ENDOCRINE PHYSIOLOGY

Module 4

The Thyroid and

Parathyroid Hormones
CORE KNOWLEDGE

 HYPO/HYPERPITUITARISM
 GIGANTISM, ACROMEGALY, PROLACTINEMIA,
 DIABETES INSIPIDUS & SIADH
 DIABETES MELLITUS
 HYPO/HYPERTHYROIDISM (MYXOEDEMA, CRETINISM,
THYROIDITIS, THYROTOXICOSIS)
 HYPER/HYPO PARATHYROIDISM
 HYPER/HYPO CORTISOLISM
 CUSHING’S DISEASE/SYNDROME
 ADDISON’S DISEASE
 HYPER/HYPO ALDOSTERONISM
 PHAEOCHROMOCYTOMA
 HORMONES RELATED TO STRESS

Prof. Dr. Hamdan Noor

March, 2017

2
Module 4. The Thyroid and Parathyroid
Hormones
Sub-topics:

1. Functional Anatomy of the Thyroid and Parathyroid Glands

1.1. General introduction to Thyroid and Parathyroid glands
1.2. Thyroid gland
1.3. Parathyroid gland

2. Thyroid Hormones
2.1. Chemistry of Thyroid Hormones
2.2. Synthesis and Secretion of Thyroid Hormones
2.3. Control of Thyroid Hormone Synthesis and Secretion
2.4. Mechanism of Action and Physiologic Effects of Thyroid Hormones
2.5. Thyroid hormone disease states

3. Calcitonin
3.1. Control of calcitonin secretion
3.2. Physiologic effects of calcitonin
3.3. Calcitonin disease states

4. Parathyroid Hormone
4.1. Control of parathyroid hormone secretion
4.2. Physiologic effects of parathyroid hormone
4.3. Parathyroid hormone disease states

5. Vitamin D

6. Endocrine Control of Calcium and Phosphorus Homeostasis

6.1. Body distribution of calcium and phosphate
6.2. Fluxes of calcium and phosphate
6.3. Hormonal control systems

7. Summary

8. Conclusion

3
Learning Outcomes:
On completion of this Module you should be able to:

1. Describe the functional anatomy and histology of the thyroid and parathyroid glands.

2. Describe the chemistry, mechanism of synthesis and secretion, regulation of

synthesis and secretion, mechanism of action and physiological effects, and disease
states related to thyroid hormones.

3. Describe the chemistry, mechanism of synthesis and secretion, regulation of

synthesis and secretion, mechanism of action and physiological effects, and disease
states related to calcitonin.

4. Describe the chemistry, mechanism of synthesis and secretion, regulation of

synthesis and secretion, mechanism of action and physiological effects, and disease
states related to parathyroid hormones.

5. Describe the chemistry, mechanism of synthesis and secretion, regulation of

synthesis and secretion, mechanism of action and physiological effects, and disease
states related to Vitamin D.

6. Describe the endocrine control of calcium and phosphorus homeostasis.

Additional objectives
1. Identify the steps in the biosynthesis, storage, and secretion of tri-iodothyronine (T 3) and thyroxine
(T4) and their regulation.
2. Describe factors that control the synthesis, storage, and release of thyroid hormones. Explain the
importance of thyroid hormone binding in blood on free and total thyroid hormone levels.
3. Explain the significance of the conversion of T 4 to T3 and reverse T 3 (rT3) in extra-thyroidal tissues.
4. Describe the actions of thyroid hormones on development and metabolism.
5. Explain the causes and consequences of a) over-secretion and b) under-secretion of thyroid hormones.
Explain why either condition can cause an enlargement of the thyroid gland.
6. State the cells of origin for parathyroid hormone, its biosynthesis, and mechanism of transport within
the blood (bound or free).
7. List the target organs and cell types for parathyroid hormone and describe its effects on each.
8. Describe the functions of the osteoblasts and the osteoclasts in bone remodeling and the factors that
regulate their activities.
9. Identify the time course for the onset and duration for each of the biological actions of parathyroid
hormone.
10. Describe the regulation of parathyroid hormone secretion and the role of the calcium-sensing
receptor.
11. Explain the causes and consequences of a) over-secretion, and b) under-secretion of parathyroid
hormone.
12. Identify the sources of vitamin D and diagram the biosynthetic pathway and the organs involved in
modifying it to the biologically active 1,25(OH 2)D3 (1-25 dihydroxy cholecalciferol).
13. Identify the target organs and cellular mechanisms of action for vitamin D.
14. Describe the negative feedback relationship between the parathyroid hormone and the biologically
active form of vitamin D [1,25(OH2)D3].
15. Describe the consequences of vitamin D deficiency and vitamin D excess.

4
16. List the cell of origin and target organs or cell types for calcitonin.
17. Name the stimuli that can promote secretion of calcitonin.
18. Describe the actions of calcitonin and identify which (if any) are physiologically important.

Learning Resources:

1. Notes in this Module

2. Boron and Boulpaep, Ch. 48 and 51
3. Widmaier, Raaf and Strang (Vander’s Human Physiology) Ch. 11
4. Marieb. Ch. 17
5. Tortora and Derrickson. Ch. 18
6. Guyton and Hall. Ch. 74
7. Ganong. Ch.18

Terms to Know:

Please list down all the terms that you ought to know in this module. Make sure that you
are able to explain the terms in your own words.

5
1. Functional Anatomy of the Thyroid and Parathyroid Glands

1.1. General introduction to Thyroid and Parathyroid glands

In Module 1 we mention three series of hormones that are involved in the hypothalamo-
pituitary-adrenal (HPA), hypothalamo-pituitary-thyroidal (HPT), and hypothalamo-gonadal
(HPG) axis respectively (please recall the hormones involved). In Module 2 we explore the
hormones of the hypothalamus and pituitary, focusing on those that are not involved in the
axis. In Module 3, we focus on the hypothalamo-pituitary-adrenal axis and discuss in detail
the hormones of the adrenal gland. In this module, we’ll shift to the hypothalamo-pituitary-
thyroidal axis and discuss in detail the hormones involved. In addition, we’ll also discuss
the parathyroid hormone which is associated with the thyroid gland in terms of location, but
differs in terms of function.

Fig. 4.1. The hypothalamo-pituitary-thyroid axis

6
The thyroid gland produces thyroid hormones (T3 and T4) and calcitonin. The parathyroid
glands secrete parathyroid hormone.

Thyroid hormones affect three fundamental physiologic processes:

• cellular differentiation (physical and mental development)
• growth
• metabolism

Parathyroid hormone and calcitonin

• participate in control of calcium and phosphorus homeostasis
• have significant effects on bone physiology.

Activity 4.1. The hypothalamo-pituitary-thyroidal (HPT) axis

List the hormones involved in the HPT axis (sequentially) (Fig. 4.1). Explain the negative
feedback mechanism that operates within this system. Give examples of conditions that would
make the negative feedback system unable able to operate properly. Hint: Cushing syndrome,
Addison disease

What is the hormone that is secreted with the thyroid gland but not associated with the HPT
axis. What is its function?

1.2. Thyroid gland

The thyroid gland is located in the neck, in close approximation to the first part of the
trachea. In humans, the thyroid gland has a "butterfly" shape, with two lateral lobes that
are connected by a narrow section called the isthmus. Thyroid glands are brownish-red in
color.

Close examination of a thyroid gland reveals one or more small, light-colored nodules on
or protruding from its surface - these are parathyroid glands (meaning "beside the
thyroid").

The microscopic structure of the thyroid is quite distinctive. Thyroid epithelial cells - the
cells responsible for synthesis of thyroid hormones - are arranged in spheres called thyroid
follicles. Follicles are filled with colloid, a proteinaceous depot of thyroid hormone
precursor. In addition, the thyroid gland houses one other important endocrine cell.
Nestled in spaces between thyroid follicles are parafollicular or C cells, which secrete the
hormone calcitonin.

