ENDOCRINOLOGY

Elizabeth H., MD.

Pathologist
 Course Outline:
I. Introduction in Endocrine Pathophysiology
II. Pituitary Gland Disorders
III. Parathyroid Gland Disorders
IV. Thyroid Gland Disorders
V. The Endocrine Pancreas
VI. Adrenal Glands
 INTRODUCTION
• What is endocrine system?
– Group of organs that maintain body homeostasis
– Signaling by extracellular secreted molecules
• Hormones are molecules secreted by various endocrine
glands and are released into the circulation to act on various
site.
• These hormones can be classified according to the distance
over which the signal acts as,
– Autocrine,
– Paracrine, or
– Endocrine
Action on cell Hormones can be
surface receptors: classified into

• Growth hormone
• Insulin
• Epinephrine
• Histamine Action on intracellular
receptors:
- In the cytosol
- in the nucleus

-Steroids:
- Estrogen
- Progesterone
- Glucocorticoid
- Thyroxin
- Retinoid acid
 Chemical Nature of Hormones
• Hormones are derived from other molecules used
by the body
 Amino acid derivatives: thyroxin
 Modified amino acid: epinephrine
 Peptide: ACTH
 Glycoprotein: Growth hormone, luteinizing
hormone
 Cholesterol derivatives: sex hormone,
glucocorticoids, Vitamin D
 Endocrine
• Functions by release of hormones (secreted
molecules) that travel via blood to distant
organs
• "Feedback" mechanisms control hormone
release.
– Increased activity of the target tissue often
downregulates the activity of the gland that
secretes the stimulating hormone.
 "Feedback" mechanisms
• Negative feedback loops
Control an increase or a decrease in hormone
production (inverse relationship)
– Example - ↑calcium, ↓PTH; ↑ACTH, ↓cortisol
• Positive feedback loops
Positive relationship
Example—In the proliferative phase of the
menstrual cycle, ↑estrogen, ↑LH > FSH which
is the stimulus for ovulation
Assessment of endocrine function
• Two ways:
1. Measurement of basal hormone levels; and
2. Dynamic endocrine testing
 Basal hormone level measurement:
• Measures blood and/or urine levels of active, precursor, or
breakdown product of hormones
• Very high/very low levels (together with clinically overt disease)
usually helpful in diagnosing suspected endocrine dysfunction
• But, measurement of basal levels may not distinguish the
affected person from normal population…because:
- Extensive overlap between “normal” & “abnormal” levels
- Short half-lives of hormones
- Episodic release of hormones due to physiologic diurnal rhythms
- Intermittent secretion by tumors
- Etc.
 Dynamic endurance testing
• This approach is based on our knowledge of
the physiologic control mechanism of the
endocrine system (e.g., dehydration test)
• Divided into:
I. Stimulation testing
II. Suppression testing
 Endocrine Diseases
• Divided into
– Diseases of overproduction or underproduction of
hormones (hyperfunction or hypofunction
respectively)
– Diseases associated with the development of mass
effect
 Endocrine Hypofunction causes
Autoimmune destruction
most common cause of hypofunction
 Examples—Addison disease, Hashimoto thyroiditis
 Infarction
Example—Sheehan postpartum necrosis, Waterhouse-
Friderichsen syndrome
Decreased gland stimulation
Example—decreased thyroid-stimulating hormone in
hypopituitarism causes a decrease in thyroid production of
thyroxine
Enzyme deficiency, infection, metastasis, congenital
disorder
 Evaluate hypofunctioning disorders
• Endocrine gland with hypofunction: use
stimulation tests
– Example—ACTH stimulation test is used in the
workup of hypocortisolism to see if hypocortisolism
is due to adrenal hypofunction or pituitary/
hypothalamic hypofunction
– Example—gonadotropin-releasing hormone (GnRH)
stimulation test to distinguish hypothalamic
dysfunction causing amenorrhea (lack of menses) or
hypopituitarism
Causes of endocrine hyperfunction
• Adenoma
– most common
• Acute inflammation
– causes release of stored hormone,
• Hyperplasia,
• Cancer
 Evaluate hyperfunctioning endocrine
disorders
• Endocrine gland with hyperfunction: use
suppression tests
– Eg. Dopamine analogues can suppress prolactin
secretion from a prolactinoma.
– Eg. High-dose dexamethasone can suppress ACTH
production in pituitary Cushing syndrome causing
a decrease in cortisol.
PITUITARY
The Hypothalamus Gland
• Located in the lower
brain, it is the sole link
between the endocrine
and nervous systems,
wrapped around the
third ventricle and
containing two sets of
neurosecretory cells.
• Neurosecretory neurons
secrete hormones that
control the pituitary
gland, located directly
below it; together they
control multiple
hormones.
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 Hypothalamic Hormones:
Produces ADH and oxytocin.
Secretes:
Thyrotropin-releasing hormone (TRH)
Gonadotropin-releasing hormone (GnRH)
Growth hormone-releasing hormone (GHRH)
Corticotropic-releasing hormone (CRH)
Somatostatin
Dopamine
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TRH GnRH
Tropic hormone that Released at the onset of
targets the anterior lobe. puberty.
Stimulates the release of: Increases FSH and LH
TSH (Thyroid- Also increases estrogen and
progesterone in females,
stimulating hormone)
and testosterone in males.
Prolactin
GHRH
• Targets anterior pituitary.
• Stimulates release of GH.
Somatostatin
•Targets anterior pituitary.
•Inhibits the release of both GH
and TSH.
•Can be secreted by pancreas
and intestine
CRH
• Targets anterior pituitary.
• Stimulates release of ACTH.
• Also made in the placenta;
may determine length of
pregnancy.
Dopamine
•Targets anterior pituitary.
•Inhibits prolactin release.
The pituitary gland is a small, bean-shaped structure that
lies at the base of the brain within the confines of the sella
turcica.
It is intimately related to the hypothalamus, with which it
is connected by both a stalk, composed of axons extending
from the hypothalamus, and a rich venous plexus
constituting a portal circulation.
• The pituitary is composed of two
morphologically and functionally distinct
components: the anterior lobe
(adenohypophysis) and the posterior lobe
(neurohypophysis).
 Diseases of the Pituitary
• Divided into those that primarily affect the
anterior lobe and those that primarily affect
the posterior lobe.
• Rarely, signs and symptoms of pituitary
disease may be caused by excess or lack of the
hypothalamic factors, rather than by a primary
pituitary abnormality.
• Signs and symptoms of pituitary disease
– Hyperpituitarism
– Hypopituitarism
– Local mass effects
 Hypopituitarism
• Infarction: panhypopituitarism
• Types of pituitary dysfunction
– (1) Primary hypopituitarism (pituitary dysfunction)
• Approximately 75% of the gland must be destroyed.
– (2) Secondary hypopituitarism (hypothalamic
dysfunction)
• Decreased hypothalamic releasing factors
 Causes of hypopituitarism
• Nonfunctioning (null)
pituitary adenoma
– Most common cause of
hypopituitarism in adults
– Microadenoma <10 mm;
macroadenoma >10 mm
– Association with multiple
endocrine neoplasia
(MEN) I syndrome
 Causes of hypopituitarism
• Craniopharyngioma
– Most common cause of hypopituitarism in
children
– Benign pituitary tumor derived from Rathke
pouch remnants (derived from the oral ectoderm
develops into anterior pituitary)
– Extends into the sella turcica and destroys the
gland
Sheehan syndrome  Panhypopituitarism
parturition

