Disorders of Endocrine Systems: Mechanisms and Pathophysiology

Disorders of Endocrine
Systems
Unit- 9, PC- 511 (Pathophysiology)
M.S.- Pharm- Pharmacology & Toxicology
NIPER- Guwahati
Monday, December 13, 2021
Department of Pharmacology & Toxicology

Endocrine System
• Pituitary Gland
• Adrenal Gland
• Thyroid Gland
• Parathyroid Gland
• Pancreatic Gland
• Gonads

Mechanisms of hormonal alterations
A. elevated hormones level
B. depressed hormones level
may be caused by:
1. Failure of feedback systems
2. Dysfunction of endocrine gland or endocrine function of cells:
a) secretory cells are unable to produce or do not obtain an
adequate quantity of required hormone precursors
b) secretory cells are unable to convert the precursors to the
appropriate active form of hormone
c) secretory cells may synthetize but release excessive amounts
of hormone

3. Degradation of hormones at an altered rate or they may be
inactivated by antibodies before reaching the target cell
4. Ectopic/abnormal sources of hormones
C. Failure of the target cells to respond to hormone
May be caused by:
1. receptor-associated disorders
2. intracellular disorders
Mechanisms of hormonal alterations contd...

C 1. Receptor associated disorders
a) Decrease in the number of receptors   hormone - receptor binding
b) Impaired receptor function  sensitivity to the hormone
c) Antibodies against specific receptors
d) Unusual expression of receptor function
C 2. Intracellular disorders- disorders present inside the
target cell
a) inadequate synthesis of the second messengers
b) number of intracellular receptors may be decreased or they may
have altered affinity for hormones
c) alterations in generation of new messenger RNA or absence of
substrates for new protein synthesis

Pituitary
Gland

Secretions of Pituitary Gland
Anterior Pituitary
• GH: growth hormone
• ACTH: adrenocorticotropic
hormone
• TSH: thyroid-stimulating hormone
• PRL: prolactin
• FSH: follicle-stimulating hormone
• LH: luteinizing hormone
• MSH: melanocyte stimulating
hormone
Posterior Pituitary
• ADH: anti-diuretic
hormone (vasopressin)
• OT: oxytocin

Anterior Pituitary Secretes
• GH: stimulates growth of bone and muscle , promotes
protein synthesis and fat metabolism.
• ACTH (Adrenocorticotropin ): stimulates adrenal gland
cortex secretion of mineralocorticoids (aldosterone) &
glucocorticoids (cortisol).
• TSH: stimulates thyroid to increase secretion of
thyroxine, its control is from regulating hormones in the
hypothalamus.
Monday, December 13,
2021

Anterior Pituitary Cont’d
• Prolactin: stimulates milk production from the breasts
after childbirth to enable nursing. Oxytocin from
posterior lobe controls milk ejection.
• FSH: promotes sperm production in men and stimulates
the ovaries to enable ovulation in women. LH and FSH
work together to cause normal function of the ovaries
and testes.
• LH: regulates testosterone in men and estrogen,
progesterone in women.

Posterior Pituitary
• Antidiuretic hormone or ADH - also called
vasopressin, vasoconstricts arterioles to increase
arterial pressure; increases water reabsorption in
distal tubules.
• Oxytocin: stimulates uterus to contract at
childbirth; stimulates mammary ducts to contract
(milk ejection in lactation).

Anterior Pituitary Disorders
Hormone Increased level Decreased level
GH Gigantism (child)
Acromegaly (adult)
Dwarfism (child)
Lethargy, premature aging
ACTH Cushing’s Disease Addison’s Disease
TSH Goiter, increased BMR, HR,
BP, Grave's disease
Decreased BMR, HR, CO, BP
Cretinism (children)
Prolactin amenorrhea Too little milk
FSH Late puberty, infertility
LH Menstrual cycle disturbance Amenorrhea, impotence
2021

Posterior Pituitary Disorders
Hormone Increased Decreased
Oxytocin Precipitates
childbirth, excess
milk
Prolonged childbirth,
diminished milk
Anti-Diuretic
Hormone
(vasopressin)
Increased BP,
decreased urinary
output, edema.
SIADH
Diabetes insipidus,
dilute urine &
increased urine
output
2021

Disorders of Pituitary Glands
• Hyperpituitarism
• Hyperfunction of Anterior Pituitary
• Gigantism and Acromegaly
• Hyperprolactinaemia
• Cushing’s Disease
• Hyperfunction of Posterior Pituitary and Hypothalamus
• Inappropriate release of ADH
• Precocious Puberty
• Hypopituitarism
• Hypofunction of Anterior Pituitary
• Panhypopituitarism
• Pituitary Dwarfism
• Hypofunction of Posterior Pituitary and Hypothalamus
• Diabetes insipidus
• Pituitary Tumours

Diseases of the anterior pituitary gland
Hypopituitarism is caused e.g. by infarction of the gland, removal, or
destruction of the gland
Hyperpituitarism – due to adenoma
Causes: idiopathic, organic damage of adenohypophysis or hypothalamus,
eg.- pituitary infarction (Sheehan syndrome), pituitary apoplexy, shock,
DM, head trauma, infections, vascular malformations, tumours
Hypopituitarism- insufficient secretion of one (selective form), more than
one or all (panhypopituitarism) hormones of adenohypophysis

Consequences - they depend on the affected hormones of pituitary
gland, if all hormones so secreted by the gland are deficient 
panhypopituitarism and then the patients suffer from:
- cortisol deficiency - because of lack of ACTH
- thyroid hormones deficiency - because of lack of TSH
- ADH deficiency - diabetes insipidus
- Deficiency of FSH and LH - gonadal failure and loss of secondary sex
characteristics
-  growth hormone   somatomedin (they affect children growth)
- absence of prolactin  postpartum women are unable to lactate
Diseases of the anterior pituitary gland contd...