7
Fig. 4.2. Anatomy and histology of the thyroid gland

8
Fig. 4.3. Histology the thyroid
gland.
The thyroid gland is located anterior
to the cricoid cartilage in the anterior
neck. The gland comprises numerous
follicles, which are filled with colloid
and lined by follicular cells. These
follicular cells are responsible for the
trapping of iodine and the synthesis
of thyroglobulin, which contains
thyroid hormone as part of its
primary structure. These cells also
secrete thyroglobulin - the major
protein of the thyroid colloid - into
the lumen of the follicle. The
thyroglobulin protein that is stored in
the follicular lumen contains
numerous iodinated tyrosines and
thyronines, which are derivatives of
the amino acid tyrosine. On
command, the follicular cells take up
the thyroglobulin and release the
thyroid hormones triiodothyronine
(T3) and thyroxine, or
tetraiodothyronine (T 4), into the
blood

Activity 4.2: Anatomy of the thyroid gland

Describe the location of the thyroid gland, its blood supply and innervation.

Using a labeled diagram (follicle, follicular cell, parafollicular cell or C cell, colloid,
blood capillary, red blood cell), describe the microscopic structure of the thyroid.
Relate the structure to the synthesis of thyroid hormones.

State the function of follicular cells and parafollicular cells (C cells).

9
1.2. Parathyroid gland

The structure of a parathyroid gland is distinctly different from a thyroid gland. The cells
that synthesize and secrete parathyroid hormone are arranged in rather dense cords or
nests around abundant capillaries.

Fig. 4.4. Anatomy and histology of the parathyroid gland

7
 There are 4 parathyroid glands, 2 located on the posterior surface of the left lobe of the
thyroid, and 2 more on the right. Combined, these 4 glands weigh <500 mg. They are
largely composed of the chief cells, which are responsible for the synthesis and secretion
of PTH.

Activity 4.3: Parathyroid gland

Label the diagram:

follicle, follicular cell, colloid,
blood capillary, parathyroid
gland. State the functions.

Fig. 4.5. Histology of the parathyroid gland

Activity 4.4: Anatomy of the parathyroid gland

• Describe the location of the parathyroid gland, its blood supply and innervation.
• Using a labeled diagram, describe the microscopic structure of the parathyroid thyroid
gland in relation to the thyroid gland. Relate the structure to the synthesis of parathyroid
hormones.
• What cells constitute the parathyroid gland? What are their functions?

In summary, thyroid gland consists of follicles lined by follicular cells, and parafollicular
cells. Follicular cells are responsible for production of TH whereas parafollicular cells
are responsible for production of calcitonin. Parathyroid gland consists of chief cells and
oxyphil cells. Chief cells are responsible for synthesis and secretion of PTH whereas
oxyphil cells have no known function.

8
2. Thyroid Hormones

2.1. Chemistry of thyroid hormones

Thyroid hormones are derivatives of the amino acid tyrosine bound covalently to iodine.
The two principal thyroid hormones are:

• Thyroxine (known as T4 or L-3,5,3',5'-tetraiodothyronine)

• Triiodothyronine (T3 or L-3,5,3'-triiodothyronine).

As shown in the following diagram, the thyroid hormones are basically two tyrosines
linked together with the critical addition of iodine at three or four positions on the
aromatic rings. The number and position of the iodine is important. Several other
iodinated molecules are generated that have little or no biological activity; so called
"reverse T3" (3,3',5'-T3) is such an example.

A large majority of the thyroid hormone secreted from the thyroid gland is T4, but T3 is
the considerably more active hormone. Although some T3 is also secreted, the bulk of the
T3 is derived by deiodination of T4 in peripheral tissues, especially liver and kidney.
Deiodination of T4 also yields reverse T3 (rT3), a molecule with no known metabolic
activity.

Fig. 4.6. Structure of tyrosine

Activity 4.5. Structure of tyrosine

• How many carbon atoms are present in a tyrosine molecule?

• Number the carbon atoms according to the standard nomenclature.
• Mark the section of the tyrosine molecule that is part of the backbone of the thyroglobulin
and the section that is jutting out of the backbone.
• Show the connection of the carboxyl (–COOH) group and the amino (–NH2) group in the
backbone to the adjacent amino acids that form the backbone.
• Show the position of the iodine on the T3 and T4 molecules. Hint: the process is called
iodination of tyrosine or organification of iodine. What about the rT3 molecule?
• How does conjugation take place? Hint: 2 tyrosine molecules on thyroglobulin combine. 1
MIT + 1 DIT = 1 T3; 1 DIT + 1 DIT = 1 T4. Number the carbon atoms again after
conjugation.

9
 Fig. 4.7: The structure of thyroxine (T4),
triiodothyronine (T3), and reverse T3 (rT3).

T4, T3, and rT3 all are products of the coupling of two
iodinated tyrosine derivatives. Only T 4 and T3 are
biologically active, and T 3 is far more active than T 4
because of a higher affinity for thyroid hormone
receptors. Reverse T 3 forms as an iodine is removed from
the inner benzyl ring (labeled "A") of T 4; rT3 is present in
approximately equal molar amounts with T 3. However,
3
rT is essentially devoid of biologic activity. As shown in
the bottom panel, T 4 is part of the peptide backbone of the
thyroglobulin molecule, as are T 3 and rT3. Cleavage of the
two indicated peptide bonds would release T 4.

Activity 4.6: Chemistry of the thyroid hormones

• Draw the structures of two tyrosine molecules

and combine them (with addition of iodine) to
form T3 and T4.
• What is thyroglobulin? Where is it produced?
How is thyroid hormone related to thyroglobulin
molecule?
• Explain the formation of thyroid hormone on the
thyroglobulin molecule in the follicular lumen of
the thyroid gland.

Thyroid hormones are poorly soluble in water, and more than 99% of the T3 and T4
circulating in blood is bound to carrier proteins. The principle carrier of thyroid
hormones is thyroxine-binding globulin, a glycoprotein synthesized in the liver. Two
other carriers of import are transthyrein and albumin. Carrier proteins allow
maintenance of a stable pool of thyroid hormones from which the active, free hormones
are released for uptake by target cells.

10
2.2. Synthesis and Secretion of Thyroid Hormones

2.2.1. The Hypothalamic-pituitary-thyroid axis

Please refer to Fig. 4.8.

• TRH (hypothalamus)  TSH (anterior pituitary)  TH (thyroid gland).

• TRH (tripeptide) mainly found in the arcuate nucleus and the median eminence of the
hypothalamus.
• TRH receptor (G-protein-coupled receptor) on the membrane of the tyrotrophs is
activated to stimulate:
a. Phospholipase C pathway  DAG/IP3  ↑ [Ca2+]i  ↑ synthesis and release
of TSH which is stored in the secretory granules.
b. Phospholipase A2  release of arachidonic acid and the formation of a variety
of biologically active eicosanoids.
• TSH (28-kDa glycoprotein with  and  chains). The  chain is unique to TSH and
confers the specificity of the hormone that acts on the thyroid follicular cell via a
specific receptor.
• TSH has G-protein-coupled receptors  activate adenylyl cyclase via Gs  ↑
cAMP stimulates a diverse range of physiological processes or events  synthesis
and secretion of TH.

11
Fig. 4.8: The hypothalamic-pituitary-
thyroid axis. Small-bodied neurons in
the arcuate nucleus and median
eminence of the hypothalamus secrete
thyrotropin-releasing hormone (TRH), a
tripeptide that reaches the thyrotrophs
in the anterior pituitary via the long
portal veins. TRH binds to a G protein-
coupled receptor on the thyrotroph
membrane, triggering the DAG/IP 3
pathway, leading to protein
phosphorylation and raising [Ca2+]i.
These pathways stimulate the
thyrotrophs to synthesize and release
thyrotrophin (or thyroid-stimulating
hormone [TSH]), which is a 28-kDa
glycoprotein stored in secretory
granules. The TSH binds to receptors
on the basolateral membrane of thyroid
follicular cells, stimulating Gs, which
in turn activates adenylyl cyclase and
raises [cAMP]i. As outlined in Figure
4.7, TSH stimulates a number of steps
in the synthesis and release of T 4 and
T3. Inside the pituitary, the type-2 form
of 5'/3'-monodeiodinase converts T 4 to
T3, which negatively feeds back on the
thyrotrophs as well as on the TRH-
secreting neurons. Somatostatin and
dopamine released by hypothalamic
neurons-inhibit TSH release and thus
can influence the "set point" at which
TSH is released in response to a given
amount of T 3 in the pituitary.

Activity 4.7: The hypothalamic-pituitary-thyroid axis

Explain the relationship between TRH, TSH, and thyroid hormones at the molecular level,
including the type or receptors, receptor activation, signal transduction mechanisms, and the
final physiological response.

