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Chapter 7
The Hypothalamus—Pituitary—
Thyroid (HPT) Axis of NonMammalian Vertebrates
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Figure 7-1 Location of thyroid tissue in non-mammalian vertebrates. (A) Scattered thyroid follicles in a
hagfish (Eptatretus burgeri). (B) Discrete thyroid gland of the shark Triakis scyllium. (C) Diffuse thyroids of the
Japanese eel (Anguilla japonica) (left) and the Pacific salmon (Oncorhynchus masou) (right). (D) Paired thyroids
in the bullfrog (Rana catesbeiana). (E) Medial thyroid gland in neck of the lizard Takydromas tachydromoides. (F)
Paired thyroid glands in a bird, the Japanese quail (Coturnix coturnix japonicus). (Dissections of thyroid regions
adapted with permission from Matsumoto, A. and Ishii, S., “Atlas of Endocrine Organs,” Springer-Verlag,Berlin,
1989.)
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Figure 7-2 Salmon thyroid follicles. Cross-section through the lower jaw of a fingerling chinook salmon
(Oncorhynchus tshawytscha) near the second aortic arch. Five thyroid follicles filled with colloid appear to the
right of the ventral aorta (VA) and below the supporting cartilage (C).
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Figure 7-3 Evolution of major events in thyroid physiology. Thyroid receptors (TRs) appeared prior to the
divergence of the proterostome and deuterostome invertebrates (1). Endogenous thyroid hormone production
was next (2), and linkage to TRs and involvement with metamorphosis represent perhaps the earliest roles of
thyroid hormone, appearing first among deuterostome invertebrates (3). A thyroid-synthesizing organ first
appears among the protochordates (4), but neuroendocrine control probably originated among the first
vertebrates as evidence from extant cyclostomes (5). (Adapted with permission from Paris, M. et al., Integrative
and Comparative Biology, 50, 63–74, 2008.)
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Figure 7-4 Generalized pattern for evolution of the thyroid gland. (A) Initially, iodinated mucoproteins were
distributed over the body surface of marine invertebrates and in the anterior digestive tract and later became
restricted more to the mouth region, where iodinated mucoproteins related to a ciliary–mucus feeding mode were
released from the mouth region and entered the gut. Once in the gut, the iodinated mucoproteins were digested,
liberating iodinated tyrosines and thyronines. (B) The cephalochordate amphioxus has iodinated protein
production confined to the endostyle in the mouth and pharynx. (C) Metamorphosis of the larval endostyle to a
thyroid gland occurs during transformation of the ammocete larvae to the adult lamprey.
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Figure 7-5 Amphioxus thyroid hormone events. Genomic evidence for the beginnings of the thyroid hormone
synthesis and mode of action of thyroid hormones is present in this protochordate. Extracellular iodide is
transported by a sodium-iodide pump symporter (NIS), incorporated into a glycoprotein forming T 4 through the
actions of a thyroid peroxidase (TPO). The T 4-containing glycoprotein is hydrolyzed to release T4, which is
converted to triiodothyronine (T3) by a deiodinase. T3 binds to a thyroid receptor (TR) and forms a dimer with the
RXR receptor prior to binding to a thyroid response element (TRE) and altering the target gene’s activity
(transcription). A gene coding for thyroglobulin apparently is absent in amphioxus.
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Figure 7-6 Metamorphosis of the cephalochordate amphioxus. This process is controlled by thyroid
hormones synthesized in the endostyle. The adult amphioxus closely resembles the ammocoetes larva of the
vertebrate lamprey (Agnatha, Cyclostomata). (Photographs courtesy of Dr. Mathilde Paris.)
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Figure 7-7 Oocytes of control (A) and radioiodide-treated (B) yearling rainbow trout (Oncorhynchus
mykiss). The ovaries of fishes and other non-mammalian vertebrates readily concentrate iodide in the oocytes.
The control ovary at the left exhibits a size range of developing oocytes. The ovary at the right is from a fish that
accumulated radiodide (131I) shortly after hatching. Although the radioactivity quickly decayed to undetectable
levels, the ovary at the right contained only the largest class of oocytes when examined a year later.
