NERVOUS AND ENDOCRINE SYSTEMS • Paracrine – act on neighboring cells

• Act together to coordinate functions of all body systems • Autocrine – act on the same cell that secreted them (ex.
in response to changing internal (low Ca 2+in blood) & Ovaries, release progesterone & estrogen affecting
external stimuli to normalize or maintain homeostasis ovaries itself)
• The hypothalamic-pituitary-adrenal axis (HPA axis) links
the central nervous system to the endocrine system FORMS OF SIGNALLING
• The HPA axis affects physiologic functions through the • paracrine signaling, endocrine signaling, autocrine
release of inhibitory (limit prdxn of hormones), releasing signaling, and direct signaling across gap junctions.
(enhance), & tropic hormones (Produced by A. Pituitary) • The main difference between the different categories of
signaling is the distance that the signal travels through
the organism to reach the target cell.
• not all cells are affected by the same signals.

Nervous system
• Nerve impulses/ Neurotransmitters
• Faster responses, briefer effects, acts on specific target
Endocrine system
• Hormone – mediator molecule released in 1 part of the
body but regulates activity of cells in other parts
• Slower responses, effects last longer, broader influence •

• Paracrine signaling: a form of cell signaling in which the

2 types of glands
target cell is near (para = near) the signal-releasing cell
• Paracrine signals move by diffusion through the
extracellular matrix.
• These types of signals usually elicit quick responses that
last only a short amount of time.
• To keep the response localized, paracrine ligand
molecules are normally quickly degraded by enzymes or
removed by neighboring cells.

• Endocrine Signaling are Signals from distant cells

Endocrinology • they originate from endocrine cells.
• Is Intercellular Chemical Communication • signals usually produce a slower response, but have a
• is about communication systems & information transfer. longer-lasting effect.
• Is the study of the glands that produce hormones and the • The ligands released in endocrine signaling are called
effects of hormones on organs hormones.
• Endo=within; crine= to secrete
• ductless glands • Autocrine signals means the signaling cell and the target
• Release secretions into the tissue fluid cell can be the same or a similar cell
• This type of signaling often occurs during the early
Hormones development of an organism to ensure that cells
• to excite; chemical messengers develop into the correct tissues and take on the proper
• regulate the activity of other cells function.
• produced by specialized cells (ex. Tropic cells in A. pituitary) • Autocrine signaling also regulates pain sensation and
• Blood transfers hormones to target sites inflammatory responses.
• Target cell have specific receptors that bind to and carry out • if a cell is infected with a virus, the cell can signal itself
the action of a hormone. to undergo programmed cell death, killing the virus in
the process. In some cases, neighboring cells of the
Hormone secretion is dictated by- same type are also influenced by the released ligand.
• circadian rhythms/diurnal patterns (moment in time where in
the hormone is higher in volume. Ex. Menstrual period) Hormonoids (tissue hormones)
• pulsatile patters (prodxn in a regular pattern. Ex growth • compounds that are produced not in glands but in
hormone) different tissues and regulate metabolic processes on the
• cyclic patterns local level, but some of them (serotonin, acetylcholine)
• levels of chemical substances (ex. Abnormal levels will serve enters blood and regulate processes on the organism
as stimulus. Ex in blood sugar conc. Body responses level.

Hormone types Hormone producing cells

• Circulating – circulate in blood throughout body • Arranged in cords & branching network=maximizes
• Local hormones – act locally contact between them & capillaries surrounding them
 Specific stimulus for hormones secretion: Chanel-linked receptors: would bind ligand and open a
• nervous impulse (fast approaching car= adrenaline) channel that’ll allow ions to pass through that would
• concentration of the certain compound in blood passing interact with the phospolipid F.A tails
through the endocrine gland

Hormones control several major processes

 Reproduction
 Growth and development
 Mobilization of body defenses
 Maintenance of much of homeostasis
 Regulation of metabolism
CONFORMATIONAL CHANGE: G-protein link receptors would
CHEMISTRY OF HORMONES
show this change in protein structure that allows ions like Na,
Mechanism of hormone action
Ca, Mg and H to pass through
• All major hormones circulate to all tissues but influences the
activity of only those tissue cells that have receptors for it.
• Hormones bring about their characteristic effects by altering
target cell activity.

G PROTEIN RECEPTORS: The activated form will then interact

with an ion channel or enzyme in membrane. G link receptors
Synergism- coupled with other hormones expression is more have 7 transmembrane domains each wit its own
defined. (ex. Epinephrine, glucagon and cortisol against low extracellular domain and g-protein binding site
blood sugar).
Permissiveness- one hormone may not be able to function,
another may have low effect but together will make full
expression (ex. Thyroid h. + epinephrine= large F.A released)
THE FINAL EFFECTS OF HORMONES ACTION
1. Change the permeability of cell
membrane, accelerate the penetration 3. Affect the activity of enzymes through
of substrates, enzymes, coenzymes into the messengers (cAMP). (Hormones that
the cell and out of cell. can not penetrate the membrane).
2. Acting on the allosteric centers affect 4. Act on the genetic apparatus of the cell
the activity of enzymes (Hormones (nucleus, DNA) and promote the synthesis
penetrating membranes). of enzymes (Steroid and thyroid hormones).

How does a hormone communicate with its target cell?

• This depends on the chemical nature of hormone and the
cellular location of the receptor.
ENZYME-LINKED RECEPTORS: with intracellular domain ass.
Hormone Receptors With enzyme. Normally have large extra and intracellular
• are cellular proteins that bind with high affinity to hormones domains but the spanning region consists of a single a-helical
& are altered in shape & function by binding. region of a peptide bond
• Binding to hormone is noncovalent & reversible.
• Hormone binding will alter binding to other cellular proteins
& may activate any receptor protein enzyme actions.

Kinds of hormone receptors

A) Cell surface receptors- peptide, proteins & prostaglandin
 also called membrane receptors, transmembrane receptors B) Internal receptors- steroid & thyroid hormones
 are embedded in the membranes of cells.
 act in cell signaling by receiving (binding to) extracellular Internal receptors are also
molecules. called intracellular or
 allow communication between the cell and the extracellular cytoplasmic receptors. They are
space. found in the cytoplasm of the
 Each cell-surface receptor has three main components: cell and respond to hydrophobic
 an external ligand-binding domain (extracellular domain) ligand molecules that are able
 a hydrophobic membrane-spanning region to travel across the plasma
 an intracellular domain inside the cell. membrane. Once inside the cell, many of these molecules
bind to proteins that act as regulators of mRNA synthesis to
mediate gene expression.
Transducers
• proteins that convert the information in hormonal Tropic hormones
signals into chemical signals understood by cellular • Target other endocrine glands
machinery (translation) • are important to understanding chemical
EFFECTORS coordination.
• are the enzymes & other proteins that convert the
transduced hormonal signal into biochemical changes Hormones according to structure- most are peptide (stored
that generate the cellular response to hormone binding. in secretory
granules and are
Can single cells make or sense more than one hormone at a prom placenta,
time? pancreas and
Yes, cells can make multiple hormones, even of differing parathyroid
chemical classes, & they can sense multiple signals -- & glands. GH,
integrate them -- all at once. (ex. Ovarian granulosa cells= Insulin, PTH,
inhibin, estradiol and androstinine, also respond to FSH a GH) neptine, ACTH, prolactin, ADH, calcitonin, endorphin,
glucagon, hypothalamic H, lipotropines, MSH, oxytocin,
How do hormone levels vary? somatostatin, thymusine and TRH) and polypeptide, water
Hormone levels rise & fall due to synthesis (prdxn), soluble and circulate freely but short half-lie of 10-30 min and
degradation and clearance. Target cell binding accounts for attach to cell membrane receptors and activate 2nd
only small fraction of removal of hormone from circulation. messenger inside the cell. Glycoprotein hormones (FSH, LH,
Target cell receptor, transducer and effector cells can also TSH) , half-life is a few minutes and don’t bind to other
change with sex, age, physiological/developmental stage. proteins in blood. Amine Hormones (T3, t4 nor and
These will also vary among cell types resulting to different epinephrine) derived from tyrosine. They exert their actions
hormone tissue sensitivity by activating 2ndary messenger system. They cross cell
membrane and binds with specific intracellular receptor and
Category of hormones: nuclear DNA. in cell Thyroid hormones-lipid soluble, half-life=
According to source few days. Catecholamine – water soluble, half-life= few mins.
Steroid (cortisol, aldosterone, testosterone, progesterone,
estrogen) derived from cholesterol, and quickly secreted from
cell. But being lipophlic, there’s no storage, production is as
needed basis, require protein to transport precursors in
cytoplasm to the blood since they are non-water soluble.
Arachidonic acid/ sinusoids (prostaglandins, leukotrienes,
prostacyclins and thromboxanes), derived hormones form
polyunsaturated FA, metabolized soon after produced and
are typically localized (paracrine or autocrine).Types of
eicosanoids are leukotrienes-signaling inflammatory
chemicals and allergic reaxns, prostaglandins have multiple
targets and effects (increasing blood pressure and expulsive
uterine contractions at birth to enhance blood clotting, pain.
Hormone control
• Regulated by stimuli
• Signals from nervous system [ neural]
• Chemical changes in the blood [humoral]
• Other hormones [ hormonal]
• Most hormonal regulation by negative feedback
 Humoral stimuli o 2 other hormones oxytocin & ADH are not tropic
• Humor means various body fluids hormones (direct effectors).
• Secretion of hormones in direct response to changing
blood levels of certain ions and nutrients. Hypothalamus Releasing Hormones: Secretion
• This is different from hormonal stimuli o Is influenced by emotions
• This is the simplest endocrine control o Can be influenced by the metabolic state of the
individual
Neural stimuli o is delivered to the anterior pituitary via the
• In few cases, nerve fibers stimulate hormone release. hypothalamic-hypophyseal portal system- connects brain
• The classic example is response to stress, in which to A. pituitary. Made up of 2 (in median eminence and A.
sympathetic nervous system stimulates the adrenal pituitary) capillary beds. Its transports and exchange
medulla to release catecholamines. hormones to allow fast communication of both glands.
o Usually initiates a (The secretion is influenced by) three-
Hormonal stimuli hormone sequence
• This is best exemplified by the hypothalamic-pituitary-
target endocrine organ

What does concentration of circulating hormone in blood

reflect?
Rate of release- Speed at which hormone is inactivated and
removed from the body

