Download The Evolution of Thyroidal Function in Fishes

AMER. ZOOL., 13:899-905 (1973).
The Evolution of Thyroidal Function in Fishes
MARTIN SAGE
University of Texas, Marine Science Institute, Port Aransas, Texas 78373
SYNOPSIS. Although the thyroid gland evolved from the gut, there is no evidence that
thyroxine functions as part of the gastrointestinal endocrine system nor does it have
any major function analogous to the control of glucose by the pancreatic islets. The
control of the thyroid evolved from the pituitary control of the gonad suggesting that
an early role of thyroxine was in reproduction. This idea is supported by the presence
of cycles of thyroid activity associated with reproduction in both elasmobranchs and
teleosts. In teleosts thyroxine is necessary for gonadal maturation. The numerous
other effects of thyroxine in teleosts may have evolved from this maturational effect or
have been added to it during the course of teleost evolution.
The role of the thyroid gland in fishes changed and been added to in the teleosts.
has been reviewed many times (Goldsmith, It may also be meaningful to ask why some
1949; Fleischmann, 1951; Lynn and Wa- hormones such as thyroxine and prolactin
chowski, 1951; Gorbman, 1955, 1959; Berg have acquired such a variety of functions,
et al., 1959; Hoar, 1959; Leloup and Fon- whereas many other hormones appear to
taine, 1960; Roche, 1960; Dodd and Matty, have retained a single or relatively few func1964; Bern and Nandi, 1964 Matty, 1966; tions throughout the whole of vertebrate
Barrington, 1968; Gorbman, 1969; Barring- evolution. This approach may at least proton and Sage, 1972). The thyroid has been vide the framework on which to organize
implicated in almost every aspect of teleost the data already available, while more hopephysiology including growth, differentia- fully it may provide some impetus and dition, metamorphosis, maturation, reproduc- rection for future research.
tion, the integument, respiration, various
The presence of a thyroid gland and its
aspects of metabolism, behavior, the central ability to produce the thyroid hormones
nervous system, seasonal adaptation, tem- thyroxine and triiodothyronine are striking
perature tolerance, osmoregulation, and characteristics of vertebrate organization.
several others (see reviews, especially Dodd The thyroid gland is composed of hollow
and Matty, 1964). The resulting confusion follicles of cells surrounding a liquid colloid.
has probably discouraged people from work- This colloid forms a reserve of potential
ing in this field with the result that there hormone. The thyroid gland is the only verhas been very little published since the sub- tebrate endocrine organ with such an extraject was last reviewed and no recent work cellular store. In most agnathans and telehas led to any new insight into the role of osts, thyroid follicles are scattered around
thyroid hormones in teleosts. There is no the ventral aorta while in other vertebrates
justification at this time for yet another the follicles are aggregated into one or two
review, whereas there is a great need for an discrete thyroid glands. Such an evolution
attempt to discern some order in the already of scattered elements into a compact gland
available data. Accordingly, I have chosen is a common feature of endocrine evolution.
to examine what we know of the evolution- Similiar changes have occurred in the evoluary history of the thyroid gland, its function tion of the adrenal medulla and cortex and
and its control in the hope that from such to a lesser extent the pancreatic islets. The
an approach we may suggest reasonable possible advantages of such a trend are not
hypotheses for the original functions of the often discussed. It is, however, known that
thyroid and how these functions may have part of the control of the human adrenal
is exerted by modifying the flow of blood
through the gland (Dobbie et al., 1968).
Supported by N.S.F. Grant GB 22995.
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MARTIN SAGE
Such a method of control is only possible
in a compact structure with an independent
blood supply.
The thyroid is unique amongst endocrine
organs in that we can clearly trace its evolution from another structure present in the
protochordates. A clue to this origin is seen
in the lamprey where at metamorphosis the
thyroid differentiates from parts of the larval endostyle, a complex structure in the
floor of the pharynx (Barrington and Sage,
1972^. Strikingly similar endostyles are
found in the cephalochordate amphioxus
and in the tunicates (Barrington, 1959). We
also know that in spite of anatomical differences these endostyles have the biosynthetic
properties of thyroid glands (Barrington,
1968; Salvatore, 1969) as well as other activities associated with the alimentary nature of the endostyle (Barrington, 1965).
In the protochordates the endostyle is a
longitudinal groove in the mid-ventral line
of the pharynx lined with alternating longitudinal bands of glandular and ciliated cells.
