Unit

Endocrine System
8
General Principles of Endocrinology
General

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1. Endocrine or ductless glands – secrete hormones directly into the blood.

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2. Major Endocrine Gland (Fig. 8.1)
Pineal Gland
Melatonin

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Hypothalamus
Releasing hormones: GHRH, CRH,
Pituitary gland
TRH, GnRH, PRF
TSH, MSH, ACTH, GH, FSH, LH,

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Inhibitory hormones: GHIH, PIF
ADH, Oxytocin, β-LPH

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Thyroid gland
Parathyroid glands
Thyroid hormones: T3, T4 Calcitonin
Parathyroid hormone
Thymus gland (in children) Thymosin

Adrenal glands

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Adrenal cortex: Aldosterone, DOC
Cortisol, Corticosterone, Androgen (DHEA)
Oestrogen and progesterone
Pancreas
Adrenal medulla: Epinephrine, NE
Insulin, Glucagon, GHIH, Gastrin

Testes
Testosterone

Ovaries
Oestrogens
Progesterone

Fig. 8.1 The major endocrine glands and the hormones they secrete (abbreviations as given in the text)

3. Characteristic Features of Hormones

(i) Definition

Note: Metabolic end products e.g., CO2, H+ etc., are secreted in large amounts directly into the circulation called
Parahormones.

(ii) 2000–1,00,000 receptor molecules per target cell.

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(iii) Regulate rate and magnitude of biochemical reactions by their control of enzymes →
morphological, biochemical and functional changes in target tissues.
(iv) Have a longer latency (few minutes) compared to neurons (few msec) following their
stimulation.
(v) Metabolised in liver and kidney
(vi) Number of receptors and affinity of the receptors show down regulation or up regulation
(vii) Hormone interactions
(a) In synergism: Ep. and glucagon ↑s blood glucose 5 and 10 mg/dL respectively; together they
↑ blood glucose to 22 mg/dL.
(b) In antagonism: e.g. glucagon and insulin.
(c) In permissiveness: T4 with reproductive hormones → complete normal development of

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reproductive system.

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Chemistry of Hormones
Three major types of hormones: Steroids, Peptides and Amino Acid Derivatives

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Amino Acid Derivatives
Parameter Steroid hormones Peptide hormones
hormones

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Examples Sex steroids (oestrogen, Insulin, parathyroid (a) Catecholamines
progestgerone, androgen), (b) Thyroid hormones

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cortisol,
1. Derived from Cholesterol Three or more amino Tyrosine(mainly) or
acids tryptophan

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2. Synthesis and Synthesized on demand Made in advance & Made in advance &
storage stored stored

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3. Transport in blood Bound to carrier proteins Dissolved in plasma (a) is dissolved in plasma
(b) is bound to carrier
4. Half life Long (60-90 minutes) Short (few minutes) (a) i s very short, few

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seconds.
(b) is long (7-9 days)
5. Location of Cytoplasm or nucleus Cell membrane surface For (a): cell membrane
receptors For (b): nucleus
6. Response to Activation of genes Activation of 2nd For (a) activation of 2nd
receptor - ligand for transcription and messenger via cAMP. messenger system, for
binding translation (b) activation of genes
for transcription and
translation
7. General target Induction of new protein Rapid, modification of (a): M
 odification of
response synthesis existing proteins and existing proteins
induction of new protein (b): Induction of new
synthesis protein synthesis
  8: Endocrine System ❑ 3

Mechanisms of Hormone Action Two Mechanisms:

A. cAMP Mediated Hormone Activity (Fig. 8.2)
Cytoplasm membrane

Outer Inner Effector cell

membrane membrane

Protein and
polypeptide hormones Cytoplasm
(first messenger) Activated
enzyme (AC)

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ATP
5‘-AMP

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(inactive)

Mg2+ Phosphodiesterase

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cAMP
Second

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messenger

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Effect on cellular function,
such as secretion, glycogen
Receptor
breakdown etc.
protein (R)

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Plasma membrane

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of target cell

Fig. 8.2 cAMP mediated hormone activity. Cascade of enzyme

A
reactions (R: Receptor; AC: Adenylyl cyclase; cAMP: 3′ 5′
Adenosine monophosphate)

B. Transcription and Translation Effect (Fig. 8.3)

Cytoplasm Steroid
Nucleus
hormone
Receptor
- hormone
complex
Receptor
New
Steroid protein
Phosphorylation hormone
DNA-
associated
Translation
receptor
Transcription
Chromatin
Ribosome
mRNA

Fig. 8.3 Steroid hormones action on target cell. The hormone is

separated by receptor molecule; ‘receptor-hormone complex’ enters
the nucleus and becomes attached to the chromatin to stimulate
‘transcription’; on ribosomes, mRNA is translated into new protein.
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Regulation of Secretion of Hormones

A. Direct Control by the hormones themselves, e.g.,
↑ blood sugar → ↑ insulin secretion → ↓ blood sugar; keep the blood sugar within normal limits in
spite of variations in carbohydrate intake in the diet.

B. Nervous Control: 3 mechanisms: (Fig. 8.4)

1. Direct innervation via ANS
2. Neurosecretory neurons control of post. pituitary
3. Neurosecretory neurons control of ant. pituitary

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(A) (B)

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(i) (ii) Hypothalamus

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Preganglionic Releasing factors
neuron Posterior A-ch
pituitary Anterior
A-ch pituitary

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A-ch

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Postganglionic ADH Trophic hormones
neuron and (ACTH, TSH, GH, LH, FSH, Prolactin)
oxytocin
Adrenal
medulla cell

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A-ch

A
Pancreatic islets of Langerhans

Fig. 8.4 Neuroendocrine transducers. (A) direct innervation via autonomic fibers; (B) neurosecretory neurons control of the
(i) posterior pituitary and of (ii) anterior pituitary

Anterior pituitary hormone secretion is also controlled by feedback control (positive or negative) at 3
levels: (Fig. 8.5)
(a) Long loop feedback
(b) Short loop feedback
(c) Ultrashort loop feedback
  8: Endocrine System ❑ 5

Hypothalamus (–)

(–)
(–)
(C) (*)

(A)

(+) (B)

Anterior
Pituitary

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(–)

a
Target gland Pituitary trophic

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hormone (free) hormone

(A)

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Gland
(+)

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Fig. 8.5 Negative ‘feedback control’ of hormone secretion. long
loop (A); short loop (B) and ultra-short loop (C) feedback

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mechanisms. (*) Hypophysiotropic hormone
{(+): stimulation; (–): negative feedback control mechanism}

Control Versus Regulation

Control Regulation
1. Maintain any variation of a variable (never 1. Operate to maintain a variable within a narrow
succeed bringing the variable precisely to range under several conditions.
normal)
2. Generally a conscious mechanism. 2. Involuntary action.
3. Involves a partially closed feedback loop. 3. Involves a closed feedback loop.
4. Example: 4. Example: Regulation of BP or body temperature
Control of HR and SV to regulate BP

Note: Controls are required to obtain regulation. For example: Heat production and heat loss are controlled
for the regulation of body temperature.
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The Pituitary Gland

Physiological Anatomy (Fig. 8.6)
Supraoptic nucleus

Paraventricular
Hypothalamic neuron nucleus

Arterial Hypothalamus
blood flow
Hypothalamic
releasing or inhibiting

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hormone

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Hypothalamo Hypothalamo
hypophyseal neural tract hypophyseal portal
Arterial vessels

a
blood flow
Anterior pituitary
gland cell
ADH
Anterior pituitary
Oxytocin

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hormone
Posterior pituitary Anterior pituitary

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Venous
outflow

Fig. 8.6 Hypothalamic relationship with anterior and posterior

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pituitary gland

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Pituitary hormones
(i) Anterior lobe
(a) TSH

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(b) ACTH
(c) GH
(d) Gonadrotrophins: FSH & LH
(e) Prolactin
(f) β-Lipotropin
(ii) Intermediate lobe: α, β MSH
(iii) Posterior lobe: ADH & Oxytocin.

Note: Anterior pituitary hormones are all trophic hormones

Anterior Pituitary (Adenohypophysis)

A. Growth Hormone (GH)
1. Daily output (adult/children): 0.2 to 1 mg/day.
2. Exhibit a species specificity.
3. Structural resemblance to prolactin and HCS
4. Normal plasma level
(i) adults: 2-4 ng/mL.
(ii) in growing children: higher by 5-8 ng/mL.
5. Control of Secretion (Fig. 8.7)
  8: Endocrine System ❑ 7

Hypothlamus
GHIH • Growth hormone excess
• Glucocorticoids
• S
 ubstrate deficiency within body GHRH • Glucose
cells (due to hypoglycemia severe • REM sleep
exercise, fasting or starvation) • FFA
• Oestrogen • Aging, late pregnancy,
• Increased amino acid levels Obesity
Ghrelin
• Decrease in FFA
• Glucagon
• Stress, Pyrogen; Cold exposure
• Deprivation of REM sleep
• Dopamine and its agonists
Anterior
pituitary
Inhibition
Stimulation

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GHRH : Growth hormone Growth
hormone

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releasing hormone Negative
GHIH : Growth hormone feedback
inhibiting hormone
(or somatostatin)

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Liver (mainly
kidney, muscles
and other organs

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Somatomedins

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(mainly IGF-I) and
other growth factors

Body growth

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Fig. 8.7 Feedback control of growth hormone secretion

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Important Note

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GH increases circulating IGF-I (somatomedin C) which in turn exert a direct
inhibitory action on GH secretion from the anterior pituitary. It also stimulates
secretion of somatostatin from the hypothalamus.

Actions of GH
1. Stimulation of growth of bone, cartilage and connective tissues
(i) (a) GH → ↑ number of cells
(b) Insulin → ↑ cytoplasmic growth
(c) Thyroid hormone → ↑ effect of GH on DNA replication and helps in tissue differentiation
and maturation.
(ii) Receptors for somatomedins exist in chondrocytes, hepatocytes, adipocytes and muscle cells.
(iii) Before epiphyseal closure →
(a) proliferation of chondrocytes, appearance of oestoblast;
(b) incorporation of sulphates into cartilage;
(c) ↑ thickness of epiphyseal plate → ↑ linear skeletal growth.
(iv) After epiphysial closure: ↑ bone thickness through periosteal growth → acromegaly

Note: Somatomedin levels are better correlated with growth than plasma GH levels.