blood loss

hypotension
(hypovolemic shock)

pregnancy

ischemic
necrosis
 Causes of hypopituitarism
• Pituitary apoplexy
– Most often due to hemorrhage/infarction of a preexisting pituitary adenoma
– Predisposing factors - trauma, pregnancy (Sheehan postpartum necrosis, a
nontumorous cause),
• Sickle cell anemia (HbSS)
– Pituitary infarction from vascular occlusion by sickled cells
• Lymphocytic hypophysitis
– autoimmune destruction during/after pregnancy
• Empty sella syndrome
– Radiologic studies show an empty sella turcica.
– Primary and secondary types
• Hypothalamic dysfunction
 Causes of hypopituitarism
CONGENITAL BENIGN MALIGNANT
• Pituitary adenoma • Metastatic disease
• Craniopharyngiom • Lymphoma
a • Plasmacytoma
• Meningioma • Germ cell tumors
• Optic glioma
GRANULOMATOUS CYSTS VASCUALR DISORDERS
• Sarcoidosis • Rathke cleft cyst • Infarction
• Histiocytosis X • Dermoid cyst (ischemic necrosis
• Eosinophilic • Epidermoid cyst & Sheehan
granuloma syndrome)
• Aneurysm
AUTOIMMUNE DISEASES INFECTIONS OTHERS
• Vasculitis • Tuberculosis • Traumatic
• Meningitis • Radiation
• Surgery
• Less common causes of anterior pituitary
hypofunction, including inflammatory lesions
such as sarcoidosis or tuberculosis, trauma,
and metastatic neoplasms involving the
pituitary
• The clinical manifestations of anterior pituitary
hypofunction depend on the specific
hormones that are lacking.
Hyperpituitarism and Pituitary Adenomas

