1/1996
Enigmas of the Thyroid Gland
VRATISLAV SCHREIBER, MD, DrSc
Prof. Clin. Physiol., Lab. for Endocrinology & Metab., IIIrd Med.
Dept., lst Sch. of Med., Charles University (General University Hospital)
Prague 128 21, Czech Republic
Motto:
To whom everything is clear has one sorrow less (J. Charvát)
Introduction
It may seem trivial, but there really are unanswered questions - even enigmas
- pertaining to the thyroid gland. To a simple- minded thyroidologist,
to whom everything may be clear, let me mention seven enigmas of the thyroid
gland. All these enigmas may be characterized in that we know the answer
to the question "how", but we lack the answer to the question "why".
Enigma No.1.: The thyroid gland is (or was) a part of the gastrointestinal
system
In the lowest animals (invertebrates) (Gorbman I958) iodoproteins are formed
in fibrous exoskeletal tissues - to be mentioned - in the pharynx. The
iodoproteins formed in the pharynx - originally in the pharyngeal teeth,
another part of the skeleton - were released into the gastrointestinal
tract, where they were hydrolyzed to provide the "thyroid" hormones. Later
in the evolutionary series (Amphioxus, Ammocetes) the pharyngeal organ
became enlarged and the iodoproteins were products of an exocrine glandular
activity. After metamorphosis in Ammocetes, the iodoprotein-forming tissue
was separated from the rest of the pharynx, the duct was lost, and in the
evolving - now separate - pharyngeal organ active proteinase started to
occur to hydrolyze the iodoproteins. The products of hydrolysis - of course,
the hydrolysis of thyreoglobulin - are released into the blood as thyroid
hormones. Thus the definitive type of the thyroid gland evolved, including
the human thyroid gland. But, even in humans, the iodine-accumulating activity
remains present in the stomach and in the salivary glands, although these
other parts of the gastrointestinal tract do not produce significant amounts
of thyroid hormones. But the question arises: what is the biological advantage
of this iodine-accumulating activity of the human stomach and the salivary
glands? Why was this function preserved?
Enigma No. 2.: Thyroxine is a prohormone
It is well known that thyroxine (T4) is a prohormone, the iodinated protein
thyreoglobulin being a pre-prohormone. Triiodothyronine (T3) is more active
than thyroxine, is less avidly bound to the transport protein (TBG), and
in fact is the really active hormone reaching the cell nuclei to perform
its action. Vertebrate (and human) tissues, however, learned to transform
the prohormone (T4) to the active hormone (T3) by monodeiodase activity.
In this way, the tissues convert T4 to T3 according to their metabolic
demands: they decrease this conversion activity in fever, in starvation,
and in severe catabolic disease states. How does it happen that the monodeiodinase
activity in the tissues is able to perceive the desired metabolic level
and to adjust the T4 to T3 transformation according to the metabolic needs
of the body? Why is the type 1,5' - monodeiodinase (present in peripheral
tissues) inhibited by propythiouracil? Why is the type 2,5' - monodeiodinase
(present in the brain and in the pituitary) not? Why does the type 3,5'
- monodeiodinase protect the fetus against high T4 levels by converting
T4 to T3 and by converting T3 to diidothyronine? We clearly understand
what that all is good for, but it remains to be shown how that all happens.
Enigma No. 3.: Why do T4 and T3 act as steroid hormones?
Although T4 and T3 are derivatives of an amino acid, they do not act in
the manner of other amino acid derivatives, i. e. on the plasma membrane
receptors (and cAMP or other second messenger routes) but, like the steroid
hormones, by the nuclear mechanism. There are, however, some differences
between thyroid and steroid hormones: first, the thyroid hormones utilize
intracellular binding proteins, which - being similar to TBG - procure
a reserve of the thyroid hormones in the cell. Second: while the steroid
hormones bind to an intracellular receptor and release the heat- shock
proteins (HSP), the thyroid hormones do not. This is astonishing, since
the thyroid hormones are more closely associated with thermoregulation
and temperature than are the steroid hormones. However, liposolubility
(similar to that of steroid hormones) might be an explanation of thyroid
hormone behavior. On the other hand, of course, the elucidation of the
nuclear mechanism of thyroid hormone action has helped a lot in understanding
the physiological roles of the thyroid hormones.
Enigma No. 4.: Thyroid hormones induce catabolism by enhancing proteoanabolism
Take the tadpole tail: it is catabolized (resorbed) at the moment when
the thyroid hormones start to act in a metamorphosing tadpole (becoming
a frog). On the other hand, the human brain needs thyroid hormones for
its development - a clearly anabolic effect. The thyroid hormones are indispensable
for proteosynthesis and development in surplus; they are, however, catabolic
and produce tissue wasting, as in Graves-Basedow's disease. It is relatively
easy to explain this controversy by thyroid-hormone stimulation of the
proteosynthesis of catabolically acting enzymes. But important questions
remain. Take the bones: an excess of thyroid hormones leads to bone wasting,
to osteoporosis. This is an important problem in the treatment of hypothyroidism
in the menopausal age. Question: does not the thyroid gland, forecasting
the detrimental effect of its hormones on the bone, start to produce calcitonin?