HYPOTHALAMUS AND PITUITARY

Hypothalamus
o Integrates functions that maintain chemical and temperature
homeostasis
o Controls the release of hormones from the anterior and
posterior pituitary
o Neurosecretory cells of the hypothalamus produce
hormones
o Releasing hormones stimulate the anterior pituitary
(adenohypophysis) to secrete hormones.
o Inhibiting hormones prevent the anterior pituitary from
secreting hormones.
Hormones are transported down the axon and released via PITUITARY GLAND- Hypophysis (to spit mucus), grape-sized,
nerve endings by pulses hangs from a stalk from hypothalamus and protected by
o Hormones of the hypothalamus are called hypophysiotropic sphenoid bone. Function is detected in 7-9 week of gestation
hormones- they are also found in intestine, CNS and pancreas o “Master gland” : without pituitary there is:
Hormone meaning Action but
acronym * cessation of growth
TRH Thyrotropin-releasing Releases TSH & functions * profound alterations in intermediary metabolism
hormone prolactin
GnRH Gonadotropin- Releases LH & FSH
outside * failure of gonadal, thyroidal, adrenal functions
releasing hormone
pituitary and
CRH Corticotropin-releasing Releases ACTH
hormone hypothalam Change of concept about pituitary
GHRH Growth hormone- Releases GH
releasing hormone us are o Rather than a “master gland”, it is appropriately
PRH Prolactin-releasing poorly
hormone recognized as transponder that translates neural
Somatostatin Inhibits GH, TSH understood. input into a hormonal product.
release
Dopamine Inhibits prolactin
release
 o Distinguishing features : feedback loops, pulsatile • The largest portion of the gland. originates from Rathke’s
secretions, diurnal rhythms, and environmental or pouch, an evagination of buccal ectoderm that
external modification of its performance progressively extends upward and is eventually
enveloped by the sphenoid bone.
The Hypophyseal Portal System • Synthesizes various hormones in various specific cell
The creation of populations
the median
eminence, Adenohypophysis hormone can be classified as
the inferior o tropic ( actions are specific for another endocrine glands)
portion of the o direct effectors ( act directly on peripheral tissues) GH
hypothalamus, has direct effects on substrate metabolism in numerous
tissues and also stimulates the liver to produce growth
and the
factors that are critical in enhancing linear growth
pituitary
stalk is the
other critical
event in the
formation of
the
hypothalamic–
hypophyseal
unit.
The pituitary
resides in a pocket of the sphenoid (the sella turcica, meaning
“Turkish saddle”) and is surrounded by dura mater. The
reflection of dura that separates the superior portion of the
pituitary from the hypothalamus, the diaphragma sella, is The ultimate determination of anterior pituitary cell types is
penetrated by the infundibulum, or pituitary stalk, that dependent on the spatial relationships of progenitor cell
connects the adenohypophysis to the median eminence and types and an integrated flow of transcription factors that
hypothalamus. ultimately form lactotrophs (prolactin-secreting cells),
The pituitary stalk contains both neural and vascular somatotrophs (growthhormone [GH]–secreting cells),
structures that terminate in the hypophysis. The posterior thyrotrophs (thyroid-stimulating hormone [TSH]–secreting
pituitary is connected to the supraoptic and paraventricular cells), corticotrophs
hypothalamic nuclei (where vasopressin and oxytocin are (adrenocorticotropin hormone [ACTH]–secreting cells), and
produced) by way of two, distinct neurosecretory tracts, the gonadotrophs (luteinizing hormone [LH]– and follicle-
supraopticohypophyseal and tuberohypophyseal tracts, stimulating hormone [FSH]–secreting cells)
which pass through the stalk. The anterior pituitary receives Pituitary tumors
80% to 90% of its blood supply and many hypothalamic o Prolactin-secreting tumors= most common
factors via the hypothalamic– hypophyseal portal system, o Nonfunctioning or null cell tumors
also contained in the stalk. o Tumors secreting GH, gonadotropins, ACTH, TSH
The primary plexus of this portal system is located in the
median eminence and is composed of capillaries lacking a Growth Hormone [GH]; Somatotropin:
blood–brain barrier (fenestrated capillaries), where the o Produced by somatotrophic cells or somatotrophs
hypothalamic nuclei that modulate pituitary function o structurally related to prolactin and human placental
terminate their axons. In turn, the long portal vessels connect lactogen
o Major effects are directed to growth of skeletal
the primary plexus to the anterior pituitary and serve as a
muscles and long bones
conduit for these hypothalamic–hypophysiotropic hormones.
The somatotrophs comprise over 1/3 of normal pituitary
3 distinct parts:
weight. GH is secreted in pulses, with an average interpulse
o anterior pituitary- glandular tissue [adenohypophysis]
interval of 2 to 3 hours, with the most reproducible peak
o Intermediate lobe [pars intermedialis]- is poorly
occurring at the onset of sleep (2-4 am peak, in kids 1-2 hours
developed in humans and has little functional capacity
deep sleep
other than to confuse radiologists by forming
As a metabolic hormone,
nonfunctional, benign, cystic enlargements of the
o GH is considered an amphibolic hormone because it
pituitary.
directly influences anabolic and catabolic processes:
o Posterior pituitary- nervous tissue [ neurohypohysis]
 Mobilizing fatty acids [lipolysis]
Neurohypophysis
 Decreases rate of glucose uptake and metabolism;
o arises from the diencephalon, is responsible for the
promotes gluconeogenesis
storage and release of oxytocin and vasopressin (also
One major
called antidiuretic hormone [ADH] that have effect on
effect of GH is that it allows an individual to effectively
non-endocrine glands
transition from a fed state to a fasting state without
Adenohypophysis
experiencing
a shortage of substrates required for normal
intracellular oxidation. GH directly antagonizes the effect o Diffuse overgrowth of ends of long bones/spine can result
of insulin on glucose metabolism, promotes hepatic to debilitating form of arthritis
gluconeogenesis, o Sleep apnea is common
and stimulates lipolysis o Teeth gaps are observed
 Increase amino acid uptake in cells Hyperthyroidism is exceedingly rare unless the tumor
cosecretes tsh.
GH Mediates most of its growth-enhancing effects indirectly
via a family of growth-promoting proteins called insulin-like o Acromegaly if not treated can result to early death.
growth hormones (IGFs) o It is a progressive disease that affects the whole body.
What produce IGFs? o Tumors are the common cause for the irregular and excess
o Liver, skeletal muscle, bone tissue produce IGFs in GH secretion
response to GH. o The procedure of choice for treatment of acromegaly is
o Liver IGFs act as hormones; in other tissues IGFs act as Transsphenoidal adenomectomy
paracrines After surgey, External beam or focused irradiation is frequently
IGF-I becomes a biologic amplifier of GH levels used. The goal of acromegaly treatment is to suppress GH. Three
IGFs stimulate actions required for growth: different classes of agents, SS analogs (octreotide and
o Uptake of nutrients from blood and their incorporation lanreotide), dopaminergic agonists (cabergoline and
into proteins and DNA bromocriptine), and GH receptor antagonists (pegvisomant)
o Formation of collagen and deposition of bone matrix
Gigantism
Modifiers of growth hormone secretion o Occurs before closure of epiphyseal bones
o Person grows abnormally tall often reaching 8-9 ft with
normal body proportions
Because GH is an insulin antagonist, ther is high blood glucose
in gigantism and acromegaly

GH deficiency: Pituitary dwarfism

o in adults, as a result of structural or functional
abnormalities of pituitary
o In children, this could be due to genetic or tumor such as
GH regulation of secretion craniopharyngiomas.
o Stimulated by GHRH (growth hormone releasing
hormone) & “hunger hormone” or ghrelin (produced by Not all short stature have GH deficiency but on genetic
the stomach & important in appetite, nutrient sensing defects:
and glucose regulation) o More common type is recessive mutation of GHRH gene
o Inhibited by GHIH (growth hormone inhibiting hormone); o Other causes: loss of GH gene & GH insensitivity
also called somatostatin [SS]
o GHIH is also produced in GIT & pancreatic secretions GH deficiency: Adult symptoms
GH testing o Social withdrawal
o Measurement of IGF-1 [previously called o Fatigue
somatomedins] & IGFBP-3 o Loss of motivation
o 100 g Oral glucose loading – after overnight fast, GH o Osteroporosis
measured at time 0, 60 and 120 min. o Alterations of body composition
o Insulin-induced hypoglycemia- gold standard
o Combined infusions of GHRH coupled with oral L-DOPA- Popular GH deficient test
new gold standard. GH >3-5 nm/mL= unlikely to br gh o Combination infusions of GHRH and L-arginine
deficient o L-arginine coupled with oral L-DOPA
o Interpretation: GH level rise above 3-5 ng/mL
GH pathology (normal)
o acromegaly or gigantism ( excess) occurs after GH deficiency: treatment
epiphyseal plates close o GH replacement [costly] RGH employed s
o Characterized by overgrowth of bony areas like feet, performance enhancing substance and aid in injury
hands, feet, face recovery
o Women most often affected
PROLACTIN-a protein structurally related to GH and human
placental lactogen
o Females: Stimulates and maintains milk production
following childbirth
o Males: involved in testicular function
o Considered as stress hormone
o Classified as direct effector hormone
 o Unique among anterior pituitary hormones because Hyperprolactinemia tests
its major mode of hypothalamic regulation is tonic - TSH and Free T4 or total thyroxine and T3 resin uptake to
inhibition (key regulator of neuronal excitability and eliminate primary hypothyroidism as a cause for the elevated
network fxn in the brain) rather than intermittent prolactin. If normal levels, then tumor is possible
o If tumor is suspected, tests of other pituitary function
stimulation.
(basal cortisol, LH, FSH, & gender specific gonadal
steroid ( either estradiol or testosterone)
Prolactin regulation is stimulated by:
o TRH
Management of prolactinemia
o Estrogen [ decrease level allows prolactin to induce lactation]
o Dopamine agonists are most common treatment to shrink
o stressors [exercise, seizures]
tumor. Ex are: Bromocriptine mesylate or cabergoline
o Stimulation of breast
o Side effect of Bromocriptine mesylate: orthostatic
o PIF once believed to be an inhibitor
hypotension, dizziness and nausea
o Dopamine is now the PIF- is the only neuroendocrine signal o Cabergoline has fewer adverse effects
that inhibits prolactin o Neurosurgery is not a primary mode of prolactinemia
Any compound that affects dopaminergic activity in the management.
median eminence of the hypothalamus will also alter o External beam radiotherapy is reserved for high surgical
prolactin secretion risk patients with locally aggressive macroadenomas who
MEDICATIONS CAUSING HYPERPROLACTINEMIA are unable to tolerate dopamine agonists
o Phenothiazines
o Butyrophenones Thyroid Stimulating Hormone [TSH]- glycoprotein
o Metoclopramide o Also called thyrotropin
o Reserpine o stimulates normal secretion of thyroid hormone &
o Tricyclic antidepressants growth of thyroid gland
o Alpha methyldopa
o Antipsychotics Regulation of TSH
Physiologic effect of prolactin is lactation o Released from thyrotropic cells or Thyrotropes
Consequence of excess prolactin is hypogonadism either by after TRF stimulation
suppression of gonadotropin secretion from the pituitary or o regulation by hypothalamus –pituitary
by inhibition of gonadotropin action at the gonad. The o Inhibited by GHIH or somatostatin [SS]
suppression of ovulation seen in lactating postpartum
mothers is related to this phenomenon

