Charged with the task of covering both pediatric endocrine as well as the H/P/T axis, I found these talks most interesting.
Dr. Hernandez of Maine Medical Center taught me a great deal about T3 metabolism in the brain. As we all know, the thyroid hormones include T4 and T3, with T3 being the active form. T4 and T3, as well as other forms of thyroid hormone, are metabolized by enzymes called deiodinases. In the brain, two types of deiodinases are important. Type 2 (D2) converts T4 to T3, thereby increasing the more potent form for use in the brain. D2 is increased in the setting of hypothyroidism in order to continue to provide active thyroid hormone to the brain even in this compromised state. On the other hand, Type 3(D3) converts T3 to the inactive T2 and can protect the brain from states of thyroid hormone excess, such as hyperthyroidism.
We already know that thyroid hormone is important for the developing brain because the birth defect of being born without one (Congenital Hypothyroidism) is associated with poorer learning, and if left untreated, marked mental under-development. This is painted with a wide brush: thyroid hormone important for brain, but a recent paper by Ng in Nature Reviews of Endocrinology and Diabetes 2013 p. 246 details the importance of both the location (spatial) and time (temporal) of the activity of the deiodinases to lead to the development of the cochlea in the inner ear.
The speaker's group from Maine examined mice to see the detailed ways in which thyroid hormone helps our brain develop. They did this by examining mice without D2 expression in the brain (also called D2 knockout, or D2KO, without D3 expression in the brain (D3KO), or both. Mice from the Ng study above, both D2KO and D3KO, were found to have hearing loss.
As D3 protects against hyperthyroidism, a knockout creates hyperthyroidism in the brain. These mice were noted to have mild hydrocephalus (water on the brain), a brain of smaller dimensions, in particular, "shorter" from front to back, and a smaller cerebellum, which helps to control our motor functions. I addition, these animals had malformed skulls (craniofacial abnormalities) which left less room for the cerebellum to grow, and were also noted to have a thicker cortex.
T3 is crucial in the part of the brain called the hypothalamus, in particular the pre-optic nucleus and the amygdala. The timing is important too: late gestation and just after being born, a time when the brain is enriched with sex-steroid receptors (meaning when the brain is "listening intently" for either the testosterone present in baby boys or estrogen in baby girls). This led the investigators to wonder if D3KO boys were different than D3KO girls, and indeed they were.
Not only that, but the offspring (kiddoes) of male D3KO and normal females still had problems with less gene expression (activity) in the thalamus and hypothalamus than offspring of female D3KO and normal males, which is called imprinting. Now, (here is where I got a little lost), even the grandchildren of D3KO have some residual effects via a phenomenon called epigenetics.
So, in addition to exploring the role of deiodinases in the brain, they reinforced to me that there is quite a bit more to genetics than just sequencing the genome.
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The next speaker Heike ????? Of Germany spoke about the transport of the various thyroid hormones from one cell type to another in the developing brain. Both T4 and T3 pass the blood-brain barrier. T4 is taken up by the astrocytes, converted to T3, and released for use by other brain cells oligodendricytes and neurons. So, just like we're flying home today, those hormones have got to get there from here.
A protein called MCT8 is a thyroid hormone transporter (think "tunnel") in humans. When there are problems with MCT8, patients have psychomotor retardation, developmentaldelays, speech delays, marked muscle weakness, and seizures. In addition, they have abnormal thyroid labs, with low Free T4 and elevated Total T3.
Mice are a great way to learn more about humans. These scientists created a MCT8KO mouse which had similar thyroid labs, but otherwise acted like a normal mouse. On closer look, transport of T4 into the brain was mildly impaired, and markedly impaired transport of T3. However, the mice compensated by increasing D2 (remember this enzyme? It converts T4 to T3). So even though T3 wasn't being effectively transported into the brain, the brain just made it locally.
Mice have other transport proteins, so to create a mouse with differrent problems with transport, they knocked out another gene, Oatp1C1. These knockouts (I don't mean "gorgeous" here) acted similarly to the MCT8KO, so they just added them up together and created, yes, a double-Knockout. Finally, they got what they were looking for. Thyroid hormone uptake into the brain, normal in healthy mice, was about 50% in each of the MCT8KO and Oatp1C1KO, but down by 95% in the double KO (2KO).
Careful examination of the 2KO mice showed the cells of the cerebellum, called Purkinje fibers, were less branched and developed than the normal mice. As those branches are what forms connections throughout the cerebellum, once could suspect these mice would be more clumsy than normal.
The hypothalamus is transiently less developed in 2KO, but recovery was noted by adulthood. (Begs the question, how? Upregulation of other transporters?) The cerebral cortex was permanently underdeveloped. Interestingly (well, it's ALL interesting), the specific neurons that keep us calm, the GABA-Ergic tone was less in the 2KO, which increased their likelihood to have seizures.