2. On protein metabolism: Anabolic

3. On mineral metabolism
(i) ↑ Ca2+ absorption from GIT.
(ii) ↓ Na+, K+, Ca2+ and phosphorus excretion.
4. On carbohydrate metabolism: diabetogenic
5. On fat metabolism: catabolic and ketogenic
6. ↑ milk production in lactating women.
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Applied Aspect
1. Growth retardation: Occurs when GH levels ↑s and somatomedin levels ↓s e.g., kwashiorkor.
2. African pygmies: Lack of tissue response to the action of GH although both GH and somatomedin
levels are normal.
3. Laron dwarfism (or GH insensitivity syndrome) due to congenital abnormality of GH receptors
4. Giantism (or Gigantism) (Fig. 8.8)
(i) Cause:
(ii) Features
(a) tall stature (2.5 mt. or 8 ft.)
(b) bilateral gynaecomastia
(c) large hands and feet

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(d) coarse facial features

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(e) loss of libido/impotence

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A . Fig. 8.8 Giantism (Gigantism), occurs during adolescence before
epiphysial closure.
(Note: Excessive tallness more than 2 mts, i.e. 7 ft; hand and foot
(left) compared with those of a normal subject (right)

5. Acromegaly means enlargement of peripheral region.

(i) Cause:
(ii) Features (Fig. 8.9)
(a) Prognathism
(b) Prominent brow
(c) Acromegalic facies
(d) Acral parts
(e) Organomegaly; abnormal GTT
  8: Endocrine System ❑ 9

Acromegalic facies Acral parts: a

 cromegalic foot and hand (left) compared
and Prognathism with those of a normal subject (right)

Fig. 8.9 Acromegaly, occurs during adulthood after epiphysial closure

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6. Major Causes of Dwarfism (short stature)

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(i) Familial – Commonest cause.
(ii) Nutritional: Protein calorie malnutrition.
(iii) Endocrine disorders

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Pituitary dwarf (Fig. 8.10) Hypothyroid dwarf (Fig. 8.11)

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(a) Cause: ↓ GHRH → ↓ GH → ↓ S. GH level (a) Cause: ↓ thyroid hormone
(b) Mentally sound; fatness; immature facies (b) Gross retardation of ‘mental’ and ‘physical’

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development
(c) Small genitalia (c) Body proportion remains infantile

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(d) Delicate extremities, body proportion according (d) Bone age is retarded more than height
to the chronological age.

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(e) Delayed skeletal and dental development (e) Associated hypothyroidism features

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Fig. 8.10 {A 9-year old pituitary dwarf (left) Fig. 8.11 {A 8 year old hypothyroid child with
compared with age and sex matched control growth retardation (right) for comparison with
(right)} age and sex matched control (left).}

B. Physiology of Growth
1. Growth is ↑ in size and number of cells
2. Development maturation of functions.
3. General Growth Curves (skeletal growth, muscles thorax and abdominal viscera).
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Phases

Note: Two periods of rapid growth: growth spurt 1st in infancy and 2nd at the time of puberty. It is due to sex
hormones, GH and IGF-I.)

4. Distinctive Growth Curves: 3 types (Fig. 8.12)

(i) Neural type – 60% and 90% of the adult size by approx. 2 and 6 years of age respectively.
(ii) Lymphoid type. in early childhood (40% of adult size by the age of 2 years); maximum size
(20%) at puberty; decreases there after.
(iii) Reproductive type. Remain undeveloped until puberty (<10%)

200

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180

160
Lymphoid Type
Percent of size at age 20 years

a
(2 yr.: 40%)
140

120

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Neural Type
(2 yr.: 60%; 6 yr.: 90%)
100

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General Growth Curve
80 (12 yr: 60%)

60 Reproductive Type

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(12 yr < 10%)
40

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20

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0
0 2 4 6 8 10 12 14 16 18 20
Age in Years

Fig. 8.12 Growth curves of various body organs after birth (growth at 20 years taken as 100% growth)

5. Factors Affecting Growth

(i) Genetic
(ii) Nutritional
(iii) Environmental
(a) Diseases: → catch-up-growth growth rate 400% above normal.
(b) Exercise
(c) Emotional disturbances
(d) Old age
(iv) Hormonal (Fig. 8.13)
(a) After birth
• During infancy: due to T4 and GH.
• At puberty: by androgens and GH.
• In between continuous growth: by T4 and GH.
• At puberty: T4, GH and androgen.
(b) GH and T4
• Utero and neonatal growth are independent of GH.
• GH and T4 show permissive action. → (+) growth via potentiation.
• Role of T4
  – necessary for tissue
   differentiation and maturation;
  – necessary for completely normal rate of GH secretion;
  – stimulates ossification of cartilage, growth of teeth and proportions of the body.
  8: Endocrine System ❑ 11

(c) Androgen
• protein anabolic → growth spurt.
• ↑s GH secretion → ↑ IGF-I (androgens → ↓ linear growth).
(d) Oestrogen → ↑ androgen → ↑ growth.
(e) Adrenocortical hormones → permissive action on growth
(f) Insulin hormone of energy storage.
0 4

Thyroid 20
hormone

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2 8

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Growth 20
hormone

a
15

Androgen

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and 9 20
oestrogen

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0 4 8 12 16 20
Age in years

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Fig. 8.13 Hormonal contribution to growth after birth

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C. Prolactin or Lactogenic or Galactopoietic hormone

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1. Normal serum levels in adults: males: 6–25 ng/mL; females: 6–50 ng/mL.
2. Control of Secretion
(i) ↑ secretion via PRF.
(a) during sleep;
(b) exercise, stress;
(c) pregnancy: begin to ↑ by 8th wk; peak levels (50-600 ng/mL) at term.
(d) nursing and breast stimulation: level ↑s 250 ng/mL
(e) primary hypothyroidism
(f) dopamine antagonist:
(ii) ↓ secretion via PIF. Dopamine is main PIF.
3. Actions
(i) During pregnancy – prolactin along with O & P → mammary duct differentiation → ↑
lobules of alveoli. (Fig. 8.14)
(ii) Following pregnancy, prolactin with GH and T4 → ↑ milk secretion.
(iii) During lactation → anovulation and amenorrhoea.
(iv) Hyperprolactinemia → ↓ FSH and LH →
(a) in women → infertility; amenorrhoea
(b) in men → ↓ libido; ↓s spermatogenesis and impotence.
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Pectoralis
major muscle
Adipose (fat) tissue
Intercostal
muscle

Rib Nipple

Lactiferous
ducts
Gland lobules

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Alveoli

a
Fat droplets
Lactiferous
duct

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Fig. 8.14 Gross structure of mammary gland/breast

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Posterior Pituitary (Neurohypophysis)

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A. ADH – Vasopressin

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1. Synthesized in supraoptic nucleus of hypothalamus → bound to neurophysin  II and stored in the
posterior pituitary.
2. Acts via 3 types of receptors: V1A, V1B and V2, all coupled to G. proteins.

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Control of Secretion (Fig. 8.15)
↑ Secretion of ADH
1. Hyperosmolality – Even 1% change → (+) osmoreceptors by their shrinkage in anterior hypothalamus.
Dehydration

in CVP and BP Water loss

Baroreceptor activity Plasma osmolality

Stress (+) (osmoreceptors)

SON
(–)
Hypothalamus
(–)

Posterior
pituitary
Baroreceptor Plasma
activity osmolality

CVP and BP
ADH secretion
Plasma volume
Water reabsorption
by collecting duets
(+) : Stimulation
Fig. 8.15 Control of ADH secretion (–) : Inhibition

(SON: supraoptic nucleus; CVP: central venous pressure;

BP: arterial blood pressure
  8: Endocrine System ❑ 13

Note: The osmoreceptors normally function as Na+ receptors. Hyperglycemia or uremia are less potent stimulator
of ADH secretion (as they get metabolized)

2. Hypovolemia, potent stimulus 10-25% ↓ BV → ↓ stretch of volume receptors

3. Pain, nausea, vomiting, post-operative stress, exercise, fear, anger (direct action on supraoptic
NU.).
4. Geriatic hyponatremic patients.
5. Liver and kidney disease (main site of ADH inactivation).
↓ Secretion of ADH
1. Hyposmolality of ECF → expansion of osmoreceptors

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2. ↑ ECFV.

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3. ↑ systemic arterial BP → ↑ intrathoracic BV → ↑ ‘LA’ pressure
4. Lying down position
5. CO2 inhalation.

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Actions of ADH
1. In physiological doses

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(i) Via V2 (vasopressin) receptors → ↑ permeability of DCT and CT to water via aquaporin‑2 → ↑
water reabsorption (upto 12%) → ↓ urine volume with ↑ osmolality.

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(ii) ↓ medullary blood flow.
(iii) Via V1A receptors → glycogenolysis in liver.
(iv) Via V1B receptors → ↑ ACTH release from anterior pituitary → ↑ aldosterone secretion.

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2. In high dose via V1A receptors → VC → ↑ BP (also called vasopressin).

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APPLIED
1. Syndrome of Inappropriate ADH Secretion (SIADH)
Major cause: ↑ ADH secretion; bronchogenic carcinoma.

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Features
(i) Water retention with ↑ Blood volume and ECFV.
(ii) ↓ aldosterone secretion → ↑ urinary Na+ excretion → ↓s [Na+].
(i) and (ii) → hyposmolality.

Note: It is the ↑ ADH secretion despite the presence of hyposmolality which is inappropriate.

(iii) ↑ urine osmolality.

(iv) Oedema → ↓ interstitial osmolality → further shift of water into ICF. Therefore, SIADH →
water intoxication (overhydration or dilution syndrome).
2. Diabetes Insipidus (DI)
Defition: A disorder of salt and water intoxication marked by heavy urination and thirst.
Causes:
(i) central or neurogenic DI
(ii) nephrogenic DI
Features:
(i) ↓ water reabsorption by CT → polyuria → ↑ dilute urine
(upto a volume 3-20 L/day) → (+) thirst → polydipsia (↑ water intake).

Note: Alcohol causes frequent and abundant urination by decreasing ADH secretion.

B. Oxytocin
1. Synthesis: paraventricular nucleus of hypothalamus and stored in the posterior pituitary.
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2. Actions
(i) Milk ejection from lactating breasts.
(ii) (+) release of lactogenic and galactopoietic factors from anterior pituitary.
(iii) (+) contraction of smooth muscles of the myometrium → induction of labour.
(iv) Facilitates transport of sperm to uterus.
(v) In high doses → blood vessels relaxation → ↓ BP.
(vi) In males, facilitates the transport of sperms towards urethra.
(vii) Social behaviour (love, intimacy, mother-child bonding, feeling of sexual pleasure), thus
called love hormone.
3. Control of Secretion
(A) ↑ Secretion (brought about by stimulation of cholinergic nerve fibers).

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(i) Milk let down reflex or Milk ejection latent period of 30–60  secs. (Fig. 8.16)

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Paraventricular
Hypothalamus nucleus

a
Posterior
pituitary

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Oxytocin

Myoepithelial
cells contraction

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Infant's suckling Milk ejected
at the breast

Touch receptors

A
in nipple
Spinal cord

Fig. 8.16 Pathway for milk let down reflex or milk ejection reflex

Notes:
1. Release can be conditioned, as lactating in response to sight and sound of a baby.
2. Suckling at breast also → (–) PIF → ↑ prolactin secretion, therefore, suckling causes both secretion and
ejection of milk.

(ii) Genital tract stimulation e.g., during coitus or parturition → ↑ oxytocin release.
Mechanism
Dilation of cervix
↓ Afferent impulses
Stimulate paraventricular
nucleus in the hypothalamus
↓
Oxytocin release

(B) ↓ Secretion
(i) Emotional stress and psychic factor
(ii) Sympathetic neurons activation →
(iii) Drugs e.g. ethanol and enkephalins.
  8: Endocrine System ❑ 15

Intermediate Lobe of Pituitary

Features
1. Secretes MSH or melanotropin.
2. MSH is of 2 types: α and β-MSH; ACTH has 1/200 α-MSH and 1/100 β-MSH activity. Therefore,
hypersecretion of ACTH (Addison’s disease) → hyperpigmentation of skin.
3. Control of Secretion
(i) Pro-opiomelanocortin which splits into ACTH and β-lipotropin.
(ii) Pro-opiomelanocortin is further hydrolysed to α-MSH, β-MSH, β‑endorphin and CLIP
(corticotropin like intermediate lobe peptide).