 (within 2 weeks) symptoms of cortisol insufficiency are developed
- nausea, vomiting, anorexia, fatigue, weakness
- hypoglycaemia (it is caused by increased sensitivity of tissues to
insulin, decreased glycogen reserves, decreased gluconeogenesis)
- in women, loss of body hair and decreased libido  due to
decreased adrenal androgen production
- limited maximum aldosterone secretion
ACTH Deficiency

 TSH deficiency  (within 4-8 weeks) symptoms of TSH
deficiency are developed:
- cold intolerance
- dryness of skin
- decreased metabolic rate
- mild myxoedema
- lethargy
 FSH and LH deficiencies  in female of reproductive age:
- amenorrhea
-atrophic changes of vagina, uterus and breasts
- atrophy of the testicles
- decreased beard growth
 in post-pubertal men:

Hyperpituitarism - excessive production of adeno-hypophyseal hormones
Causes: - adenoma of adeno-hypophysis
- hypothalamic form of Hyperpituitarism
Consequences:
a) excessive secretion of prolactin   secretion of GnRH 
gonadotropins
In men: impotency, decreased libido
In women: amenorrhea, galactorrhea
b) excessive secretion of somatotropin (growth hormone)
 acromegaly (in adults)
 gigantism (in adolescents whose epiphyseal plates have not yet closed)

b) Continuing Patho-mechanisms for excess GH secretion involved:
-The usual GH baseline secretion pattern is lost (as are sleep related GH peaks)
- A totally unpredictable secretory pattern of GH occurs
- GH secretion is slightly elevated  somatomedin  stimulation of cell
growth and division (in adolescent)
- Connective tissue proliferation
- Bony proliferation  characteristic appearance of acromegaly
- phosphate reabsorption in renal tubules  hyperphosphatemia
- Impairment of carbohydrate tolerance
-  metabolic rate
- hyperglycaemia - it is a result of GH inhibition of peripheral glucose
uptake and increase hepatic glucose production  compensatory
hyperinsulinism  insulin resistance  diabetes mellitus
In adults

c) excessive secretion of corticotrophin (ACTH)  central form of
Cushing syndrome (Cushing disease)
Causes: micro- or macro-adenomas of adenohypophysis, hypothalamic
disorders
Pathophysiology:
Chronic hypercortisolism is the main disturbance of  ACTH
Symptoms and signs:
 weight gain: - accumulation of adipose tissue in the trunk, facial, and
cervical areas (truncal obesity, moon face, buffalo hump)
- weight gain from Na and water retention
 glucose intolerance  DM type 2
 polyuria: osmotic polyuria due to glycosuria

 protein wasting: due to catabolic effects of cortisol on peripheral tissue
(muscle wasting  muscle atrophy and weakness  thin lower
extremities)
 in bone: - loss of protein matrix  osteoporosis
- blood calcium concentration  renal stones
 in skin: - loss of collagen  thin, weakened integumentary
tissues  purple striae; rupture of small vessels
- thin, atrophic skin is easily damaged, leading to skin breaks
and ulceration- zombie faced!!!!!!
 hyperpigmentation: due to very high levels of ACTH - manifestation in:
mucous membranes, hair, and skin
 hypertension: results from permissive effect of cortisol on the actions of
the catecholamines (KA)   vascular sensitivity to KA 
 vasoconstriction  hypertension

 suppression of the immune system   susceptibility to infections
 alteration of mental status - from irritability and depression
up to schizophrenia
 symptoms and signs of adrenal androgens level in women:
-  hair growth (especially facial hair)
- acne
- oligoamenorrhea
- changes of the vois
 hyperglycaemia, glycosuria, hypokalaemia, metabolic alkalosis
 excessive secretion of thyrotrophin and gonadotrophins is rare

THYROID GLAND
DISORDERS

THYROID GLAND DISORDERS
• GENERAL ASPECTS OF THYROID GLAND
• Anatomy: weight range from 12 to 30g
• Located in the neck, anterior to the trachea
• Produces: T4 & T3 (active hormone)
• Regulation: “negative feed-back” axis

• Thyroid hormones:
• T4: (Thyroxine) is made exclusively in thyroid gland
• Ratio of T4 to T3- 5:1
• Potency of T4 to T3- 1:10
• T4 is the most important source of T3 by peripheral tissue
deiodination “T4 to T3”
• T3: (Triiodothyronine) main source is peripheral deiodination
• Ratio of T3 to T4- 1:5
• Potency of T3 to T4- 10:1
• T3 is the most important because more than 90% of the
thyroid hormones physiological effects are due to the
binding of T3 to Thyroid receptor in peripheral tissue.

THYROID GLAND DISORDERS- PHYSIOLOGICAL
EFFECTS OF THYROID HORMONES
• THEY ARE NOT ESSENTIAL FOR LIFE, BUT ARE
EXTREMELY HELPFUL
• THYROID HORMONE EFFECTS:
• Effects every single cell in the body
• Modulates:
• Oxygen consumption
• Growth rate/ BMR
• Maturation and cell differentiation
• Turnover of Vitamins, Hormones, Proteins, Fat, etc.