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Figure 7-8 Heterotopic thyroid tissue. This teleostean fish Xiphophorus maculatus has thyroid follicles (yellow
dots) located not only throughout the pharyngeal region but also in the heart, head kidney, and sometimes even
in the gonads and liver. (Adapted with permission from Baker-Cohen, K.F., in “Comparative Endocrinology” (A.
Gorbman, Ed.), John Wiley & Sons, New York, 1959, pp. 283–319.)
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Figure 7-9 Phylogeny of deiodinase genes in vertebrates. Some species are omitted for whom there is
evidence for deiodinases because the responsible genes have not been analyzed. Note that Xenopus has all
three genes although evidence for other amphibians does not support the presence of a D1 deiodinase.
(Adapted with permission from Johnson, K.M. and Lema, S.C., General and Comparative Endocrinology, 172,
505–517, 2011.)
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Figure 7-10 Phylogeny of vertebrate thyroid receptors. Tissue-specific thyroid hormone regulation of gene
transcripts encoding thyroid hormone receptors in striped parrotfish (Scarus iseri). (Adapted with permission from
Johnson, K.M. and Lema, S.C., General and Comparative Endocrinology, 172, 505–517, 2011.)
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Figure 7-11 Metamorphosis of the flounder Pleuronectes platessa. During metamorphosis (C-F), which is
controlled by thyroid hormones, one eye migrates from one side of the body to the other. (Adapted with
permission from Blaxter, J.H.S., in “Fish Physiology” (W.S. Hoar and D.J. Randall, Eds.), Academic Press, San
Diego, CA, 1988, pp. 11A, 1–58.)
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Figure 7-12 Life cycle of Pacific salmon and steelhead (Oncorhynchus spp.). This pattern is characteristic
of most species; however, in pink and chum salmon that spawn in coastal streams, the fry are washed directly
into the ocean. (Adapted with permission from Ueda, H., General and Comparative Endocrinology, 170, 222–
232, 2011.)
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Figure 7-13 Plasma hormone levels during Parr smoltification of coho salmon. Prolactin, growth hormone,
thyroxine, and cortisol all peak during smoltification. Insulin peaks in the parr and declines as smoltification gets
under way. (Adapted with permission from Dickhoff, W. et al., Journal of Experimental Zoology, 256 (Suppl. S4),
90–97, 1990. © John Wiley & Sons.)
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Figure 7-14 Smolting in steelhead trout (Oncorhyncus mykiss). Thyroid hormone stimulates deposition of
guanine in the scales. (A) Smolts. (B) Parr.
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Figure 7-15 Histological appearance of thyroid epithelium of a migrating adult sockeye salmon
(Oncorhynchus nerka). Note that the epithelium appears goitrous in that it is highly columnar, indicative of
intense TSH stimulation. Little colloid is associated with the lumen, suggesting depletion. Arrow indicates colloid
droplet endosome in the apical end of the follicle cell. Would you consider this a hyperthyroid or hypothyroid
condition? Why?
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Figure 7-16 Effect of T4 treatment on growth of radiothyroidectomized steelhead trout. (Adapted with
permission from Norris, D.O., Transactions of the American Fisheries Society, 97, 204–206, 1969.)
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Figure 7-17 Comparison of morphological changes during metamorphosis of an anuran (left) and a
urodele (right) amphibian. Urodeles quickly reach stage 4 and remain in this stage with external gills most of
their larval lives. Anurans may spend a few weeks or up to 2 years at stage 2 before limbs emerge. Resorption of
the anuran tail (metamorphic climax) may be delayed for some time after emergence of the hind limbs but occurs
rapidly once the forelimbs emerge. Note that when urodeles undergo metamorphosis, the external gills are
resorbed as is the tail fin (stages 5 and 6).
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Figure 7-18 Urea–ammonia excretion during anuran metamorphosis. Aquatic animals excrete ammonia as
their principal nitrogenous wastes, whereas terrestrial amphibians produce urea. Immersion of tadpoles in water
containing thyroxine induces a switch from ammonia excretion to urea excretion similar to that observed during
normal metamorphosis. A similar pattern to the ammonia change is seen for other metamorphic changes such as
regression of tail whereas growth of hind limbs exhibits a urea-like pattern.
