This power point has 24 slides. These are prepared to provide relevant information for interested students & faculty in the areas of human & Veterinary endocrine & metabolic physiology.

1. THYROID GLAND
Dr. E. Muralinath
Associate Professor & Head
Dept. of Veterinary Physiology
College of Veterinary Science, Proddatur, Andhra Pradesh

2. THYROID GLAND
• Butterfly shaped, red − brown, vascular gland
• Located on anterior mid neck line region
• Extends from C5 − T1 vertebrae in humans
• A largest endocrine glands, weighs ~15 − 25 g
• Major laryngeal cartilages serve as scaffold
• First endocrine gland to start developing (≈ 22 days,
humans)
• Secretes thyroid hormone & maintains iodine balance
• 90% of hormone secreted is inactive (T4), while 10% is
active (T3)
• Superior & Inferior thyroid arteries, both bring O2 &
nutrients to thyroid gland

3. • Thyroid gland is predominantly endodermal in origin
• Fully formed gland has two lobes joined by an isthmus
• Lobes consists of two cell types
• Follicular cells / thyrotrophs – T4 (L-3,5,3',5'-
tetraiodothyronine) & T3 (3,5,3'-Triiodothyronine, T3)
• Parafollicular cells/ C cells – Calcitonin
• Differences in T4 compared to T3
• Shortened C4'-O4' bond
• Contraction of C3'-C4'-C5' angle
• ↑ C3' and C5' angles in T4
THYROID HORMONES

4. • Thyroid glands secretions, known as colloid, are
stored in their follicular lumen
• Thyroid follicles cluster together to form numerous
lobules
• Each follicle consists of either a simple
columnar/cuboidal epithelium surrounding a central
lumen
• Thyrocytes (follicular cells) have rounded nucleus,
and abundant numbers of mitochondria, rough
endoplasmic reticulum, Golgi bodies
• The rough endoplasmic reticula are more abundant
near the base, while Golgi bodies are more at the
apex
HISTOLOGY OF THYROID GLAND

5. NEGATIVE FEEDBACK CONTROL
High levels of circulating T3 &
T4 feedbacks
Inhibition of TRH & TSH
T4 is converted to T3 and
reverse T3 (rT3 - during stress)
in both circulation & in
tissues
Thyroid hormones
transported in serum bound
to TBG (75%), Transthyretin &
albumin
T3 & T4 secretion is mediated via negative feedback
loop among hypothalamus, anterior pituitary & thyroid gland

6. THYROTROPIN RELEASING HORMONE (TRH)
Thyrotropin releasing hormone
 TRH (pGlu-His-Pro-NH2) functions both as a tropic & non-
tropic hormone
 Secreted by cell bodies of PVN in hypothalamus
 Transduced by coupled Gq/11 protein & β-Arrestin receptors
 TRH activates anterior Pituitary cells (AP) that secrete TSH
 Norepinephrine & Histamine stimulate TRH release
 Signal Cascade
 Activates PLC → PIP2 hydrolysis → IP3 & 1,2-diacylglycerol
(DAG)
 ↑intracellular ca2+ & PKC activation → ras/cRaf1 →ERK1/2
 Stimulates ca2+ /calmodulin-dependent protein kinase & MAPK
 TRH Stimulates acidophilic lactotrophs’ in Anterior Pituitary to
produce prolactin (non-tropic)

7. THYROID STIMULATING HORMONE (TSH)
• TSH is synthesized by basophilic thyrotropes of anterior
pituitary gland
• Glycoprotein of 211 amino acids & has an α & a β chain
• Molecular mass is ≈ 28 kDa, plasma half life is ≈ 60 minutes
• TSH maintains growth, secretory activity & structure of
thyroid by augmenting
• HMP Shunt, Glycolysis, Protein synthesis & TCA cycle
• Oxygen consumption & thyroidal uptake of I-
• TSH (& LH, FSH, HCG) share same α chain & function via. cAMP
• cAMP & IP3/Ca2+ cascades lead to downstream physiological
effects of TSH
• Somatostatin & Dopamine inhibits TSH release from AP
• Cortisol & Estrogen ↓ Pituitary response to TRH

8. T3/T4 SYNTHESIS & SECRETION
There are seven steps:
Thyroglobulin (TG) synthesis & secretion into follicular
lumen
a. Macromolecular precursor of thyroid hormone
b. Synthesized in thyrocyte endoplasmic reticulum (ER)
c. Large glycoprotein, synthesized as 12S molecule (330
kDa), and forms 19S homodimer (660 kDa)
Iodine uptake into thyroid follicular epithelial cells
a. Na+/I- symporter (NIS), TSH sensitive, active uptake
b. Intracellular I- conc. 20 − 40 times > plasma
c. NIS essential for iodine uptake or trapping in thyrocytes
d. Daily recommended uptake : 150 μg/day or 1 mg/week