THYROID GLAND DISORDERS-MECHANISMS
OF THYROID HORMONE ACTION
• Act by binding to Nuclear receptors, termed Thyroid
Hormone Receptors (TRs), Increasing synthesis of
Proteins
• At mitocondrial level increases number and activity to
increasing ATP production
• At Cell membrane increases ions and substrates
transmembrane flux

THYROID GLAND DISORDERS- THYROID
HORMONE EFFECTS
• CALORIGENESIS
• GROWTH & MATURATION RATE
• C.N.S. DEVELOPMENT & FUNCTION
• CARBOHYDRATE, FAT & PROTEIN METABOLISM
• MUSCLE METABOLISM
• ELECTROLYTE BALANCE
• VITAMIN METABOLISM
• CARDIOVASCULAR SYSTEM
• HEMATOPOIETIC SYSTEM
• GASTROINTESTINAL SYSTEM
• ENDOCRINE SYSTEM
• PREGNANCY

HORMONE EFFECTS
• CALORIGENESIS
• Controls the Basal Metabolic Rate (BMR)
• CARBOHYDRATE METABOLISM
• Increases:
• Glucose absorption of the GI tract
• Glucose consumption by peripheral tissue
• Glucose uptake by the cells
• Glycolysis
• Gluconeogenesis
• Insulin secretion

THYROID GLAND DISORDERS- EFFECTS OF
THYROID HORMONES
• GROWTH & MATURATION RATE
• C.N.S. DEVELOPMENT & FUNTION
• “ESSENTIAL” in the newborn to prevent development of
“CRETINISMS” & to a normal “IQ”
• Modulation of brain cerebration
• Mood modulation

THYROID GLAND DISORDERS-
THYROID HORMONE EFFECTS
• FAT & PROTEIN METABOLISM
• Increase lipolysis and lipid mobilization with:
• Cholesterol
• Triglycerides
• Free fatty acids
• MUSCLE METABOLISM
• Modulates;
• Strength & velocity of contraction

THYROID GLAND DISORDERS- EFFECTS
• ELECTROLYTE BALANCE
• Low Thyroid hormones could induce hypernatremia
• VITAMIN METABOLISM
• Modulates vitamin consumption
• HEMATOPOIETIC SYSTEM
• Could induce anemia

HORMONE EFFECTS
• CARDIOVASCULAR SYSTEM
• Hyperthyroidism, increases:
• Heart rate & myocardial strength
• Cardiac output
• Peripheral resistances (Vasodilatation)
• Arterial pressure
• Hypothyroidism, reduces:
• Heart rate & myocardial strength
• Cardiac output
• Peripheral resistances (Vasodilatation)
• Arterial pressure

HORMONE EFFECTS
• GASTROINTESTINAL SYSTEM
• Modulate bowel movements and absorption
• ENDOCRINE SYSTEM
• Modulates pituitary axis, affecting GH, ACTH, FSH, LH, so on
• PREGNANCY
• Modulates growth rate and affects lactation

Diseases of Thyroid Glands
• Functional Disorders
• Hyperthyroidism (Thyrotoxicosis)
• Hypothyroidism
• Cretinism
• Myxedema
• Thyroiditis
• Acute Thyroiditis
• Bacterial infection
• Fungal infection
• Radiation injury
• Subacute Thyroiditis (inflammation)
• Subacute Granulomatous Thyroiditis
• Subacute Lymphocytic Thyroiditis
• Tuberculotic Thyroiditis
• Chronic Thyroiditis
• Autoimmune Thyroiditis
(Hashimoto’s thyroiditis)
• Reidel’s Thyroiditis
• Graves’ Disease
• Goiter
• Diffuse Goiter
• Nodular Goiter
• Thyroid Tumors
• Follicular Adenoma
• Thyroid Cancer
• Papillary Thyroid Carcinoma
• Follicular Thyroid Carcinoma
• Medullary Thyroid Carcinoma
• Anaplastic Carcinoma

• DIVIDED INTO:
• THYROTOXICOSIS (Hyperthyroidism)
• Overproduction of thyroid hormones
• HYPOTHYROIDISM (Gland destruction)
• Underproduction of thyroid hormones
• NEOPLASTIC PROCESSES
• Benign
• Malignant

• LABORATORY EVALUATION
TSH normal, practically excludes abnormality
• If TSH is abnormal, next step: Total & Free T4 & T3
- TSI (Thyroid Stimulating Ig)
- TPO (Thyroid Peroxidase Ab)
- Anti-mitochondrial Ab
- Serum Tg (Thyroglobulin)
- Radioiodine uptake & Thyroid scanning
- FNA, Fine-needle aspiration
- Thyroid ultrasound

• TSH High usually means Hypothyroidism
• Rare causes:
• TSH-secreting pituitary tumor
• Thyroid hormone resistance
• Assay artifact
• TSH low usually indicates Thyrotoxicosis
• Other causes
• First trimester of pregnancy
• After treatment of hyperthyroidism
• Some medications (Steroids-dopamine)

• THYROTOXICOSIS:
• is defined as the state of thyroid hormone excess
• HYPERTHYROIDISM:
• is the result of excessive thyroid gland function

• Abnormalities of Thyroid Hormones
• Thyrotoxicosis
• Primary
• Secondary
• Without Hyperthyroidism
• Exogenous or factitious**
• Hypothyroidism
• Primary
• Secondary
• Peripheral
**Factitious hyperthyroidism is
higher-than-normal thyroid
hormone levels in the blood
and symptoms that suggest
hyperthyroidism. It occurs
from taking too much thyroid
hormone medicine.

• Causes of Thyrotoxicosis:
• Primary Hyperthyroidism**
• Grave´s disease
• Toxic Multinodular Goiter
• Toxic adenoma
• Functioning thyroid carcinoma
metastases
• Activating mutation of TSH receptor
• Struma ovaries
• Drugs: Iodine excess
**Primary hyperthyroidism
is the term used when the
pathology is within the
thyroid gland.
Iodine excess-
It causes stored thyroid
hormone to leak out of
your thyroid gland. Too
much iodine. Iodine is
found in some medicines,
cough syrups, seaweed and
seaweed-based
supplements. Taking too
much of them can cause
your thyroid to make too
much thyroid hormone.