Note: Albinos congentially a +++ ↓ of melanin pigment in eyes, hair and skin.

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Effects of Hypophysectomy
1. Anterior pituitary has a large reserve; GH secretion is the first function to be impaired with its progressive

a
loss, followed by deficiency of gonadotropin, T4 and adrenal secretion.
2. Signs and symptoms are seen when >90% of anterior pituitary is lost.

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(not fatal provided that glucocorticoids are given.)

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The Thyroid Gland
Physiological Anatomy
1. Largest endocrine gland. It differs from other endocrine glands in storing its active principles in the

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cavity of a vesicle. (Fig. 8.17)

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Columnar
(A) epithelium (B)
Reabsorption Thyroid follicle
Hyoid bone
lacuna

A
C-cell
Thyroid cartilage

Pyramidal lobe

Isthmus Flat epithelium

Colloid
Thyroid gland

Trachea
Active Inactive
Follicles: small, columnar Follicles: large flat
epithelium, less colloid epithelium with
with reabsorption lacunae plenty of colloid
due to colloid reabsorption

Fig. 8.17 Thyroid gland: Gross anatomy (A) and histology (B)

2. Thyroid cells – Functions

(i) Collection of iodine and transport it to the colloid for hormone synthesis.
(ii) Synthesize thyroglobulin.
(iii) Remove thyroid hormones from thyroglobulin.
3. Thyroid Hormones:
(i) T4; T3; and Calcitonin.
4. Functions
(i) Foetal bone maturation and for normal development of CNS.
(ii) O2 consumption of most of body tissues → their optimal function.
(iii) Regulate the fat and carbohydrate metabolism.
(iv) Necessary for normal tissue differentiation growth and maturation.
16

Note: Thyroid-not absolutely essential for life, but its removal in adults → cold intolerance with mental and
physical slowing; and in children, mental retardation and dwarfism.

Formation and Secretion of Thyroid Hormones (Fig. 8.18)

1. Iodine (I2  )
(i) Sources:
(ii) Daily intake: 500 µg.
(iii) Daily requirement: 100-200 µg.
(iv) Normal plasma iodide (I–) level: 0.15-0.3 µg/dL.
(95% of total body I2 is in the thyroid gland; enough to maintain euthyroid state for

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3 months.)

i
500 µgm/day l– (in diet)

a
120 µgm/day l–
ECF
thyroid

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40 µgm/day l– due

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to deiodination of 80 µgm/day l–
MIT and DIT as T3 and T4
demetabolised in

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liver

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and other
60 µgm/day l– Tissues

Bile

A
600 µgm/day (Enters ECF) 20 µgm/day l– in stool
(120 µgm/day i.e. 20% enters
the thyroid and 480 µgm/day
i.e. 80% excreted in urine)

Fig. 8.18 Iodine (I2) metabolism; (I– : iodide)

2. Iodide (I–) Pump

(i) Location: cell membrane of thyroid cells; working depends on the activity of Na+ – K+ pump.
(ii) Inhibited by: monovalent anions (chlorate, perchlorate, thiocyanate) compete with I– for active
transport into the thyroid.
(iii) Stimulated by: TSH → ↑ I– transport into the cell.
  8: Endocrine System ❑ 17

3. I– Transport into the Colloid (Fig. 8.19)

Inhibited by monovalent
anions, metabolic poisons

Thyroid HO CH2CH(NH2)COOH
Plasma Colloid
cell Tyrosine
I
HO CH2 CH

–50 mV (MIT), 3-Mono-iodotyrosine

Active Passive Oxidised by
I
transport diffusion peroxidase enzyme
I– I– I HO CH2 CH
I–
by l– pump (within seconds) I

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(DIT), 3.5-Di-iodo-tyrosine
I I

i
HO O CH2 CH
I I
T4 (Thyroxine)
This enzyme can be inhibited Thyroglobulin

a
by antithyroid drugs (thiouracil, molecule
Stimulated by TSH iodine and carbimazole)

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Fig. 8.19 Formation of thyroid hormones (I : Iodine; I– : Iodide)

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4. Secretion and interconversion of thyroid hormones (values in μgm/day)

Thyroid

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4 80 2

.
T3 – 31 T4 – 80 RT3 – 38
27 36
17

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conjugates etc.

Transport and Metabolism of Thyroid Hormones

1. Transport
Binding capacity Affinity for T3, T4
(i) Thyroid binding globulin (TBG) Least Maximum
(ii) Transthyretin (or thyroid binding pre-albumin (TBPA) Moderate Moderate
(iii) Albumin Greatest Least

2. Free T4 and T3 in plasma (Fig. 8.20)

(i) Physiologically active
(ii) Are in equilibrium with protein bound thyroid hormones in plasma and tissues
Note: individuals with ↑ thyroid binding proteins are neither hyper nor hypothyroid, they are
euthyroid (normal clinical thyroid state).

Thyroid T4 Pituitary TSH

(–)
Free T4
(0.002µg/dL)
Plasma protein Tissue protein
bound T4 bound T4
(8 µgm/dL)

Degradation
products

Fig. 8.20 T4 distribution in the body. (– –): inhibition

18

3. Metabolism
(i) T4 deaminated (removal of I–) to T3 and then → its actions, i.e., T4 is metabolically inert until it
forms T3, therefore, T4 is a prohormone.
(ii) T4 → RT3 (inactive) and TETRAC (tetra-iodo-thyroacetic acid).
(iii) T3 → TRIAC (Tri-iodo-thyroacetic acid).
4. T3 and T4 compared
Features Tri-iodo-thyronine (T3) Thyroxine (T4)
(i) Total plasma level 0.15 µg/dL 3-8 µg/dL.
(50 times < T4).
(ii) Secretion into plasma 4 µg/day. 80 µg/day.

n
(iii) Distribution T3 penetrates tissue fluids Extracellular hormone and acts as

i
(intracellular hormone). a prohormone.
(iv) Protein binding 99.8%. 99.95% to 99.98%.

a
(v) Free plasma level More; (0.2%), 4 times more free Less;
(0.05%)

J
(vi) Duration of action Shorter rapid onset of action Longer onset of action on tissues
more potent and more active is slow.

.
Regulation of Thyroid Secretion
Two mechanisms: TSH and thyroid autoregulation.

K
A. Thyroid Stimulating Hormone (TSH or thyrotrophin)

.
1. Normal plasma level: 0.2-5.0 µIU/mL.
2. Mechanism of Action via thyroid receptors → (+) adenylyl cyclase through Gs in thyroid cell
membrane → ↑ intracellular cAMP.

A
3. Effects on thyroid gland
(i) ↑ I– trapping → ↑ synthesis of T4 and T3.
(ii) ↑ release of stored T4 and T3.
(iii) ↑ thyroglobulin synthesis into the colloid.
(iv) Produces hyperplasia and hypertrophy of thyroid gland
(Therefore, ↑ TSH secretion → goiter).
(v) ↑ blood flow of thyroid gland.

Note: TSH not only stimulates the secretion of stored thyroid hormones from follicular colloid but also promotes synthesis
of fresh thyroid hormones.

4. Control of Secretion (Fig. 8.21)

(i) By hypothalamus → TRH, (secretion is pulsatile in nature; peak at midnight and ↓s during
the day time).
  8: Endocrine System ❑ 19

Warmth Exposure to cold

Stress Prolonged anxiety
Anxiety Hypothalamus Prolonged excitement
Excitement (TRH)

Anterior
pituitary
TSH

i n
Free

a
T3 and T4 TSH

J
Thyroid

.
Stimulation
Inhibition

K
Fig. 8.21 Control of TSH (thyroid stimulating hormone) secretion

.
(ii) Feedback control: measurement of plasma TSH levels is one of the best tests of assessing thyroid
functions.)
Mechanism: Anterior pituitary is the main site of negative feedback mechanism
(iii) Other factors

A
(a) Oestrogen → ↑ TSH secretion.
(b) Large dosage of I– → ↓ release of T3 and T4 → ↑ TSH secretion.
(c) Somatostatin (GHIH) → ↓ TSH and response to TRH.

Important Note: The day-to-day maintenance of thyroid secretion depends on interplay between TSH and
thyroid hormones by anterior pituitary; while hypothalamus adjust TSH secretion in special situations.

B. Thyroid Autoregulation: intrinsic control systemic sensitivity of thyroid response to TSH;

1. I2 deficiency ↑s this sensitivity.
2. Role of I2 in diet: Paradoxical effects:
(i) small dose necessary for normal thyroid functions;
(ii) high dosage → ↓ thyroid gland functions → ↓ formation and release of T4 and T3
(Wolff-Chaikoff Effect)

Important Note: In doubtful cases of thyrotoxicosis, the clinical response to I– therapy can be used as a diagnostic
test.

Actions of Thyroid Hormones

1. Calorigenic Action (Thermogenesis – heat production): T4 → ↑ BMR (T3 is 3-5 times more effective
than T4).
Effects of T4 secondary to calorigenesis:
(i) On protein metabolism
(a) in physiological doses: anabolic
(b) in high doses: catabolic →
• thyrotoxic myopathy; osteoporosis → hypercalcemia and hypercalciuria.
20

(c) Hypothyroidism → myxoedema; non-pitting oedema, commonly seen around the eyes,
hands, supra-paraocular fossa.
(ii) On CVS
T4 and catecholamines potentiate the effect of each other on the heart,
T4 excess →↑s sleeping pulse rate high output cardiac failure → dyspnoea.
(iii) On bone marrow metabolism
↓ T4 → dimorphic anaemia due to: ↓ erythropoiesis & ↓ vit. B12 absorption from GIT
(iv) On vitamins
(a) → ↑ demand for vitamins → vitamin deficiencies
(b) carotenemia
(v) On gonads: gonadal development and for maintenance of lactation.

n
(a) Cretins show poor gonadal development;
(b) hypothyroid women → ↑ menstrual bleeding whereas in hyperthyroidism bleeding is scanty

i
or absent.
2. On Carbohydrate Metabolism: Two opposite effects which balance each other.

a
(i) ↑s peripheral utilization of glucose → hypoglycemia.
(ii) hyperglycemia due to:
(a) ↑ glucose absorption from GIT

J
(b) ↑ glucose output by the liver
(c) ↓ rate of secretion of insulin

.
(d) ↑ breakdown of insulin
(hyperthyroid patients, T4 precipitates diabetes mellitus.)
3. On Lipid Metabolism – Two opposing effects:

K
(i) ↑ synthesis within the liver; and

.
(ii) ↑ breakdown in liver and ↑ excretion in bile, therefore, T4 → ↓ S. cholesterol and ↓s stored
triglycerides and phospholipids.

A
Note: D-T4 and TETRAC are used clinically as S. cholesterol lowering agents in atherosclerosis.

4. On Growth and Development

(i) Important for normal body growth and skeletal maturation.
(ii) Helps in tissue differentiation and maturation.
5. Effect on Nervous System
(i) Necessary for normal development and activity of nervous system
(ii) T4 deficiency after birth → infantile brain → idiot child.
(Critical period is upto 1 year of life) afterwards → irreversible mental retardation develops.)
(iii) T4 deficiency in adults → myxoedema madness.
(iv) T4 excess → (+) RAS → overexcitability & tremors
6. On GIT
↓ T4 → ↓ intestinal motility → constipation
7. Relations to Catecholamines:

Note: Catecholamines and T4, both potentiate the action of each other.