Then came the important-yet-could-be-perceived-as-cruel tests of their musculoskeletal function. The normal mice (scientifically referred to as "wild-type", as in found in the "wild") and 2KO mice were made to walk on a rotating rod (Rotarod test) until they fell off. They were also made to hang from a wire, and their grip strength was measured. Guess who did better.
Overall, these mice seem to have a very similar profile as the MCT8-challenged humans, and offer a model to study further the effects of thyroid hormone transport.
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The third and last speaker compared the neurological outcomes of two different populations: babies born to under-treated hypothyroid mothers, and babies born without thyroids. Babies as fetuses rely completely on their mothers for thyroid hormone. They begin to make their own thyroid hormone in the second trimester, and rely more and more on their own thyroid than their mothers' until they reach independence at delivery. (Thyroid independence only. They're pretty much dependent on us for everything else). Anyhow, armed with this knowledge, we can classify these groups into early, fetal hypothyroidism (FH) and late, congenital hypothyroidism (CH).
FH was recently studied by Dr. Haddow (NEJM) which showed a direct correlation between maternal Free T4 and baby's IQ. If the mother's Free T4 was in the lowest 10%ile, the children did less well on the Bailey test (a tool used to objectively measure intelligence in kids). If the low level persisted into the 3rd trimesters, IQ was further decreased. Similar findings were seen in other cohorts (Project VIVA, "Maine", ABLD, and Generation R).
CH patients, even with optimal thyroid hormone replacement, have, on average, 7.5 fewer IQ points, and seem to struggle with visuospatial understanding and memory.
Now for some more mice studies. In 2007, Dr. Mary Gilbert treated pregnant mice with an anti-thyroid drug called methimazole for 1-3 days (thereby making her hypothyroid) before replacing thyroid hormone afterward, effectively creating the same scenario as FH when done in early pregnancy, and similar to CH when done in later pregnancy.
Careful study of the FH pups revealed inadequate migration of the various brain cells in the hippocampus and cortex, leading to a thickened cortex. Behaviorally, tFH mice were prone to seizures and "wild runs". (Incidentally, I did not know running wildly about was bad, but in mice, apparently so.)
On anatomy studies, the development of the cortex (corticogenesis) was altered, with persistence of symmetric division of the progenitor cells, and less asymmetric division into more specified cells. (Mohan 2012).
Back to the humans, CH and FH patients were noted to have alterations on MRI. Older patients of both types had impaired memory of events in their own lives.
Overall, in both mouse and human models, both FH and CH caused independent problems in development of the human brain.
Then came the important-yet-could-be-perceived-as-cruel tests of their musculoskeletal function. The normal mice (scientifically referred to as "wild-type", as in found in the "wild") and 2KO mice were made to walk on a rotating rod (Rotarod test) until they fell off. They were also made to hang from a wire, and their grip strength was measured. Guess who did better.
Overall, these mice seem to have a very similar profile as the MCT8-challenged humans, and offer a model to study further the effects of thyroid hormone transport.
------------
The third and last speaker compared the neurological outcomes of two different populations: babies born to under-treated hypothyroid mothers, and babies born without thyroids. Babies as fetuses rely completely on their mothers for thyroid hormone. They begin to make their own thyroid hormone in the second trimester, and rely more and more on their own thyroid than their mothers' until they reach independence at delivery. (Thyroid independence only. They're pretty much dependent on us for everything else). Anyhow, armed with this knowledge, we can classify these groups into early, fetal hypothyroidism (FH) and late, congenital hypothyroidism (CH).
FH was recently studied by Dr. Haddow (NEJM) which showed a direct correlation between maternal Free T4 and baby's IQ. If the mother's Free T4 was in the lowest 10%ile, the children did less well on the Bailey test (a tool used to objectively measure intelligence in kids). If the low level persisted into the 3rd trimesters, IQ was further decreased. Similar findings were seen in other cohorts (Project VIVA, "Maine", ABLD, and Generation R).
CH patients, even with optimal thyroid hormone replacement, have, on average, 7.5 fewer IQ points, and seem to struggle with visuospatial understanding and memory.
Now for some more mice studies. In 2007, Dr. Mary Gilbert treated pregnant mice with an anti-thyroid drug called methimazole for 1-3 days (thereby making her hypothyroid) before replacing thyroid hormone afterward, effectively creating the same scenario as FH when done in early pregnancy, and similar to CH when done in later pregnancy.
Careful study of the FH pups revealed inadequate migration of the various brain cells in the hippocampus and cortex, leading to a thickened cortex. Behaviorally, tFH mice were prone to seizures and "wild runs". (Incidentally, I did not know running wildly about was bad, but in mice, apparently so.)
On anatomy studies, the development of the cortex (corticogenesis) was altered, with persistence of symmetric division of the progenitor cells, and less asymmetric division into more specified cells. (Mohan 2012).
Back to the humans, CH and FH patients were noted to have alterations on MRI. Older patients of both types had impaired memory of events in their own lives.
Overall, in both mouse and human models, both FH and CH caused independent problems in development of the human brain.
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