Exocrine systems (glands with ducts)
Exocrine glands
Gland portion + ducts
• Salivary glands
• Lacrimal glands
• Sweat glands and sebaceous glands
• Mammary glands
• Prostate glands
• Exocrine pancreas and liver
• Etc. etc.
Secretion products include
• Enzymes (amylase, proteases, lysozymes, immunoglobulins, etc.)
• Mucus (mucins, glycoproteins, lactoferrins)
• Water and salts
Many exocrine glands have acinar structures that initiate secretion process
Eccrine sweat gland Pancreas
Mammary gland Prostate gland
Saliva formation occurs in two stages
1. Primary secretion by the acinus
2. Modification by duct cells (reminiscent of renal tubular function)
1. 2.
Reaborption of Na+ and secretion of K+ in second stage
(making saliva hypotonic)
Role of myoepithelial cells in acini
Cancers affecting exocrine organs are widespread
• Breast cancer
• Prostate cancer
• Pancreatic cancer
Adenocarcinomas of the ducts are very common forms
Introduction to endocrine systems
Hormones and Endocrine Glands
• Substance produced by a specific cell type usually
concentrated in a single relatively small organ
• Hormones are transported by blood to target tissues (no
duct is present).
• Activates specific receptors to produce stereotypical
responses that are long in duration compared to neuronal
responses.
• A single hormone may affect many or just a few target
tissues.
Hormone production by “classic” endocrine glands
Pituitary: Hypothalamus: Pineal gland:
•Growth hormone •GHRH, CRH, TRH, GnRH •Melatonin
•Prolactin •Somatostatin
•ACTH, MSH Thyroid gland:
•TSH Pancreas: •T3, T4
•FSH and LH •Insulin •Calcitonin
•Glucagon
•Oxytocin
Adrenal cortex: Parathyroid glands:
•Vasopressin (ADH)
•Cortisol •PTH
Ovaries: •Aldosterone
•Estrogens •Androgens
•Progesterone
Adrenal medulla:
Testes: •Epinephrine
•Androgens
Examples of hormone secretion from organs
that have other primary functions
Blood vessel endothelium: Heart muscle:
•Endothelins •ANP
•NO
•Prostanoids Kidney:
•Erythropoietin
Immune system: •Renin
•Cytokines
Intestines:
•Gastrin
Placenta: •Cholecystokinin
•Many hormones •Secretin
•Incretins
Adipocytes: •Many others
•Leptin
•Adiponectins This list is not complete!
Classifications of non-neuronal signals between cells
• Endocrine: from gland via blood to a distant target
• Neurocrine: secretion from a nerve terminal into blood to a distant target
• Paracrine: signaling through ECF to neighboring cells of different types
• Autocrine: signaling to neighboring cells of the same type or to the
secreting cell itself
A substance secreted from a cell can work in more than one of these ways
Chemical classes of hormones
• Amines (derived from amino acids)
• Peptides and proteins (many different hormones)
• Steroids (derived from cholesterol)
• Glucocorticoids (cortisol)
• Mineralocorticoids (aldosterone)
• Sex hormones (estrogens, androgens, progestins)
• Other highly lipophilic molecules
• Melatonin
• Thyroid hormones
• Active forms of vitamin D
Biosynthesis of a protein hormone: Insulin
Cleavage of signal
peptide
Folding and formation of
disulfide bonds in ER
proinsulin as it enters the Golgi
Additional processing in
trans-Golgi
Biosynthesis of peptide hormones: ACTH (corticotrophin) and
bioactive peptides derived from pro-opiomelanocortin (POMC)
POMC cleavage products
POMC
Anterior and intermediate
lobes of pituitary
-MSH ACTH -lipotropin
Anterior and
Intermediate lobe
intermediate lobes
-MSH CLIP -lipotropin -endorphin
-MSH Met-enkephalin
POMC is expressed in the pituitary gland in two types of cells known as corticotrophs (in the
anterior lobe) and melanotrophs (in the intermediate lobe)
Biosynthesis of the lipophilic hormone melatonin
Tryptophan 5-OH-Tryptophan
hydroxylase decarboxylase
Serotonin N-
Acetyltransferase
Hydroxyindole-O-
methyl transferase
Serotonin N-Acetyltransferase is regulated by cAMP, Ca2+, and many other signals
Major pathways of steroid biosynthesis:
Progestins Glucocorticoids
Mineralocorticoid
Estrogens
Don’t freak out, I don’t expect you
to remember these!
Androgens
Release of protein, peptide and
amine hormones
Exocytosis from secretory granules (similar to synaptic vesicles)
• Peptide and protein hormones produced by proteolytic cleavage from
precursors, occurs partly within the secretory granule.
• Stimulus for release is [Ca2+]i (influx from outside or mobilization of
internal stores).
• Release is triggered by cell receiving some other neuronal or
endocrine stimulus. Often this will trigger an action potential in the
secretory cell.