• Causes of Thyrotoxicosis
• Thyrotoxicosis without hyperthyroidism (due to inflammation)
• Subacute thyroiditis
• Silent thyroiditis
• Other causes of thyroid destruction:
• Amiodarone, radiation, infarction of an adenoma
• Exogenous/ Factitia
• Secondary Hyperthyroidism (due to pituitary gland)
• TSH-secreting pituitary adenoma
• Thyroid hormone resistance syndrome
• Chorionic Gonadotropin-secreting tumor
• Gestational thyrotoxicosis
Factitious
hyperthyroidism is
higher-than-normal
thyroid hormone
levels in the blood
and symptoms that
suggest
hyperthyroidism. It
occurs from taking
too much thyroid
hormone medicine.
Thyrotoxicosis without hyperthyroidism is a condition of thyroid hormone excess not caused by
increased biosynthesis of thyroid hormones in the thyroid gland. The thyroid hormone excess in such
cases originates either from the thyroid gland as a result of destructive lesions or from extra-
thyroidal sources.

Alterations of thyroid function
Hyperthyroidism is a condition in which thyroid hormones (TH) exert
greater-than-normal response
Causes:
- Graves disease
- exogenous hyperthyroidism (iatrogenic, iodine induced)
- thyroiditis
- toxic nodular goitre
- thyroid cancer
 All forms of hyperthyroidism share some common characteristic:
 metabolic effect of increased circulating levels of thyroid
hormones   metabolic rate with heat intolerance and increased
tissue sensitivity to stimulation by sympathetic division of the
autonomic nervous system;

The major manifestations of hyperthyroidism
and mechanisms of their onset
a) Endocrine:
- Enlarged thyroid gland (TG) with systolic or continuous bruit (vascular murmur) over
thyroid due to blood flow
-  cortisol degradation – due to metabolic rate
- Hypercalcemia and decreased PTH secretion - due to excess bone resorption
- diminished sensitivity to exogenous insulin- due to hyperglycemia
(glycogenolysis and gluco-neogenesis)
b) Reproductive:
- oligomenorrhea or amenorrhea due to hypothalamic or pituitary
disturbances
- impotence and decreased libido in men
Thyroid hormones T3 and T4 maintain a fine balance of glucose homeostasis by acting
as insulin agonistic and antagonistic. Hypothyroidism can break this equilibrium and
alter glucose metabolism, which can lead to insulin resistance.

c) gastrointestinal:
- weight loss and associated increase in appetite due to increased catabolism
- increased peristalsis  less formed and more frequent stools - due to
malabsorption of fat
- nausea, vomiting, anorexia, abdominal pain
- increased use of hepatic glycogen stores and adipose and protein stores
- decrease of tissue stores of vitamins
- hyperlipid – acidemia (due to lipolysis)
- excessive sweating, flushing, and warm skin
- heat loss
- hair faint, soft, and straight, temporary hair loss
- nails that grow away nail beds
d) integumentary:
All these signs and symptoms are due to metabolic effect of TH

Grave’s Disease
• Graves' disease (or Flajani-Basedow-Graves disease) is
an autoimmune disease
• To enlarge to twice its size or more (goiter), become
overactive, with related hyperthyroid symptoms
• It can also affect the eyes, causing bulging eyes
(exophthalmos)

Hypothyroidism - deficient production of TH by the thyroid gland and/or 
their action to the tissue
A. Primary hypothyroidism is caused by:
1. congenital defects or loss of thyroid tissue
2. defective hormone synthesis - due to: autoimmune thyroiditis,
endemic iodine deficiency, anti thyroid drugs
B. Secondary hypothyroidism is caused by:
1. insufficient stimulation of the normal gland
2. peripheral resistance to TH
HYPOTHYROIDISM

Hypothyroidism
• Etiology:
• Primary:
• Hashimoto’s thyroiditis with or without goiter
• Radioactive iodine therapy for Graves’ disease
• Subtotal thyroidectomy for Graves’ disease or nodular goiter
• Excessive iodine intake
• Subacute thyroiditis
• Rare causes
• Iodide deficiency
• Goitrogens such as lithium; anti thyroid drug therapy
• Inborn errors of thyroid hormone synthesis
• Secondary: Hypopituitarism
• Tertiary: Hypothalamic dysfunction (rare)
• Peripheral resistance to the action of thyroid hormone

Hypothyroidism
• Clinical features
• Cardiovascular signs:
• Bradycardia
• Low voltage ECG
• Pericardial effusion
• Cardiomegaly
• Hyperlipidemia
• Constipation, ascites
• Weight gain
• Cold intolerance
• Rough, dry skin
• Puffy face and hands
• Hoarse, husky voice
• Yellowish color of skin due to reduced
conversion of carotene to vitamin A
• Respiratory failure
• Menorrhagia, infertility, hyper- prolactinemia
• Renal function:
• Impaired ability to excrete a
water load
• Anemia:
• Impaired Hb synthesis
• Fe deficiency due to:
• Menorrhagia
• Reduced intestinal absorption
• Folate def. due to impaired
intestinal absorption
• Pernicious anemia
• Neuromuscular system:
• Muscle cramps, myotonia
• Slow reflexes
• Carpal tunnel syndrome
• CNS symptoms:
• Fatigue, lethargy, depression
• Inability to concentrate

Hypothyroidism
• Diagnosis:
• A iFT4 and hTSH is diagnostic of primary hypothyroidism
• Serum T3 levels are variable (maybe in normal range)
• +ve test for thyroid auto-antibodies (Tg Ab & TPO Ab) PLUS an
enlarged thyroid gland suggest Hashimoto’s thyroiditis
• With pituitary myxedema FT4 will be i but serum TSH will be
inappropriately normal or low
• TRH test may be done to differentiate pituitary from
hypothalamic disease. Absence of TSH response to TRH indicates
pituitary deficiency
• MRI of brain is indicated if pituitary or hypothalamic disease is
suspected. Need to look for other pituitary deficiencies.
• If TSH is h & FT4 & FT3 are normal we call this condition
subclinical hypothyroidism