Explain the negative feedback mechanism for TSH secretion and how this is related to
secretion from the thyroid gland.

12
2.2.2. Synthesis and Secretion of Thyroid Hormones

Thyroid hormones are synthesized by mechanisms fundamentally different from what is

seen in other endocrine systems. Thyroid follicles serve as both factory and warehouse
for production of thyroid hormones.

The entire synthetic process occurs in three major steps:

• Production and accumulation of the raw materials (iodide and tyrosines on

thyroglobulin)
• Fabrication or synthesis of the hormones on a backbone or scaffold of precursor
• Release of the free hormones from the scaffold and secretion into blood

Production and accumulation of the raw materials

• Tyrosines are provided from a large glycoprotein scaffold called thyroglobulin,

which is synthesized by thyroid epithelial cells and secreted into the lumen of the
follicle. Colloid is essentially a pool of thyroglobulin. A molecule of
thyroglobulin contains 134 tyrosines, although only a handful of these are actually
used to synthesize T4 and T3.

• Iodine, or more accurately iodide (I-), is avidly taken up from blood by thyroid
epithelial cells, which have on their outer plasma membrane a sodium-iodide
symporter or "iodine trap". Once inside the cell, iodide is transported into the
lumen of the follicle along with thyroglobulin.

Fabrication of thyroid hormones

This is conducted by the enzyme thyroid peroxidase, an integral membrane protein

present in the apical (colloid-facing) plasma membrane of thyroid epithelial cells.
Thyroid peroxidase catalyzes two sequential reactions:

1. Iodination of tyrosines on thyroglobulin (also known as "organification of

iodide").
2. Synthesis of thyroxine or triiodothyronine from two iodotyrosines.

Fig. 4.9. Synthesis of thyroid hormone

13
Through the action of thyroid peroxidase, thyroid hormones accumulate in colloid, on the
surface of thyroid epithelial cells. Remember that hormone is still tied up in molecules of
thyroglobulin - the task remaining is to liberate it from the scaffold and secrete free
hormone into blood.

Release of the free hormones from the scaffold and secretion into blood

Thyroid hormones are excised from their thyroglobulin scaffold by digestion in

lysosomes of thyroid epithelial cells. This final act in thyroid hormone synthesis proceeds
in the following steps:

• Thyroid epithelial cells ingest colloid by endocytosis from their apical borders -
that colloid contains thyroglobulin decorated with thyroid hormone.

• Colloid-laden endosomes fuse with lysosomes, which contain hydrolytic enzymes

that digest thyroglobulin, thereby liberating free thyroid hormones.

Fig. 4.10: The follicular cell and its role in the synthesis of thyroxine (T4) and
triiodothyronine (T3). The synthesis and release of T 4 and T3 occurs in seven steps. Inside the
follicular cell, a deiodinase converts some of the T 4 to T3. Thyrotropin (or thyroid-stimulating
hormone [TSH]) stimulates each of these steps except step 2. In addition, TSH exerts a growth
factor or hyperplastic effect on the follicular cells. DIT, diiodotyronine; MIT, monoiodotyronine. 13
Finally, free thyroid hormones apparently diffuse out of lysosomes, through the basal
plasma membrane of the cell, and into blood where they quickly bind to carrier proteins
for transport to target cells.

Summary of physiological processes involved in TH production:

1. Iodide uptake by the Na/I- cotransporter on the basolateral membrane of the

thyroid follicular cell. Stimulation of this cotransporter by TSH allows for the
trapping of the dietary iodine within the thyroid gland. The ratio of follicular
cell iodine to serum iodine (thyroid/serum or T/S ratio) is 30:1 in euthyroid
individuals. The T/S ratio increases under conditions of high TSH (e.g. TSH-
secreting pituitary adenoma) and decreases under conditions of low TSH (e.g.
hypophysectomy).
2. Iodide enters lumen and converted to iodine by thyroid peroxidase
3. Iodination of thyroglobulin in the follicular lumen by thyroid peroxidase.
4. Conjugation of iodinated tyrosines to form T4 and T3 linked to the
thyroglobulin by thyroid peroxidase.
5. Endocytosis of iodinated thyroglobulin in the follicular cells.
6. Proteolysis of the iodinated thyroglobulin in the follicular cells.
7. Secretion of T4 and T3 into the circulation.

Activity 4.8: Synthesis of thyroid hormone

• What are the raw ingredients needed for thyroid hormone synthesis?

• Describe the origin and presence of the ingredients in the thyroid follicular lumen.

• Using a suitable diagram, describe the process of

o Iodination of tyrosine molecules in thyroglobulin inside the follicular lumen.
o Conjugation of iodinated tyrosines to form T4 and T3 linked to the thyroglobulin.
o Endocytosis of iodinated thyroglobulin in the follicular cells.
o Proteolysis of the iodinated thyronines in thyroglobulin inside the follicular cells.
o Secretion of T4 and T3 into the circulation.

• How is TSH involved in the above processes?

14
 Fig. 4.11. Summary of thyroid hormone synthesis

Activity 4.9: Summary of thyroid hormone synthesis

What is the source of iodine in the follicular cells? How is I- transported into the cell? How is I-
transported out of the cell into the lumen of the follicle? How is it oxidised to form Io?

What is the source of thyroglobulin that forms the colloid in the lumen of the follicle? How many
tyrosine molecules does a thyroglobulin molecule have? This constitutes what percentage of the
total amino acid molecules in a thyroglubulin molecule?

Explain the process of iodination of the tyrosine molecules in the colloid. Hint: it mostly forms DIT.

Explain the process of conjugation. Hint: it mostly forms T4.

Describe the processes of endocytosis, proteolysis and secretion that finally put T3 and T4 into
circulation.

Which of the above processes are stimulated by signal transduction mechanism after TSH receptor
activation?

15
2.3. Control of Thyroid Hormone Synthesis and Secretion

The chief stimulator of thyroid hormone

synthesis is TSH from the anterior pituitary.
Binding of TSH to receptors on thyroid
epithelial cells seems to enhance all of the
processes necessary for synthesis of thyroid
hormones, including synthesis of the iodide
transporter, thyroid peroxidase and
thyroglobulin.

The magnitude of the TSH signal also sets the

rate of endocytosis of colloid - high
concentrations of TSH lead to faster rates of
endocytosis, and hence, thyroid hormone
release into the circulation. Conversely, when
TSH levels are low, rates of thyroid hormone
synthesis and release diminish.

The thyroid gland is part of the hypothalamic-

pituitary-thyroid axis, and control of thyroid
hormone secretion is exerted by classical
negative feedback, as depicted in Fig. 4.12.
Thyroid-releasing hormone (TRH) from the Change to fig 13.15 R&P
hypothalamus stimulates TSH from the
pituitary, which stimulates thyroid hormone
release. As blood concentrations of thyroid
hormones increase, they inhibit both TSH and
TRH, leading to "shutdown" of thyroid
epithelial cells. Later, when blood levels of
thyroid hormone have decayed, the negative
feedback signal fades, and the system wakes
up again.

A number of other factors have been shown to

influence thyroid hormone secretion. In
rodents and young children, exposure to a
cold environment triggers TRH secretion,
leading to enhanced thyroid hormone release.
This makes sense considering the known
ability of thyroid hormones to spark body heat
production.
Fig. 4.12. Control of thyroid hormone synthesis
and secretion

16
Circulating free T4 and T3 exerts negative feedback on TRH and TSH secretion. At the
level of the thyrotroph, the sensor in this feedback mechanism monitors the concentration
of T3 inside the thyrotroph. The T3 can either enter directly from the blood plasma, or
can form inside the thyrotroph by deiodination of T4. T3 feeds back on the thyrotroph by
modulating gene transcription:

• Direct feedback mechanism. Intracellular T3 inhibits the synthesis of

both the  and  chains of TSH
• Indirect feedback mechanism. Intracellular T3 decreases the number of
TRH receptors on the surface of the thyrotroph

Activity 4.10: Control of thyroid hormone synthesis and secretion

Describe the direct and indirect negative feedback mechanism of thyroid hormone synthesis
and secretion at the molecular level.