Applied
A. Goiter
1. It does not denote the functional state of the thyroid gland.
2. Mechanism: Goitrogens → ↑ TSH → hypertrophy of thyroid gland.
3. Goitrogenic agents
(i) I2 deficiency <10 µg/day → ↓ T4 → ↑ TSH → goiter, called iodine deficiency goiter or
endemic goiter. (Fig. 8.22)
  8: Endocrine System ❑ 21

(A) (B)

Fig. 8.22 Iodine Deficiency goiter or Endemic goiter ( )

n
(ii) Excess iodide:

i
(iii) Monovalent ions such as perchlorate and thiocyanate → block I– pump.
(iv) Thiocarbamides ( propylthiouracil and methimazole) → block coupling of I2 with tyrosine

a
and MIT.
(v) Vegetables of Brassicaceae family

J
B. Hypothyroidism
Cause: ↓ circulating levels of free T3 and T4.

.
Forms: Myxoedema and cretinism.
Myxoedema: (Fig. 8.23)

K
1. Goiter.
2. Puffiness of face with periorbital swelling.

.
3. Coarsening and loss of scalp hair.
(A) (B) (C)

A Ptosis Puffiness of face with

periorbital swelling and
loss of scalp hair
Dry, thickened rough
and yellow skin

Fig. 8.23 Myxoedema, hypothyroidism in adults

4. Ptosis.
5. Others: Cold intolerance, low BMR, low voltage ECG, hoarseness of voice, myxoedematous madness,
memory loss; ↑ S. cholesterol.
Cretinism i.e., children or infants who are hypothyroid from birth. (Fig. 8.24)
Cause: maternal iodine deficiency.
Features:
1. Mental retardation.
2. Dwarfism, stunted growth due to failure of skeletal and muscular growth.
3. Protruded abdomen, enlarged protruded tongue.
4. Sexual immaturity.
5. Other features of hypothyroidism.
22

(A) (C)

(B)

{A 8 year old hypothyroid child

i n
a
with growth retardation (right)
for comparison with age and sex
matched control (left).}

J
Fig. 8.24 Cretinism, hypothyroidism in neonates (A),
in an infant (B) and in a child (C).

.
C. Hyperthyroidism
Commonest cause: Grave’s disease (Exophthalmic goiter or thyrotoxicosis).

K
Pathogenesis: (Fig. 8.25) Autoimmune disorders → activated plasma cells →

.
1. LATS (long acting thyroid stimulator) or thyroid stimulating immunoglobulins (TSI), and
2. LATS protectors.

A
[(1) and (2) are immunoglobulins of IgG class.]
Mechanism: LATS combine with receptors in thyroid cell membrane → goiter with ↑ formation and
release of T3 and T4.
Hypothalamus

Anterior
pituitary

Free
T3 and T4 TSH

Thyroid

Stimulation LATS (TSI)

Inhibition

LATS: Long acting thyroid stimulator

TSI: Thyroid stimulating immunoglobulins

Fig. 8.25 Control of T3, T4 and TSH secretion in Grave’s disease (size type arrows)
  8: Endocrine System ❑ 23

Features:
1. ↑ BMR.
2. Heat intolerlance.
3. Thyrotoxic myopathy, osteoporosis.
4. High output cardiac failure.
5. Thyroid diabetes.
6. S. TSH normal or ↓s.
7. Exophthalmos
8. Lid retraction

n
(A) (B)

(C)

a i
. J
Fig. 8.26 (A) Hyperthyroidism, results from increased circulating

K
levels of “free” thyroid hormones (T4 and T3);

.
(B) Exophthalmos (eye ball pushed forward); and (C) Lid retraction­
—Note: Visibility of sclera between upper lid and cornea

A
Antithyroid Drugs
1. Drugs which inhibit trapping of I– by the thyroid
2. Thiourylenes
3. Iodine
4. β-adrenergic blocking drugs → ↓ CVS, CNS symptoms of hyperthyroidism.
5. Radioactive I2 (131I) → destroy overactive thyroid tissue.

Thyroid Function Tests:

Test Hypothyroidism Hyperthyroidism

A. Based on metabolic functions

1. BMR (normal: ±10%) decreases to –30% to –40% increases from

+10% to +100%

2. S. Creatinine (normal: 0.2-0.6 mg/dL) decreases increases

3. Fasting blood sugar (normal: 50-90 mg/dL) decreases increases

4. S. Cholesterol (normal: 120-200 mg/dL) increases decreases

B. Based on handling of Iodine

1. Total S.T4 (3-8 µg/dL); S.T3 (0.15 µg/dL) decreases increases

2. Free S.T4 (2 ng/dL); free S.T3 (0.3 ng/dL) decreases increases

3. Protein Bound Iodine (PBI) (normal: 3.5-7.5 µg/dL) decreases increases

24

4. B
 utanol Extractable Iodine (BEI) decreases increases
normal: 3-5 µg/dL

5. RAI123 uptake (normal: 20-40%) decreases <20% increases >60%

6. Serum TSH level (normal 2.5 µIU/mL) (i) primary hypothyroidism: increases decreases or
by 10 folds undetectable
(ii) secondary hypothyroidism:
decreases

C. Others

1. Urine Ca2+ loss (normal 100 mg/day) decreases increases

i n
Parathyroids, Calcitonin and Vitamin D
Calcium Metabolism

a
1. Total body calcium: 1100-1200 g (>99% in bones).
2. Normal S.Ca: 9-11 mg/dL, 2 forms:
(i) 55% Diffusible: 5.36 mg/dL; two types:

J
(a) Ionized (free) Ca2+: Physiologically active.

.
(b) Non-ionized Ca2+; physiologically inactive.
(ii) 45% non-diffusible: 4.64 mg/dL; bound to albumin, physiologically inactive.
3. Daily dietary intake: 1 g; absorbed mainly in the duodenum, jejunum and ileum (actively).

K
Factors affecting calcium absorption from GIT

.
Increased by Decreased by
(i) Acidity (i) Alkalies
(ii) Bile and bile salts (ii) ↓ secretion of bile and bile salts

A
(iii) Phosphate and high protein diet (iii) Excess of inorganic phosphate, oxalate or phytic acid
(iv) Hypocalcemia (iv) Hypercalcemia
(v) Vitamin D3, parathormone, GH

4. Calcium distribution in the body (Fig. 8.27)

  8: Endocrine System ❑ 25

I.C.F. 11 gm Bone
Diet 1000 mg

1000 gm
Exchangeable 20,000 mg 980 gm
GIT Absorption 700 mg (Rapid exchange) (stable)

E.C.F.
Secretion 600 mg Ca pool Accretion (accumulation) 300 mg
1000 mg
1600 Reabsorption 300 mg
mg (Net gain 100 mg)
Glomerular filtrate
load 10000 mg
Reabsorption
9900 mg

i n
Faeces 900 mg

Kidney

a
Net balance = Net absorption – loss
(... mg Ca/day) = Diet – (faeces + urine)
= 1000 – (900 + 100)

J
= Zero

.
Urine 100 mg

K
Fig. 8.27 Calcium distribution in the body

.
5. Functions:
(i) blood coagulation.
(ii) membrane excitation.

A
(iii) muscular contraction.
(iv) excitation – secretion processes.

Phosphate Metabolism
1. Found in: ATP; cAMP; 2, 3 DPG.
2. Total body phosphate (inorganic): 500-800 g
3. S. inorganic phosphate level (HPO42–)
(i) in adults: 2.5-4 mg/dL;
(ii) in children: 5-6 mg/dL.
4. Functions
(i) rigidity to bones and teeth.
(ii) in regulation of pH of blood and urine.
(iii) in regulation of energy metabolism.
(iv) Forms a part of DNA.
5. Mainly absorbed in the duodenum; ↑ed by: 1, 25 DHCC; GH, parathormone, acids, low calcium
diet.
6. Relation between plasma calcium and phosphate
(i) S. Ca2+ 1/α S. inorganic PO43– level. However, product [Ca2+] × [PO43–], remains constant,
called solubility product (Normal: 60).
(ii) The calcium phosphorus ratio in bone is: 1.7:1.

Hormone Regulating Calcium and Phosphate Metabolism

26

Feature PTH (Parathormone) 1,25 DHCC (Vit. D) Thyrocalcitonin

1. On Bone ↑s bone resorption Mobilizes calcium and Inhibits bone resorption →
(osteolytic effect) phosphate ↓ s Ca2+ mobilization
2. On GIT ↑s calcium and phosphate ↑s calcium and phosphate ↓s calcium and phosphate
absorption absorption. absorption.
3–
3. On Kidney (i) ↑PO4 reabsorption ↑s reabsorption of calcium ↑s excretion of
↑ & excretion → from DCT and that of calcium and
phosphaturia HPO42– from PCT. phosphate in urine.
(ii) ↑Ca2+ reabsorption
and ↓ excretion
→hypocalciuria

n
4. Effect on ↑s ↑s ↓s

i
S.Ca2+
5. Effect on ↓s ↑s ↓s

a
S.PO43–

6. Regulation of ↑ed by: ↓ed by: (Fig. 8.28) (i) ↑ed by: ↑ S.Ca2+,

J
secretion (i) ↓ S.Ca2+ (i) ↑ S.Ca2+; (ii) ↑ S.PO43–; oestrogen, gastrin,
(ii) ↑ S.PO43– → ↓ S.Ca2+ (iii) 1,25 DHCC; (iv) T4; CCK–PZ; secretin and

.
and (–) 1,25 DHCC (v) metabolic acidosis dopamine
↑ed by: (Not secreted until S. Ca2+
(i) ↓ S.Ca2+; (ii) ↓ S.PO43–; > 9.5 mg/dL) (Fig. 8.29)

K
(iii) oestrogen; (iv) prolactin;
(v) GH; (vi) calcitonin

.
7. Other (i) Secreted by chief cells Formation (i) Thyrocalcitonin.
features or of parathyroid gland. Vitamin D → 1,25 DHCC (ii) Normal secretion: 0.5

A
actions (ii) Essential for life as (physiologically active) mg/day.
their removal → death (iii) Normal plasma level:
from asphyxia 0.2 ng/mL.
(iii) ↑s conversion of (iv) More active in young
25 – HCC to 1,25 people.
DHCC (v) Protects bones of the
mother from excess
(iv) ↑s urinary excretion Ca2+ loss during
of Na+, K+ and HCO3– pregnancy.
and ↓s excretion of
NH4+ and H+.
(v) ↓s Ca2+ secretion in
milk during lactation

3–
Inhibition Decrease S.PO4
Decrease S.Ca2+
Stimulation
3–
Decrease S.PO4
Oestrogen PTH Ca2+
prolactin

Renal Acts on Bone &

25, hydroxylase 25 DHCC 1, 25 DHCC GIT to
24, 25 DHCC 1α-hydroxylase increase
(Inactive) (Kidneys)

3–
PO4

Fig. 8.28 Feedback control of formation of 1,25 DHCC (Abbreviations as given in the text)
  8: Endocrine System ❑ 27

Normal : S.level :

Normal : S.level :
Calcitonin

0.2 ng/mL
1 ng/mL
(ng/mL)

(ng/mL)
PTH
0 5 10 15 20 25
S. Ca2+ (mg/dL)

Fig. 8.29 Serum parathyroid hormone (PTH) and calcitonin

n
concentrations against serum [Ca2+]

i
Role of other hormones

a
1. Adrenal glucocorticoids → ↓ protein synthesis in bone → osteoporosis and ↓ S. Ca2+.
2. GH → ↑ S. Ca2+, calciuria, ↑ Ca absorption form GIT.
3. T4 → ↑ S. Ca2+ and hypercalciuria.