• Cause of hyperpituitarism
– adenoma arising in the anterior lobe
• most common cause
– Hyperplasia
– Carcinomas of the anterior pituitary,
– Secretion of hormones by some extrapituitary
tumors,
– Certain hypothalamic disorders.
 Pituitary adenomas
• Classified on the basis of hormone(s) produced by the
neoplastic cells, which are detected by
immunohistochemical stains performed on tissue sections
• Can be functional (i.e., associated with hormone excess
and clinical manifestations there of) or nonfunctioning (i.e.,
demonstration of hormone production at the tissue level
only, without clinical manifestations of hormone excess).
• Usually pituitary adenomas composed of a single cell type
and produce a single predominant hormone, but there are
some exceptions.
 Pituitary adenomas
• Most occur as sporadic (i.e., nonfamilial) lesions.
– In about 5% of cases, inherited predisposition
• Are designated, as microadenomas and macroadenomas
• Nonfunctioning and hormone-negative adenomas are
likely to come to clinical attention at a later stage and
are, therefore, more likely to be macroadenomas than
are lesions associated with endocrine abnormalities.
• Nonfunctioning adenomas may cause hypopituitarism as
they encroach on and destroy adjacent anterior pituitary
parenchyma.
 PATHOGENESIS
• Genetic abnormalities associated with pituitary
adenomas:
• Guanine nucleotide–binding protein (G protein)
mutations
– Critical role in signal transduction, transmitting
signals from cell surface receptors to intracellular
effectors , which then generate second messengers
– A stimulatory G protein (Gs) that has a pivotal role in
signal transduction in several endocrine organs,
including the pituitary.
• Arise as a consequence of an inherited predisposition. Four
genes have been identified thus far as a cause of familial
pituitary adenomas:
– MEN1,
• responsible for multiple endocrine neoplasia syndrome type 1 (MEN-1)
– CDKN1B,
• The product of the gene is the cell cycle checkpoint regulator p27 or KIP1;
germline mutations of CDKN1B are responsible for a subset of patients with a
“MEN-1 like” syndrome who lack MEN1 abnormalities.
– PRKAR1A, and
– Aryl hydrocarbon receptor–interacting protein (AIP).
Germline inactivating
• often develop GH-secreting adenomas at a younger age (before 35 years)
than that typical for sporadic GH adenoma patients.
• Mutations of TP53 in pituitary adenomas are associated with a
propensity for aggressive behavior, such as invasion and
recurrence.
 Prolactinomas
• Prolactinomas are the most common type of
hyperfunctioning pituitary adenoma.
• Prolactin is demonstrable within the cytoplasm of the
neoplastic cells by immunohistochemical techniques.
 Clinical findings
Women
• Secondary amenorrhea
(loss of menses)
– Prolactin inhibits GnRH.
– Decrease in FSH/LH causes
decrease in estrogen
synthesis in the ovaries.
• Galactorrhea
Men
• Impotence
• Loss of libido (sexual desire)
– due to decrease in
testosterone from decrease in
serum LH.
• Headache
– larger in men than in women
• Not enough estrogen-
dependent breast tissue to
produce galactorrhea
 Laboratory findings
• Serum prolactin level is usually >200 ng/mL.
• Decreased serum FSH and LH
– Due to decreased GnRH
– Decreased estrogen and progesterone due to
decrease in FSH/LH, respectively
 Other causes of Hyperprolactinemia

• Pregnancy,
• High-dose estrogen therapy,
• Renal failure,
• Hypothyroidism,
• Hypothalamic lesions, and
• Dopamine-inhibiting drugs (e.g., reserpine).
• Any mass in the suprasellar compartment
(stalk effect.)
 Growth Hormone Producing (Somatotroph
Cell) Adenomas
• Second most common type of functional pituitary
adenoma
• Including those that produce a mixture of growth
hormone and other hormones (e.g., prolactin)
• Quite large by the time they come to clinical attention.
• Persistent hypersecretion of growth hormone
stimulates the hepatic secretion of insulin-like growth
factor I (somatomedin C), which causes many of the
clinical manifestations.
 Microscopic
• Composed of densely or sparsely granulated
cells, and immunohistochemical staining
demonstrates growth hormone within the
cytoplasm of the neoplastic cells. Small
amounts of immunoreactive prolactin often
are present as well.