Draw a diagram showing the hypothalamo-pituitary-thyroid axis. Show how TRH affects the
synthesis and secretion of TSH from the tyrotrophs and how TSH affects the synthesis and
secretion of T3 and T4 from the follicular cells of the thyroid.

Also show the negative feedback mechanism that regulates thyroxine levels in the circulation.
Explain the mechanism in detail.

Summary of effect of TSH on TH production:

In the thyroid follicle cell, TSH stimulates:

1. Iodide uptake by activating Na/I- cotransporter

2. Thyroglobulin synthesis
3. Reactions resulting in the oxidation and organification of iodide.
4. Microvilli formation and engulfment of colloid at the apical cell surface.
5. Movement of lysosome from the basal toward the apical surface of the follicle
cell.
6. Movement of phagolysosomes from apical to basal surfaces of cells.
7. Activity of the deiodinase enzymes.
8. Growth of the follicle cell.

17
2.4. Mechanism of Action and Physiologic Effects of Thyroid Hormones

2.4.1. Thyroid Hormone Receptors and Mechanism of Action

Receptors for thyroid hormones are intracellular DNA-binding proteins that function as
hormone-responsive transcription factors, conceptually very similar to the receptors
for steroid hormones.

Thyroid hormones enter cells through membrane transporter proteins. A number of

plasma membrane transporters have been identified, some of which require ATP
hydrolysis; the relative importance of different carrier systems is not yet clear and may
differ among tissues. Once inside the nucleus, the hormone binds its receptor, and the
hormone-receptor complex interacts with specific sequences of DNA in the promoters of
responsive genes. The effect of receptor binding to DNA is to modulate gene expression,
either by stimulating or inhibiting transcription of specific genes.

Fact: Total concentration of T4 in the circulation is 50-fold or higher than T3. But why is
T3 biologically more active than T4?

• T4 is bound (only 0.02% is free) more tightly to plasma proteins than T3 (0.50%
is free) i.e. a 25-fold higher ratio of free to bound. Net effect: the amount of free
T4 in the circulation is only about two fold higher than T3.
• The target cells convert T4 to T3, the concentration of T3 and T4 in the cytoplasm
of the cell is similar.
• Thyroid hormone receptor in the nucleus has approximately a 10-fold greater
affinity for T3 than T4. T3 is responsible for approximately 90% of the
occupancy of thyroid hormone receptor in euthyroid state.

Activity 4.11: Mechanism of action of thyroid hormone

Describe how thyroid hormone is transported to the intracellular space and binds to the
intracellular receptor. Differentiate between T3 and T4 in terms of their availability and effect
of the target cells.

Describe the signal transduction mechanism once thyroid receptor is activated.

Using examples describe how thyroid hormone exerts its physiological effect.

18
2.4.2. Physiologic Effects of Thyroid Hormones

It is likely that all cells in the body are targets for thyroid hormones. While not strictly
necessary for life, thyroid hormones have profound effects on many "big time"
physiologic processes, such as development, growth and metabolism. Many of the
effects of thyroid hormone have been delineated by study of deficiency and excess states,
as discussed briefly below.

Metabolism: Thyroid hormones stimulate diverse metabolic activities most tissues,

leading to an increase in basal metabolic rate. One consequence of this activity is to
increase body heat production, which seems to result, at least in part, from increased
oxygen consumption and rates of ATP hydrolysis. By way of analogy, the action of
thyroid hormones is akin to blowing on a smouldering fire. A few examples of specific
metabolic effects of thyroid hormones include:

• Lipid metabolism: Increased thyroid hormone levels stimulate fat mobilization,

leading to increased concentrations of fatty acids and glycerol in plasma. They
also enhance oxidation of fatty acids in many tissues. Finally, plasma
concentrations of cholesterol and triglycerides are inversely correlated with
thyroid hormone levels - one diagnostic indication of hypothyroidism is increased
blood cholesterol concentration.
• Carbohydrate metabolism: Thyroid hormones stimulate almost all aspects of
carbohydrate metabolism, including enhancement of insulin-dependent entry of
glucose into cells and increased gluconeogenesis and glycogenolysis to generate
free glucose. TH induces the expression of several key gluconeogenic enzymes,
including phosphoenolpyruvate carboxykinase, pyruvate carboxylase, and
glucose-6-phosphatase.
• Protein metabolism: The amino acids required for increased hepatic
gluconeogenesis, stimulated by TH, come from increased proteolysis,
predominantly in muscle. TH also increases protein synthesis. Because the
increases in protein degradation usually outweigh the increases in synthesis, a net
loss of muscle protein occurs. The catabolic effect is exaggerated when T3 is
present in great excess, so that muscle wasting and weakness, as well as increased
nitrogen loss in the urine as urea can be a prominent feature of clinical
thyrotoxicosis (hyperthyroidism).

By accelerating the rates of glucose production, protein synthesis and degradation, as

well as lipogenesis and lypolysis, the TH stimulates energy consumption. Therefore, to
the extent that TH stimulates both synthesis and degradation, they promote futile cycles
that contribute significantly to the increased oxygen consumption seen with
thyrotoxicosis (hyperthyroidism).

19
 Fig. 4.13: Action of thyroid hormones on target cells.
Free extracellular thyroxine (T 4) and triiodothyronine (T 3) enter the target cell either by diffusion or by carrier-mediated
transport. Once the T 4 is inside the cell, a cytoplasmic 5'/3'-monodeiodinase converts much of the T4 to T3, so that
cytoplasmic levels of T 4 and T3 are about equal. Both T 4 and T 3 enter the nucleus. Thyroid hormone receptors bind to
DNA at thyroid response elements in the promoter region of genes regulated by thyroid hormones. The binding of T 3 or
T4 to the receptor regulates the transcription of these genes. The receptor preferentially binds T 3. Therefore, of the total
thyroid hormone bound to receptor, approximately 90% is T 3. The receptor that binds to the DNA is preferentially a
heterodimer of the thyroid hormone receptor and retinoid X receptor. Thyroid hormone promotes the transcription of
genes encoding a wide range of proteins. mRNA, messenger RNA.

Growth: Thyroid hormones are clearly necessary for normal growth in children and
young animals, as evidenced by the growth-retardation observed in thyroid deficiency.
Not surprisingly, the growth-promoting effect of thyroid hormones is intimately
intertwined with that of growth hormone, a clear indication that complex physiologic
processes like growth depend upon multiple endocrine controls.

Development: A classical experiment in endocrinology was the demonstration that

tadpoles deprived of thyroid hormone failed to undergo metamorphosis into frogs. Of
critical importance in mammals is the fact that normal levels of thyroid hormone are
essential to the development of the fetal and neonatal brain.

Other Effects: As mentioned above, there do not seem to be organs and tissues that are
not affected by thyroid hormones. A few additional, well-documented effects of thyroid
hormones include:

• Cardiovascular system: Thyroid hormones increases heart rate, cardiac

contractility and cardiac output. They also promote vasodilation, which leads to
enhanced blood flow to many organs.

20
 • Central nervous system: Both decreased and increased concentrations of thyroid
hormones lead to alterations in mental state. Too little thyroid hormone, and the
individual tends to feel mentally sluggish, while too much induces anxiety and
nervousness.
• Reproductive system: Normal reproductive behavior and physiology is
dependent on having essentially normal levels of thyroid hormone.
Hypothyroidism in particular is commonly associated with infertility.

Activity 4.12: Mechanism of action of thyroid hormone

• List down the physiological effects of TH.

• Explain how these physiological effects are achieved starting with TH receptor
activation.

Summary of effects of thyroid hormone:

• Stimulate calorigenesis in most cells

• Increase cardiac output
o Increase rate of cardiac contraction
o Increase strength of cardiac contraction
• Increase oxygenation of blood
o Increase rate of breathing
o Increase number of red blood cells in the circulation
• Effects on carbohydrate metabolism
o Promote glycogen formation in the liver
o Increase glucose uptake into adipose and muscle
• Effects on lipid turnover
o Increase lipid synthesis
o Increase lipid mobilization
o Increase lipid oxidation
• Effects on protein metabolism
o Stimulate protein synthesis
o Stimulate growth hormone secretion
o Promote bone growth
o Promote insulin-like growth factor I (IGF-1) production by liver
• Promote development and maturation of nervous system
o Promote neural branching
o Promote myelination of nerves

21
2.5. Thyroid Disease States

Disease is associated with both inadequate production and overproduction of thyroid

hormones. Both types of disease are relatively common afflictions of man and animals.