Hashimoto’s Thyroiditis
• Hashimoto’s thyroiditis is a common cause of hypothyroidism and
goiter especially in children and young adults.
• It is an autoimmune disease that involves heavy infiltration of
lymphocytes that totally destroys normal thyroidal architecture
• Three different autoantibodies are present: Tg Ab, TPO Ab, and TSH-R
Ab (block)
• It is familial and may be associated with other autoimmune diseases
such as pernicious anemia, adrenocortical insufficiency, idiopathic
hypoparathyroidism, and vitiligo.
• Schmidt's syndrome [combination of autoimmune adrenal
insufficiency (Addison's disease) with autoimmune hypothyroidism
(Hashimoto’s thyroiditis) and/or type 1 diabetes mellitus (T1DM)] and
(rarely) candidal infections.

Hashimoto’s Thyroiditis
• Symptoms & Signs:
• Usually presents with goiter in a patient who is euthyroid or has mild
hypothyroidism
• Sex distribution: four females to one male
• The process is painless
• Older patients may present with severe hypothyroidism with only a small, firm
atrophic thyroid gland
• Transient symptoms of thyrotoxicosis can occur during periods of hashitoxicosis
(spontaneously resolving hyperthyroidism)
• Lab:
• Normal or low thyroid hormone levels, and if low, TSH is elevated
• High Tg Ab and/or TPO Ab titres
• FNA bx reveals a large infiltration of lymphocytes PLUS Hurthle cells
• Complications:
• Permanent hypothyroidism (occurs in 10-15% of young patients)
• Rarely, thyroid lymphoma

THE MAJOR MANIFESTATIONS OF HYPOTHYROIDISM
AND MECHANISM OF THEIR ONSET
- Hypothyroidism generally affects all body systems with the extent of the
symptoms closely related to the degree of TH deficiency.
- The individual develops a low basal metabolic rate, cold intolerance,
slightly lowered basal body temperature
- A decrease in TH   production of TSH  goitre
Increased amount of protein and mucopolysaccharides in dermis   water
binding  nonpitting edema, thickening of the tongue, and the laryngeal
and pharyngeal mucous membranes  thick slurred speech and hoarseness
- Characteristic sign of hypothyroidism is myxoedema 

OTHER MANIFESTATIONS:
a) Neurologic: - confusion, syncope, slowed thinking, memory loss,
lethargy, hearing loss, slow movements
- cerebellar ataxia
Mechanisms involved:
- decreased cerebral blood flow  cerebral hypoxia
- decreased number of beta-adrenergic receptors
b) Endocrine: -  TSH production (in primary hypothyroidism)
-  serum prolactin levels with galactorrhea
-  rate of cortisol turnover, but normal cortisol levels
-  TH   TSH
- stimulation of lactotropes by TRH   prolactin
- decreased deactivation of cortisol

c) Reproductive: -  androgen secretion in men
-  estriol formation in women due to altered
metabolism of estrogens and androgens
- anovulation, decreased libido
- spontaneous abortion
d) Hematologic: -  RBC mass  normocytic, normochromic anemia
- macrocytic anemia due to vitamin B12 deficiency
and inadequate folate absorption
-  basal metabolic rate   oxygen requirement   erythropoietin production

f) Pulmonary: - dyspnoea - due to pleural effusions
- myxedematous changes of respiratory muscles
 hypoventilation
g) Renal: - renal blood flow   GFR  renal excretion of water
total body fluid  dilutional hyponatremia
-  production of EPO
Mechanisms involved: - hemodynamic alteration
- mucinous deposits in tissue
h) Gastrointestinal:  appetite, constipation, weight gain
 absorption of most nutrients
 protein metabolism,  glucose uptake
 sensitivity to exogenous insulin
 concentration of serum lipids

i) Musculosceletal: - muscle aching and stiffness
- slow movement and slow tendon jerk reflexes
- decreased bone formation
and resorption   bone density
- aching and stiffness in joints
- decreased rate of muscle contraction and relaxation
j) integumentary: - dry flaky skin
- dry, brittle head and body hair
- reduced growth of nails and hair
Mechanisms involved: reduced sweat and sebaceous gland secretion

PATHOLOGICAL
MANIFESTATIONS
OF
HYPOTHYROIDISM

Riedel's Thyroiditis
• Riedel's struma is a chronic form of thyroiditis
• Replacement of the normal thyroid parenchyma
by a dense fibrosis
• Inflammatory process infiltrates muscles and
causes symptoms of tracheal compression.

DIABETES MELLITUS

Diabetes mellitus
The term “Diabetes Mellitus” a metabolic disorder of
multiple etiology characterized by chronic hyperglycemia
with disturbance of carbohydrate, fat and protein
metabolism resulting from defect in insulin production,
insulin action, or both.
Diabetes mellitus is a disease marked by high level of
sugar in blood.
Mellitus is Latin for “sweet as honey”. Hyperglycemia
lead to spillage of glucose into the urine.
The effect of diabetes mellitus include long term damage,
dysfunction and failure of various organ.

EPIDEMIOLOGY
Global scenario
Prevalence of diabetes worldwide (WHO global report,2016)
• As per the WHO, diabetes is one of the biggest health concern that
the world is faced with.
• About 422 million people world wide have diabetes, a number likely
to more than double in the next 20 year. That is 1 person in 11.
• The International Diabetes federation estimate more than 371 million
people have diabetes as of 2012.

EPIDEMIOLOGY
• China, India and USA are top three countries with a high
number of diabetes population. Diabetes will be world’s
seventh largest killer by 2030.
Indian scenario
• India is known as “Diabetes capital of world”.
• Diabetes is fast gaining the status of potential epidemic in India
with more than 69.1 million with Type 2 DM diabetic
individual in 2015.
• Indian Council of Medical Research revealed that a lower
proportion of the population is affected in state of northern
India as compared to southern India.