A: A DGGH cell adenoma showing large cells with eosinophilic, granular cytoplasm,
and a central nucleus with prominent nucleoli (H & E). B: The tumor shows intense
and diffuse immunostaining for GH.
• Functions of GH
– Stimulates liver synthesis/release of insulin-like
growth factor (IGF)-1
• Enhanced Protein Synthesis
• Stimulation of Skeletal Growth
• Cell Proliferation
• Immunomodulation
– Stimulates gluconeogenesis and amino acid (AA)
uptake in muscle
– Antinatriuretic action (retains sodium)
 Clinical findings
• Children develop
gigantism.
– ↑linear/lateral bone
growth in children;
epiphyses not fused
 Clinical findings
• Adults develop acromegaly
– Increased lateral bone growth (e.g., hands, feet, jaw)
• No linear growth because the epiphyses are fused.
– Prominent jaw
• Spacing between the teeth
– Frontal bossing
– Enlarged frontal sinus
– Macroglossia (large tongue),
– DCMP
• (most common cause of death)
ACROMEGALY:
(excess
somatotropin [GH]
AFTER
epiphyseal closure)
Clinical findings Diagnosis
• DM • Imaging with CT scan, MRI
• Hypertension, (best study)
• Organomegaly, • Suppression tests
• Myopathy,
• Headache,
• Arthritis,
• Osteoporosis,
• Nelson syndrome,
– results from loss of the inhibitory effect of adrenal
corticosteroids on a preexisting corticotroph
microadenoma.
• Because the adrenals are absent in persons with
Nelson syndrome, hypercortisolism does not develop.
– Patients present with the mass effects of the pituitary
tumor.
– Melanocyte-stimulating hormone (MSH),
hyperpigmentation also may be a feature.
 Clinical
Manifestations:
General Cardiovascular Psychiatric
Central Obesity Hypertension Depression
Cutaneous Musculoskeletal Metabolic
Glucose
Facial Plethora Proximal Myopathy
Intolerance
Hirsutism Osteopenia Diabetes Mellitus
Wide Striae
Osteoporosis Hypokalemia
(>1cm)
Bruising Back Pain Hypercalcuria
Supraclavicular
Muscle Wasting
Fullness
Other Anterior Pituitary Neoplasms
• Gonadotroph (luteinizing hormone [LH]–producing
and follicle-stimulating hormone [FSH]–producing)
adenomas
– Secrete hormones inefficiently
– detected when the tumors have become large enough to
cause neurologic signs and symptoms
• Thyrotroph (thyroid-stimulating hormone [TSH]–
producing) adenomas
– for about 1% of all pituitary adenomas
– a rare cause of hyperthyroidism.
Other Anterior Pituitary Neoplasms
• Nonfunctioning pituitary adenomas
– Comprise both clinically silent counterparts of the
functioning adenomas and true hormone-negative
(null cell) adenomas;
– Constitute approximately 25% of all pituitary
tumors.
– Characterized by mass effects.
• Pituitary carcinomas are exceedingly rare.
– always demonstrate distant metastases
 POSTERIOR PITUITARY SYNDROMES
• The hypothalamic neurons produce two peptides:
antidiuretic hormone (ADH) and oxytocin; and stored in
axon terminals in the neurohypophysis and released into
the circulation in response to appropriate stimuli.
• a. Stores antidiuretic hormone (ADH)
– ADH controls total body water.
– Presence of ADH induces concentration of urine.
• b. Releases oxytocin after suckling
– Primarily produced in the paraventricular nucleus in the
hypothalamus
– Causes milk ejection and uterine contractions
• The clinically important posterior pituitary
syndromes involve ADH production.
– diabetes insipidus and secretion of inappropriately
high levels of ADH.
THANK YOU!