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