PROLACTIN PATHOLOGY
causes of prolactin increase: Tumors [prolactinomas]
o the most common type of functional pituitary tumor
o Prolactin is more than 150 ng/mL

Adrenocorticotropic hormone [ACTH]-peptide

o Also called corticotropin
o Secreted by corticotropic cells or Corticotropes
o It is split from a prohormone: pro-opiomelanocortin
(POMC)
o stimulates growth & secretion of adrenal cortex
regulation of ACTH
o Follows a circadian rhythm
o Released by corticotropin release hormone (CRH) &
ADH
The clinical presentation of a patient with a prolactinoma
o Regulated by hypothalamic-pituitary
depends on the age and gender of the patient and the size of
o Affected by both internal & external factors: fever,
the tumor. The decline in reproductive function in older
hypoglycemia, stressors
patients may be overlooked as an inexorable consequence of
“aging.” One recently recognized complication of prolactin-
Gonadotropins-glycoproteins
induced hypogonadism is osteoporosis
o Produced by Gonadotropes
o they are: Luteinizing hormone (LH) and Follicle-
Idiopathic galactorrhea
stimulating Hormone (FSH)
o Seen in women who have been pregnant several times
o Gonadotropins regulate functions of gonads
and has no pathologic implication
 FSH function there are variations in their hormone receptors, causing
o Females: stimulates growth & development of ovarian them not respond to MSH in the blood.
follicles, promotes secretion of estrogen by ovaries.
o Males: required for sperm production Endorphins=peptide
o any of a group of hormones secreted within the brain
LH function and nervous system
In females: o They activate the body's opiate receptors, causing an
o Works with FSH to cause egg-containing follicles to mature analgesic effect  Inhibit pain perception.
o Triggers ovulation and promotes synthesis of ovarian o Effects mimicked by heroin and other opiate drugs.
hormones
In males: ANTERIOR PITUITARY HORMONE CONTROL
o LH stimulates the interstitial cells of the testes to produce
testosterone

Gonadotropin regulation
o Gonadotropins are virtually absent in pre-pubertal age

Pulsatility
o All anterior pituitary hormones are secreted in a pulsatile
fashion.
o The pulse frequency of secretion is regulated by neural
modulation and is specific for each hypothalamic-
pituitary-end-organ unit.

Pulsatility: Three Levels of Integration

Melanocyte- o Hypothalamic stimulation–from CNS
stimulating H.
o Pituitary stimulation–from hypothalamic trophic Hs
o Endocrine gland stimulation–from pituitary tropic Hs
Adrenocorticotropic

MELANOCYTE STIMULATING HORMONE [ MSH]-peptide

o Precursor is proopiomelanocortin(POMC)
o also known as melanotropins or intermedins
o MSH stimulate the production and release of melanin (a
process referred to as melanogenesis)
by melanocytes in skin and hair
o MSH actions in the brain have effects
on appetite and sexual arousal
o May play a role in fat metabolism. Cyclicity
o The nervous system regulates the cyclic nature of
High MSH seen in: hormone through external signals
o pregnancy
o Cushing's disease due to excess ACTH (MSH and ACTH Zeitgeber (time giver)
share the same precursor) o It is the process of entraining or synchronizing external
o acanthosis nigricans in the axilla/ armpit cues into the function of internal biologic clocks.
o Hormones are secreted in different amounts depending
Hyperpigmentation occurs in of the time of the day [circadian or diurnal pattern]
o Hands, Nipple & buccal mucosa
o new scars become hyperpigmented, whereas older ones do Ex. ACTH nadir of secretion- 1pm-3am, peak on awakening or
not darken. 6-9 am. TSH is 2x higher during night. This is the result of an
o Different levels of MSH are not the major cause of racial increased pulse amplitude.
variation in skin colour. However, in many red-
headed people, and other people who do not tan well,
 HYPOPITUITARISM- The failure of either the pituitary or the o Hormones are stored in vesicles in the posterior
hypothalamus results in the loss of anterior pituitary function. pituitary until release into the circulation
o PANHYPOHYPITUITARISM means all pituitary hormones are
low or zero resulting to complete loss of pituitary function
o MONOTROPIC HORMONE DEFICIENCY means a loss of only
one pituitary hormone

Causes of hypopituitarism
o Parapituitary/hypothalamic tumors
o Trauma
o Radiation therapy/surgery
o Infarction
o Infection
o Infiltrative disease
o Immunologic
Oxytocin- a peptide Oxy: rapid; tocia: childbirth
o Familial
• Is synthesized as the precursor hormone: prepro-
o Idiopathic
oxyphysin
o Pituitary tumors
• Is a cyclic nonapeptide, with disulfide bridge connecting
o Direct effects of tumors or the sequelae of treatment of tumors
amino acid residues 1 & 6.
are the most common causes of pituitary failure
• Secretion is increased during labor resulting to
o Tumors compress or replace normal tissue or interrupting the
contraction of uterine smooth muscles
flow of hypothalamic hormones by destroying the pituitary
• Acts primarily on the mammary gland (“letdown reflex”)
stalk
and uterus
Hypopituitarism causing tumors
• increases contraction of smooth muscle of the vas
o Parasellar tumors [meningiomas and gliomas]
deferens thus may also act to facilitate sperm transport
o Metastatic tumors [ breast & lung]
(non-pregnancy state)
o Hypothalamic tumors [craniopharyngiomas or
• oxytocin has been shown to have effects on pituitary,
dysgerminomas]
renal, cardiac and immune function.
o Postpartum ischemic necrosis of the pituitary following a
Pitocin
complicated delivery (Sheehan’s syndrome) typically presents
o Synthetic oxytocin which is used in obstetrics to induce labor.
as profound, unresponsive shock or as failure to lactate in the
Recent studies have linked oxytocin to maternal nurturing
puerperium (6 weeks after childbirth during which the
behavior and mother–infant bonding
mothers reproductive organs return to their original position
AVP-arginine vasopressin- a peptide
Panhypopituitarism causing tumors
o Is also known as antiduretic hormone (ADH-old name)
Most common are:
o Also a cyclic nonapeptide with an identical disulfide bridge
o Large, nonsecretory pituitary tumors
o Differs from oxytocin by only 2 amino acids
(Chromophobe adenomas or null cell carcinomas)
o causes vasoconstriction, primarily of visceral blood
o Macroprolactinomas
vessels, raising blood pressure. This response targets ADH
Rarer type:
receptors found on vascular smooth muscle
o Hemorrhage or pituitary tumor apoplexy
Vasopressin is also a potent pressor agent and effects blood
Treatment: replacement therapy through thyroxine,
clotting by promoting factor VII release from hepatocytes and
glucocorticoids, and gender-specific sex steroids.
von Willebrand factor release from the endothelium.

POSTERIOR PITUITARY
Regulation of AVP Secretion
o Extension of the forebrain
* Response to changes in blood pressure:
o Comprised of the endings of axons from cell bodies in the
- Blood pressure receptors in heart, aortic arch, and carotid
hypothalamus (supraoptic and paraventricular)
o Axons pass from the hypothalamus to the posterior artery
pituitary via the hypothalamohypophysial tract - Increased blood pressure results in decreased AVP release
o Posterior pituitary hormones are synthesized in the cell - decreased water reabsorption
bodies of neurons in the supraoptic and paraventricular - decreased blood volume, blood pressure
nuclei and is closely linked to the production of - Decreased blood pressure results in increased AVP release
neurophysin - increased water reabsorption
- increased blood volume, pressure
Vasopressin major action is to regulate renal free water
excretion The vasopressin receptors in the kidney (V2) are
concentrated in the renal collecting tubules and the
ascending limb of the loop of Henle. They are coupled to
adenylate cyclase, and once activated, they induce insertion
of aquaporin-2, a water channel protein, into the tubular
luminal membrane
AVP and Water Balance Tests
Action: increases permeability of the distal convoluted tubule o Water deprivation
and collecting ducts to water o Monitoring of fluid osmolality

Result: ADH hypersecretion

- increased water reabsorption from urine o Can occur in children with meningitis or in adults
- decreased urine volume who have neurosurgery, hypothalamic injury, or
- decreased osmolality of interstitial fluids cancer [particularly lung cancer]
- increased blood pressure o Can also occur after general anesthesia
SIADH
Regulation of AVP Secretion o Syndrome of inappropriate ADH secretion
Response to osmolality of interstitial fluid: o Marked by retention of fluid, headache,
- Osmoreceptors in the brain detect changes in osmolality of disorientation due to brain edema, weight gain &
the interstitial fluid or blood. decreased solute concentration in the blood
- Increased osmolality results in increased [solutes] AVP o Manage through: fluid restriction; monitoring of Na
release levels
- increased water reabsorption
- decreased osmolality of fluids
- Decreased osmolality results in decreased ADH release =
NEGATIVE FEEDBACK!
- decreased water reabsorption
- increased osmolality of fluids

Regulation of AVP Secretion

AVP release is also inhibited by alcohol, caffeine (diuretics) –
dehydrating effect “dry mouth” or intense thirst morning
after  INCREASED urine output.
- decreased water reabsorption Treatment of vasopressin excess
- increased urinary volume o Conivaptan and tolvaptan (vasopressin V2 receptor
- potential for dehydration antagonists)
Some drugs can also antagonize ADH release: diuretics used ADRENAL GLANDS/
to treat high bp, edema, or CHF. suprarenal glands- because they are above our kidneys

Feedback mechanisms in the control of blood osmotic Adrenal glands are multifunctional organs that produce
pressure—the control of ADH. steroid hormones and neuropeptides [ such as vasoactive
inhibitory peptide (VIP), adrenomedullin, and atrial
natriuretic peptide (ANP) ] essential for life. Most
pathological conditions of the adrenal gland are manifested
by their impact on blood pressure, electrolyte balance, and
androgen excess.
• Is located above (or attached to) the upper pole of the
kidney. [ ad= near; renal= kidney]
• Is pyramidal in structure and weighs ~ 4 g.
• Enclosed in fibrous capsule and a cushion of fat
2 distinct parts
• adrenal cortex = part of hypothalamic-pituitary-adrenal
endocrine system; outer glandular region in three layers
• adrenal medulla= part of sympathetic nervous system;
Cortex –Medulla – inner neural tissue region
POSTERIOR PITUITARY PATHOLOGY
DIABETES- overflow INSIPIDUS- tasteless (DI)= Insufficient 2 embryologically distinct
AVP; mellitus - honey tissue= adrenal (outer) and
medulla (inner) the cortex is
o increase urine volume 10 times [polyuria]
derived from mesenchymal
o intense thirst [ polydipsia] cells located near the
o Hypothalamic DI urogenital ridge that
o Idiopthic DI differentiate into 3
The causes of hypothalamic DI include apparent structurally and functionally
autoimmunity to vasopressin-secreting neurons, trauma, distinct zones. The medulla arises from neural crest cells
diseases affecting pituitary stalk function, and various central that invade the cortex during the 2nd month of fetal
development. By adulthood. The medulla contributes 10% of
nervous system or pituitary tumors. A sizable percentage of
total adrenal weight.
patients (up to 30%) will have idiopathic DI
 Adrenal cortex A. Cortisol
 Forms the bulk of the adrenals  Circulating cortisol is bound to cortisol-binding globulin [
 Glandular tissue derived from embryonic mesoderm CBG;transcortin] and to albumin
 Only 5% is unbound and physiologically active

B. cortisone
 Not secreted in significant amount
 Inactive until converted in vivo to cortisol
[hydrocortisone]

Cortex appears yellow while medulla is dark mahogany.