Alterations of thyroid functions is categorised as primary or secondary.

1. primary dysfunction or disease of the thyroid gland: alterations of TH levels
with secondary feedback effects on pituitary TSH
2. secondary dysfunction: pituitary or hypothalamic alterations  alterations in TSH
production. ↑ TSH  ↑ TH; ↓ TSH  ↓ TH.

Hypothyroidism is the result from any condition that results in thyroid hormone
deficiency. Well-known examples include:

• Iodine deficiency: Iodide is absolutely necessary for production of thyroid

hormones; without adequate iodine intake, thyroid hormones cannot be
synthesized. Historically, this problem was seen particularly in areas with iodine-
deficient soils, and frank iodine deficiency has been virtually eliminated by iodine
supplementation of salt.

• Primary hypothyroidism:
1. defective hormone synthesis due to autoimmune (circulating antithyroid
antibodies) thyroiditis, endemic iodine deficiency, or antithyroid drugs
2. congenital defects or loss of thyroid tissue after treatment for hyperthyroidism.

• Secondary hypothyroidism (less common): conditions that cause either pituitary

or hypothalamic failure.

Common symptoms of hypothyroidism arising after early childhood include lethargy,

fatigue, cold-intolerance, weakness, hair loss and reproductive failure. If these signs are
severe, the clinical condition is called myxedema. In the case of iodide deficiency, the
thyroid becomes inordinately large and is called a goiter. This is due to
overstimulation of the thyroid gland by increased TSH because of low TH. Loss of
functional thyroid tissue can also lead to goiter i.e.  ↓ production of TH  ↑ TSH
secretion  goiter

Hashimoto thyroiditis is the most common cause for hypothyroidism in adults. Various
autoantibodies may be present against thyroid peroxidase, thyroglobulin and TSH
receptors. Though the thyroid may initially have been painlessly enlarged (due to thyroid
cell destruction  decrease TH production  stimulate TSH production  cellular
proliferation), over time the inflammation leads to atrophy of the thyroid with
hypothyroidism. Anti-thyroid autoantibodies are helpful in establishing the diagnosis

The most severe and devastating form of hypothyroidism is seen in young children with
congenital thyroid deficiency. If that condition is not corrected by supplemental therapy
soon after birth, the child will suffer from cretinism, a form of irreversible growth and
mental retardation.
22
 Most cases of hypothyroidism are readily treated by oral administration of synthetic
thyroid hormone. In times past, consumption of desiccated animal thyroid gland was used
for the same purpose.

Hyperthyroidism results from secretion of thyroid hormones. In most species, this

condition is less common than hypothyroidism. In humans the most common form of
hyperthyroidism is Grave’s disease, an immune disease in which autoantibodies bind to
and activate the thyroid-stimulating hormone receptor, leading to continual stimulation of
thyroid hormone synthesis. Another interesting, but rare cause of hyperthyroidism is so-
called hamburger thyrotoxicosis i.e. consumption of hamburgers made from meat
derived partly from the neck region that contains thyroid gland.

Primary thyrotoxicosis: excess TH secreted by the thyroid gland.

Causes:
1. Grave’s disease: autoimmune disease.
2. Toxic multinodular goiter.
3. Solitary hyperfunctioning nodules.
4. Follicular thyroid carcinoma (rarely).

Secondary hyperthyroidism: very rare

Cause: TSH-secreting pituitary adenomas.

.
Common signs of hyperthyroidism are basically the opposite of those seen in
hypothyroidism, and include nervousness, insomnia, high heart rate, eye disease and
anxiety.

Patients are normally treated with antithyroid drugs that works on

1. iodide trapper. E.g. Thiocynate and perchlorate: competitive inhibitor for iodide
i.e. block entry of I- from capillaries.
2. thyroid peroxidase. Propylthiouracyl and carbamizole.

Activity 4.13. Thyroid disease states

List and describe disease states due to inadequate and overproduction of TH.

23
Fig. 4.14. Signs and symptoms of hypothyroidism and hyperthyroidism

24
Goitre

The term “goiter” simply refers to the abnormal enlargement of the thyroid gland. It is
important to know that the presence of a goiter does not necessarily mean that the thyroid
gland is malfunctioning. A goiter can occur in a gland that is producing too much hormone
(hyperthyroidism), too little hormone (hypothyroidism), or the correct amount of hormone
(euthyroidism). A goiter indicates there is a condition present which is causing the thyroid
to grow abnormally.

An enlarged thyroid gland may be diffuse or nodular. A goiter may extend into the
retrosternal space, with or without substantial anterior enlargement. Because of the
anatomic relationship of the thyroid gland to the trachea, larynx, superior and inferior
laryngeal nerves, and esophagus, abnormal growth may cause a variety of compressive
syndromes.

Stimulation of the TSH receptors of the thyroid by TSH, TSH-receptor antibodies, or TSH
receptor agonists, such as chorionic gonadotropin, may result in a diffuse goiter. When a
small group of thyroid cells, inflammatory cells, or malignant cells metastatic to the thyroid
is involved, a thyroid nodule may develop.

A number of factors can cause your thyroid gland to enlarge. Among the most common are:

• Iodine deficiency.

• Graves' disease. Overactive thyroid (hyperthyroidism)

• Hashimoto's disease. Underactive thyroid (hypothyroidism).

• Multinodular goiter. In this condition, several solid or fluid-filled lumps called

nodules develop in both sides of your thyroid, resulting in overall enlargement of the
gland.
• Solitary thyroid nodules. In this case, a single nodule develops in one part of your
thyroid gland. Most nodules are noncancerous (benign) and don't lead to cancer.
• Thyroid cancer. Thyroid cancer is far less common than benign thyroid nodules. A
biopsy of a thyroid nodule is very accurate in determining if it's cancerous.
• Pregnancy. A hormone produced during pregnancy, human chorionic gonadotropin
(HCG), may cause your thyroid gland to enlarge slightly.
• Inflammation. Thyroiditis is an inflammatory condition that can cause pain and
swelling in the thyroid. It may also cause an over- or underproduction of thyroxine.

25
3. Calcitonin
Calcitonin is a hormone known to participate in calcium and phosphorus metabolism.
The major source of calcitonin is from the parafollicular or C cells in the thyroid gland,
but it is also synthesized in a wide variety of other tissues, including the lung and
intestinal tract.

Calcitonin is a 32 amino acid peptide cleaved from a larger prohormone. It contains a

single disulfide bond, which causes the amino terminus to assume the shape of a ring.

The calcitonin receptor has been cloned and shown to be a member of the seven-
transmembrane, G protein-coupled receptor family.

3.1. Control of Calcitonin Secretion

The most prominent factor controlling calcitonin secretion is the extracellular

concentration of ionized calcium. Elevated blood calcium levels strongly stimulate
calcitonin secretion, and secretion is suppressed when calcium concentration falls below
normal. A number of other hormones have been shown to stimulate calcitonin release in
certain situations, and nervous controls also have been demonstrated.

3.2. Physiologic Effects of Calcitonin

A large and diverse set of effects have been attributed to calcitonin, but in many cases,
these were seen in response to pharmacologic doses of the hormone, and their
physiologic relevance is suspect. It seems clear however, that calcitonin plays a role in
calcium and phosphorus metabolism. In particular, calcitonin has the ability to decrease
blood calcium levels at least in part by effects on two well-studied target organs:

• Bone: Calcitonin suppresses resorption of bone by inhibiting the activity of

osteoclasts, a cell type that "digests" bone matrix, releasing calcium and
phosphorus into blood.

• Kidney: Calcitonin inhibits tubular reabsorption of calcium and phosphorus,

leading to increased rates of their loss in urine.

It seems clear that there are species differences in the importance of calcitonin as a factor
affecting calcium homeostasis. In humans, calcitonin has at best a minor role in
regulating blood concentrations of calcium. One interesting piece of evidence to support
this statement is that humans with chronically increased (medullary thyroid cancer) or
decreased (surgical removal of the thyroid gland) levels of calcitonin in blood usually do
not show alterations from normal in serum calcium concentration. Additional information
on calcitonin and calcium balance can be found in the Section 6 on Endocrine Control of
Calcium and Phosphate Homeostasis.