Release of lipophilic hormones
Steroid hormones, vitamin D, melatonin
Cannot be stored in vesicles and are released upon synthesis
by simple diffusion across the plasma membrane
Rate of release is determined by the activity of the rate-limiting
enzyme in their biosynthetic pathway.
Negative feedback regulation of hormone secretion
Hormone
Gland Target tissue(s)
inhibition
Product(s)
The negative feedback pathway may entail several different steps and
there may be a delay, resulting in oscillating blood concentrations
The hypothalamic/pituitary axis I
The hypothalamic/pituitary axis II
Hypophyseal portal veins
Anterior pituitary
(adenohypophysis)
Posterior pituitary
(neurohypophysis)
Definition (from Latin) Definition (from Greek)
adeno meaning “like a gland” physis meaning “an object that sticks out”
neuro meaning “like a neuron” hypo meaning “less than” or in this case “below or underneath”
Control of peripheral tissues by anterior pituitary hormones (secreted from
different types of anterior pituitary cells)
1.
2.
3.
Feedback loops between hypothalamus-anterior pituitary-peripheral tissues
(-)
CRH 1. Hypothalamus
(+)
Negative feedback
loop ACTH
2. Corticotrophs in
anterior pituitary
(+)
cortisol 3. Adrenal cortex
Many other cortisol-sensitive
target organs
Negative feedback often occurs at several levels
Stress etc.
inhibition
CRH secretion in hypothalamus
stimulation
ACTH secretion in pituitary
inhibition
plasma ACTH
cortisol secretion in adrenals
plasma cortisol
Clinical correlation: Cushing’s Disease from a pituitary microadenoma
• A 36 year old female with back pain of several months duration (ranging from 4-7 on a 1-10 scale).
Complaint of fatigue and muscle weakness and recent menstrual irregularity. The face was quite red
and flushed (facial plethora) and had a somewhat rounded appearance from fat redistribution (moon
face) with unusual amounts of fine hair and some acne. Bruises were present on back and legs. Patient
gained 35 lbs. over recent five months and there were some supraclavicular fat deposits on the top of
the back. Patient was not taking any medications except ibuprofen for pain. Patient is not pregnant.
• Blood pressure 142/95, normal heart rate and respiration. Blood glucose elevated.
• Following lab tests were obtained after referral to endocrinologist:
Glucose tolerance test suggested moderate insulin resistance.
X-rays showed marked osteoporosis.
Thyroid hormones were normal.
Urinary and serum cortisol and serum ACTH were markedly elevated. Serum corticotrphin was
very low. Overnight administration of dexamethasone (a cortisol analog) only caused slight
reduction in serum cortisol and serum ACTH.
MRI examination revealed small pituitary tumor.
• Patient was referred to neurosurgeon who ablated tumor by transsphenoidal resection. ACTH levels
and serum cortisol were minimal after tumor ablation and remained very low 6 weeks after operation
• Patient was maintained on current dose of hydrocortisone (morning and late afternoon).
• MRI revealed no recurrence of tumor one year later. Most patient symptoms were markedly improved
Symptoms of Cushing’s disease (and also chronic prednisone treatment)
Mid-scapular fat deposit Facial plethora Purple striations in
abdominal area
Osteoporosis
Example of Cushing’s disease before and after pituitary surgery
Typical target tissue responses to peptides and amines
The time frame is seconds to minutes
Tyrosine kinase type receptors
Tyrosine kinase type receptors and the responses to
hormones and growth factors: Insulin signaling
PI3 kinase
GRB2
SOS
ERK-MAPK
Many substrates Many substrates
The time frame is minutes to hours
Different limbs of a tyrosine kinase receptor signaling
cascade affect different cellular functions
Tyrosine kinase type receptors initiate the most
pleiotropic of all classes of signaling cascades
Nuclear receptors and cell signaling: General scheme
These receptors are classically regarded as affecting cell function
primarily by regulating gene transcription. This imposes a time frame
of several hours to several days.
DNA-binding domain of nuclear receptors
The receptor
here is a dimer
Nuclear receptors enhance (and in some cases repress) gene
expression as part of a large transcriptional regulatory complex
Nuclear receptors comprise a large family: 48 encoded in the human genome
‘Orphan receptors’: Receptors for
which the physiological ligand is
unknown.
Transport of hormones to target tissues
• Move freely in blood:
– Amines (e.g. epinephrine)
– Most proteins and peptides (e.g. ADH, ACTH, insulin)
• Specific transport globulins (secreted from liver):
– Steroids (e.g. estrogen, aldosterone, testosterone)
– Vitamin D
– Thyroid hormones
Binding of lipophilic hormones to specific plasma
proteins increases their half-life in the circulation
% Bound to plasma Half-life in plasma
proteins
Thyroxine (T4) 99.7 6 days
T3 91 1 day
Cortisol 72 2 hr
Testosterone 61 < 30 min