ETIOLOGY/CONTRIBUTING FACTOR
Type 1 Diabetes:
Genetic susceptibility-T1D have susceptibility gene located in the HLA
region of chromosome 6, particularly HLA DR3, HLA DR4, and HLA
DQ locus, CTLA-4 mutation.
Autoimmune destruction of β- cells (autoantibodies to insulin
receptor).
Environmental trigger (virus and infection)
Type 2 Diabetes:
Genetic predisposition- PPARγ mutation, ABCC8 mutation, insulin
gene mutation, insulin receptor mutation.
Obesity and physical inactivity
Insulin resistance
Gestational diabetes
Excessive glucocorticoids(cushing syndrome, and steroid therapy)

ETIOLOGY/CONTRIBUTING FACTOR
Genetic mutation affecting beta cells, insulin, insulin action-
monogenic diabetes MODY (Maturity-Onset Diabetes of the
Young) and NDM (Neonatal Diabetes Mellitus).
Other genetic disease- diabetes occur in people with Down
syndrome, Klinefelter syndrome, and Turner syndrome.
Pancreatitis, cancer and trauma harm the pancreatic beta cells
or impair insulin secretion.

CLASSIFICATION OF DIABETES MELLITUS
Types of Diabetes:
Type 1
Diabetes
Type 2
Diabetes
Gestational
Diabetes

TYPE 1 DIABETES MELLITUS
• Type 1 diabetes mellitus (T1DM) is characterized by loss of
insulin producing beta cells leading to absolute deficiency of
insulin.
• T1DM is increasing worldwide at a rate of about 3% per year.
• The majority of T1DM is of immune mediated variety, where β-
cells loss is a T-cell mediated autoimmune attack.
• T1DM most commonly develops in childhood mainly at
puberty and progress with age.
• Traditionally termed as “Juvenile Diabetes”.
• The treatment of T1DM is the delivery of exogenous insulin,
previously T1DM is known as Insulin Dependent Diabetes
Mellitus.

TYPE 2 DIABETES MELLITUS
• Type 2 Diabetes Mellitus (T2DM) is most common form of
diabetes, accounting for 90% of all cases of diabetes.
• This type of diabetes usually appears in people over the age of
40.
• T2DM is previously called adult onset diabetes or non-insulin
dependent diabetes mellitus.
• It usually begins as insulin resistance, and relative insulin
deficiency.
• T2DM is associated with older age, obesity, family history of
diabetes, history of gestational diabetes, impaired glucose
metabolism.

GESTATIONAL DIABETES
• It results when the body of a pregnant woman does not
secrete excess insulin required during pregnancy leading
to increased blood sugar levels.
• Between 5% to 10% of pregnant woman will develop
gestational diabetes.
• Woman who had gestational diabetes have 20% to 50%
chance of developing diabetes in the next 5-10 years.
• A form of glucose intolerance that is diagnosed in some
woman during pregnancy around third trimester.

NORMAL INSULIN PHYSIOLOGY
• Insulin is anabolic hormone produced by β-cells, found in the
islet of Langerhans in pancreas and it is principle hormone to
regulating carbohydrate and fat metabolism in the body.
Figure 4: Regulation of insulin action (Indian Journal of Endocrinology and
Metabolism,2014)

Figure 4: Action of insulin (Indian Journal of Endocrinology and Metabolism,2014)

PATHOGENESIS OF TYPE 1 DIABETES MELLITUS
• T1DM is a chronic autoimmune disease associated with selective
destruction of insulin producing pancreatic beta cells.
• Pathogenesis of T1DM explained on the basis of 3 mutually
interlinked mechanism: genetic susceptibility, autoimmune factors,
and environmental factor.
T1DM susceptible gene located in the HLA region of chromosome 6
(MHC class II region), HLA DR3, DR4 DQ locus.
Autoantigen glutamic acid decarboxylase, insulin insulinoma-
associated protein and other protein released during beta cell injury
(due to infection), activating T-cell mediated immune response
resulting in beta cell destruction (insulitis).
Three types autoantibodies: Islet cell cytoplasmic antibodies (ICCA),
Islet cell surface antibodies (ICSA), Anti-insulin antibodies (IAA)
has been identified in T1DM patients.

Figure 5: Pathogenesis of T1DM (Beverly T, Pathophysiology of diabetes mellitus, 2009.

PATHOGENESIS OF TYPE 2 DIABETES MELLITUS
• T2DM is characterized by both defect in insulin action
(insulin resistance), and relative insulin deficiency.
• T2DM has greater genetic association than T1DM.
• common in overweight or obese, high level
intracellular triglycerides is increased in obese
persons, FFA are potent inhibitor of insulin signaling.
• Islet amyloid polypeptide (amylin) which forms
protein deposits in pancreatic islet affects the insulin
secretion.
• Glucolipotoxicity cause the impairment in islet cell
function.