26
3.3. Disease States

A large number of diseases are associated with abnormally increased or decreased levels
of calcitonin, but pathologic effects of abnormal calcitonin secretion per se are not
generally recognized.

There are several therapeutic uses for calcitonin. It is used to treat hypercalcemia resulting
from a number of causes, and has been a valuable therapy for Paget disease, which is a
disorder in bone remodeling. Calcitonin also appears to be a valuable aid in the
management of certain types of osteoporosis.

Activity 4.14: Calcitonin

Describe the chemistry of calcitonin, the control of calcitonin secretion, and the physiological
effects of calcitonin. The description should be at the molecular level.

27
 4. Parathyroid Hormone
Parathyroid hormone (PTH) is the most important endocrine regulator of calcium and
phosphorus concentrations in extracellular fluid. This hormone is secreted from cells of
the parathyroid glands and finds its major target cells in bone and kidney. Another
hormone, parathyroid hormone-related protein, binds to the same receptor as parathyroid
hormone and has major effects on development.

Like most other protein hormones, parathyroid hormone is synthesized as a

preprohormone. After intracellular processing, the mature hormone is packaged within
the Golgi into secretory vesicles, the secreted into blood by exocytosis. Parathyroid
hormone is secreted as a linear protein of 84 amino acids.

Fig. 4.15: Parathyroid

hormone (PTH) synthesis.
The synthesis of PTH begins
with the production of pre-pro-
PTH (115 amino acids) in the
rough endoplasmic reticulum
(ER). Cleavage of the signal
sequence in the ER lumen
yields pro-PTH (90 amino
acids). During transit through
the vesicular pathway, enzymes
in the Golgi cleavage the "pro"
sequence, yielding the mature
or "intact" PTH (84 amino
acids), which is stored in
secretory granules. Beginning
in the secretory granule,
enzymes cleave PTH into two
fragments. The N-terminal
fragment is either 33 or 36
amino acids in length and
contains all of the biologic
activity.

4.1. Control of Parathyroid Hormone Secretion

Parathyroid hormone is released in response to low extracellular concentrations of free

calcium. Changes in blood phosphate concentration can be associated with changes in
parathyroid hormone secretion, but this appears to be an indirect effect and phosphate per
se is not a significant regulator of this hormone.

The major regulator of PTH secretion is ionized plasma Ca2+, although vitamin D also
plays a role. Both inhibit the synthesis or release of PTH. When calcium concentrations
fall below the normal range, there is a steep increase in secretion of parathyroid hormone.

28
Low levels of PTH are secreted even when blood
calcium levels are high. The figure to the right
depicts PTH release from cells cultured in vitro in
differing concentrations of calcium. The parathyroid
cell monitors extracellular free calcium
concentration via an integral membrane protein that
functions as a calcium-sensing receptor.

Fig. 4.16: Parathyroid hormone (PTH) secretion and its dependence on ionized Ca 2+ in the plasma. A, Four
parathyroid glands lie on the posterior side of the thyroid. The chief cells synthesize, store, and secrete PTH. Increases
in extracellular [Ca2+] inhibit PTH secretion in the following manner: Ca2+ binds to a receptor that is coupled to a
heterotrimeric G protein, Gαq, which activates phospholipase C (PLC). This enzyme converts phosphoinositides
(PIP 2) to inositol triphosphate (IP 3) and diacylglycerols (DAG). The IP3 causes the release of Ca2+ from internal
stores, whereas the DAG stimulates protein kinase C (PKC). Paradoxically, both the elevated [Ca2+]i and the
stimulated PKC inhibit release of granules containing PTH. Increased [Ca2+]o also inhibits PTH synthesis. Thus,
increased levels of plasma Ca 2+ lower PTH release, and thus tend to lower plasma [Ca2+]. B, Small decreases in free
plasma [Ca2+] greatly increase the rate of PTH release. About half of the total plasma Ca 2+ is free. In patients with
familial hypocalciuric hypercalcemia (FHH), the curve is shifted to the right; that is, plasma [Ca 2+] must rise to higher
levels before inhibiting PTH secretion. As a result, the patients have normal PTH levels, but elevated plasma [Ca2+].
ER, endoplasmic reticulum.

29
Ca-sensing receptor is a member of G-protein-coupled receptor family  activates
phospholipase C  ↑ IP3 + DAG  release of Ca2+ from internal stores and activation
of protein kinase C  inhibit secretion of PTH. Note: this is unlike most endocrine
tissues in which activation of the signaling systems promotes a secretory response.
Another example is the granular cells of juxtaglomerlar apparatus (JGA), in which an
increase in Ca2+ inhibits secretion of renin.

4.2. Physiologic Effects of Parathyroid Hormone

If calcium ion concentration in extracellular fluid falls below normal, PTH brings it back
within the normal range. In conjunction with increasing calcium concentration, the
concentration of phosphate ion in blood is reduced. PTH accomplishes its job by
stimulating at least three processes:

• Mobilization of calcium from bone: Although the mechanisms remain obscure,

a well-documented effect of parathyroid hormone is to stimulate osteoclasts to
resorb bone mineral, liberating calcium into blood.

• Enhancing absorption of calcium from the small intestine: Facilitating

calcium absorption from the small intestine would clearly serve to elevate blood
levels of calcium. Parathyroid hormone stimulates this process, but indirectly by
stimulating production of the active form of vitamin D in the kidney. Vitamin D
induces synthesis of a calcium-binding protein in intestinal epithelial cells that
facilitates efficient absorption of calcium into blood.

• Suppression of calcium loss in urine: In addition to stimulating fluxes of

calcium into blood from bone and intestine, parathyroid hormone puts a brake on
excretion of calcium in urine, thus conserving calcium in blood. This effect is
mediated by stimulating tubular reabsorption of calcium. Another effect of
parathyroid hormone on the kidney is to stimulate loss of phosphate ions in urine.

30
 Activity 4.15:
Mechanism of action
of PTH

Describe the
mechanism of signal
transduction in the
chief cells when
2+
extracellular Ca is
low.

Describe the
mechanism of action
of PTH on the bone,
kidney and GIT.

Fig. 4.17: Control of plasma PTH concentration.

Additional information on how parathyroid hormone and vitamin D control calcium

balance can be found in the Section 6 on Endocrine Control of Calcium Homeostasis.

Kidney and bone have the greatest abundance of PTH receptor. Within the kidney, the
PTH receptors are most abundant in the proximal and distal convoluted tubules. In the
bone, the osteoblast appears to be the important target cell. The PTH receptor appears to
be coupled to 2 G-proteins and thus 2 signal transduction systems.

a. binding of PTH to receptor stimulates Gs  activates adenylyl cyclase

 release of cAMP  stimulates protein kinase A.

b. binding of PTH to receptor stimulates Gq  stimulates phospholipase C

 generate IP3 and DAG. The IP3 releases Ca2+ from internal stores ->
increase [Ca2+]i  activate Ca2+-dependent kinases.

The net effects of PTH on kidney and bone are to increase plasma [Ca2+] and lower
plasma [phosphate].

In the kidney, PTH promotes Ca2+ reabsorption, phosphate loss, and 1-hydroxylation of
25-hydroxyvitamin D.

In bone, PTH promotes net resorption thus increasing plasma [Ca2+].

31
 Fig. 4.18. Feedback loops in the control
of plasma Ca2+ levels.

Parathyroid hormone (PTH) released from

the parathyroid glands acts via receptors in
both bone and kidney. In kidney, PTH has
three effects. First, PTH promotes Ca2+
reabsorption and, thus, an increase in
plasma [Ca2+]. Second, PTH inhibits
phosphate reabsorption. Third, PTH
promotes the hydroxylation of 25-hydroxy-
vitamin D, creating the active metabolite
1,25-dihydroxy-vitamin D. This metabolite
further promotes renal Ca2+ reabsorption. In
bone, PTH promotes net bone resorption
and, thus, an increase in plasma [Ca2+]. In
intestine, the 1,25-dihydroxy-vitamin D
(produced indirectly as the result of PTH)
enhances Ca2+ absorption. Thus, net effect
on bone, kidney, and gut, as far as Ca2+ is
concerned, is to increase plasma [Ca2+]. The
increased plasma [Ca2+] feeds back on the
parathyroid glands, inhibiting the release of
PTH.