J
4. Oestrogen → (–) effects of cytokines and interleukins on osteoclasts → prevents osteoporosis.

.
5. Insulin → ↑s S. Ca2+ bone formation (uncontrolled DM patients shows significant bone loss).

Applied

K
A. Rickets

.
1. Cause: ↓ Vitamin D → ↓ Ca absorption → ↓ bone mineralization → bone deformity in young
children.
2. Precipitating factors

A
(i) inadequate intake of provitamins (7 DHCC and 1, 25 DHCC);
(ii) inadequate exposure to sun;
(iii) kidney or liver dysfunction → ↓ 25 DHCC formation;
(iv) defects in target cell receptors.
3. Features (Fig. 8.30)
(i) The disease sets in about 6th month of life.
(ii) Knock knees.
(iii) Thickening of wrists and ankles.
(iv) Retarded growth, shortness of stature; delayed dentition.
(v) X-ray bone: widening and cupping of epiphyseal cartiligenous plate.
(vi) Others: hypotonia, myopathy; prominence of costochondral junction, frontal bossing.
 28

Frontal bossing

Prominence of the costochondral Short stature Bowing: B

 ones bent under
junctions (arrows) body weight

i n
Delayed dentition Thickening of wrists

a
Rickets

. J
Widening and cupping of
Knock knees
epiphyseal plate (arrow)

. K
Fig. 8.30 Rickets: Characteristic features

A
B. Osteomalacia (or Adult Rickets)
1. Cause: Deficiency of vitamin D and Ca in diet → ↓ mineralization of the bones.
2. Limited to females, appears after multiple pregnancies and lactation.
3. Specially pelvic girdle, ribs and femur become soft, painful and deformed. (Fig. 8.31)
4. (i) S. Ca2+ is low: 6-7 mg/dL.
(ii) S. inorganic PO43– is low.
(iii) S. alkaline phosphate ↑s.
5. Fractures and proximal myopathy is common.

Normal anatomy Osteomalacia (arrow)

Fig. 8.31 Osteomalacia (Adult ricket): Deformed femur

C. Hypoparathyroidism
1. Cause: accidental removal of parathyroids during thyroidectomy. (Fig. 8.32)
  8: Endocrine System ❑ 29

2. Total S. Ca2+ ↓s to 4-8 mg/dL; ionized Ca2+ ↓ to 3 mg/dL (↓ by 50%) → Tetany;

S. inorganic PO43– ↑ to 6-16 mg/dL.

Pharynx

Thyroid gland

Left middle

n
thyroid vein

i
Left inferior
thyroid artery

a
Oesophagus

Fig. 8.32 Positions of 4 parathyroid glands (arrow)

J
(2 superior and 2 inferior) (viewed from behind)

.
3. Tetany: Neuromuscular hyperexcitability (potentiated by ischaemia).
(i) Mechanism: numbness, tingling of extremities and feeling of stiffness with cramps in
extremities. → laryngeal strido → asphyxia and death.

K
(ii) Clinical tests

.
(a) Facial irritability: Chvostek’s Sign.
(b) Obstetric hand or carpopedal spasm (Trousseau’s sign) (Fig. 8.33)

A (A) (B)

Fig. 8.33 Carpopedal spasm or obstetric hand in tetany (A) and

Trousseau’s sign (B)

Notes:
1. S. Ca2+ level at which tetany occurs, is well above the level at which clotting defects would occur.
2. Hyperventilation → CO2 washout →↓ plasma H+ →↑ ionization of proteins →↑ binding of Ca2+ → precipitate
tetany.

D. Hyperparathyroidism
1. Causes
(i) Diffuse hyperplasia of parathyroids.
(ii) Chronic renal disease → ↓ 1, 25 DHCC → ↓ S. Ca2+ → compensatory parathyroids hypertrophy,
called secondary hyperparathyroidism.
2. Features
(i) ↑ S. Ca2+ → weakness, loss of muscle tone, thirst, polyuria, anorexia, constipation.
30

(ii) Kidney stones (nephrocalcinosis).

(iii) Bones demineralization → painful bones and spontaneous fractures.
(iv) Biochemical changes:
(a) ↑ S. Ca2+ (mainly ionized Ca2+).
(b) ↓ S. PO43–
(c) S. alkaline phosphatase normal.
(d) Hypercalciuria (Normal Ca excretion: 100 mg/day).

Adrenal Cortex
Physiological Anatomy

n
1. Adrenal (or suprarenal) glands: 2 parts.

i
(i) Outer: Adrenal cortex: Essential for Life
(ii) Inner: Adrenal medulla.

a
2. Adrenal cortex: 3 zones (from outer to inner) (Fig. 8.34)
(i) Zona glomerulosa → mineralocorticoids
(together called cortiosteroids)
(ii) Zona fasculata → glucocorticoids.

J
(iii) Zona reticulata → sex steroids.

.
Adrenal cortex
Adrenal medulla

.
Zona glomerulosa

K
A
(secretes
mineralocorticoids: Smooth endoplasmic reticulum
aldosternone, DOC)

Zona fasiculata
(secretes
glucocorticoids:
cortisol,
corticosterone)
Lipid droplets
Zona reticularis Mitochondrion
(secretes sex
steroids:
androgen-DHEA) Cholinergic nerve supply

Medulla
(secretes
epinephrine
and nor-
epinephrine)
Storage
granules

Fig. 8.34 Section through an adrenal gland showing both adrenal medulla and
adrenal cortex (DOC: deoxycorticosterone; DHEA: dehydro-epiandrosterone)

3. Adrenocortical hormones
Mineralocorticoids Glucocorticoids Sex steroids
(i) C21 steroids. C21 steroids. C21 steroids.
  8: Endocrine System ❑ 31

(ii) More effect on mineral More effect on carbohydrate Minor effect on reproductive functions.
metabolism. and protein metabolism;
mineralocorticoid activity 1/3rd
of aldosterone.
(iii) Examples (a) Cortisol or hydrocortisone. (a) Androgen (mainly) (DEA/DHEA
(a) Aldosterone. (b) Corticosterone. (b) Oestrogen.
(b) Deoxycorticosterone (c) Progesterone.
(DOC).

4. Characteristic features – adrenal cortex.

(i) In foetus, adrenals are larger than the kidneys → secrete DHEA.
(ii) Three differentiated zones formed in 3rd year of life.

n
(iii) Contain high amounts of lipids (specially cholesterol) and vitamin C.

i
(iv) Zona glomerulosa can form the other two layers.
(v) All its hormones being steroids and lipid soluble can diffuse across the cell membranes into
target organs.

a
Transport, Metabolism and Excretion

J
A. Glucocorticoids (GCs)

.
1. To transcortin or CBG; small amounts to albumin.
2. Plasma and urine concentration
Cortisol Corticosterone

K
(i) Plasma conc. 10–25 µg/dL 0.2–1.0 µg/dL

.
(free and (14 µg/dL) (0.4 mg/dL)
bound)
(ii) Amount 5–30 mg/day 1.5–4.0

A
secreted mg/day

3. Free cortisol (physiologically active)

Adrenal ACTH Anterior

cortex pituitary

FREE CORTISOL
(~ 0.5 µg/dL)

Protein bound Tissue cortisol

cortisol in (? bound)
plasma
(13 µg/dL) cortisol metabolites

Fig. 8.35 Cortisol distribution in the body

4. Metabolism and Excretion

(i) Average amount of derivatives excreted in urine per day:
(a) Free cortisol : 0.03 mg
(b) Glucocorticoids conjugates : 14.00 mg
(c) 17 ketosteroids : 1.0 mg
(d) Unidentified metabolites : 7.0 mg
Total : 22 mg/day
(ii) Normal 24 hours urinary ketosteroids concentration:
(a) In males: 15 mg (2/3rd from adrenal cortex; 1/3rd from testes).
(b) In females: 10 mg.
32

B. Aldosterone
1. Transport: 60% bound to CBG
2. Plasma and urine concentration
Aldosterone DOC
(i) Total plasma conc. (free + bound) 0.007 µg/dL 0.006 µg/dL
(ii) Average amount secreted 0.15 mg/day 0.2 mg/day

3. Metabolism: in liver
4. Excretion: in urine in conjugated form and <1% as free form.

n
Regulation of Glucocorticoids Secretion

i
Two mechanisms: by ACTH and by GCs feedback.

A. Regulation of ACTH Secretion

a
1. Under nervous control, hypothalamic neurons release CRH → ACTH secretion from anterior
pituitary. (Fig. 8.36)
2. Mechanism of Action: cAMP mediated

J
Emotions via
Baroreceptor discharge

.
limbic system
Trauma via
reticular
formation Drive for
diurnal variation

K
Chemical rhythm from
stimuli suprachiasmatic

.
Hypothalamus nucleus

A
CRH (from median eminence)

Anterior
pituitary

Cortisol ACTH

Adrenal cortex Stimulation

Inhibition

Fig. 8.36 Regulation and factors affecting ACTH secretion (CRH:

Corticotrophin releasing hormone)
  8: Endocrine System ❑ 33

3. Factors affecting
(i) Diurnal variation (or circadian rhythm) (Fig. 8.37)
(a) The normal resting morning plasma ACTH concentration: 25 pg/mL.
(b) Control is via a biological clock located either in limbic system or suprachiasmatic nucleus
of hypothalamus.
20 125
Plasma 11-OHCS (µgm/dL) sleep Awake
16 100

Plasma ACTH (pg/mL)

12 75

n
8 50

i
4 25

a
0
2 am
12 4 am 8 am 12 4 pm 8 pm 12
Midnight Noon Midnight

J
Fig. 8.37 Variation of plasma cortirol measured as

.
11-Hydroxycorticosteroid (11-OHCS) and ACTH levels in 24 hrs.

