fT3, fT4 levels). I suspect the brain uses T4 as a reservior for when it needs extra T3 and also to keep its T3 levels hunky dory when blood levels are out. This would explain why my memory concentration falls after about 20 minutes studying. It would also explain why this group of patients, with a subnormal TSH require higher than normal serum fT3 levels, to compensate for the loss of local T4 to T3 conversion in the brain.

[helvella Administrator Thyroid UK in reply to jimh111]

Do we know anything of the process by which TSH gets through the blood-brain barrier?

[jimh111 in reply to helvella]

I certainly don't! Cellular transport is an active process with a number of cellular transporters such as MCT8. If it were passive thoses pesky little T3s would always get in.

[jimh111 in reply to helvella]

I misread your question (on my mobile), I thought you wrote 'T3'. I don't know how TSH gets across the blood brain barrier, assuming it does. I will research this as it's interesting.

There's a study that shows TSH stimulates deiodinase in some brain cells but this was an in vitro study so doesn't cover transport of TSH into the brain. As far as I remember the anterior pituitary is outside the BBB but I think the hypothalamus is inside.

TSH is in the CSF.

[helvella Administrator Thyroid UK in reply to jimh111]

There is a bit of discussion and a diagram in Tanya's piece:

thyroidpatients.ca/2020/01/...

As I see it:

We have little understanding of TSH levels in the brain/CSF. Do they closely follow blood levels (or vice versa!)?

What route does TSH take? A relatively large molecule (compared to T4 or T3).

What factors influence its transport?

[jimh111 in reply to helvella]

It looks like CSF has TSH although at much lower levels than serum touchendocrinology.com/pitu... .

[helvella Administrator Thyroid UK in reply to jimh111]

Interesting but we need to understand how it happens.

[TSH110 in reply to jimh111]

Small wonder I felt brain dead on t4 then!

[JGBH in reply to jimh111]

I understand that high-ish levels of T3 naturally bring the levels of T4 down and give very very low level of THS. In fact that T3 brings TSH levels at a very low mark and that is not dangerous. Is this the case?

[jimh111 in reply to JGBH]

Liothyronine is about 3x as potent as levothyroxine in terms of suppressing TSH. A suppressed TSH is associated with osteoporosis and cardiac problems. It’s not so simple though. Often TSH is low because the pituitary is not fully functioning and it’s these patients that often need T3. So, we have the problem: is TSH low because of too much hormone or because the pituitary is underperforming?

Also, some people need higher doses of T3 to lead a reasonable life, even if it carries some risks. I would try to avoid a low TSH but it isn’t always possible.

[JGBH in reply to jimh111]

Thank you for your prompt reply. My test results dated Mayb2022 are:

Serum TSH < 0.05 miu/L (0.3 - 5.5) BELOW RANGE

Sérum Free T4 17.4 pmol/L (12.0 - 22.0)

Serum Free T3 4.7 pmol/L (3.1 - 6.8)

I take 75 mcg Levothyroxine/day and 20 mcg Liothyronine/day. I take these together at 6.30 am, 2 hours before food.

I am awaiting new test results this week prior to my phone appointment with my endocrinologist.

I feel very tired (but also have RA and osteoporosis which are very painful thus make me tired).

Any idea/opinion? What do you suggest I should ask the Endo?

I take VitD3 plus VitK2-MK7, a superB vit complex, and inject B12. I also use BetterYou Magnesium spray on my legs.

I used to take levothyroxine only, 100 mcg/day. So I was advised to reduce this to 75 mg and slowly increase Liothyronine.

I must admit I am concerned about cardiac problems…

Any advice/suggestions would be most appreciated.

[jimh111 in reply to JGBH]

You are not on a very high dose so should be reasonably OK (I’m definitely not a doctor). If you want to discuss your case you need to do a separate post as we are drifting a long way off topic (I’m always doing that).

[JGBH in reply to jimh111]

Again, thank you for replying. Of course I know you’re not a doctor… (although I often wonder why, we poor patients, trust some doctors, but that’s another story). I will do a separate post.

[Zephyrbear in reply to jimh111]

I have had a suppressed TSH (comes back as unreadable) for around 10 years now and my latest DEXA scan showed my bone density was very good (in fact, the endo said I had the bones of a 35 year old) and, monitoring my ecg daily on my watch, I’ve never had AF either! Quite frankly, I think that’s another one of these convenient urban myths doctors like to use to frighten people into compliance…

[jimh111 in reply to Zephyrbear]

It's a complex subject. Many studies on suppressed TSH were done in people who had various thyroid diseases which may also affect the parathyroid glands and hence bone density. In general a suppressed TSH means the body reckons the combined fT3 and fT4 are too high and so indicate hyper activity. However, it seems that liothyronine may suppress TSH a little more than T3 slowly released from the thyroid and so give a TSH a little lower than it would be for the same hormone load. Also, quite a few patients have a pituitary that isn't as vigorous as it should be, it releases less TSH than might be expected for their fT3, fT4.

I always try to differentiate between a suppressed TSH caused by too much hormone and a subnormal TSH due to insufficient secretion from the pituitary. Unfortunately doctors don't bother to check this. So, in general a suppressed TSH is associated with osteoporosis but this tends to be exaggerated due to earlier studies that didn't exclude potential parathyroid damage. Also, in many cases the TSH is not suppressed, it is subnormal.

[helvella Administrator Thyroid UK in reply to jimh111]

And too much about the effects of relatively high thyroid hormone levels, low TSH are inferences from medical histories which suggest long term overt hyperthyroidism. (Even if it had not been recognised for years.)

In my view, there is a world of difference between having a TSH that is just about suppressed due to medication (whether T3, T4 or any combination), and seeing it at the same value due to levels of FT4/FT3 which are miles over the top of any reference interval - as in active Graves' disease.

But, when looking at suppressed TSH, the distinction is all too often lost.

[TSH110 in reply to greygoose]

and a lot of us on t4 monotherapy had very suspect brain function

[TSH110]

Seems absurd reasoning to me that we need T3 to function but somehow a fetus doesn’t!

[jimh111]

I haven’t had time (and won’t have) time to dig through the research but I think the studies on T3 crossing the placenta were done in animals close to term. It’s quite possible and logical that the placenta starts to inhibit T3 after the foetus has developed its own thyroid system but during the early stages when dependent on the mother’s hormones allows T3 to cross.

In any event all the ‘authorities’ state categorically that T3 therapy in pregnancy is dangerous in spite of evidence over the past century.

[jimh111]

Another consideration is that the placenta starts to take over around weeks 8 to 12 of pregnancy. Thus for much of the time when T3 is critical there is no placenta.

[helvella Administrator Thyroid UK in reply to jimh111]

At 8 weeks of pregnancy, the placenta and fetus have been developing for 6 weeks. The placenta forms tiny hairlike projections (villi) that extend into the wall of the uterus.

msdmanuals.com/home/women-s...