Activity 4.16: Parathyroid hormone (PTH)

Describe the chemistry of PTH, the control of PTH secretion, and the physiological effects of
PTH. The description should be at the molecular level.

32
4.3. Parathyroid Disease States

Both increased and decreased secretion of parathyroid hormone are recognized as causes
of serious disease in man and animals.

Excessive secretion of parathyroid hormone is seen in two forms:

• Primary hyperparathyroidism is the result of parathyroid gland disease, most

commonly due to a parathyroid tumor (adenoma) which secretes the hormone
without proper regulation. Common manifestations of this disorder are chronic
elevations of blood calcium concentration (hypercalcemia), kidney stones and
decalcification of bone.

• Secondary hyperparathyroidism is the situation where disease outside of the

parathyroid gland leads to excessive secretion of parathyroid hormone. A
common cause of this disorder is kidney disease - if the kidneys are unable to
reabsorb calcium, blood calcium levels will fall, stimulating continual secretion of
parathyroid hormone to maintain normal calcium levels in blood. Secondary
hyperparathyroidism can also result from inadequate nutrition - for example, diets
that are deficient in calcium or vitamin D, or which contain excessive phosphorus
(e.g. all meat diets for carnivores).

A prominent effect of secondary hyperparathyroidism is decalcification of bone,

leading to pathologic fractures or "rubber bones".

There is no doubt that chronic secretion or continuous infusion of parathyroid hormone

leads to decalcification of bone and loss of bone mass. However, in certain situations,
treatment with parathyroid hormone can actually stimulate an increase in bone mass and
bone strength. This seemingly paradoxical effect occurs when the hormone is
administered in pulses (e.g. by once daily injection), and such treatment appears to be an
effective therapy for diseases such as osteoporosis.

Inadequate production of parathyroid hormone - hypoparathyroidism - typically results in

decreased concentrations of calcium and increased concentrations of phosphorus in
blood. Common causes of this disorder include surgical removal of the parathyroid
glands and disease processes that lead to destruction of parathyroid glands. The resulting
hypocalcemia often leads to tetany and convulsions, and can be acutely life-threatening.
Treatment focuses on restoring normal blood calcium concentrations by calcium
infusions, oral calcium supplements and vitamin D therapy.

33
5. Vitamin D
Although vitamin D is not secreted by the thyroid or parathyroid gland, it is discussed
here because of its involvement in calcium and phosphate homeostasis.

Vitamin D exists in the body in 2 forms: vitamin D3 and vitamin D2. Vitamin D3 can be
synthesized from the 7-dehydrocholesterol that is present in the skin with sufficient uv
light. It is also available from a number of natural resources including cod liver, eggs,
and fortified milk.

Vitamin D2 is obtained from the diet, largely from vegetables. Absorption of vitamin D3
and D2 from the GIT depends on its solubilisation by bile salts.

It is considered a vitamin because of its dietary requirement, but it is also considered a

hormone because it is endogenously synthesized and because even the fraction that arises
from the diet must be metabolized to a biological active form.

The principle active form of vitamin D is not vitamin D3 or D2, but rather a dihydroxylated
metabolite of either (1,25-dihydroxyvitamin D) which proceeds in 2 steps (Fig. 4.19).

Activity 4.17: Vitamin D

Why is vitamin D considered a vitamin as well as

a hormone?

What are the sources of Vitamin D?

Describe the process of formation of vitamin D3,

I,25 (OH)2D3, and vitamin D2 from the original
source. Name the enzymes involved. What do
you think stimulate these enzymes? How is
vitamin D transported in the blood?

Why is 1’25 dihydroxyvitamin D the principle

active form of vitamin D?

What are the target organs for vitamin D? How

does vitamin D exert its effect on the target
cells?

Where are the receptors for vitamin D? What

would the signal transduction involve?

What is the physiological effect of vitamin D?

How does it exert its effect?

How can a person be deficient in vitamin D?

What would happen to this person?

Fig. 4.19. Vitamin D 31

In circulation: bound to vitamin-D-binding protein.

Receptor for vitamin D: nuclear receptor (a transcription factor).

Physiological action: via regulation of the transcription of a variety of proteins.

Physiological effect:
1. action on classic target tissues to regulate body mineral and skeletal
homeostasis and a more general action that regulates cell growth.
2. action on small intestine, bone, and kidney serve to prevent any abnormal
decline or rise in plasma [Ca2+].

Action of vitamin D on small intestine:

In duodenum, 1,25-dihydroxyvitamin D increases the production of several proteins that

enhance Ca2+ absorption (Fig. 4.20A).

Ca2+ moves from the intestinal lumen via paracellular and transcellular routes.
Paracellular route occurs passively throughout the intestine, and not regulated by vitamin
D. Transcellular route occurs only in the duodenum via three steps:

1. Ca2+ enters the cell across the apical membrane via Ca2+ channels and possibly
endocytosis.
2. the entering Ca2+ binds to several high-affinity binding proteins, particularly
calbindin. This will buffer the [Ca2+]i and maintain a favorable gradient for Ca2+
entry.
3. the entrocyte extrudes Ca2+ absorption primarily by genomic effects that involve
induction of the synthesis of Ca2+ channels and pumps and Ca2+-binding proteins
as well as other proteins (e.g. alkaline phosphatase)

The active form of vitamin D-1,25-dihydroxyvitamin D-stimulates all three steps of

transcellular Ca2+ absorption.

32
Fig. 4.20: Intestinal absorption of Ca 2+ and
phosphate.

A, The small intestine absorbs Ca2+ by two

mechanisms. The passive, paracellular
absorption of Ca2+ occurs throughout the small
intestine. This pathway is the predominant one
but is not under the control of vitamin D. The
second mechanism-the active, transcellular
absorption of Ca2+-occurs only in the duodenum.
Ca2+ enters the cell across the apical membrane
via a channel. Inside the cell, the Ca2+ is
buffered by binding proteins, such as calbindin,
and is also taken up into intracellular organelles,
such as the ER. The enterocyte then extrudes
Ca2+ across the basolateral membrane via a Ca2+
pump and a Na-Ca exchanger. Thus, the net
effect is Ca2+ absorption. The active form of
vitamin D-1,25-dihydroxyvitamin D-stimulates
all three steps of transcellular Ca2+ absorption.
B, Inorganic phosphate enters the enterocyte
across the apical membrane via an Na/P i (NaPi)
cotransporter. Once inside the cell, the P i is
extruded across the basolateral membrane. Thus,
the net effect is Pi absorption. ATP, adenosine
triphosphate; mRNA, messenger RNA; P i,
inorganic phosphate.

The effect of PTH to stimulate intestinal Ca2+ absorption is thought to be entirely indirect
and mediated by increasing the renal formation of 1,25-dihydroxyvitamin D, which then
enhances Ca2+ absorption.

Vitamin D also stimulates phosphate absorption from the small intestine (Fig. 4.20B):

Action of vitamin D on the kidney:

Vitamin D appears to act synergistically with PTH to enhance Ca2+ reabsorption in the
distal convoluted tubule. PTH is a more potent regulator of Ca2+ reabsorption than
vitamin D is. Vitamin D also promotes phosphate reabsorption in the kidney although
the effect is less dramatic than that of PTH.

Action of vitamin D on bone:

Indirect effect: vitamin D’s action on the intestine and kidney makes more Ca2+ available
to mineralize the osteoid.

33
Direct effect: to mobilize Ca2+ out of bone

Activity 4.18: Vitamin D

Describe the involvement of Vitamin D on calcium and phosphate homeostasis.

6. Endocrine Control of Calcium and Phosphate Homeostasis

It would be very difficult to name a physiologic process that does not depend, in one way
or another, on calcium. Some examples are: hormone secretion, muscle contraction,
nerve conduction, exocytosis, and the activation and inactivation of many enzymes. Ca2+
also serves as an intracellular second messenger by carrying information from the cell
membrane into the interior of the cell. It is critical to maintain blood calcium
concentrations within a tight normal range. Deviations above or below the normal range
frequently lead to serious problems.

Activity 4.19: Mechanism of action of calcium

2+
Explain how Ca is involved in:

• hormone secretion
• muscle contraction
• nerve conduction
• exocytosis
• activation of enzymes

Hypocalcemia refers to low blood calcium concentration. Clinical signs of this disorder
reflect increased neuromuscular excitability and include muscle spasms, tetany and
cardiac dysfunction.