Is there a link between hyperthyroidism and calcitonin secretion? We all
know that calcitonin is a physiological antagonist of parathyroid hormone:
but is it not also an antagonist of T3?
Enigma No. 5.: The thyroid gland is immunologically privileged
In a negative sense, of course. Perhaps because it is so strongly linked
with the environment, we do see in our out-patient departments so many
hypothyroid patients with the sequelae of several kinds of thyroid autoimmune
derangement. Although we can sometimes see the sequelae of an autoimmune
adrenalitis as a cause of Addison's disease (tuberculous lesions being
the chief cause in the past), the patients with sequelae of the autoimmune
thyroiditis are much more common than the patients with sequelae of the
autoimmune adrenalitis. What is more, the Graves' disease, caused by an
autoimmune thyroid-stimulating antibody (thyroid-stimulating immunoglobulin,
TSI) is an important point. TSI was the first antibody possessing hormonal
function to be discovered. So we encounter not only autoimmune thyroid
hypofunction, but also thyroid hyperfunction, caused by an autoimmune mechanism.
Although ASI (adrenal stimulating immunoglobulin) may also exist as a cause
of Cushing's syndrome, TSI-induced Graves' disease is much more common.
The unresolved linkage with stress - an immunosuppression by the stress
hormones (CRH, glucocorticoids) in the sense of anti- antibodies - when
antibodies to TSI are suppressed is another enigma.
Enigma No. 6.: Mutations of the TSH receptor
This is a most important achievement in the thyroid pathophysiology in
recent years. We now know (Utiger 1995) that a mutation of the TSH receptor
in the thyroid can cause hypothyroidism (resistance to TSH) as well as
hyperthyroidism with diffuse thyroid hyperplasia (goitre) or hyperfunctioning
(toxic) thyroid adenomas. The long-sought cause of toxic adenomas is coming
to be understandable. We probably will never get a medical treatment for
this mutation: propylthiouracil or methimazole or else surgical ablations
of the toxic adenomas will remain our treatment of choice. In this way,
the thyroid gland is joining other well-known causes of hormonal insensivity
- androgen resistance syndrome, non-immunogenic diabetes mellitus (NIDDM)
and pseudohypoparathyroidism. But it is obvious that we now know the cause
of toxic adenomas. Will that occur in other fields - e. g. adrenal cortex
adenomas with Cushing's syndrome? So, the sixth enigma starts to be explained.
Enigma No. 7.: Dependence of the thyroid gland on environment (iodine intake)
It is common knowledge that the citizens of the USA receive five times
as much iodine in the food (mostly from preserved bread and fishes) than
do the Europeans (except in Scandinavia). Especially in Central and East
Europe the deficiency of iodine is great. It is also possible that the
intelligence quotient depends on iodine intake (field studies in mainland
China). The question arises: does our (European) lower intellectual capacity,
lower aggressivity, lower market success depend on the iodine intake? Be
it as it may, at present it seems that the iodine uptake should be kept
in the region of 200-300 µg/day in Central and East European countries.
The danger of overdosing is, however, real. It is true that too much iodine
may be a factor in the development of thyroiditis. Why can the thyroid
gland - badly needing iodine - overreact by inflammation to iodine excess?
This is another, the last enigma. It pertains to another problem: Chernobyl
radioactive iodine release and cancer of the thyroid. Is it possible to
prevent of such harmful radioiodine intake by stable iodine? Did not the
children in Byelorussia suffer from the coincidence of two harmful factors,
namely low basal stable iodide uptake + high radioiodine uptake after the
Chernobyl disaster? The real enigma is: what should we do?
The magic number 7
Seven is in many European countries considered as a lucky number (thirteen
being an unlucky). Seven (Concise Oxford Dictionary) is one more than six,
or three less than ten, the sum of four units and three units. The Seven
Wonders of the World were seven buildings or monuments, regarded in antiquity
as specially remarkable. But endocrinology and seven? Sure: the TSH thyroid
receptor, as well as other transmembrane polypeptide hormone receptors,
has seven transmembrane domains. Why seven? The other similar receptors
(for catecholamines, insulin) possess only one or two. Recently I learned
from my immunology friends that some immunological membrane receptors have
ten transmembrane domains, but not the hormones. The number of seven for
peptide hormone transmembrane receptor domains is open for an explanation.
All readers of the journal "Thyroid Gland - Clinical and Experimental"
are invited to comment, discuss, or oppose any of the seven thyroid gland
enigmas, as well as the magic number seven. Your contributions will be
published in the next issues of the Journal.
References
Gorbman A (Ed.): Problems in the comparative morphology and physiology
of the vertebrate thyroid gland. In: Comparative Endocrinology. New York,
John Wiley 1958.
Greenspan FS, Baxter JD (Eds.): Basic and Clinical Endocrinology A Lange
Medical Book. Norwalk, Appleton and Lange 1994.
Utiger RD: Thyrotropin - receptor mutations and thyroid dysfunction.
N Engl J Med, 1995, 332:183.