(ii) Response to stress (Fig. 8.38)

K
(i) (a) Emotions: such as: anger,
anxiety, apprehension, impulse via portal

.
Act via Limbic hypothalamus ACTH Secretion GC
fear, fatigue frustration reach hypophysial
system (amy- (median from anterior secretion
(b) Physical stimuli such as: gdaloid nucleus) eminence) system pituitary
pain, trauma, exercise,

A
exposure to cold, burns inhibit via nucleus
of tractus solitarius
(ii) Baroreceptor Discharge
Stimulate
(iii) Biological stresses
such as: surgical operation,
injury, administration of act via reticular
anaesthetics, infectious formation
diseases, toxins, haemorrhage,
hypoglycemia, hypoxia

Fig. 8.38 Role of stress on ACTH secretion

B. Glucocorticoid Feedback Mechanism

1. Free GCs via anterior pituitary and hypothalamus → ↓ ACTH secretion.
2. Prolonged treatment with GC → adrenocortical atrophy. Sudden stoppage → adrenal crisis

Actions of Glucocorticoids
Mechanism of Action: DNA dependent mRNA synthesis in the nuclei of their target cells.
1. On protein metabolism: Catabolic
2. On carbohydrate metabolism → Hyperglycemia
3. On fat metabolism: Lipolytic action
4. On electrolyte and water metabolism: Paradoxical effects
(i) Mild mineralocorticoid activity
(ii) Antagonises the action of ADH on renal tubules → diuresis.
34

In health (i) and (ii) balance each other. However, in adrenal cortex insufficiency → ↓ diuretic effect
→ water intoxication
5. Restore vascular reactivity → maintain normal BP.
6. Permissive action i.e., GC must be present for catecholamines to produce pressor response and
bronchodilation.
7. Resistance to stress: Stressful stimuli → ↑ ACTH → ↑ GC (called general adaptation syndrome).
8. Anti-inflammatory and anti-allergic action: With high output of GC (50-75 mg/day; normal: 25 mg/day).
In high dose GC →
(i) ↓ local reaction
(ii) Prevents tissue damage
(iii) ↓s fibroblastic activity.

n
(iv) ↓ release of endogenous pyrogens from granulocytes

i
(v) ↓ antibody formation
(vi) ↓s histamine induced features of allergy

a
Note: GC thus acts like an asbestos suit against fire

9. Other actions: Helps maturation of surfactant.

J
Summary: The principal actions of Glucocorticoids

.
Permissive action with Stress response Immunosuppressive
Catecholamines and —increased and Anti-inflammatory
Glycogen vascular tone actions

.
Fat cells -

K Skeletal muscle and

A
Cortisol
increased Lipolysis other tissues (Catabolic)

Liver
Increased mobilization increased Gluconeogenesis,
Increased mobilization
of Glycerol and glycogenesis, glycogen storage, and
of Amino acids
Fatty acids enzyme activity (e.g., glucose-6-
phosphate (diabetogenic)

Applied: Cushing Syndrome

Cause
Characteristic features (Fig. 8.39)
1. ↑ protein catabolism →
(i) growth retardation;
(ii) Skin paper-like and transparent;
(iii) steroid myopathy; → +++ muscular weakness;
(iv) poor wound healing;
(v) hair to become thin and rough
(vi) osteoporosis.
  8: Endocrine System ❑ 35

Hair: Thin and rough

Narrow eye slit

(A) Hirsutism
Fish like mouth

Skin: Thin paper

like transparent

Muscle weakness and wasting

Thin extremity

n
(B) Buffalo hump (arrow)
Centripetal distribution
of fat

i
Central obesity

Purple striae
(red stretch Others:

a
marks) • Poor wound healing
• Psychosis
• Hypertension
• Hyperglycemia

J
(C) Moon like face (D) Cushing dwarf (E) Systemic features • Osteoporosis
with acne (Short stature)

.
Fig. 8.39 Cushing’s syndrome, characteristic features results from an excess of circulating glucocorticoids.

2. Deranged carbohydrate metabolism steroid (adrenal) diabetes.

K
3. ↑ Fat metabolism centripetal distribution of fat →

.
(i) extremities thin;
(ii) prominent reddish-purple striae;
(iii) moon-like face;

A
(iv) buffalo hump;
(v) atherosclerosis.
4. Oedema and hypertension.
5. Blood: Eosinopenia, ↓ lymphocytes, neutrophilia, polycythemia.
6. On CNS: ↑ brain excitability → restlessness, psychosis and convulsions.
7. On GIT → promotes peptic ulcer formation.
(i) ↑ acid and pepsin
secretion
(ii) ↓ gastric mucosal
cell proliferation.
8. ↑ susceptibility to infection and delayed wound healing.
9. Other changes
(i) Hirsuitism
(ii) Impotency and hypogonadism in males
(iii) Amenorrhoea in females.

Mineralocorticoids: Aldosterone
Mechanism of action: DNA – dependent mRNA synthesis.
Actions
1. Conservation of Na+, excretion of K+ and water
(i) Acts on DCT and CT → ↑ Na+ reabsorption in exchange for K+ and H+.
(ii) ↑ Na+ reabsorption from GIT, salivary and sweat glands
2. ECFV regulation by stimulating Na+ reabsorption
36

3. Relationship with acid base balance: Aldosterone → Na+ exchange for K+ and H+ in DCT; therefore, ↑
aldosterone secretion → hypokalemia → ↑ secretion of H+ over K+ in DCT → metabolic alkalosis.
conversely, ↓ aldosterone secretion → metabolic acidosis.
Regulation of aldosterone secretion: Extra and Intrarenal control mechanisms
1. Extrarenal control mechanism
(i) Hyponatremia via:
(a) Renin-angiotensin system; and
(b) direct stimulation of adrenal cortex.
(ii) Hyperkalemia → ↑ aldosterone secretion
(iii) Circadian rhythm: same as with ACTH
(iv) Role of ACTH in aldosterone secretion is minimal (factors which ↑ GC secretion → ↑ aldosterone

n
secretion by ↑ing ACTH secretion).

i
(v) ANP → ↓ Renin secretion → ↓ angiotensin II → ↓ aldosterone secretion.
2. Intrarenal control mechanism: Renin-angiotensin system: Any stimulus which ↑ renin release → ↑

a
aldosterone secretion and vice versa. (Fig. 8.40)
JGA Negative feedback inhibition

J
Angiotensinogen

Renin inhibitory

.
discharge of
renal nerves

s Renal arterial

K
mean pressure
Angiotensin-I (inactive, decapeptide)

.
ACE (in lungs, kidney
and plasma) s ECFV

Angiotensin-II

A
(Directly Retention of Na+
Aminopeptidase stimulate) and water
of adrenal cortex

Angiotensin-III Aldosterone
release
Adrenal cortex

Fig. 8.40 Renin-angiotensin system (ACE: angiotensin converting

enzyme; JGA: Juxtaglomerular apparatus)

Applied
A. Primary Hyperaldosteronism
Conn’s Syndrome
Cause:
Characteristic features: Secondary to Na+ reabsorption and its exchange with H+ and K+ in DCT.
1. Hypernatremia → ↑ ECFV and ↑ BP.
2. ↑ K+ excretion in urine → hypokalemia →
(i) +++ muscular weakness.
(ii) Metabolic alkalosis → ↓ free ionized Ca2+ → Tetany.
(iii) Hypokalemic nephropathy → polyuria, polydipsia, decrease concentrating ability of kidneys.
3. Absence of peripheral oedema because of escape phenomemon: Mechanism. ↑ Na+ excretion in spite of
continued action of aldosterone on DCT, probably due to ↑ ANP secretion.

B. Secondary Hyperaldosteronism
Cause: ↑ aldosterone secretion due to extra-renal factors
  8: Endocrine System ❑ 37

Predisposing factor: patients with oedematous states e.g., heart failure, cirrhosis liver, nephrosis, toxaemia
of pregnancy.
Features
1. ↑ level of angiotensin II and renin.
2. ↑ BP with oedema (due to Na+ and water retention).

C. Addisonian Crisis: Adrenal crisis

Acute form of adrenal cortex insufficiency.
Causes
1. Removal of adrenal cortex.

n
2. Abrupt withdrawal of GC.

i
3. Exposed to a sudden stress or infection.
Characteristic features

a
1. GC deficiency → ↓ catecholamines → VD and ↑ capillary permeability → circulatory collapse.
2. ↓ Aldosterone →
(i) Na+ and water loss → ↓ ECFV → ↓ BP, dehydration, circulatory collapse and death.

J
(ii) Retention of K+ → hyperkalemia, dehydration and circulatory collapse, therefore, Aldosterone

.
is essential for life.

D. Addison’s Disease: Primary Adrenocortical Insufficiency

Cause:

K
Characteristic features mainly due to GC ↓: (Fig. 8.41)

.
1. ↓ BP, water intoxication (secondary to ↓ diuretic effect).
2. Anorexia, nausea, vomiting, diarrhoea, dehydration → weight loss.

A
3. Muscular weakness, mental confusion.
4. Chronic ↑ ACTH → ↑ β-MSH → generalised pigmentation of skin.
5. ↓ ability to withstand stress.
6. Hypersensitive to taste and smell.
(A) (B) (C)

Fig. 8.41 Addison’s disease Hyperpigmentation: (A) Gums,

(B) Face and (C) Legs

Adrenal Medulla
Physiological Anatomy
1. Consists of 2 types of cells: 80% epinephrine (Ep.) and 20% nor epinephrine (NE) secreting cells.
2. Innervation by splanchnic nerve. It is in effect a sympathetic ganglion.
38

Biosynthesis (Fig. 8.42)

Phenylalanine (in diet)

Phenylalanine hydroxylase
(found in liver)
TYROSINE (also come from diet)
Tyrosine hydroxylase
* (in cytoplasm)
3,4 Dihydroxy phenylalanine (DOPA)
Dopa decarboxylase
(in cytoplasm) (inhibits)

n
DOPAMINE

i
Dopamine β-hydroxylase
(in granules)
NOR-EPINEPHRINE (NE)

a
Phenylethanolamine N-methyl transferase (PNMT)
(found in high amounts only in brain and

J
adrenal medulla)

.
EPINEPHRINE (Ep)
{* This is the rate limiting reaction since the enzyme tyrosine
hydroxylase in adrenergic nerves is inhibited by free NE, which

K
exerts a negative feedback control over the synthesis.}

.
Fig. 8.42 Catecholamines biosynthesis

Metabolism: Removal and Inactivation (Fig. 8.43)

A
Metabolism: By enzymes monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT) → nor-
metanephrine from NE; metanephrine from Ep. and VMA (vanillyl mandelic acid).
Nor-adenergic neuron

DOPA

DOPAMINE
Deaminated
MAO derivatives
NE e.g. DOMA
Reuptake
85%
NE VMA
COMT Nor
metanephrine
Receptors

Post-synaptic
tissue

Fig. 8.43 Metabolism of catecholamines (abbreviation as in the text)

  8: Endocrine System ❑ 39

Excretion in urine as
1. 50% in conjugation with sulphuric or glucuronic acid.
2. 35% as VMA.
3. 15% as Ep. and NE in free form.
Normal values

Normal urine excretion Normal ‘free’ plasma level

Nor-epinephrine (NE) 30 µg/day 300 pg/mL.

Epinephrine (Ep) 6 µg/day 30 pg/mL.

n
Vanillyl mandelic acid (VMA) 700 µg/day –

i
Dopamine – 35-40 pg/mL.

a
Note: The majority of urinary VMA is derived from NE, therefore, urinary VMA reflects the activity
of nerve terminals of sympathetic nervous system.

J
Regulation of Catecholamine Secretion

.
1. Nervous Control:
(i) Splanchnic nerve activity is controlled by medullary reticular formation and hypothalamus.
(i) Indirectly depends on GC secretion, as catecholamines synthesis is dependent on GC.

K
2. Selective Secretion (in conditions of emergency or stress)

.
Flight or Fight Reactions, :
(i) Relaxes accommodation & produces pupillary dilatation → letting more light to enter into the eyes.
(ii) ↑ HR, ↑ BP and (+) sympathetic vasodilator system → ↑ perfusion of vital organs & muscles.

A
(iii) Constrict blood vessels → ↓ bleeding, if wounded.
(iv) ↓ threshold of reticular formation → alert and arousal states.
(v) ↑ blood glucose and ↑ FFA level → ↑ energy release.

Important Notes:
1. Situation with which the individual is familiar: associated with ↑ ‘NE’ secretion. Mostly concerned with
regulation of vascular tone, blood flow and BP.
2. Situation in which the individual does not know what to expect: associated with ↑ Ep. secretion. It has its most
important action on metabolism.