Hypercalcemia indicates a concentration of blood calcium higher than normal. The

normal concentration of calcium and phosphate in blood and extracellular fluid is near
the saturation point; elevations can lead to diffuse precipitation of calcium phosphate in
tissues, leading to widespread organ dysfunction and damage.

34
Preventing hypercalcemia and hypocalcemia is largely the result of robust endocrine
control systems.

Phosphate is part of the ATP molecule, thus plays a critical role in cellular energy
metabolism. It also plays crucial role in the activation and inactivation of enzymes.
However, unlike Ca2+ the plasma phosphate concentration is not very strictly regulated,
and its levels fluctuate throughout the day, particularly after meals.

Calcium homeostasis and phosphate homeostasis are intimately tied to each other
because:

a. Calcium and phosphate are the principle components of hydroxyapatite

crystals Ca10(PO4)6(OH)2 which is the major portion of the mineral phase of
bone.

b. They are regulated by the same hormone: PTH, 1,25-dihydroxyvitamin D

(calcitriol), and to a lesser extent calcitonin.

6.1. Body Distribution of Calcium and Phosphate

There are three major pools of calcium in the body (Fig. 4.21):

• Intracellular calcium: A large majority of calcium within cells is sequestered in

mitochondria and endoplasmic reticulum. Intracellular free calcium
concentrations fluctuate greatly, from roughly 100 nM to greater than 1 uM, due
to release from cellular stores or influx from extracellular fluid. These fluctuations
are integral to calcium's role in intracellular signaling, enzyme activation and
muscle contractions.

• Calcium in blood and extracellular fluid: Roughly half of the calcium in blood
is bound to proteins. The concentration of ionized calcium in this compartment is
normally almost invariant at approximately 1 mM, or 10,000 times the basal
concentration of free calcium within cells. Also, the concentration of phosphorus
in blood is essentially identical to that of calcium.

• Bone calcium: A vast majority of body calcium is in bone. Within bone, 99% of
the calcium is tied up in the mineral phase, but the remaining 1% is in a pool that
can rapidly exchange with extracellular calcium.

As with calcium, the majority of body phosphate (approximately 85%) is present in the
mineral phase of bone (Fig. 4.21). The remainder of body phosphate is present in a
variety of inorganic and organic compounds distributed within both intracellular and
extracellular compartments. Normal blood concentrations of phosphate are very similar
to calcium.

35
Fig. 4.21:
Calcium
distribution
and balance.

Note that all

values are for a
70-kg human,
expressed in
terms of
elemental
calcium. ECF,
extracellular
fluid.

Fig. 4.22.
Phosphate
distribution
and balance.

Note that all

values are for a
70-kg human,
expressed in
elemental
phosphorus.
ECF,
extracellular
fluid.

36
6.2. Fluxes of Calcium and Phosphate

Maintaining constant concentrations of calcium in blood requires frequent adjustments,

which can be described as fluxes of calcium between blood and other body
compartments. Three organs participate in supplying calcium to blood and removing it
from blood when necessary:

• The small intestine is the site where

dietary calcium is absorbed. Importantly,
efficient absorption of calcium in the small
intestine is dependent on expression of a
calcium-binding protein in epithelial
cells.

• Bone serves as a vast reservoir of calcium.

Stimulating net resorption of bone mineral
releases calcium and phosphate into blood,
and suppressing this effect allows calcium
to be deposited in bone.
Fig. 4.23. Ca2+ fluxes
• The kidney is critically important in calcium homeostasis. Under normal blood
calcium concentrations, almost all of the calcium that enters glomerular filtrate is
reabsorbed from the tubular system back into blood, which preserves blood
calcium levels. If tubular reabsorption of calcium decreases, calcium is lost by
excretion into urine.

6.3. Hormonal Control Systems

Maintaining normal blood calcium and phosphorus concentrations is managed through

the concerted action of three hormones that control fluxes of calcium in and out of blood
and extracellular fluid:

Parathyroid hormone serves to increase blood concentrations of calcium.

Mechanistically, parathyroid hormone preserves blood calcium by several major effects:

• Stimulates production of the biologically-active form of vitamin D within the

kidney. What does active vitamin D do?
• Facilitates mobilization of calcium and phosphate from bone. To prevent
detrimental increases in phosphate, parathyroid hormone also has a potent effect
on the kidney to eliminate phosphate (phosphaturic effect).
• Maximizes tubular reabsorption of calcium within the kidney. This activity results
in minimal losses of calcium in urine.

Thus, the major effector organs for PTH are the kidney and bone.

37
Vitamin D acts also to increase blood concentrations of calcium. It is generated
through the activity of parathyroid hormone within the kidney. Far and away the most
important effect of vitamin D is to facilitate absorption of calcium from the small
intestine. In concert with parathyroid hormone, vitamin D also enhances fluxes of
calcium out of bone.

Thus, the major effector organs for PTH is the kidney which produces vitamin D that
consequently acts on the GIT.

Calcitonin is a hormone that functions to reduce blood calcium levels. It is secreted in

response to hypercalcemia and has at least two effects:

• Suppression of renal tubular reabsorption of calcium. In other words, calcitonin

enhances excretion of calcium into urine.
• Inhibition of bone resorption, which would minimize fluxes of calcium from bone
into blood.

Although calcitonin has significant calcium-lowing effects in some species, it appears to

have a minimal influence on blood calcium levels in humans.

A useful way of looking at how hormones affect tissues to preserve calcium homeostasis
is to examine the effects of calcium deprivation and calcium loading. The following table
summarizes body responses to conditions that would otherwise lead to serious
imbalances in calcium and phosphate levels in blood.

38
 Calcium Deprivation Calcium Loading
Parathyroid Secretion stimulated Secretion inhibited
hormone
Vitamin D Production stimulated by increased Synthesis suppressed due to low
parathyroid hormone secretion parathyroid hormone secretion
Calcitonin Very low level secretion Secretion stimulated by high blood
calcium
Intestinal Enhanced due to activity of vitamin D on Low basal uptake
absorption of intestinal epithelial cells
calcium
Release of Stimulated by increased parathyroid Decreased due to low parathyroid
calcium and hormone and vitamin D hormone and vitamin D
phosphate
from bone
Renal Decreased due to enhanced tubular Elevated due to decreased parathyroid
excretion of reabsorption stimulated by elevated hormone-stimulated reabsorption.
calcium parathyroid hormone and vitamin D;
hypocalcemia also activates calcium
sensors in loop of Henle to directly
facilitate calcium reabsorption
Renal Strongly stimulated by parathyroid Decreased due to hypoparathyroidism
excretion of hormone; this phosphaturic activity
phosphate prevents adverse effects of elevated
phosphate from bone resorption
General Typically see near normal serum Low intestinal absorption and
Response concentrations of calcium and phosphate enhanced renal excretion guard
due to compensatory mechanisms. Long against development of hypercalcemia.
term deprivation leads to bone thinning
(osteopenia).
Summary

39
 Fig. 4.24: Regulation of plasma calcium concentration via PTH, calcitonin, and calcitriol.

Activity 4.20: Endocrine control of calcium and phosphate homeostasis

Draw a “box diagram” that includes receptor, control centre, and effector to describe the
endocrine control of calcium and phosphate homeostasis.

40
Conclusion
Objectives Comment on mastery
1. Describe the functional anatomy and histology of
the thyroid and parathyroid glands.
2. Describe the chemistry, mechanism of synthesis
and secretion, regulation of synthesis and
secretion, mechanism of action and physiological
effects, and disease states related to thyroid
hormones.
3. Describe the chemistry, mechanism of synthesis
and secretion, regulation of synthesis and
secretion, mechanism of action and physiological
effects, and disease states related to calcitonin.
4. Describe the chemistry, mechanism of synthesis
and secretion, regulation of synthesis and
secretion, mechanism of action and physiological
effects, and disease states related to parathyroid
hormones.
5. Describe the chemistry, mechanism of synthesis
and secretion, regulation of synthesis and
secretion, mechanism of action and physiological
effects, and disease states related to Vitamin D.
6. Describe the endocrine control of calcium and
phosphorus homeostasis.

41