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Figure 7-19 Effects of TRH and CRH on metamorphosis of the coqui (Eutherodactylus coqui). Neither
saline nor TRH affected the rate of metamorphosis, but CRH treatment accelerated metamorphosis. Note tail
regression and changes in body and head shape. (Adapted with permission from Kulkarni, S.S. et al., General
and Comparative Endocrinology, 169, 225–230, 2010.)
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Figure 7-20 Hormonal changes during bullfrog metamorphosis. Thyroxine, prolactin, and corticosterone all
peak at metamorphic climax. These changes are characteristic of both anurans and urodeles. Compare to the
pattern of hormone secretion in smoltification of salmonid fishes (Figure 7-13). (Adapted with permission from
Dickhoff, W. et al., Journal of Experimental Zoology, 256 (Suppl. S4), 90–97, 1990. © John Wiley & Sons.)
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Figure 7-21 Changes in deiodinase activities during metamorphosis. The reduction of D3 deiodinase
activity in liver and increases in D2 deiodinase activity in skin and gut leads to increased conversion of T 4 to T3
and metamorphic climax. (Adapted with permission from Galton, V.A., Trends in Endocrinology & Metabolism, 3,
96–100, 1992. © Elsevier Science, Inc.)
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Figure 7-22 Expression of thyroid hormone receptors (TRα and TRβ) as well as RXRs during early
embryonic development and metamorphosis. (A) TRs are expressed very early in embryonic development,
even before the thyroid gland differentiates, possibly to respond to TH deposited into the egg by the mother.
Note the increase in tadpole synthesis of thyroid hormones (TH). (B) Na +-I symporter (NIS) and thyrotropin
(TSH) during metamorphic climax. (Adapted with permission from Furlow, J.D. and Neff, E.S., Trends in
Endocrinology & Metabolism, 17, 38–45, 2006; Korte, J.J. et al., Gen. Comp. Endocrinol., 171, 319–325, 2011;
Opitz, R. et al., J. Endocrinol., 190, 157–170, 2006.)
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Figure 7-23 Environmental factors affecting metamorphosis in amphibians. Stress (e.g., pond drying, high
population densities, salinity changes) and long photoperiods can stimulate metamorphosis in populations of
amphibians through effects on hypothalamic regulation of pituitary secretion and release of T 4 and increased
conversion of T4 to T3 as well as elevations in corticosterone (B) from the interrenal (adrenal). (Adapted with
permission from Denver, R.J., Comparative Biochemistry and Physiology C, 119, 219–228, 1998.)
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Figure 7-24 Skin changes associated with metamorphosis in a urodele amphibian. (A) Histological section
through skin of larval tiger salamander (Ambystoma tigrinum) showing prominent Leydig cells (arrows). (B)
During metamorphosis, the Leydig cells degenerate and release their secretions that are thought to contribute to
the relative impermesbility of the skin of a terrestrial adult. Arrow indicates mucous cell (slightly lower
magnification).
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Figure 7-25 Distribution of developmental and thermogenic action of thyroid hormones in vertetrates.
Perhaps developmental and/or permissive actions were the initial roles for thyroid hormones. Thermogenesis
appears with the acquisition of homeothermy possibly in the reptilian ancestors of birds and mammals. (Adapted
with permission from Oppenheimer, J.H. et al., in “Molecular Endocrinology: Basic Concepts and Clinical
Correlations” (B.D. Weintraub, Ed.), Raven Press, New York, 1995, pp. 249–268.)
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Box Figure 7A-1 Environmental perchlorate and frog thyroid histology. Thyroid tissue in a chorus frog from
a reference site in Texas appears at the left. On the right is a hyperstimulated thyroid gland from a perchloratecontaminated site, presumably a result of increased thyrotropin secretion. (Photomicrographs courtesy of Dr.
James A. Carr, Texas Tech University.)
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Box Figure 7A-2 Effect of perchlorate exposure in the laboratory. The paired thyroid glands of a control frog
can be seen at the left in marked contrast to the goitrous thyroids in the frog exposed to 14 ppm of ammonium
perchlorate. (Photomicrograph courtesy of Dr. James A. Carr, Texas Tech University.)
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