Adrenal arterial supply is symmetric. Small arterioles branch
to form dense subcapsular plexus that drains into the
sinusoidal plexus of the cortex. There is direct arterial blood
supply to middle and inner zones. In contrast, venous
drainage from the central vein displays laterally.

Zones of adult Adrenal Cortex

 Zona Glomerulosa (G-zone): thin outer layer; arranged in
clusters; 10%
 Zona Fasciculata (F zone): middle layer; arranged in liner
cords; 75%
 Zona Reticularis (R-zone) : innermost layer; netlike
Cortisol Effects: Body Responses to Stress:
arrangement; 15%

Fetal adrenal glands

• Is divided onto 4 zones.
• The three zones of the permanent cortex constitutes only
20% of the fetal gland’s size. The remaining zone (fetal
cortex) comprises up to 80% of gland’s size during fetal life.
• These zones produce estriol

Synthesis of Steroid Hormones

Permissive Effects of Cortisol on Development

• Cortisol is required for normal development:
- permissive role in final maturation of many organs
- required for synthesis of digestive enzymes, surfactant
- required for skeletal growth in children

Mechanisms of Cortisol Action

• The actions of cortisol are mediated through the
glucocorticoid receptor.
• Stimulates transcription of target genes by interaction of
bound receptor with GRE in 5’ flanking region.
Glucocorticoids • Inhibits transcription of some genes by interaction of
 Promote normal cell metabolism receptor with AP1 (jun/fos dimer), decreasing AP1-
 Help resist long-term stressors mediated gene expression.
 Released in response to increased blood levels of ACTH
 Are conjugated with glucoronate and sulphate in the liver to
form inactive metabolites= easily excreted
 Generated androgen precursor like
dehydroepiandrosterone (DHEA) is sulfated in R-zone
 Control of Cortisol Secretion: Feedback Loops Gonadocorticoids
• External stimuli • Weak androgens or male sex hormones [DHEA &
• Hypothalamic DHEAS] : Most are converted to testosterone and
• Anterior Pituitary estrogen
• Adrenal cortex • Insignificant compared to gonadal hormones
• Tissues • Responsible for axillary and pubic hair [adrenarche]
• Contribute to woman’s sex drive; account for estrogen
supply during menopause

Active form of sex steroids

A. Androgen
Cortisol: Role in  androstenedione
Medication
 Testosterone
- Use as
immunosuppressant  5-dihydrotestosterone
Ex. Hyper-immune B. Estrogen
reactions (bee  Estradiol
stings)  Estrone
- rheumatoid arthritis
Serious side effects Disorders of adrenal cortex

Mineralocorticoids
 Regulate mineral content in blood, water, and electrolyte
balance
 Target organ is the kidney
 Production stimulated by renin and aldosterone ADDISON’S DISEASE - Low
 Production inhibited by atrial natriuretic peptide corticosteroid
Caused by bilateral destruction of
Aldosterone all zones of adrenal cortex,
• Regulatory effects last for 20 minutes only commonly due to autoimmune dse
• Mechanism of activity involves activation of proteins
needed for Na transport such as Na-K ATPase pump

Regulation of Aldosterone Secretion:

 In this case, Addison’s disease occurs due to massive
hemorrhagic adrenal dysfunction. Patient may be shocked
and treatment must be urgent

Congenital adrenal hyperplasia (CAH)

• Low plasma steroids=hyperplasia of adrenals
A group of clinical entities that arise from absent or
diminished activity of enzymes involved in steroidogenesis.

Hypercortisolism assessment
• ACTH measurement
• 24-h urinary free cortisol
• Low-dose overnight dexamethasone suppression test (1 mg)
• 48-low dexamethasone suppression test (0.5 mg every 6 h)

Conn’s primary hyperaldosteronism- High Mineralocorticoids

The most common enzyme affected is 21-hydroxylase. : CAUSES
Deficiency in this enzyme results in decreased glucocorticoids, • Adrenal aldosterone-adenomas (APAs)
in some cases mineralocorticoid and increased adrenal • Unilateral or Bilateral idiopathic adrenal hyperplasia
androgen production. A very high serum 17- (IAH)
hydrozyprogesterone is diagnostic of classic 21-hydroxylase • Genetic-familial variety of PH
deficiency. The “classic” presentation is seen in infants. It
presents with features such as failure to thrive and low blood
pressure. These infants need both glucocorticoid and
mineralocorticoid replacement. A second nonclassic form is
seen in adults. Women with this form present in their
reproductive years with complaints of hirsutism, menstrual
irregularities, and infertility. They may need steroids during
pregnancy.

Frequency of signs & symptoms of adrenal insufficiency Effects on sex steroids

• There is increased cortisol
precursors before the
enzyme block, hence,
these precursors can be
metabolized into
alternative pathways like
androgen synthesis

Sex steroids excess

• Female
FEATURES OF Cushing’s syndrome pseudohermaphrodism:
• obesity. Typically involving truck & face, & a ambiguous genitalia
characteristic round, red “cushingoid” face may show phallic
• impaired glucose tolerance & hyperglycemia enlargement,
• increased protein catabolism, increased urinary protein loss clitoromegaly, early
[ neg nitrogen balance w/ muscle weakness, easily bruised pubic hair
and purple striae inthe abdominal area]
• Hypertension [ due to urinary retention of Na, water]
• Androgen excess [ greasy skin w/ acne vulgaris & hirsutism, Virilization in childhood
menstrual disturbances] • With phallic enlargement in either sex, development of
• Psychiatric disturbances pubic hair and a rapid growth rate
• Lab findings: hypokalemia, alkalosis, leukocytosis, • In females, occurs at or after
eosinophilia puberty
• Nelson’s syndrome: Removal of cortisol feedback causes • Menstrual irregularities,
further rise in plasma ACTH from already high levels resulting acne, hirsutism,
to pigmentation • Male pattern baldness
best seen on
flexural surface of Men excess estrogen
• Infertility
body.
• Feminizing effect
• Decrease testicular
Frequency of signs
testosterone production
and symptoms in
Cushing’s
syndrome
 Adrenal Medulla: A Modified l Sympathetic Ganglion Mechanism of Catecholamine degradation:
• Sympathetic stimulation • Re-uptake into secretory vesicles
• Catecholamine release to blood • Uptake in nonneuronal cells (mostly liver by catechol
• Epinephrine methyltransferase )
• Norepinephrine • Degradation (by monoamine oxidase [MAO]-within
• Travel to: neurons)= produce metabolites VMA
• Multiple targets
• Distant targets Assessment
• urine catecholamine [ NE:5%; conjugated NE: 8%;
metanephrines: :20%; VMA: 30%]
• plasma catecholamine[half life:2 min]
• measurement using LC, LC-MS/MS, fluorometry

Pheochromocytoma: Catecholamine-producing tumor

Tumor arising from adrenal medulla is referred to as
pheochromocytoma. If arising from the sympathetic ganglia is
referred to as paraganglioma

Synthesis of catecholamines:

Biochemical tests of PPGL

• Plasma-free metanephrines
• 24-hour urine fractionated metanephrines and
catecholamines
PPGL = pheochromocytoma-paraganglioma. Plasma-free
metanephrines is measured with patient in supine position for
at least 30 minutes prior to blood sampling. This is evidence
Activity of Epinephrine: that upright position activates the sympathetic nervous
system and stimulates the release of NE. For 24-hr urine
fractionated metanephrines and catecholamines, urine
volume should be quantified and creatinine tested to verify
adequacy of collection.
GONADAL FUNCTION
Sexual differentiation
By the 6th week of development in both sexes, the primordial
germ cells have migrated from their extraembryonic location
to the gonadal ridges, where they are surrounded by the sex
cords to form a pair of primitive gonads. Whether 46 XX or 46
XY, the developing gonad at this stage of development is
bipotential. The ovarian pathway is followed unless a gene on
the shirt arm of
the y
NE activity: chromosome,
designated TDF
(testis-
determined
factor) also
known as sex-
determining
region Y (SRY)
gene, makes a
DNA-binding
protein that acts
as a switch,
diverting
Catechalomines: Activity: development into
• Stimulates the “fight or fight” reaction the male
• Increased plasma glucose levels pathway.
• Increased cardiovascular function
• Increased metabolic function Regulation of gonads
• Decreased gastrointestinal and genitourinary function The hypothalamus produces GnRH which determines the
anterior production of LH and FSH
 genital ducts (ductus deferens, epididymis, seminal vesicles,
and and the ejaculatory ducts), and the Sertoli cells produce
antimulleran (AMH) that suppresses the formation of the
paramesonephric ducts.