9. Iodine transport & efflux into follicular lumen
a. Pendrin: Iodine efflux on thyrocytes’ apical surface
Oxidation of iodine, iodination of TGs’ tyrosyl residues &
coupling of iodotyrosines
a. I- oxidation essential for iodine-tyrosine coupling
b. TPO catalyses I- oxidation & iodination of
Tg tyrosyl residues, & iodotyrosine coupling into T3 & T4
c. H202 serves as an oxidant for TPO catalyzed oxidation
d. 2 DIT → T4 + Alanine; d. MIT + DIT → T3 (rT3)
e. Iodotyrosines distribution: 23 % MIT, 33 % DIT, 35 % T4 & 7 % T3
f. Dual oxidase 2 (Duox2) & its maturation factor, Duoxa2 are
responsible for H2O2 generation at the apical membrane
d. TG undergoes iodination mediated by thyroperoxidase (TPO)
and H2O2 at the apical membrane of thyrocyte
e. Iodine covalently bound to tyrosine residues in molecule
to form monoiodotyrosine (MIT) and diiodotyrosine (DIT)

10. Hydrolysis of TG − T4/T3 complex
a. Iodinated tyrosines with Tg. (colloid droplets) enters thyrocytes,
reaches lysosomes forming phagolysosomes
b. Proteolysis is key to releasing T4 and T3
Storage & Secretion of T4/T3, the thyroid hormone
a. Ratio f T4 : T3 secretion = 5:1 (dogs)
b. Ratio of circulating levels = 20 : 1 (T4 tight bound)
c. Dogs: Half life of T3 : 6 hrs; T4 : 12-24 hrs
d. Primates: Half life of T3 : 24 hrs; T4 : 7 days
e. Each Tg. molecule have, around 30 T4 & few T3 molecules
f. Thyroid gland secretes ~ 70-90 μg of T4 each day
Endocytosis of TG − thyroid hormone complex into
follicular epithelial cells
a. Iodinated Tg through micro-pinocytosis or phagocytosis,
enters thyrocytes again, through apical membrane

11. THYROID HORMONE SYNTHESIS
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12. THYROID HORMONE SYNTHESIS
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13. FUNCTIONS OF THYROID HORMONE
• Causes positive Chronotropic & Inotropic effects in
excitable tissues
• ↑CO, SV, resting HR
• ↑Myocardial intracellular Ca2+ ↑ contraction force & speed
• ↑Diameter of blood vessel in skin, muscle & heart, ↓ TPR
• ↑Renin-angiotensin-aldosterone system activity ↑ blood
volume
• Elevates BMR, thermogenesis & oxygen consumption
• Activation of UCPs
• ↑Glucose & fatty acid uptake
• ↑Glucose & fatty acid oxidation, thermogenesis (heat
intolerance) and heat dissipation
• Augmented thermogenesis causes compensatory ↑ in blood
flow, sweating & ventilation

14. • Increases pulmonary & alveolar Ventilation
• Triiodothyronine (T3) ↑ Resting respiratory rate (RR) &
Respiratory minute ventilation (RMV) to normalize arterial
O2 concentration to compensate for higher oxidation rates
• ↑ O2 delivery to tissues by
• ↑ erythropoietin production
• Hemoglobin production
• Folate & cobalamin absorption in GIT
• Augments growth & maturation of bone & cartilage
• ↑ fetal linear bone growth, endochondral ossification,
epiphyseal bone center maturation after birth
• Enhances adult bone remodelling, degradation of
mucopolysaccharides & fibronectin in extracellular
connective tissue

15. • Stimulates nervous system
• ↑ wakefulness, alertness & responsiveness to
sensory stimuli
• ↑ peripheral reflexes, gastrointestinal tone and
motility
• Promotes reproductive health & other
endocrine organ function
• Regulates both ovulatory cycle & spermatogenesis
• Regulates pituitary function
• ↑ growth hormone production & release
• ↓ prolactin production & release
• ↑ renal clearance of some medications, by
enhancing renal blood flow & glomerular filtration
rate

16. SUMMARY OF THYROID ACTION

17. GOITERS
Any enlarged thyroid is considered as a goiter
Hypothyroid Goiter
Type I (Primary)
Caused by Primary hypothyroidism, ↑TSH due to ↓ T4 &
T3 feedback
Excess TSH causes thyroid enlargement
Hyperthyroid Goiter
Type II (toxic) : Autoimmune disorder with low levels of TSH,
Grave’s disease
Type III (physiological): Seen during pregnancy, elevated TBG
synthesis & renal iodide clearance
Euthyroid Goiter
Type IV (normothyroid): Pseudo-goiter, normal functioning
gland, but enlargement due to invasion by adenomas,
carcinomas, bacteria viruses or parasites

18. Thyroid disorder manifested mainly due to T4 deficiency
Depending on the position of lesion, thyroid disorders are
Primary disorder: ↓ T3 & T4 , & compensatory ↑ in
TSH levels suggest a thyroid gland lesion
Causes: Bilateral thyroidectomy, 131I mediated thyroid
ablation, Hashimoto’s disease, Pregnancy during prior 6
months, Chromosomal disorder causing turner
syndrome, excessive use of antithyroid drugs,
lymphocytic thyroiditis, idiopathic thyroid atrophy,
neoplastic invasion, antibodies against TSH etc.
Secondary disorder: TRH levels may ↑, & TSH, T3 & T4
levels ↓, suggests an anterior pituitary lesion
Causes: Pituitary neoplasms, Cystic Rathke’s pouch &
hyperadrenocorticism, excessive use of antithyroid
drugs & Iatrogenic reasons & Glucocorticoid excess
HYPOTHYROIDISM