It produces a mucous secretion that is swept
dorsally by the cilia and is used to trap food
particles from the pharyngeal current of
water. It may have a similar though less important role in feeding in the larval lamprey
although the bulk of the mucus used in
feeding is produced elsewhere (Newth,
1930). There is considerable confusion as
to which of the endostyle components contribute to the adult thyroid gland. Type 3
cells, which are the main iodine-binding
cells, together with type 4 and 5 cells have
been implicated while there is general agreement that the prominent glandular tracts of
the endostyle disappear. The different accounts presented by various authors may be
due to the fact that not all of the work has
been carried out using the same species.
Some of the thyroid follicles derive their
lumen directly from the endostyle chambers
and, although the ducts to the pharynx are
lost, there are still ciliated cells in the lamprey follicles. Ciliated cells are also seen
in the thyroid glands of elasmobranchs and
more occasionally in higher vertebrates
especially in embryos.
Iodine binding is intracellular in both the
hagfish thyroid (Tong et al., 1962; Water-
man and Gorbman, 1963) and the larval
lamprey endostyle (Barrington and Franchi,
1956), although in mammals and other
vertebrates it occurs extracellularly at the
cell membrane. Treatment of most vertebrates with thyroxine results in an accumulation of extracellular colloid, but in the
endostyle the accumulation is intracellular
(Barrington and Sage, 1963). Thus, although
the homolog of the lumen of the thyroid
follicle is the extracellular endostyle chamber, the homolog of the thyroid colloid is
intracellular in the iodine binding cells of
the endostyle.
It is clear that the thyroid gland evolved
from the pharyngeal endostyle. We should,
therefore, consider the possibility that thyroid hormones may be a part of the gastrointestinal endocrine system. In the past
thyroxine has been claimed to promote the
absorption of various substances from the
gut in mammals. But these effects have generally not been substantiated leaving at the
present time only a possible enhancement of
the uptake of carotene (Pitt-Rivers and
Tata, 1959). In the lower vertebrates there
seems to be no evidence of any gastrointestinal role.
It seems certain that pancreatic endocrine
tissue, like the thyroid gland, also arose
originally from the gut. It now controls the
level of glucose in the blood although it may
have once been a component of the gastrointestinal system where it probably enhanced
uptake from the gut. At first sight the effect
of thyroxine on cholesterol levels in the
blood of mammals might also seem to indicate that thyroidal function evolved in a
similar manner to that of the pancreas.
Cholesterol is a major component of cell
membranes and unlike other membrane
components it is freely exchangeable (Graham and Green, 1967), thus maintenance of
some minimal level of blood cholesterol may
be a necessity. However, although the state
of thyroid physiology does alter cholesterol
levels in man, the presence of a latent period
following the administration of hormone
suggests that thyroxine is not used in any
short-term control mechanism. In mammals
this latency may be of a few hours and in
lower, poikilothermous, vertebrates it may
THYROID FUNCTION IN FISH
be much longer. We must conclude that
there is no evidence that thyroxine has a
prime role in gastrointestinal physiology
nor in the regulation of any blood component. The only feature of thyroid physiology
that the gland's evolution from the gut may
possibly help us to understand is the oral
effectiveness of thyroxine, an unusual feature for a hormone but one which may be a
consequence of its original secretion by the
endostyle into the gut and the small size of
the thyroxine molecule.
Another approach to the problem of the
original role of thyroxine is to consider the
evolution of the control of the thyroid
gland. The glycoprotein TSH is the major
influence over the thyroid gland in most
vertebrates. However we have no evidence
for its presence in the agnatha. Early demonstrations of an effect of thiourea on the
cytology of the endostyle were interpreted as
evidence of a pituitary control of the endostyle, but the effects of thiourea treatment have since been shown to occur even
in hypophysectomized larval lampreys (Barrington and Sage, 1966) while hypophysectomy of adult lampreys does not inhibit
thyroid activity (Larsen and Rosenkilde,
1971; Pickering, 1972). The only glycoprotein hormone presumed to be present in the
lamprey is a gonadotropin (Dodd et al.,
I960). We may suppose that TSH evolved
from such a glycoprotein by gene duplication and later divergence of the two genes.
Such duplications may be quite frequent
even though they do not always lead to a
new hormone. At the present time in the
rat there are two insulin molecules differing
in a single amino acid and this is presumably the result of such a gene duplication
(Steiner et al., 1969). Similar interpretations
can be applied to the peccaries which have
more than one vasopresin in the neurohypophysis (Heller, 1963).
Not only is there no evidence for a separate TSH molecule in the agnatha, there
is no evidence of any pituitary control of
either the thyroid or the thyroidal activity
in the endostyle. It is thus unlikely that the
agnathan gonadotropin molecule has acquired any control over the thyroid in this
group.