Sexual differentiation & Development of normal male

phenotype
 Differentiation of bipotential gonad primodia into the
testes
 development of the internal reproductive tract
 development of the external
First is the differentiation of bipotential gonad primodia
into the testes that secrete testosterone, which is under the
In male, LH acts primarily on Leydig cells (located in the control of the SRY protein coded by that Y chromosome gene.
intestitium) to produce testosterone. Second is the development of the internal reproductive tract,
initiated by fetal testicular androgen production. The third is
development of the external genitalia that requires
testosterone and, in some target tissues, its more potent
metabolite 5alpha-dihydrotestosterone(DHT)

Male Reproductive tract

Adult testes are paired, ovoid organs that hang from
the inguinal canal by the spermatic cord, which comprises a
neurovascular pedicle, was deferens, and cremasteric muscle.
Testes are located outside the body, encased by a muscular to
sac, which regulates the temperature of testes to 2C below
core body temperature. This is important to uninterrupted
sperm production. Also encased in the muscular sheath is the
spermatic cord, which has the ability to retract the testicles
In male, FSH acts primarily on germinal stem cells. Once high into the inguinal canal when there is threatened injury.
levels of testosterone are detected by the hypothalamus, a
negative feedback system is activated. Testosterone inhibits Testicular functions
LH production by the pituitary by deactivating the  Production of sperm
hypothalamus.  Production of reproductive steroid hormones
Testicular hormones are collectively called androgens. Main
The male hormone is called testosterone. Testosterone is responsible
Puberty marks the transition from a nonreproductive state for adult male secondary sex characteristics. Promotes growth
into a reproductive state. The earliest sign of puberty in boys is and maturation of male reproductive system and is required
testicular enlargement. for sperm cell production

Spermatogenesis- Sperm cells are formed from stem cells

called
spermatogonia
which undergo
mitosis and
meiosis.
Mature sperm
has a head,
body and tail

Hormonogenesis
The predominant hormone secreted by the testes is
In the presence of Y chromosome the fetal gonads develop in
testosterone. The first, and rate limiting step in testicular
to testes at 7 weeks’ gestation. The Sertoli cells secrete anti-
steroidogenesis is the conversion of cholesterol to
Mullerian hormone that inhibits the Mullerian ducts in the
pregnenolone. This cholesterol is either trapped by
male embryo. These testes have semineferous tubules and
endocytosis from the blood lipoproteins or synthesized within
leydig cells. Leydig cells under the stimulation of hCG become
the Leydig cells. The LH binds to the glycoprotein receptor in
capable of androgen secretion by the 10th week. The
the cell wall and induces intracellular cyclic AMP (cAMP)
spermatogonia, derived from the primordial germ cells by 200
production that in turn, activates protein kinase A, which
or more successive mitoses, form the walls of the
catalyzes protein phosphorylation. This latter step induces
semineferous tubules together with supporting Sertoli cells.
testosterone production. The
While the primordial germ cells are migrating to the genital
testicular steroidogenesis
ridges, thickenings in the ridges indicate the developing genital
pathway is similar to the
ducts and the mesonephric (formerly called wolffian) and
pathway in the adrenal
paramesonephric (formerly called mullerian) ducts. In the
cortex and they share similar
male, the Leydig cells of the fetal testes produce androgens,
enzymatic system.
which stimulates the mesonephric ducts to form the male
 often undescended, and failure to promptly remove these
organs is essential to abort malignant transformation. Lab
findings: normal or elevated testosterone, elevated FSH and
LH

Cryptorchidism
Testicular descent is regulated by
the protein product of gene Insl3,
which is a member of the insulin-
like family and is secreted by Leydig
cells.

Tanner staging of genital and pubic hair development in males C. 5α-reductase deficiency
 Rare cause of androgen insensitivity resulting to XY males
 There is reduced DHT (5α-dihydrotestosterone)
 Development is female phenotype until puberty when
Wolffian ducts virilize in response to testosterone
 No female internal genitalia; male genitalia are well
developed

C. MYOTONIC DYSTROPHY
• There is primary hypogonadism, frontal balding, DM,
muscle weakness, atrophy, & dystonia
• Testicular failure occurs at the 20s or 30s
• Primary hypogonadism (oligozoospermia, infertility)
Disorders of sexual development and testicular hypofunction
Myotonic dystrophy (type 1 caused by DMPK gene mutation
Pubertal development could be premature (precocious) or
and type 2 caused by CNBP gene mutation). Almost always an
delayed, even if development is normal at birth
affected person has one parent with the condition. Incidence
of MD is 1in 8,000 worldwide. Though with testicular failure,
HYPERGONADOTROPIC HYPOGONADISM
puberty progresses normally and secondary sexual
 Group of disorders characterized by low testosterone,
characteristics, height, bone growth are attained normally
elevated FSH or LH, & impaired sperm production
during puberal course of development. Lab results: high FSH,
A. Klinefelter’s syndrome
low testosterone.
• Caused by the presence of an extra chromosome
• Gynecomastia is common
[The DMPK gene provides instructions for making a protein
• LH & FSH= high
called myotonic dystrophy protein kinase. This protein appears
• Reduced bone density
to play an important role in muscle, heart, and brain cells].
• Breast cancer
[The CNBP gene provides instructions for making a protein
• Elevated FSH and LH induce increased aromatase activity,
called CCHC-type zinc finger nucleic acid binding protein. This
resulting in elevated estrogen levels. Men with
protein has seven regions, called zinc finger domains, which
klinefelter’s syndrome may have reduced bone density
are thought to attach (bind) to specific sites on DNA and its
and breast cancer risk comparable to women.
chemical cousin, RNA.
*dystonia is the inability of the muscle to relax adequately
Klinefelter’s syndrome occurs in about 1 of 400 to 600 men.
after contraction
The most common karyotype is 47, XXY.11. Due to reduced
production of testosterone, LH is elevated. There is small (less
E. TESTICULAR INJURY & INFECTION
than 2.5 cm), firm testicles. And then due to deficient
Causes:
seminiferous tubule mass, FSH is elevated from
 Post-pubertal mumps
underproduction of inhibin. These men have
 Viral orchitis & HIV infection
azospermia=sterility. Men with mosaicism (Genetic
 Radiation and chemotherapy
mosaicism is defined as the presence of two or more cell
Mumps orchitis develops in a 3rd postpubertal males with
lineages with different genotypes arising from a single zygote
mumps, and is the most frequent extrasalivary manifestation
in a single individual) may produce some sperm and
of this highly contagious infection.
pregnancies have been reported with such men.
F. SERTOLI CELL-ONLY SYNDROME
B. Testicular feminization syndrome
 Characterized by lack of germ cell
• Most severe form of androgen resistance
 Men affected have small testes, high FSH levels,
• Lack of androgen
azoospermia, normal testosterone
• Testicles undescended
Also known as SCO syndrome or germ cell aplasia
• Fully developed breasts, female distribution of fat & hair
• No response to exogenous testosterone
Varicocele
• Reared as girls
 is an enlargement of the veins within the
Testicular feminization syndrome is the most severe form of
loose bag of skin that holds the testicles
androgen resistance syndrome, resulting from mutations of
(scrotum).
the androgen receptor and impaired androgen actions in
 is similar to a varicose vein that can occur in
target tissues. As a result of the lack of androgen and
your leg.
unopposed estrogen effects, the physical development
Varicocele is another possible cause of low
pursues the female phenotype, with fully developed breasts
sperm production and decreased sperm quality,
and female distribution of fat and hair. Most present for
which can cause infertility. Can also cause
evaluation of primary amenorrhea, at which time the lack of
testicles to fail to develop normally or shrink
female internal genitalia becomes apparent. Testicles are
 HYPOGONADOTROPIC HYPOGONADISM Pituitary MRI is done in secondary hypogonadism in young
 Hallmark is the occurrence of low testosterone with individuals
low or inappropriately normal FSH or LH levels Clinical signs and symptoms of hypogonadism (loss of
secondary sexual characteristics, decreased muscle mass,
A. KALLMANN’S SYNDROME osteoporosis among others) should be collaborated with low
 Impaired secretion of GnRH testosterone levels.
 A result of an inherited , x-linked recessive trait that
manifests as hypogonadism during puberty Testosterone replacement
 Occurs in 1:10,000 males  Administered only to a man who is hypogonadal
 Certain men have red-green color blindness, congenital  Complications include: acne, polycythemia, prostate
blindness, or cerebellar dysfunction enlargement, possible growth-promoting effect on
undiagnosed prostate cancer, worsening of
B. hyperprolactinemia obstructive sleep apnea, peripheral edema &
 Can be drug induced or caused by tumor gynecomastia
Administration of testosterone could vary from
C. DM 2 parenteral, transdermal, gel, pellet (either buccal or
 Occurs in at least 25 to 50% of men subcutaneous), nasal.
 Low free or total testosterone; low LH
 Insulin seems to be important for LH release Monitoring of testosterone replacement therapy
 There is high C-reactive proteins  PSA
DM 1 DM is not associated with hypogonadism. C-reactive  Hematocrit
proteins are inflammatory markers.  Lipid levels
 Frequency of checking: 3 to 6 months; then yearly
D. Age In addition, routine clinical evaluation for leg edema,
 Testosterone decreases at about 110 ng/dL every worsening of sleep apnea, prostate enlargement should be
decade of life done. If PSA is elevated, biopsy of prostate can be done.
There is gradual reduction in testosterone after age of 30, with
an average decline at about 110 ng/dL every decade of life FEMALE
In the absence of Y
E. Pituitary disease chromosome, fetus starts to
 As a result of tumor, surgical-or radiation-induced develop female characteristics
trauma, vascular injury, autoimmune hypophysis, or at about 12 weeks.
granulomatous or metastatic disease.
In the female (or in an embryo
F. Opioid use without gonads), the
 Prolonged use or continuous use of narcotics is mesonephric ducts regress, and
linked to severe hypogonadotropic hypogonadism. the paramesonephric ducts
Prolonged use or continuous use of narcotics is linked to develop into the female duct
severe hypogonadotropic hypogonadism due to µ-opiod system.
receptor-mediated decreased GnRH pulsatile production. Male  Proliferation of fetal germ cells produces several millions
fertility can occur (decreased sperm motility, decreased sperm of oocytes.
counts, abnormal sperm morphology.  By late fetal life, all germ cells are degenerated and more
oocytes can be produced.
G. Obstructive sleep apnea  These oocytes decline in number throughout the rest of
 Can be sue to hypoxemia and sleep deprivation intrauterine development and childhood.
 Obesity  The inability to replenish them explains the limit of
There is unclear association if sleep apnea leads to women’s reproductive life.
hypogonadotropic hypogonadism. It can be due to hypoxemia
and sleep deprivation of if the obesity, which is often present The oogonia are derived from primitive germ cells by a series
in men with sleep apnea, leads to decreased testosterone. of 30 mitoses. Beginning of the 3rd month, the oogonia enter
But is has been found that treating with testosterone in men meiosis 1, but this process is arrested at a stage called
with sleep apnea can worsen the situation. They need to start dictyotene , in which the cell remains until ovulation occurs
first with CPAP prior to replacement therapy. many years later ( this cell is called primary oocyte). Many
*Continuous positive airway pressure therapy (CPAP) uses a oogonia degenerate before birth, and only about 400 mature
machine to help a person who has obstructive sleep apnea into ova during the sexual maturity of female. Estrogen
(OSA) breathe more easily during sleep. A CPAP machine formation in the fetal ovary begins in early development
increases air pressure in your throat so that your airway despite primordial follicles not having begun forming until the
doesn't collapse when you breathe in. second trimester of pregnancy. The gonadotropins take over
the role of maternal placental hCG, and fetal pituitary LH and
Diagnosis of hypogonadism FSH occur, which stimulates steroid secretion leading to
 Testosterone measurement neonatal milk production from the breast.
 Pituitary MRI
Testosterone concentrations have a circadian rhythm 8-10 am Female Reproductive System
sampling is recommended Ovarian Sex hormones: Estrogen and Progesterone
For primary hypogonadism: FSH & LH are elevate Like the adrenal glands and the testes, ovaries have also
For secondary & tertiary etiologies: FSH & LH are low. Older steroidogenic pathway. The major hormones produced as
individuals have often secondary or tertiary dysfunctionas a estrogen and progesterone but ovaries also produce
result of reduced hypothalamic pulse genertor frequency, androgens and other hormones
resulting in low or inappropriately normal FSH/LH levels. Ovaries are oval organs which weighs an ave of 14 g in adult.
 A. ESTROGEN The menstrual cycle consists of 2 phases of parallel events
 Promote breast, uterine, vaginal development occurring at the ovaries and endometrium. Within these
 Effect on skin, vascular smooth muscles, bone cells, & CNS events are the follicular and luteal phases, while the
During the reproductive period, it is estrogen that is concurrent endometrial events are the proliferative and
responsible for follicular phase changes in the uterus, with secretory phases.
deficiency resulting in irregular and incomplete development
of endometrium. Ovarian: Follicular phase
 begins with onset of menses
 Estradiol- principal ovarian estrogen  ends on the day of LH surge
 Estrone & estriol- primarily metabolites of intraovarian & Early follicular stage, ovary secretes very little estrogen or
extraglandular secretions progesterone. A rise of FSH stimulates estrogen production
which then stimulates uterine epithelial cells, blood vessels
B. PROGESTERONE growth, and endometrial gland development to increase the
 Induces the secretory activity of those endometrial glands thickness of endometrium.
that have been primed by estrogen
 Readying endometrium for embryo implantation, Ovarian: Luteal phase
thickening of cervical mucosa, reduction of contractions,  start with extrusion of ovum 36 hrs after LH surge
thermogenic effect  Formation of corpus luteum
 Thermogenic effect: basal body temperature rises after  secretion of progesterone to prepare for implantation
ovulation. Progesterone is the dominant hormone  ends with menstrual bleeding ( 3-5 days)
responsilbe for the luteal phase, a deficiency results in Estrogen peaks 1 day before ovulation, at which point a
failure of implantation of the embryo. positive feedback system results in an LH surge. The start of
luteal phase is extrusion of ovum 36 hrs after LH surge, with
C. ANDROGENS subsequent luteinisation of the graafian follicle to form the
 Ovaries produce androstenedione, corpus luteum. Corpus luteum secretes progesterone to aid in
dehydroandrostenedione, testosterone, 5α- the implantation of embryo or if no implantation, there is a
dihydrotestosterone (DHT) gradual decline in the production of progesterone and
 Levels continue to increase in advanced age estrogen, and loss of endometrial blood supply. This results in
Excess ovarian androgens leads to excess hair growth, loss of shedding of the endometrium 14 days after ovulation. Blood
female characteristics, and in severe cases –development of loss averages 50 mL.
overt male secondary sexual features. Unlike estrogen, which
is not produced in the ovary after menopause, ovarian
androgen synthesis continues well into advanced Age.