19. Tertiary disorder: ↓ TRH,↑TSH, secondary to
administration of TRH, suggests a hypothalamic lesion
Causes: Iatrogenic reasons, neoplasms in
hypothalamus
Other causes of hypothyroidism: Peripheral resistance
to T3 & T4 due to receptor/post-receptor defects
Comorbidities
Pernicious anemia
Type I & Type II diabetes
Lupus erythematous (AI disorder)
Sjogren’s syndrome
Rheumatoid arthritis
celiac disease
HYPOTHYROIDISM

20. Symptoms: Loss of appetite, lethargy, obesity, fatigue, weight gain,
cold intolerance, joint/muscle pains, ↓ myocardial contractility,
bradycardia, depression, fertility issues, constipation, anemia (iron,
folate, B12 & T4 deficiency, defective hemoglobin biosynthesis),
accumulation of β-Carotene pigments in liver, β-Carotenemia
(herbivores), coarse & dull hair coat (ex: dogs/cats) dry skin, hair
thinning etc.
 Cretinism (congenital hypothyroidism in newborns):
impaired neurological functions, stunted growth & physical
deformities
 Myxedema: Severe form of hypothyroidism, thickening of
hair & skin, due t accumulation of mucopolysacchrides,
hypothermic shock & coma
Incidence: Hypothyroidism is more common in females as well as
in individuals who are older than 60 years, common in dogs (95%
acquired)
Treatment: Thyroxine, Levothyroxine
HYPOTHYROIDISM

21. HYPERTHYROIDISM
• Pathogenesis arise due excess production & secretion T3 & T4
• Causes: Thyroid tumor involving follicular cells
• Symptoms:
• Weight loss: ↑BMR, muscle wasting, vitamin deficiency
• Augmented GI permeability: Diarrhea, vomition, ↑thirst,
PU/PD and azotemia
• Respiratory depression: ↓VT , ↓pulmonary compliance,
panting & hypercapnia
• Cardiovascular effects: ↓TPR, tachycardia, ↑VR, ↑CO,
dilatation & LV hypertrophy
• Blood count: ↑ Erythropoietin, erythrocytosis, leukocytosis,
eosinopenia, lymphopenia
• Serum Enzymology: ↑ALT, ↑AST, ↑AP, ↑LDH,
hyperbilirubinemia, fatty liver infiltration
• Serum Biochemistry:↑TSH, ↑T3 & T4 cells in blood (both
bound & free forms)
• Others: Heat intolerance, hyperglycemia, hyper-
cholesterolemia & hyperlipidemia

22. GOITROGENS
Thiocarbamide groups in natural goitrogens show antithyroid
activity
Synthetic drugs carrying thiocarbamide group inhibits
thyroxinogenesis
Concentrate in thyroid gland, binds thyroglobulin, gets oxidated
Interfere with thyroglobulin activity
Prevents coupling of iodotyrosyl groups into T4
Inhibits activity of Type I deiodinases ( occur in thyroid, liver,
kidney & pituitary tissues)
Examples of Synthetic Goitrogens
Thioamide drugs: Propylthiouracil, Methimazole & Carbimazole
Propylthiouracil: t1/2 = 1 h, binds plasma proteins, cross
placenta, blocks peroxidase system, forms PTU-SO2H
Methimazole: t1/2 = 2−6 h, cross, placenta & forms,
methylthiohydantoin
Thiocyanate (SCN−), pertechnetate (TCO4−), perchlorate (CIO4 −)
ions: inhibit NIS & iodine trapping
Iodides: decreases T4 & T3 release

23. DRUGS TREATING HYPERTHYROIDISM
• Lithium: Inhibit thyroid hormone synthesis &
secretion
• Amiodarone: Inhibits T4 → T3 conversion in peripheral
tissue by blocking deiodinases
• Antiepileptics/Rifampcin: Augment metabolism in
thyroid hormones
• Sulphonamides: Inhibits iodination & coupling
reactions in T4 , T3 synthesis
• Expectorants & topical agents: Iodine containing
agents may inhibit hormone synthesis & release

24. REFERENCES
Basic and Clinical Pharmacology, 13th Ed., Thyroid &
Antithyroid Drugs, Betty J. Dong & Francis S. Greenspan.
https://doctorlib.info/pharmacology/basic-clinical-
pharmacology-13/38.html
Koibuchi, N. (2018). Molecular Mechanisms of Thyroid
Hormone Synthesis and Secretion.
Belfiore, A., LeRoith, D. (eds) Principles of Endocrinology
and Hormone Action. Endocrinology. Springer, Cham.
https://doi.org/10.1007/978-3-319-44675-2_5
Text book of Medical Physiology, 11th Ed., Guyton & Hall
Dukes’ Physiology of Domestic Animals, 12th Ed., William, O
Reece
Metabolic & Endocrine Physiology, 3rd edition, Larry R
Engelking