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In elasmobranchs we can confirm the earlier observations of Dodd and his coworkers
(unpublished data summarized by Dodd et
al., 1963) that TSH activity is present and
is localized in the ventral lobe (Jackson and
Sage, 1973). This is also the site of the gonadotropin activity (Dodd et al., 1960) and it
remains to be demonstrated whether or not
there are two separate hormones or a single
one with the properties of both a TSH and
a gonadotropin. In teleosts, as in higher vertebrates, the presence of at least two glycoprotein hormones, TSH and a gonadotropin, is well established (Sage and Bern,
1971). Although TSH and gonadotropin
have evolved as distinct hormones in the
teleosts, the controls over these hormones
remain closely linked together (Sage and
Bern, 1971). Thus, thyroxine exerts a
direct negative feedback on both TSH
and gonadotropin cells. Similarly, sex
steroids influence both of these pituitary
cells (Sage and Bromage, 1970). Thyroxine
has effects on the nervous system of teleosts
and, as in higher vertebrates, is involved in
a feedback control of TSH release acting at
the hypothalamic level (Peter, 1971). The
direct activity of nerve fibers from the brain
differs in being inhibitory on TSH cells and
stimulatory on the gonadotropin cells (Sage
and Bern, 1971). The in vivo response of
both cells to androgen differs from the response to estrogens, but these differences are
not seen in organ-cultured pituitaries (Sage
and Bromage, 1970) indicating that within
the brain there are common pathways to the
control of both cell types. Peter (1970) has
shown that the hypothalamic centers controlling TSH and gonadotropic cells are
close together in the nucleus lateralis tubes.
The view that the control of TSH evolved
from the control of the original gonadotropin is further strengthened by the structural
similarity of mammalian thyrotropin releasing hormone, TRH (pyro Glu, His, Pro
NH2), to part of the gonadotropin releasing
hormone, LHRH (pyro Glu, His, Trp, Ser,
Tyr, Gly, Leu, Arg, Pro, Gly NH,).
This brief survey of the evolution of control of the thyroid indicates a very close relationship between the control of the thyroid and the control of the gonad and, not
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MARTIN SAGE
surprisingly therefore, there are many accounts of thyroid activity paralleling reproductive activity (see reviews, especially Gorbman, 1969). So close are these parallels that
it is difficult to imagine how the thyroid
could have any effect that is not closely related to reproduction.
A third and final approach to the original
role of thyroxine and how it evolved into
other functions is to consider the known effects of the hormone in the various groups
of fishes and to look for common factors.
This may seem to be the obvious approach
to have started with until you realize that
we have no idea what role, if any, is played
by thyroxine in the agnatha. Apart from a
direct effect of thyroxine on iodine binding
in the endostyle (Barrington and Sage, 1966)
I do not know of any effect that has been
demonstrated for thyroxine in the agnatha.
We should consider the possibility that thyroxine production may be a consequence of
the alimentary functions of the endostyle
and that thyroxine may not have acquired
any endocrine functions in the agnatha. If
this is so, we need to identify the selective
pressures that have maintained the production of thyroxine in the myxinoids which do
not have an endostyle.
In the elasmobranchs there is very little
work on the role of the thyroid gland. However, the gland does show cyclic changes associated with seasonal migration (Woodhead, 1966). We have recently shown that
in Dasyatis sabina the cyclic activity in the
thyroid is clearly related to reproductive development and to the reproductive cycle and
not to seasonal environmental changes since
immature animals do not show the cycle of
activity seen in adults (Sage and Jackson,
unpublished). Differences have also been reported in the size of the thyroid gland in
male and female dogfish (Woodhead, 1966).
There is, thus, circumstantial evidence that
thyroid function in elasmobranchs is associated with reproduction.
Amongst the many roles attributed to thyroxine in teleosts, we find a parallel to the
above association of thyroid activity with
elasmobranch reproduction. The thyroid
shows cyclic activity associated with the reproductive cycle of teleosts (see reviews) and
this can be isolated from seasonal factors
(Bromage and Sage, 1968).
Evidence from the evolution of the control of the thyroid, from the control of reproduction and from the role of thyroxine
in elasmobranchs suggests that some function associated with reproduction was the
original role of the thyroid hormones after
the thyroid evolved from the endostyle. The
origin of such a role will not be considered here, but the effect of thyroxine appears to be exerted on gonadal maturation
(Ball, 1960). The exact nature of the effect,
whether it occurs in both sexes and whether
it is direct or indirect is not known and requires further work.
The possibility that the relationship between the thyroid and reproduction is due
to effects of gonadal hormones on the thyroid rather than thyroxine affecting reproduction also needs to be examined. Sex
steroids can stimulate thyroid activity in
teleosts (Matty et al., 1958; Singh, 1969; Sage
and Bromage, 1970). Ovarian tissue also
binds iodine (Leloup and Fontaine, 1960),
and the enlargement of the ovaries prior to
reproduction might decrease the availability
of iodine to the thyroid which in turn might
be followed by compensatory changes in the
thyroid. It would thus seem entirely plausible that although the control system of the
thyroid evolved from that controlling the
gonad, the relationship allowed for changes
in the thyroid that would compensate for
the effects of reproduction on the thyroid.