D. other ovarian hormones

 Inhibins A & B : inhibit FSH production
 Activin: enhances FSH secretion & induces steroidogenesis
 Folliculostatin, relaxin: follicle regulatory protein, oocyte
maturation factor, meiosis-inducing substance

 FSH & LH regulate control of estrogen and

progesterone.
 Estrogen and progesterone control the FSH & LH.
Typically, all but one of these primordial follicles will then
atrophy, in a process called follicular phase. The single Pubertal development in female
remaining follicle-known as the graafian follicle-is composed  Thelarche (breast development) = earliest sign
of an outer and inner layer (the theca externa and theca  Development of pubic hair
interna, respectively) encasing a central fluid-filled cavity and  Menarche ( 2 to 3 years after onset of puberty)
a layer of cells known as granulosa layer. The maturing ovum
attaches to the inside of the follicle via cells derived from Tanner staging of breast and pubic hair devt in females
granulosa cells, called cumulus cells. During the luteal phase,
the graafian follicle releases its ovum in response to ovarian
stimulation by LH. When the ovum is extruded, the graafian
follicle undergoes a morphologic . change with hypertrophy
of the theca and granulosa cells to become corpus luteum.
This process is called luteinization. The corpus lutuem is rich
in cholesterol and acts as a substrate for continued
production of progesterone and estrogen, maintaining the
endometrium for conception. If conception or implantation
fails, the endometrium is shed and the corpus luteum
atrophies to an atretic follicle.

The menstrual cycle

PLACENTAL HORMONES Why amniotic fluid volume varies?
Pregnancy  Fetus swallows, urinates into the fluid & secretes fluids
 hCG produced by placenta through its lungs
 reaches a peak at about 13 weeks and then falls.  Normally fetus does not defecate into amniotic fluid but
Urine/plasma hCG when positive at 1-2 weeks after first when stressed, it may pass stool called meconium
missed menstrual period commonly confirms pregnancy  meconium has a large conc of bile pigment ( thus
colored amniotic fluid green)

A. Neural tube defects

 Life threatening
 Failure of neural tube to fuse
 Correlate with folic acid def in mother during
pregnancy
 show high AFP
Include:
a) Meningomyelocele or spina bifida: bottom end of
neural tube fails to fuse
b) Encephalocele : sac containing brain & membranes
that protrudes thru an abnormal opening in the skull
c) anencephaly: lack of parts of the brain & skull

B. Down syndrome
 trisomy 21
 there is low AFP, unconjugated estriol, and high hCG and
inhibin A concentrations measured between 15 to 20
week’s gestation

C. Hemolytic Disease of the Newborn

Complications of pregnancy
 Fetomaternal blood group incompatibility: shows high
 Gestational DM
amniotic fluids concentrations of bilirubin in conjunction
 Ectopic pregnancy
with maternal antibodies.
 Hyperemesis Gravidarum
 Result is read using Liley chart (relating optical density of
 Severe form of nausea & vomiting in pregnancy
amniotic fluid at 450 nm
 Nausea & vomiting is accompanied by ketosis &
weight loss = acid-base imbalances, electrolyte
D. Respiratory Distress Syndrome
imbalances, nutritional deficits, death
 Also called Hyaline membrane disease
 Preeclampsia
 Occurs in babies born before 37 weeks
 Characterized by hypertension and proteinuria after
 Babies lack pulmonary surfactant
the 20th week of gestation
 Only tx: delivery
Lab diagnosis of fetal abnormalities
 Eclampsia
 AFP testing
 Mother experiences grand mal seizures or falls into
 Screening for chromosomal abnormalities
coma
 Fetal lung maturity testing
 Can lead into intracranial hemorrhage
a. Lecithin/sphingomyelin ratio
 HELLP syndrome
b. Phosphatidyl glycerol
 Means hemolysis, elevated liver enzymes, low
c. Fluorescent polarization test
platelet with preeclampsia)
 Lecithin is a major component of airway surfactant
 Presence of thrombocytopenia & disseminated
 Sphingomyelin is a non-lung compound that serves
intravascular coagulation (DIC)
as a good internal standard
 Generally occurs between 27th & 36th weeks, but can
 Infants with mature lungs: L/S ratio is 2 or more
also occurs after delivery
 In Fetal lung maturity: L/S ratio is less than 2
 Only tx: delivery
 NOW steroids can induce surfactant synthesis
 Graves disease
 Earlier in pregnancy: fetus is dependent on mother’s
Hypogonadotropic hypongonadism
supply of thyroid hormones.
 Low sex steroid=common cause of secondary
 Thus if mother has graves disease, effects include:
amenorrhea
preterm delivery, feta death, reduced IQ
 Other causes: weight loss due to anorexia nervosa;
 On 3rd trimester of pregnancy, fetus produces own
intense physical exercise ( runner’s amenorrhea);
thyroid hormones
prolactinoma
 If mother has graves disease when she becomes
Any secondary cause of chronic hypogonadism can
pregnant, her anti-thyroid antibodies will cross the
induce pathologic bone loss, resulting in osteopenia or if
placenta- leading to fetal hyperthyroidism
severe, osteoporosis (athlete’s triad) constituted of
amenorrhea, eating disorders, and osteoporosis
Detection of Fetal abnormalities
Amniotic fluid
Hypergonadotropic hypogonadism
 Provides an environment in which fetus can move, acts
Characterized by ovarian failure resulting in elevation of FSH
as cushion against possible injuries, maintains constant
concentrations, with or without LH elevations. Exemplified by
temperature for the fetus
menopause Occurs between ages 45 to 55 years
 Transports nutrients & electrolytes into the fetal
circulation
 Menopause Female pseudohermaphroditism
 Time of permanent cessation of menstruation.  individuals with XX chromosomes but male genitalia
 Occurs when all follicles have atrophied. characteristics and virilization
 Plasma estrogen fall
Premature ovarian
failure is defined as
primary hypogonadism
in a woman before the
age of 40 years old. This
can be a result of
congenital chromosomal
abnormality (e.g.
Turner’s syndrome) or
premature menopause.

Disorders of female gonadal

function
Menstrual cycle ranges from 25
to 35 days with an average of 28
day duration.

 Amenorrhea [ primary: woman

Male pseudohermaphroditism
who has never menstruated by age of 16; secondary: has at
 individuals with XY chomosomes and possess two
least one menstruation followed by absence of menses for a
testes but female external genitalia
minimum of 3-6 months]
 Oligomenorrhea: infrequent irregular menstruation, with
cycle lengths in excess of 35 to 40 days
 Menorrhagia: uterine bleeding of more than 7 days

Polycystic ovary syndrome

 The most common disorder can present in many ways:
infertility, hirsutism, chronic anovilation, glucose intolerance,
dyslipidemia, hypertension

Hirsutism
 Abnormal, abundant, androgen-sensitive terminal hair  True hermaphroditism= individuals with both
growth in areas in which terminal hair follicles are not testicular and ovarian tissue
normally found in women
Common causes of hirsutism: idiopathic, polycystic ovary
syndrome. The uncommon causes are drugs (ex. Oral
contraceptives with adrogenic progestins), congenital adrenal
hyperplasia, hyperprolactinemia, Cushing syndrome, adrenal
tumors, and ovarian tumors.