Actions of Catecholamines
Adrenergic receptors: α and β.
1. α-adrenergic receptors are sensitive to both Ep and NE; associated with most of the excitatory functions
of the body with one inhibitory function i.e., inhibition of intestinal motility.
2. α-receptors are of two kinds α1 and α2:
(i) α1-receptors mainly excitatory, e.g., in blood vessels and the non-pregnant uterus; and
(ii) α2-receptors Activation of neuronal α2-receptors is inhibitory.
3. The β-adrenergic receptors respond to Ep associated with most of the inhibitory function with one
important excitatory function i.e. excitation of myocardium.
4. β-receptors two kinds, β1 and β2
(i) β1-receptors occur in cardiac muscle and their activation produces tachycardia and increases
myocardial contractility; and
(ii) β2-receptors associated with relaxation of smooth muscle, e.g. in skeletal muscular blood vessels,
GIT and bronchioles.
5. Ep acts equally on both α and β-receptors, while NE acts on α-receptors.
40

6. In humans, β-adrenergic mechanism predominates.

7. α-receptor activation ↑ intracellular [Ca2+] and β-receptors activation ↓s intracellular [Ca2+].

Actions
1. On CVS (heart and blood vessels)
(i) NE direct action
(a) on heart via β1-receptors → ↑ HR and ↑ FOC → ↑ SBP;
(b) on blood vessels via α1-receptors → VC → ↑ DBP.
(a) and (b) → +++ ↑ MBP → reflexely via baroreceptors → ↓ HR & ↓ FOC → ↓ ‘CO’.
(Note: Net effect →↓ HR; ↓ ‘CO’).
(ii) Ep. its direct action

n
(a) on heart via β1 → ↑ HR, ↑ FOC → ↑ SBP;
(b) on blood vessels via α → VC in skin and splanchnic area; and via β2 → VD skeletal muscle

i

and liver. Net effect, ↓ PR → ↓ DBP.
(a) and (b) → + ↑ in MBP (reflex action).

a
(Note: Direct action of Ep. on CVS is overcome by its reflex action → ↑ HR and ↑ ‘CO’).
2. On carbohydrate metabolism → Hyperglycemia by (Fig. 8.44)
(i) Via β-receptors, in liver, adipose tissue and skeletal muscle → ↑ glycogenolysis.

J
(ii) Via α-receptors → ↑ glycogenolysis.
(Ep. is 3 times more potent than NE to produce hyperglycemia as β-adrenergic mechanism

.
predominates.)
+100
Percent change from initial level

. K
+50
Liver glycogen

Blood glucose
0

A
Blood lactic acid

–50 Muscle glycogen

0 1 2 3
Time after Ep. injection (hours)

Fig. 8.44 Effects of epinephrine (Ep.) on carbohydrate metabolism

3. On lipid metabolism → Lipolytic action: NE and Ep via β-receptors → ↑ cAMP system → (+) hormone
sensitive lipase in adipose tissue and muscles → breakdown stored triglycerides to FFA and
glycerol.

Note: Ep. has predominant effect on carbohydrate metabolism, whereas NE has more potent action on lipid
metabolism.

4. On BMR → Calorigenic action: Ep. effect > NE. (Fig. 8.45)

  8: Endocrine System ❑ 41

(ii)

Rise in
BMR
(i)

injection Ep. Time

n
Fig. 8.45 Calorigenic effect of epinephrine (Ep.)
(i) initial rapid rise in BMR; (ii) slow and delayed rise in BMR

i
5. On CNS: Activates RAS by lowering its threshold → arousal and alerting response, anxiety,
apprehension, hyperventilation and coarse tremors of extremities.

a
6. On Eyes → Wide open eyes. Ep (Fig. 8.46)
(i) Via α-receptors → pupillary dilatation.

J
(ii) Via β-receptors muscles for far vision and ↑s tone of eye muscles.

.
(A)
Radial
smooth muscle
fibres of the iris
Circular

K
Pupil

A . (B)

sympathetic
motor nerve fibre
Via Ep.

Fig. 8.46 Effect of Epinephrine (Ep.) on eye,

before (A) and after (B) its administration.

7. On GIT: Ep. → constipation.

(i) β-receptors → ↓ tone and motility;
(ii) Via α-receptors → sphincters constriction.
8. On urinary bladder → Retention of urine. Ep.
(i) Via β-receptors → relaxes detrusor muscles.
(ii) Via α-receptors → contraction of trigone and sphincters.
9. On skin: Catecholamines via α-receptors →
(i) Contraction of pilomotor muscles → piloerection of hair.
(ii) On sweat glands → localized sweating on palm and sole, called adrenergic sweating. (Generalized
sweating is cholinergic)
10. On skeletal muscle: Ep. via β2-receptors → ↑ blood supply and ↑ force of contraction.
11. On bronchial muscles. Ep. via β2-receptors → relaxes bronchial musculature → bronchodilation.
12. On blood. Ep. →
(i) ↓s clotting time (↑s activity of factor V).
(ii) Constricts spleen → ↑ RBC count, PCV, and haemoglobin.
42

(iii) ↑ plasma protein concentration (moves fluid out of circulation).

(iv) +++ ↑ neutrophils (↑s sequestrated neutrophils).
(v) ↓ Eosinophils.

Actions of Dopamine
1. Produces generalised vasoconstriction by releasing NE.
2. Via β1-receptors → ↑ force of contraction of heart → ↑ SBP.
3. On kidneys →
(i) Vasodilatation.
(ii) Inhibit Na+ – K+ ATPase → Natriuresis, therefore, useful in treatment of shock.

n
Applied

i
1. Hyposecretion of catecholamines → No adverse effects (Adrenal medulla is not essential for life).
2. Hypersecretion of catecholamines: Pheochromocytoma

a
Cause: Benign tumour of adrenal medulla → release of large amounts of Ep and NE into the
circulation.

J
Features:

.
1. Sustained or paroxysmal hypertension: BP ↑ ≥ 300/200 mmHg.
2. Headache; adrenergic sweating, severe palpitation, substernal pain, anxiety, weakness, dizziness, pale,
cold and moist skin, blurred vision (due to dilated pupils).

K
3. ↑ body temperature, ↑ blood glucose, glycosuria, ↑ BMR.
4. ↑ urinary excretion of catecholamines, metanephrine and VMA.

.
Pancreas

A
General
Islets of Langerhans (0.5-1.5 million) contain 4 types of cells: (Fig. 8.47)
1. 15-20%: α-cells → secrete glucagon.
2. 70-80%: β-cells → secrete insulin.
3. 1-8%: δ-cells: → secrete somatostatin (GHIH) and gastrin.
4. 1-2%: F-cells: → pancreatic polypeptide.
Innervation: sympathetic and parasympathetic nerves.
β-cells Islet of Langerhans

α-cell
Pancreatic
acini

Erythrocytes

Fig. 8.47 Islets of Langerhans, the endocrine tissue of the pancreas

Glucagon: (Mobilizer of glucose)

Normal fasting level: 100-150pg/mL.
  8: Endocrine System ❑ 43

Actions
1. Stimulate glycogenolysis in liver → ↑ blood sugar
2. Promotes gluconeogenesis → slow and sustained ↑ in blood glucose.
3. Powerful lipolytic agents → ↑ FFA and glycerol → ↑ ketone bodies (ketogenic action).
1, 2, 3 → ↑ release of glucose, amino acid and FFA into circulation (i.e. catabolic in action). Glucagon
is thus a hormone of energy release.

Regulation of Secretion
Increased by Decreased by
1. Hypoglycemia 1. Hyperglycemia.

n
2. Protein meal. 2. FFA, ketone bodies.

i
3. GIT Hormones: CCK-PZ; GIP, gastrin. 3. Secretin.
4. Various stresses, fasting, exercise, infection → ↑ 4. α-adrenergic receptors stimulation.
sympathetic stimulation (mediated via β‑receptors).

a
5. Cortisol, A-ch 5. Insulin, somatostatin.
(Oral administration of amino acids → release of CCK-PZ, gastrin → greater secretion of glucagon as

J
compared to its I.V. administration.)

.
Insulin
General

K
1. Species specificity

.
2. Secretion depends on ATP, cAMP, Ca2+ and K+.
3. Transport – circulating protein synalbumin.
4. Metabolism

A
(i) 80% by liver and kidneys by HGIT.
(ii) 20% by enzyme insulin protease.
 44

Control of insulin secretion (Fig. 8.48)

Glucose
GLUT-2

Nucleus
β-cell
Glucose
Glucokinase
Glu-6-PO4 Mitochondrion
Endoplasmic reticulum

Glycolysis

n
Kreb’s cycle

i
Golgi complex

Intracellular ↑ ATP

a
Ca2+ stores ↑ ATP

(–)

J
Insulin containing granules Ca2+

.
ATP sensitive K+ channel

Insulin release
tion
lariza

K
Voltage dependent
Ca2+ Depo
Ca2+ channel

.
Fig. 8.48 Control of insulin secretion by carbohydrates. Glucose enters β-cells via GLUT‑2 (independent of insulin) and is metabolized by
enzyme glucokinase to pyruvic acid. ATP is generated and closes ATP‑sensitive K+ channels, the resultant decrease in K+ efflux depolarizes
the cell membrane. This opens voltage-sensitive Ca2+ channels, the increase in intracellular Ca2+ causes release of insulin by exocytosis.

A
(Metabolism of pyruvic acid via citric acid cycle also increases the intracellular glutamic acid. This primes secretory granules for secretion.)
Note: K+ depletion decreases insulin secretion; that is why patients with primary hyper-aldosteronism develop diabetic GTT.

Regulation of Secretion
Basal plasma insulin levels: 10-50 µU/mL (7–350 pmol/dL).
  8: Endocrine System ❑ 45

Summary: Factors affecting insulin secretion and principal actions of insulin. (+): stimulaiton; (–): inhibition

I Substrates I Substrate
Carbohydrates – glucose, fructose Carbohydrates – 2-deoxyglucose
Proteins – amino acids mannoheptulose

Fats – β-keto acids

II cAMP generation by II cAMP generation by

Theophylline (+) (–) β-blockers
Oral hypoglycemics (+) (–)
Catecholamines

n
III Neural III Neural

i
(+) (–)
Vagal stimulation; A-ch Vagotomy; symphathetic. stimulation
feeding Atropine; starvation

a
(+) (–)
(+) (–)
IV Hormonal
IV Hormonal

J
Glucagon; secretin
Insulin; thyroxine, glucocorticoids
Cck-pz; gastrin; GIP

.
stomatostatin

V Drugs V Drugs

K
Antidiabetics; oral hypoglycemic Antihypertensives; thiazides;
agents anticonvulsants; K+ - depletion,

.
Fig. 67.4

1. ↑ blood glucose → ↑ insulin secretion in two phases. (Fig. 8.49)

A
(i) primary response insulin release from labile pool;
(ii) secondary response release of insulin from major stable pool.
Blood glucose

300
(mg/dL)

200

100

0
10 1st phase
(primary
8
response)
Rate of insulin secretion

6
4
2
(U/hr)

1 2nd phase
(secondary
I.V. glucose response)

Basal state

0 5 60 120 180 240

Time (min)
Fig. 8.49 Effect of constant glucose infusion on insulin secretion

2. β-cells of islets have more α-receptors.