The alternative idea that thyroxine influences reproductive function is supported by
evidence that thyroidectomy or treatment of
fish with antithyroidal compounds inhibits
gonadal development (for references, see
Ball, 1960; Dodd and Matty, 1964) and degenerative changes in the ovary of captive
sturgeons can be reversed by thyroid treatment (see review by Ball, 1960). Thyroxine
has also been reported to produce precocious sexual development (Grobstein and
Bellamy, 1939). Thus, there may be a reciprocal effect, the reproductive hormones
influencing thyroid activity and the thyroid
exerting an influence over the reproductive
system. These two interacting activities appear to be inextricably interwoven.
THYROID FUNCTION IN FISH
If we now examine the various known effects of thyroxine in teleosts we can see that
some of them are closely related to each
other. The involvement of thyroxine in gonadal maturation may have led to other
morphogenic effects in growth, development, metamorphosis and on the integument, although the effect on growth may be
largely synergistic with growth hormone.
In many teleosts reproduction is seasonal.
A cycle of thyroid activity associated with
reproduction would therefore be an ideal
coordinating mechanism for seasonal adaptation to environmental changes such as
changes in sensitivity to temperature. This
may be one of the most important roles of
thyroxine in teleosts (Hoar, 1959).
The effect of thyroxine in stimulating
oxygen consumption is well known in mammals and it has often been looked for in
lower vertebrates with a consensus of reviewers considering that there is no such
effect in fish. The reported positive results
are, to quote Gorbman and Bern (1962, p.
163) "well known for their exceptional nature." In spite of this, Ruhland (1969, 1971)
has recently demonstrated positive effects of
thyroxine on teleost respiration and a reduction in oxygen consumption following
treatment with thiourea of radiothyroidectomy. From personal experience I know that
to obtain consistent results in such experiments it is necessary to take exceptional care
in standardizing the experimental conditions (e.g. time of day, lighting, handling
of fish). This is characteristic of experiments
on fish behavior and may indicate that the
respiratory changes are secondary to the
well-known effects of thyroxine on fish behavior (Hoar et al., 1955; Sage, 1968; Woodhead, 1970). Increased swimming activity
may stimulate the thyroid (Higgs and Eales,
1971). Conversely respiratory changes following altered behavior may mask the demonstration of a direct respiratory response to
thyroxine.
The effect of thyroxine on fish behavior is
doubtless due to the effect of thyroxine on
the central nervous system which may have
evolved from the feedback mechanism controlling TSH release by the action of thyroxine on the hypothalamus.
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We have so far related many of the known
effects of thyroxine in fish to two primary
effects: an effect of thyroxine on maturation
and an effect on the nervous system. These
are not separate since one of the major effects of thyroxine that may have persisted
throughout vertebrate evolution is the effect
of thyroxine on the maturation of the nervous system. This is well known in man.
Whether the effect of thyroxine on cholesterol metabolism is related to this is unknown.
In conclusion, in spite of the evolution of
the thyroid from the gut, there is no evidence that thyroxine was originally a gastrointestinal hormone, although we cannot exclude it from being so in the endostyle.
Since the control of the thyroid evolved
from the control of the gonad, an early role
of the thyroid associated with reproduction
would thus seem most likely. This association has been borne out by recent observations in elasmobranchs. In teleosts, thyroxine is necessary for the maturation of the
gonads and, perhaps, also other structures
including the nervous system. An effect on
the nervous system which evolved as part of
the control of TSH release may have further evolved to allow effects on behavior
and thus perhaps on respiration. The maturational effects of thyroxine may have
been extended to other morphogenic actions on growth, development, metamorphosis, and the integument, while the cycle
of thyroid activity associated with an annual
gonadal cycle would allow the use of thyroxine as a control of seasonal adaptation
which is a major role of thyroxine in teleost
fishes. Finally, we may ask why thyroxine
should have acquired so many functions.
The answer may be that thyroxine became
available for new roles after the endostyle
was no longer needed for feeding. It is analogous to the rapid evolutionary radiations
that follow paedomorphosis (de Beer, 1951)
when genetic material is released for new
roles. Prolactin is another hormone with a
diversity of functions. It presumably evolved
from growth hormone by gene duplication
and like thyroxine has acquired a host of
activities during the adaptive radiation of
the teleosts.
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MARTIN SAGE
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905
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