Figure 6: Pathogenesis of Type 2 Diabetes (Journal of physiology and pathophysiology, 2004)

CLINICAL MANIFESTATION OF DIABETES
MELLITUS
Type 1 Diabetes (IDDM)
 Glucose in urine (glycosuria)
 Increased urination (polyuria)
 Extreme thirst (polydipsia)
 Increased appetite (polyphagia)
 Extreme weakness & tiredness
 Nausea and vomiting
 Fruity breath
 Blurry vision
 Type 2 Diabetes (NIDDM)
 Increased urination (polyuria)
 Extreme thirst (polydipsia)
 Increased appetite (polyphagia)
 Tingling or numbness in the leg
feet or finger
 Fatigue
 Slow healing of cuts
 Frequent infection of the skin

DIAGNOSIS OF DIABETES MELLITUS
Figure 8: Blood test level for diagnosis of diabetes and prediabetes
(National Institute of Diabetes and Digestive disease, 2012)
Hemoglobin A1C or HbA1c test

DISEASES OF PARATHYROID GLANDS
Hyperparathyroidism
• Primary
Hyperparathyroidism
• Secondary
Hyperparathyroidism
• Tertiary
Hyperparathyroidism
Hypoparathyroidism
• Primary
Hypoparathyroidism
• Secondary
Hypoparathyroidism
• Tertiary
Hypoparathyroidism
Parathyroid
tumors
• Parathyroid
Adenoma
• Parathyroid
Carcinoma

ALTERATIONS OF PARATHYROID FUNCTION
• Hyperparathyroidism is characterized by greater than normal secretion
of parathormone (PTH)
Three types do exist:
Primary - PTH secretion is autonomous and not under the usual feedback control
mechanism
Secondary - compensatory response of parathyroid glands to chronic
hypocalcaemia
Tertiary - loss of sensitivity of hyperplastic parathyroid gland  level of
autonomous secretion of PTH

THE MAIN MANIFESTATIONS OF HYPERPARATHYROIDISM AND
MECHANISMS OF THEIR ONSET
a) Renal colic, nephrolithiasis, recurrent urinary tract infections,
renal failure: they result from Hypercalcemia, calciuria, hyperphosphaturia,
proximal tubular bicarbonate leak, urine pH > 6 (high concentrations of Ca2+
in urine)
Mechanisms :-
Calcium phosphate salts precipitate in alkaline urine in renal pelvis, and in collecting
ducts
b) Abdominal pain, peptic ulcer disease-result from hypercalcemia  stimulated
hypergastrinemia  elevated HCl secretion

c) Pancreatitis - due to hypercalcemia
d) Bone disease - osteitis fibrosa and cystica; osteoporosis results from
PTH hypersecretion  stimulated bone resorption
and metabolic acidosis
e) Muscle weakness, myalgia
- probably due to PTH excess and its direct effect on striated muscle
and on nerves  myopathic changes, suppressed nerve conduction
f) Neurologic and psychiatric alterations
- result from hypercalcemia  neuropathy develops

g) Polyuria, polydipsia
- they result from direct effect of hypercalcemia on renal tubule   responsiveness to
ADH
h) constipation - is due to decreased peristalsis induced by hypercalcemia (smooth muscle
weakness)
i) anorexia, nausea, vomiting - due to stimulation of vomiting centre by hypercalcemia
j) hypertension - due to secondary renal disease

Hypoparathyroidism is characteristic by abnormally low PTH levels
Causes: - damage to the parathyroid gland due to thyroid surgery
Consequences:
a) depressed serum calcium level and increased serum phosphate
level
-  resorption of Ca from GIT, from bone and from renal tubules
-  reabsorption of phosphates by the renal tubules
HYPOPARATHYROIDISM

b) Lowering of the threshold for nerve and muscle excitation
- muscle spasms, hyper-reflexia, clonic - tonic convulsions, laryngeal
spasms – tetany
c) Dry skin, loss of body and scalp hair, hypoplasia of developing
teeth, horizontal ridges on the nails, cataracts, basal ganglia
calcifications (Parkinsonian sy.)
Mechanisms involved: unknown up to now
d) Hyperphosphatemia  inhibition of renal enzyme necessary for
the conversion of vitamin D to its most active form further depression
of serum calcium level by reducing GIT absorption of calcium
HYPOPARATHYROIDISM

ADRENAL HISTOLOGY

The Adrenal Cortex
The adrenal cortex is divided into
three zones which each secrete
different hormones that carry out
specific functions throughout your
body.
1. Zone of glomerulosa
Aldosterone is secreted from this zone which is the major
hormone controlling the sodium and potassium levels, and thus
fluid balance, within your bloodstream, cells and interstitial
fluids. It is also called mineralocorticoids.
3
2
Medulla
Cortex

The Adrenal Cortex
2. Zone of Fasciculata
Cortisol (hydrocortisone) is produced, affects
glucose, amino acid and fat metabolism, which is
called glucocorticoids. Cells of this zone are
arranged into fascicles separated by venous
sinuses.
3. Zone of Reticularis
Dehydroepiandrosterone (DHEA)-precursor for androgen is
synthesized. This zona manufactures an ancillary portion of sex
hormones for each sex and also produces male hormones in
women and female hormones in men to keep the effects of the
dominant sex hormones in balance .
3
2
Medulla
Cortex

Adrenals
Zona Reticularis
Sex steroids (androgens)
Zona Fasciculata
Glucocorticoids (Cortisol)
Glucose homeostasis and many others
Zona Glomerulosa
Mineralocorticoids (Aldosterone)
Na+, K+ and water homeostasis
Medulla: “Catecholamines”
Epinephrine, Norepinephrine, dopamine
CORTEX

Adrenal Cortex
• The cortex synthesizes & secretes 30+ different
steroids.
• Glucocorticoids
• Mineralocorticoids
• Androgens

Stress
Anterior pituitary- to secrete ACTH and stimulate
the target cells on adrenal cortex to secrete cortisol
Increased metabolic activities and
thereby stress is managed
Hypothalamus
NEGATIVE FEEDBACK LOOP
NEGATIVE FEEDBACK

 There are four major categories of stress:
1. Physical stress: such as overwork, lack of sleep, athletic
overtraining.
2. Chemical stress: environmental pollutants, allergies to foods, diets
high in refined carbohydrates, endocrine gland imbalances.
3. Thermal stress: over-heating or over-chilling of the body
4. Emotional and mental stress
STRESS
 Adrenal glands are the anti-stress glands of the body.