3. GIP alone in very small concentration can increase insulin secretion, (Physiologic GUT factor). (Fig. 8.50)
4. β-cell exhaustion
46

340

300

I.V. glucose

Blood glucose (mg/dL)

Oral administration

200

100

i n
0

120

a
Plasma insulin (µU/mL)

J
80

.
40

K
0
0 1 2 3 4

.
Time (hours)

Fig. 8.50 Blood glucose and plasma insulin response to oral and I.V.
glucose administration

A
Actions of Insulin
1. On carbohydrate metabolism
(i) ↑s glucose entry into most of the tissues. Exception:
(ii) Produces hypoglycemia by
2. On fat metabolism
(i) ↑ synthesis of FFA and triglycerides in muscles, adipose tissue and liver. Mechanism:
(ii) ↑ uptake of ketone bodies in the muscle.
3. On protein metabolism → Anabolic action. Mechanism:
Summary: Insulin is glycogenic, antigluconeogenic, antilipolytic and antiketogenic (anabolic actions).
It thus favours storage of absorbed nutrients and is a hormone of energy storage or hormone of
abundance.

Insulin
(Hormone of Abundance/Energy storage)

Carbohydrates Fats Proteins

glucose uptake lipogenesis Anabolic - protein
glycogenesis lipolysis synthesis and
Antigluconeogenic Antiketogenic protein breakdown

4. Other Actions
(i) Directly ↓ urea output from the liver and ↑ uptake of K+ and phosphate.
(ii) ↑ K+ entry into the cells by ↑ activity of Na+ – K+ pump → ↓ ECF [K+].
  8: Endocrine System ❑ 47

Mechanism of Action of Insulin

1. Reversible combination with specific insulin receptor on the surface of cell membrane.
(i) ↓ cAMP formation.
(ii) ↑s transport of ions into insulin responsive cells
2. The number or affinity or both of insulin receptors is affected by:
(i) Number of receptors per cell may increase or decrease:
(a) Increase in starvation and during exercise.
(b) Decreases due to exposure to increased amount of insulin and obesity.
(ii) Affinity of receptors for insulin may also increase or decrease:
(a) Increases with exposure to decreased amount of insulin.
(b) Decreases due to excess of glucocorticoids.

i n
Regulation of blood glucose level (Fig. 8.51)

Factors affecting blood glucose (Normal fasting: 70-90 mg/dL)

a
Tend to raise (during hypoglycemia) Tend to lower
1. Hunger 1. Satiety; starvation

J
2. Glucose absorption from GIT 2. Insulin
3. H
 epatic glycogenolysis 3. Muscular exercise

.
(a) Epinephrine
(b) Glucagon
4. Gluconeogenesis (in liver)

K
5. I nsulin antagonists i.e.
(a) Growth hormone

.
(b) Cortisol

A
Diet

Intestine
Amino Acids
Lactic Acid
Liver
Glycerol Gluconeogenesis
Glycogen Synthesis
Glycogenolysis
Cortisol
GH, Ep Glucagon Insulin
Glucagon Ep
u lin
Insulin Venous Blood Glucose Ins Muscles
Fat (fasting) 7090 mg/dL Glycogen and
protein
In
su
lin

Venous Blood Glucose

if > 180 mg/dL

Glands and
Brain
other tissues

Kidneys

Filters and appears

in urine (Glycosuria)
Fig. 8.51 Hormonal regulation of blood glucose concentration
(Ep: Epinephrine; GH: growth hormone)
48

Important Note: Exercise is beneficial for diebetic patients because:

1. ↑s entry of glucose into skeletal muscle cells
2. ↑s insulin sensitivity of muscle by ↑ in number of GLUT-4 in muscle cell membrane.

Applied Aspect
A. Diabetes Mellitus (DM)
Diabetes means a siphon or running through. Mellitus means sugar.
Causes:
1. insulin deficiency;

n
2. excessive secretion of either GH or glucagon or GC or catecholamines.

i
Predisposing factors
1. Hereditary.

a
2. Increasing age.
3. Obesity (i.e., body mass index > 30). {BMI = body weight (in kg)/(height)2 in mt.} (Fig. 8.52)
(Adipose tissues in obese persons are more resistant to insulin action)

J
2.0

.
1.90 Normal Over-
Underweight Obese
weight

1.80

K
Height (mt)

.
1.70

1.60
Morbidly Obese

A
1.50

1.40
40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130
Weight (kg)

Fig. 8.52 Body mass index (BMI)

Signs and Symptoms – (due to hyperglycemia)

1. hyperglycemia → predisposes to infections.
2. Glycosuria
3. Polyuria
4. Dehydration.
5. Polydipsia
6. Polyphagia
7. Loss of weight (1 g of glucose loss in urine → loss of 4.1 kcals from the body.)
8. Ketonuria
9. Poor resistance to infections
  8: Endocrine System ❑ 49

Pathophysiology of DM

Insulin Lack

On proteins On carbohydrates On fats

↑ Catabolism ↑ Blood glucose ↓ Lipogenesis

(i) ↑ gluconeogenesis > renal threshold Mobilization of fat depot

(ii) Loss of cellular K+ to ECF (180 mg/dL)

n
(iii) Muscular wasting and ↑ FFA

i
weight loss Glycosuria
↑ Ketogenesis
Polyuria

a
Ketoacidosis
Water and electrolytes loss
Kussmaul Breathing

J
Dehydration (deep, rapid breathing)

.
Circulatory failure

↓ BP

K
Coma and death

.
Important Notes:

A
1. Once diabetic ketoacidosis develops, there is marked resistance to insulin due to ↑  activities of glucagon, GH
or GC.
2. Degree of ketoacidosis α amount of fat stores, therefore, it is more severe in obese compared to thin
individuals. Moreover, disturbances in fat metabolism is so prominent in diabetes mellitus, that it has been
called more a disease of lipids than of carbohydrate metabolism.
3. FFA levels parallel the blood glucose level in diabetes mellitus, therefore, in some way FFA estimation is a
better index to assess the severity of diabetes mellitus than the blood glucose.
(Normal plasma FFA : 10–30 mg/dL)

Complications
1. Acute
(i) Dehydration → circulatory failure.
(ii) Ketoacidosis.
(iii) Convulsions, coma and death.
2. Chronic
(i) Atherosclerosis, MI and stroke.
(ii) Microangiopathy →
(a) Neuropathy
(b) Retinopathy
(c) Nephropathy
Glucose Tolerance Test (GTT): also called oral GTT. (Fig. 8.53)
Conclusions
1. Normal GTT
2. Diabetic GTT
3. Impaired GTT
50

180

Blood glucose levels (mg/dL)

Diabetic
160
Impaired
140
126
120
Normal
100

80
0 1 2
Hours after

n
Glucose administration (75 gm orally)

i
Fig. 8.53 Oral glucose tolerance test (GTT), normal and diabetic
type of response

a
B. Hypoglycemia
Normal fasting glucose: 70-–90 mg/dL. Blood glucose <60 mg/dL whereas in DM, levels <100 mg/dL

J
→ signs and symptoms of hypoglycemia.

.
Signs and Symptoms
Neuroglycopenic symptoms →
1. Mental confusion, irritability, marked fatigue, difficulty in walking, convulsions and coma.

K
2. ↓ glucose utilization by hypothalamus →
(i) polyphagia

.
(ii) ↑ catecholamine release → nervousness, pallor, ↑ HR, sweating, tremors, headache, anxiety.
3. Involvement of medulla → cardiorespiratory failure.

A
Compensatory Mechanisms
1. Early: ↑ sympathetic stimulation
2. Late: ↑ ACTH → ↑ GC, GH and TSH →
Hyperglycemic coma versus hypoglycemic coma
Hyperglycemic Coma Hypoglycemic Coma
1. Cause High blood glucose level, above Fall in blood glucose level, below 40 mg/dL.
400 mg/dL. (medical emergency).
2. Rate of onset Slow Rapid, develops within minutes.
3. Precipitating factors Insulin under dosage, infection, Overdosage of insulin, missed meal, undue
trauma. exercise.
4. Signs and symptoms
(i) Breathing Deep and rapid (air hunger), Laboured breathing.
called kussmaul breathing.
(ii) Sweating Absent Usually marked.
(iii) Hydration Marked dehydration Normal, fairly hydrated.
(iv) CNS symptoms Diminished reflexes Various, often bilateral extensor plantar
responses.
(v) Urine Marked glycosuria and No specific characteristic features seen.
examination ketonuria.
  8: Endocrine System ❑ 51

The Thymus
Functions
A lymphoid organ; removal in a newborn →
1. Lymphopenia and atrophy of all lymphoid tissues.
2. Failure to produce antibodies to antigens → ↑ susceptibility to infections.

i n
J a
Fig. 8.54 Location of thymus gland in foetus (arrow)

.
3. ↓ in delayed hypersensitivity reaction
4. Failure to reject foreign tissue transplants.
5. Initiates development of immunologically competent T-lymphocytes.

K
Immunological Role of Thymus

.
1. Provides an environment favourable to lymphopoiesis.
2. Secretes, thymosin → (+) lymphopoiesis → development of immunologically competent lymphocytes.

A
3. Secretes thymopoietin (thymin) → inhibit A-ch release at motor nerve endings in myasthenia gravis.

Note: Autoimmune diseases → hyperplasia of thymus and lymphoid tissue → thymus become immunologically
responsive → antibody formation.

The Pineal Gland

Features
1. A neuroendocrine transducer; forms and secretes, melatonin in response to sympathetic nerve
activity.
2. Lacks blood brain barrier; large in infants.
3. In adults, calcified deposits appear radiopaque, which can be seen with X-ray as pineal sand.
4. Contains high amounts of 5HT and NE; (required for synthesis of melatonin). (Fig. 8.55)

5 HT
N-acetylation N-acetyltransferase
and acetyl CoA

N-acetyl 5 HT
5-methylation Hydroxy indole-O-
(HIOMT) methyl transferase
(found only
in pineal)
N-Acetyl-5-methoxytryptamine
or Melatonin

Fig. 8.55 Synthesis of melatonin

52

5. Secretion ↑ed during dark period of the day and maintained at low level during day light hours.
(Fig. 8.56)
6. Normal plasma conc. of melatonin: ↓ with aging:
(i) in children (1-3 years) : 250 pg/mL.
(ii) during adolescent : 120 pg/mL.
(iii) young adults : 70 pg/mL.
(iv) old age (>65 years) : 30 pg/mL.

50

40

n
Melatonin (pg/mL plasma)

i
30

a
20

J
10

.
0
Noon 9 P.M. Midnight 6 A.M. Noon 3 P.M.

K
Fig. 8.56 Variation of plasma melatonin levels in 24 hours

.
7. Functions of Melatonin
(i) Regulation of onset of puberty by secreting gonadotrophin inhibiting peptide.
(ii) Produces slowing of EEG rhythm, sleep and rise in convulsive threshold.

A
(iii) Responsible for schizophrenia.
8. Control of melatonin secretion (Fig. 8.57)
(i) Exposure to darkness → ↑ melatonin.
(ii) Exposure to light → ↓ melatonin.
Pathway: Retina → optic tract → brain stem → superior cervical ganglion → sympathetic
nor‑adrenergic pathway to pineal gland → melatonin secretion.
H 3C O Melatonin
H
N CH3

HN O

Pineal gland
Inhibition

Retino-
hypothalamic
tract
Suprachiasmatic
Superior cervical
nucleus
ganglion

Fig. 8.57 Pineal gland and its innervation