Estrogen replacement therapy

 Increased incidence of breast cancer & venous clot
formation *Males and females both have male and female sex
hormones, but in varying levels.
Other disorders of reproductive organs
 Precocious puberty: appearance of THYROID GLANDS
secondary sexual characteristics before the
THYROID GLAND ANATOMY
age of 8 and can be
a. true (central)= caused by cerebral • Positioned in the lower
tumors, infection, trauma anterior neck
b. psuedoprecocious= puberty caused by • Shaped like a butterfly
adrenal or gonadal tumor • Made up of 2 lobes on
each side of the trachea,
with a band of thyroid tissue –called – isthmus-running
anterior to the trachea and bridging the lobes
• Fetal thyroid develops from an outpouching of the foregut
at the base of the tongue and migrates to its normal
location over the thyroid cartilage in the first 4-8 weeks
• By 11 weeks, thyroid gland begins to produce measurable
thyroid hormones
• Principal function of thyroid gland is to secrete hormones
that regulate neurologic development, oxygen
consumption, heat production, growth, sexual maturity, &
metabolism of proteins & carbohydrates
 • Thyroid hormones are unique biological molecules in that concentrated iodide is oxidized and bound with tyrosyl
they incorporate iodine in their structure. residues on thyroglobulin. This residues in production of
• Thus, adequate iodine intake (diet, water) is required for monoiodothyronine (MIT) and diiodothyronine (DIT) . This
normal thyroid hormone production. same enzyme also aids in coupling of two tyrosyl residues to
Major sources of iodine form triiodothyronine (T3) (one MIT residue + 1 DIT residue)
Iodized salt, iodine-enriched bread, dairy products, shellfish or thyroxine (T4 ) ( 2 DIT residues). The thyroglobulin complex
and Vitamins ( with branches now holding T3 and T4 is stored in the core
Iodine minimum requirement of thyroid follicle. TSH signals the follicular cell to ingest a
• Minimum requirement: 150 µg/day microscopic droplet of colloid by endocytosis. Inside the
• US intake: 240 - 740 µg/day follicular cell, these droplets are digested by intracellular
• If iodine intake drops below 50 µg/day, thyroid gland is lysosomes into T4, T3, and other products. T4 and T3 are then
unable to manufacture adequate amounts of thyroid secreted by the thyroid cell into the circulation. T4 is
hormones produced at a higher level than T3 . But T3 is 3 to 8 times
more metabolically active than T4 ( 80% of T4 is metabolized
into T3 ( 35%) o reverse T3 (rT3) (45%). ”T4 is considered as
the prehomone , while thyroglobulin is the prohormone”

Forms of iodothyronine 5--deiodinase

• Type 1: most abundant form; mostly in liver and kidneys;
largest contributor to the circulating T3
• Type 2:; found in brain and pituitary; maintains constant
THYROID HORMONES level of T3 in CNS
• Thyroglobulin is a glycoprotein manufactured by follicular cells.
• Between follicles are clear parafollicular C cells, which produce Carrier proteins
calcitonin •After thyroid hormones are produced, they are attached to:
• They are derived modification of tyrosine. o thyroglobulin/tyroxine-binding globulin (TBG)=(70%)
 These are: o transthyretin- previously called Thyroid binding
 tetraiodothyronine (T4; usually called thyroxine) prealbumin or TBPA (20%)
 triiodothyronine (T3) o albumin (10%) and stored in colloid until they are
excreted.
Thyroglobulin is rich in tyrosine • Level of thyroid hormones in the circulation can be
affected by the amount of binding protein available for
carrying these hormones
• Ex. High estrogen=high TBG; high TBG=high bound
thyroid hormones = leading to high total T3 & T4
• When released into the circulation, only 0.04% of T4 and
0.4% of T3 are unbound by proteins and available for
hormonal activity
• Unbound Thyroid T3 & T4 are called free T3 & freeT4 (f T3
& fT4)

Inhibition of thyroid hormone synthesis

• Thiocyanate & perchlorate inhibit Iodine uptake
• Iodination of tyrosine residues in thyroglobulin is
inhibited by carbimazole & propylthiouracil

Peripheral conversion of thyroid hormones

• 80% of T3 comes from T4 which is de-iodinated (outer
β ring) in the liver, muscles, kidneys
• 20% of T3 comes from thyroid glands

T4 to T3 conversion is reduced by:

• Systemic illness
• Prolonged fasting
Tyrosyl residues are iodinated to become the building blocks • β- blockers like propranolol or amiodarone (200 mg
of the thyroid hormones. On the other side of the follicle, of this drug contains 75 mg of iodine)
iodine is actively transported into the cell by Na/I symporter T4 to T3 conversion is increased by:
located on the basement membrane. Inside the thyroid cell, • Drugs that induce hepatic enzyme activity like
iodine diffuses across the cell to the apical side of the follicle. phenytoin
On reaching the core of colloid, it is catalyzed by a
membrane-bound enzyme called thyroid peroxidase (TPO),
 Control/Regulation of thyroid hormones Effects of thyroid hormones
• Thyroid hormone synthesis and secretion is regulated by two • Thyroid hormones are essential for normal growth of
main mechanisms: tissues, including the nervous system.
- an “autoregulation” mechanism, which reflects the available • Lack of thyroid hormone during development results in
levels of iodine short stature and mental deficits (cretinism).
- regulation by the hypothalamus-anterior pituitary-thyroid • Thyroid hormone stimulates basal metabolic rate.
axis
What are the specific actions of thyroid hormone on body
Autoregulation of Thyroid Hormone Production systems?
• The rate of iodine uptake and incorporation into • Required for GH and prolactin production and secretion
thyroglobulin is influenced by the amount of iodide available: • Increases intestinal glucose reabsorption (glucose
- low iodide levels increase iodine transport into follicular transporter)
cells • Increases mitochondrial oxidative phosphorylation (ATP
- high iodide levels decrease iodine transport into follicular production)
cells • Increases activity of adrenal medulla (sympathetic;
Thus, there is negative feedback regulation of iodide glucose production)
transport by iodide. • Induces enzyme synthesis
• Result: stimulation of growth of tissues and increased
metabolic rate. Increased heat production (calorigenic
effect)

Effects of Thyroid Hormone on Nutrient Sources

• Effects on protein synthesis and degradation:
-increased protein synthesis at low thyroid hormone
levels (low metabolic rate; growth)
-increased protein degradation at high thyroid hormone
levels (high metabolic rate; energy)
• TSH is composed of one alpha subunit & one beta subunit. • Effects on carbohydrates:
• The alpha subunit is similar with alpha subunits in LH, FSH, -low doses of thyroid hormone increase glycogen
hCG synthesis (low metabolic rate; storage of energy)
• The beta subunit is specific for stimulating the thyroid gland - high doses increase glycogen breakdown (high metabolic
• The thyroid gland is capable of storing many weeks’ worth rate; glucose production)
of thyroid hormone (coupled to thyroglobulin).
• If no iodine is available for this period, thyroid hormone One Major Target Gene of T3: The Na+/K+ ATPase Pump
secretion will be maintained. • Pumps sodium and potassium across cell membranes to
• Laboratory assessment of TRH is not clinically useful maintain resting membrane potential
• Measurement of TSH & fT4 are more useful in assessing • Activity of the Na +/K+ pump uses up energy, in the form of
hyperthyroid or hypothyroid states ATP
Stimuli to release thyroid hormones : • About 1/3 of all ATP in the body is used by the Na +/K+
ATPase
• T3 increases the synthesis of Na+/K+ pumps, markedly
increasing ATP consumption.
• T3 also acts on mitochondria to increase ATP synthesis
• The resulting increased metabolic rate increases
thermogenesis (heat production).

Thyroid Hormone Actions which Increase Oxygen

Consumption
• Increase mitochondrial size, number and key enzymes
Other Factors Regulating Thyroid Hormone Levels • Increase plasma membrane Na-K ATPase activity
• Diet: a high carbohydrate diet increases T3 levels, • Increase futile thermogenic energy cycles
resulting in increased metabolic rate (diet-induced • Decrease superoxide dismutase activity
thermogenesis).
• Low carbohydrate diets decrease T3 levels, resulting in Effects of Thyroid Hormones on the Cardiovascular System
decreased metabolic rate. • Increase heart rate
• Cold Stress: increases T3 levels in other animals, but not in • Increase force of cardiac contractions
humans. • Increase stroke volume
• Other stresses: increased or decreased? • Increase Cardiac output
• Any condition that increases body energy requirements • Up-regulate catecholamine receptors
(e.g., pregnancy, prolonged cold) stimulates
hypothalamus  TRH  TSH (Pit)
Effects of Thyroid Hormones on the Respiratory System • Its sensitivity led to detect “subclinical disease” or a
• Increase resting respiratory rate mild degree of thyroid dysfunction
• Increase minute ventilation
• Increase ventilatory response to hypercapnia and B. SERUM fT4 & total T4
hypoxia  measured using RIA, chemiluminometric assay
 Since 99% of thyroid hormone is protein bound, any
Effects of Thyroid Hormones on the Renal System non-thyroid disease may also result to elevation of
• Increase blood flow result
• Increase glomerular filtration rate  In Euthyroid , about a third of the binding sites on TBG
are occupied by T4 and the remainder are unoccupied
Effects of Thyroid Hormones on Oxygen-Carrying Capacity  In hyperthyroidism, both total and fT4 concentrations
• Increase RBC mass are increased and the number of unoccupied binding
• Increase oxygen dissociation from hemoglobin sites on TBG is decreased
 In hypothyroidism, opposite of the above
Effects of Thyroid Hormones on Intermediary Metabolism
• Increase glucose absorption from the GI tract An increase in plasma TBG causes increase in bound
• Increase carbohydrate, lipid and protein turnover T4, unoccupied binding sites but no change in fT4;
• Down-regulate insulin receptors brought by:
• Increase substrate availability • High estrogen concentration during pregnancy or in
newborn infant
Effects Thyroid Hormones in Growth and Tissue • Estrogen therapy
Development • Inherited TBG excess
• Increase growth and maturation of bone
• Increase tooth development and eruption An decrease in plasma TBG causes decrease both in
• Increase growth and maturation of epidermis, hair bound T4, unoccupied binding sites but no change in
follicles and nails fT4; brought by:
• Increase rate and force of skeletal muscle • Severe illness
contraction • Loss of low-molecular-weight proteins like nephrotic
• Inhibits synthesis and increases degradation of syndrome
mucopolysaccharides in subcutaneous tissue • Androgen treatment
• Inherited TBG deficiency
Effects of Thyroid Hormones on the Nervous System
• Critical for normal CNS neuronal development C. PLASMA TOTAL or fT3
• Enhances wakefulness and alertness  Not routinely done because normal T3conc is very low
• Enhances memory and learning capacity  In hyperthyroidism, Plasma total or fT3 is high, usually
• Required for normal emotional tone occurs earlier than T4 or fT4
• Increase speed and amplitude of peripheral nerve  Due to binding to protein, it is preferable to measure
reflexes fT3 than total T3