Stress: During stress cortisol must
simultaneously provide more blood
glucose, mobilize fats and proteins for
a back-up supply of glucose, modify
immune reactions, heartbeat, blood
pressure, brain alertness and nervous
system responsiveness.
If cortisol level cannot rise in response
to these needs, maintaining your body
under stress is nearly impossible.

Adrenals
Kidney
Posterior
Pituitary Gland
Hypothalamus
Anterior
Pituitary Gland
ACTH
Stress
Circadian
rhythm
CRH
(-)
Glucocorticoids,
Catecholamines, etc.
Muscle:
Net loss of amino
Acids (glucose)
Liver:
Deamination of
proteins into amino
acids,
gluconeogenesis
(glucose)
Fat Cells:
Free fatty
acid
mobilization
Heart rate:
Increased
Immune
system:
altered
HYPOTHALAMOPITUITARY ADRENAL (HPA) AXIS

Disorders of Adrenal Glands
• Hyperadrenalism (Adrenocortical Hyper function)
• Cushing’s Syndrome
• Conn’s Syndrome
• Adrenogenital Syndrome
• Hypoadrenalism (Adrenocortical insufficiency)
• Primary adrenocortical insufficiency (Addison’s Disease)
• Secondary adrenocortical insufficiency
• Hypoaldosteronism
• Tumours of Adrenal Glands
• Adrenocortical Tumours
• Cortical Adenoma
• Cortical Carcinoma
• Medullary Tumours
• Benign Tumours
• Pheochromacytoma
• Myelolipoma
• Tumours arising from nerve cells
• Neuroblastoma
• Ganglioneuroma

Cushing disease/ syndrome
• Cortisol Excess
• Pathophysiology
• Diurnal rhythm
• h in AM
• Normal secretion of cortisol h in times of stress
• In Cushing's, cortisol is hyper secreted without regard
to stress or time of day.

• Etiology/ Types of Cushing
• Pituitary Cushing’s syndrome
• Adrenal Cushing’s syndrome
• Ectopic Cushing’s syndrome
• Iatrogenic Cushing’s syndrome

• Etiology
• Iatrogenic (Caused by treatment or diagnostic procedure)
• Prolonged use of glucocorticoid meds for inflammatory
disorders
• Rheumatoid arthritis
• COPD
• Females > Male

The possible causes of Cushing Syndrome

• Signs & Symptoms
• Adiposity
• Deposits of adipose tissue in the face, neck & trunk
• Moon shaped face
• Buffalo hump
• Weight gain
• Na & H20 retention
• K+ is lost- Hypokalemia
• Purple striae on the abdomen
• Hirsutism

• Signs & Symptoms
• Boys = early onset of puberty
• Girls = masculine characteristics
• Fatigue, muscle weakness, sleep disturbance, amenorrhea, i
libido, irritability, emotional labiality
• Petechiae (a small red or purple spot caused by bleeding into the
skin.)
• Eccymoses (injury to tissues with skin discoloration and without
breakage of skin; called also bruise. Blood from the broken vessels
accumulates in surrounding tissues, producing pain, swelling, and
tenderness, and the discoloration is the result of blood seepage just
under the skin.)
• decreased wound healing
• Swollen ankles

Complications
• h calcium reabsorption from the bone leading to
osteoporosis & pathologic fractures
• Cortisol causes insulin resistance and ↑hepatic
gluconeogenesis and insulin resistance
• Leads to glucose intolerance and diabetes mellitus

Complications
• Frequent infections & slow wound healing
• Suppressed inflammatory response can mask severe
infections
• Cortisol is an immunosuppressive
• Deceased ability to handle stress
• Psych problems i.e. mood swings

• Diagnosis
• Plasma Cortisol level
• ACTH level
• Adrenal angiography

Adrenalectomy

Causes of Adrenal insufficiency
• Addison disease
• Congenital adrenal hyperplasia
• Infection (TB, sepsis)
• Adreno-leuko-dystrophy

Addison’s Disease
• Autoimmune disorder
• Isolated or associated with other autoimmune disease
• Presents with tiredness, weight loss, skin pigmentation
• Aldosterone & cortisol low, high ACTH, high renin
• Low sodium , high potassium
• ACTH stimulation test
• Adrenal antibodies

Addison’s Disease
• Pathophysiology
• 90% of adrenal gland destroyed
• Autoimmune disease
• Primary- ACTH may be high
• Secondary- ACTH will be low

Addison’s Disease
Etiology :-
• Primary- Bilateral Adrenalectomy
• Secondary-i ACTH from pituitary & i hypothalamus
stimulation
• Prolonged use of corticosteroid Rx Low ACTH  Low
hormonal release from adrenal gland
• *** esp. at risk if drugs abruptly decreased
• Taper dose

Addison’s Disease: Signs & Symptoms
• Hypotension
• Lack of aldosterone 
• Na+ & H2O loss
• K+ reabsorption 
• Tachycardia
• Orthostatic hypotension
• Bronze coloration of skin
(Hyperpigmentation)
• Hypoglycemia
• Vitiligo
• Fatigue, muscle weakness
• Weight loss
• Crave salty foods
• Decreased Tolerance for stress-
Anxious, Irritable, Confused
• Pulse
• Weak
• GI upset
• N/V
• Anorexia

Addison’s disease: Complications
• Adrenal crisis
• Acute Addison’s disease
• May occur
• Trauma
• Surgery
• Stress
• Abrupt withdrawal of cortisone meds
• Na+ & H20 loss
• Hypotension
• Dehydration
• Tachycardia

Hypo-function Hyperfunction
Usual
treatment
Glucocorticoids
Mineralocorticoid
Restore fluid
Alter steroid Rx
Surgery
Diagnosis Fluid volume deficit Fluid volume excess
Glucose intolerance
Diet high Na+
low K+
low Na+
high K+

Disorders of Endocrine Systems: Mechanisms and Pathophysiology

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