Effects of Thyroid Hormones on the Reproductive System D. THYROGLOBULIN

• Required for normal follicular development and  A prohormone protein synthesized and secreted
ovulation in the female exclusively by thyroid follicular cells.
• Required for the normal maintenance of pregnancy
 An ideal tumor marker
• Required for normal spermatogenesis in the male
 Measured by double antibody RIA, ELISA,
immunoradiometric assay, immunochemilumiscent
TESTS FOR THYROID EVALUATION
assay methods
A. THYROID STIMULATING HORMONE
 Result is affected by presence of antithyroglobulin
 TSH generation assays are capable of diagnosing
autoantibodies
primary hypothyroidism with elevated levels of TSH:
 2nd generation TSH immunometric assays, with
E. THYROID AUTOIMMUNITY
detection limits of 0.1 mU/L, can screen
 Tests for TSH receptor antibodies [ Trab, TSHRab]
hyperthyroidism.
 Tests for thyroid stimulating antibodies
 3rd generation TSH chemiluminometric assay, with
[ Trab, thyroid stimulating immunoglobulin (TSI)]
detection limits of 0.01 mU/L, can distinguish
euthyroidism and hyperthyroidism

3rd generation TSH assay

• Routinely used to monitor and adjust thyroid
hormone replacement therapy
 Prevalence of thyroid autoantibodies Interpretation of thyroid tests
Low free T4 Normal free T4 High free T4
antibody Gen Graves’ Autoimmune
Low Secondary Subclinical Hyperthyroidism
pop dse hypothyroidism TSH hypothyroidism hyperthyroidism
Secondary severe Nonthyroidal
Antithyro 3% 12-30% 35-60% nonthyroidal illness illness
globulin Normal Primary Normal Artifact
TSH hypothyroidism
Thyroid 10- 45-80% 80-99% Severe nonthyroidal Primary hyperthyroidism
peroxidase 15% illness
Laboratory draw within 6
Anti-TSH 1-2% 70-100% 6-60% h of thyroxine dose
receptor High Primary Subclinical Test artifact
TSH hypothyroidism hypothyroidism
Secondary
hyperthyroidism
Thyroid hormone
F. THYROTROPIN RELEASING HORMONE TEST resistance
• Used to confirm diagnosis of 2º hypothyroidism or
rarely used to detect early primary hypothyroidism
Disorders of the thyroid
• May cause allergic reactions
Hypothyroidism is defined as low free T4 level with a
normal or high TSH
G. OTHER EVALUATIVE THYROID TOOLS
G.1. Nuclear medicine evaluation
• Radioactive iodine is useful in assessing the metabolic
function of the thyroid and for evaluation and treatment of
thyroid cancer.
• When Radioactive iodine is orally given, a percentage of the
dose is taken up by the thyroid.
• This percentage is called radioactive iodine uptake [RAIU]
• RAIU is tested along with TSH
• TSH stimulates iodine uptake

Interpretation of RAIU Due to many metabolic effects of thyroid hormone,

• High uptake; high TSH = metabolically active thyroid gland. hypothyroidism can lead to:
This also means active hypothalamus-pituitary stimulation • hyponatremia [ due to low ADH secretion]
• High uptake; undetectable TSH= primary hyperfunction • high CK [due to myopathy]
• Low uptake; Low TSH= metabolically inactive thyroid. • hyperlipidemia
• hyperprolactinemia
Other uses of RAIU • macrocytic anemia, with high MCV [ either as a
• “hot nodules” are NOT thyroid cancer and take up much result of a decreased demand for oxygen carrying
radioactive iodine capacity or autoimmune pernicious anemia]
• “cold nodules” or intermediate nodules maybe cancerous or • Reduced sex-hormone-binding globulin (SHBG)
benign. They less likely take up iodine. • Reduced glomerular filtration rate

G.2. Thyroid ultrasound Types of hypothyroidism

• For characterization of palpable thyroid abnormalities • Primary: thyroid gland dysfunction
• Can detect less than 1 cm nodules • Secondary: pituitary dysfunction
• Tertiary : hypothalamic dysfunction
G.3. Fine-needle aspiration biopsy
• FNAB is the 1st step and accurate tool in the evaluation of
thyroid nodules
• Allows prompt identification and treatment of thyroid
malignancies
• Avoids unnecessary surgery in benign cases

Manner of reporting FNAB

• Nondiagnostic
• Malignant  Impairment leads to compensatory ↑ in TSH levels
• Suspicious for malignancy → hypertrophy and hyperplasia of follicular cells →
• Indeterminate or suspicious for neplasm gross enlargement of gland
• Follicular lesion of undetermined significance
• Benign American Thyroid Association Guidelines for
hypothyroidism Screening: Measurement of TSH
• At age 35
• Every 5 years after age 35
• More frequently with risk factors or symptoms:
goiter, family history, lithium or amiodarone use
 Myxedema Symptoms of thyrotoxicosis
• Means “mucous swelling”. increased in metabolic rate evidenced by
• It is a full blown hypothyroid • heat intolerance fine tremor
syndrome among adults • Tachycardia weight loss
• if due to iodine deficiency, goiter • Tiredness Anxiety
occurs • Sweating diarrhea

Thyroid hormone resistance Biochemical features of hyperthyroidism

• An autosomal dominant disorder characterized by diminished • Hypercalcemia
responsiveness of target tissues to thyroid hormone • Hypocholesterolemia [ due to high LDL clearance]
• Hypokalemia
HASHIMOTO THYROIDITIS • Plasma SHBG is increased
• Most common cause of hypothyroidism • Plasma CK maybe increased with thyrotoxic myopathy
• Autoimmune.
• Abnormalities with binding of Causes of hyperthyroidism
proteins & thyroid hormones A. Autonomous secretion
• 45-65 years, F:M = 10-20:1 • Graves’ disease
• Painless symmetrical • Toxic multinodular goiter (Plummer’s disease) or a
enlargement single functioning nodule (occasionally adenoma)
• Risk of developing • Subacute thyroiditis
• B-cell non-Hodgkin’s • Some metastatic thyroid carcinomas
lymphoma
• Other concomitant autoimmune diseases B. Excessive ingestion of thyroid hormones or iodine
• Endocrine and non-endocrine • Amiodarone
• Immune systems reacts against a variety of thyroid antigens • Thyrotoxicosis factitia ( self-administration of thyroid
• Progressive depletion of thyroid epithelial cells which are hormones)
gradually replaced by mononuclear cells → fibrosis • Administration of iodine to a subject with iodine
deficiency goiter
CRETINISM • Jod-Basedow syndrome
• it is a severe hypothyroidism in infants.
• it reflects a genetic deficiency of the C. Rare causes
fetal thyroid gland or maternal factors. • Tumor secreting TSH
• The child is mentally retarded, has a • Struma ovarii ( thyroid tissue in an ovarian teratoma)
short disproportionately sized body and • Excess hCG (ex. Molar pregnancy or
thick tongue and neck choriocarcinoma)
• Replacement hormone therapy can prevent it to happen. • Pituitary resistance to thyroid hormone
• Developmental abnormalities and mental retardation are
not reversible once they appear

HYPERTHYROIDISM OR THYROTOXICOSIS
• is a constellation of findings
that result when peripheral
tissues are presented with,
and respond to, an excess of
thyroid hormone
• Is a result of excessive
thyroid hormone ingestion,
leakage of stored thyroid hormone, excessive thyroid gland
production.

Laboratory investigation of suspected hyperthyroidism

• Plasma fT4 and fT3 are elevated and TSH is low in clinically
thyrotoxic patients
• Suppressed plasma TSH and elevated plasma fT3 confirms
the diagnosis of hyperthyroidism. In T3 thyrotoxicosis, fT4 Rare hyperthyroidism states
maybe normal. • Metastatic thyroid carcinoma can produce thyroid
• If plasma fT4 is raised and TSH concentration is normal, this is hormones
biochemical euthyroid hyperthyroxemia • Patients with choriocarcinoma or molar hydatidiform
pregnancy have high hCG hormone that can
stimulate TSH receptor
 Graves’ Disease Euthyroid hyperthyroxinemia
• Most common cause of thyrotoxicosis. • Either the plasma total or fT4 concentration is abnormally
• Autoimmune disease with genetic raised without clinical evidence of thyroid disease.
susceptibility associated with HLA-B8 • Maybe transient or persistent, with high, normal, or low
and DR3 total fT3 concentrations.
• Characterized by goiter, • When doing lab assessment, heterophilic Ab to fT4 must
ophthalmopathy with exophthalmos and dermopathy be removed with polyethylene glycol (PEG) to avoid
(pretibial myxedema- there is orange peel texture) interfering the test

Grave’s ophthalmopathy Nodular disease

• There is orbital soft tissue swelling, injection of conjunctivae, • As one ages, chance of developing nodular disease
proptosis (forward protrusion of eye), double vision (due to increases.
orbital muscle involvement), corneal disease ( due to • Most benign but may develop to toxic multinodular goiter
difficulty of closing the eyelids) • A toxic multinodular goiter involves an enlargement of the
thyroid gland with low TSH and normal thyroxine levels
Interpretation of thyroid function tests

• Female:Male = 7:1
• 3rd to 4th decades
• ↑ levels of fT4 &/or T3
• ↓ levels of TSH in blood
• ↑ uptake of radioactive iodine
• (+) TSIs & TSH receptor Ab

Toxic adenoma and multinodular gioter

• Caused by autonomously functioning thyroid gland
• Treatment includes surgery, radioactive iodine

Drug induced thyroid dysfunction

Amiodarone-induced thyroid disease
• Amiodarone is for cardiac arrhythmias
• 37% of MW is iodine
• Blocks T4 to T3 conversion = hypothyroidism
• Amiodarone can lead to hyperthyroidism in 3% of patients

SUBACUTE THYROIDITIS
• A destructive thyroiditis resulting in the release of preformed
thyroid hormones
• Subtypes: granulomatous or painful, lymphocytic or silent and
painless, and postpartum
• Painful or granulomatous subacute thyroiditis is thought to be
viral & is associated with Human Leucocyte Antigen (HLA)-
Bw35
• Lymphocytic is autoimmune
• Post-partum thyroiditis is also an autoimmune thyroiditis
• Very high thyroid hormones, no radioactive iodine uptake by
thyroid glands
• Clinical course :
a) 6-8 weeks of thyrotoxicosis
b) 2-4 months of hypothyroidism
c) return to euthyroidism in 90% of patients
• Post partum thyroiditis is usually self limiting ; occurs 1-6
months after delivery

Euthyroid sick syndrome

• Normal functioning thyroid gland woth abnormal levels of TBG
• Low plasma total of fT4
• TSH maybe normal or slightly low or high
• TSH response to TRF maybe impaired
• There maybe impaired conversion of fT4 to fT3
= difficult interpretation of thyroid function tests