MD4 Endocrinology

Hormone Classification and Synthesis

Peptide/Proteins synthesized from A.A.
o Biosynthetic pathway similar to any other protein mRNA transcription from a gene,
translation
o Each hormone generally from 1 gene
o Nucleus mrNA transcription mRNA to cytoplasma and translated on ribosomes
preprohormone (with signal peptide at N terminus) in ER, signal peptide is removed
converting it into prohormone in Golgi packaged into secretory vesicles in vesicles,
prohormone is cleaved into final hormone
o Stored in secretory vesicles until stimulation
Steroid derivatives of cholesterol
o Synthesized and secreted by adrenal cortex, gonads, corpus luteum, and placenta
o E.g. cortisol, aldosterone, estradiol and estriol, progesterone, testosterone, and
1,25-dihydroxycholecalficerol
Amine derivatives of tyrosine
o Catecholamines and thyroid hormones
o Derivatives of A.A. tyrosine
Summary of Hormones:

Classic Endocrine Glands:

Hypothalamus
Anterior Pituitary
Posterior Pituitary
Thyroid
Parathyroid

Adrenal Cortex
Adrenal Medulla
Gonads
Placenta
Pancreas
Kidney

Regulation of Hormone Secretion:

Neural mechanisms nerves cause secretion of hormones
Feedback mechanisms physiologic response to a hormone has effects upstream affecting secretion rate
Negative Feedback:
Hormone action, directly or indirectly, inhibits further secretion of hormone
Long-loop feedback hormone has feedback on hypothalamic-pituitary axis
Short-loop feedback anterior pituitary hormone feedback on hypothalamus (ultra-short loop is
hypothalamic hormone feedback inhibition on hypothalamus itself)
Positive Feedback:
Hormone action, causes further secretion of the hormone (more secretion)
Example: in follicular phase of menstrual cycle, ovaries secrete estrogen acting on AP to secrete
FSH and LH FSH and LH cause ovulation and stimulation of estrogen secretion AP secretes
more FSH and LH more estrogen
Example: Oxytocin dilation of cervix causes posterior pituitary to secrete oxytocin uterine
contraction more dilation of cervix more oxytocin repeat
Regulation of Hormone Receptors:
Dose-response relationship: magnitude of response correlated with hormone concentration, up to a point
then levels off
Sensitivity: hormone concentration that produces 50% maximal response
More hormone needed to produce 50% maximal response decreased sensitivity
Less hormone needed to get 50% maximal response increased sensitivity
Responsiveness:
Changing number of receptors
Changing affinity of receptors for hormone
Down-regulation:
Number or Affinity of receptors decreased on target tissue
Can be degradation of existing receptors, decreasing synthesis of new receptors or inactivating
receptors
Reduction in sensitivity of target tissue
Can reduce affinity of other hormone receptors e.g., T3 decreases sensitivity of TRH receptors on
AP
Up-regulation:
Number or Affinity of receptors increased
Can be increasing synthesis of new receptors, decreasing degradation of existing receptors, or
activation of receptors
Example: prolactin receptors in breast; GH number of receptors in skeletal muscle and liver

Mechanism of Hormone Action and Second Messengers:

Hormone-receptor complex are often coupled to effector proteins by G proteins (GTP-binding proteins)
G-Proteins are usually enzymes (eg adenylyl cyclase or phospholipase C)

Activation of effector proteins second messenger (eg cAMP or IP3) is produced amplification of
original signal and causes downstream actions
Major Mechanisms of hormone action on target cells
1) G Proteins
a. Membrane-bound proteins that couple hormone receptors to effector enzymes (e.g. adenylyl
cyclase)
b. Heterotrimeric (, , subunits)
i. can bind GDP (G-protein inactive) or can bind GTP (G-protein active)
ii. G-protein activity can be modified with GTPase activating factors or GRFs (facilitate
GDP leaving)
c. Stimulatory or inhibitory (also activity)
2) Adenylyl Cyclase/cAMP
a. Hormone binds to receptors, coupling by a Gs or Gi protein activation or inhibition of
adenylyl cyclase increase or decreases in intracellular cAMP
b. cAMP (second messenger) amplifies signal
c. cAMP is degraded to 5AMP by phosphodiesterase

3) Phospholipase C
a. IP3/Ca2+ is second messenger
b. Hormone binds to a receptor and coupling via Gq protein to phospholipase C increase in
intracellular levels of IP3 and Ca2+ final actions
c. IP3 and diacylglycerol from PIP2 (membrane phospholipid)
d. Diacylglycerol + Ca2+ activate protein kinase C

4) Steroid Hormone (and Thyroid Hormone Mechanism)

a. Binding to cytosolic or nuclear receptors initiating DNA transcription and synthesis of new
proteins
b. Act slowly (hours)
Process:
1) Steroid diffuses across cell membrane and enters cell and binds to receptor in cytosol or
nucleus
2) Receptor conformational change enters nucleus of target cell
3) Complex dimerizes and binds to Steroid-Responsive Elements (SREs) Acts as a
transcription factor new mRNA transcribed leaves nucleus and is translated new
proteins

5) Tyrosine Kinase
e. Insulin and insulin-like growth factors (IGFs) act through this mech

Hypothalamus-Pituitary Relationships
Infindibulum: stalk that connects the hypothalamus to pituitary
Hypothalamus Posterior Pituitary Relationship:
Posterior Pituitary
Derived from neural tissue
Secretes neuropeptides (secreted by neurons)
o ADH acts on kidney (supraoptic)
o Oxytocin acts on breast and uterus (paraventricular)
Neural connection between hypothalamus and posterior lobe
Posterior pituitary is collection of nerve axons with cell bodies in hypothalamus (Supraoptic and
paraventricular nuclei within hypothalamus)
Hypothalamus Anterior Pituitary Relationship:
Anterior Pituitary
Derived from primitive foregut
Collection of endocrine cells
Secretes neuropeptides (secreted by neurons)
o TSH
o FSH
o LH

o GF
o Prolactin
o ACTH
Linked by Hypothalamic-hypophysial portal blood vessels
Most of blood supply is venous blood from hypothalamus
Basic Mechanism
o Hypothalamic neurons, upon stimulation, release hormones into hypothalamic tissue and
enter capillary plexuses
o Blood drains (venous blood) into the hypophysial portal vessels and is delivered to anterior
lobe of pituitary
o Hypothalamic hromones act on cells of anterior lobe causes release or inhibition of release
of anterior pituitary hormones

Hormones of AP:
Anterior Pituitary:
Hormone
Synthesized by
GH
Somatotrophs

Stimulated by
GHRH

Inhibited by
GHIH and IGF-1
(feedback
inhibition)

Target Organ
Liver

TSH

Thyrotrophs

TRH

T3

Thyroid Gland

ACTH

Corticotrophs

CRH

Adrenal Cortex

LH + FSH

Gonadotrophs

Prolactin

Lactotrophs

GnRH, sex
steroids
PRH and TRH

Glucocorticoids
(eg cortisol)
negative
feedback
Prolactin, sex
steroids
Dopamine

MSH

Corticotrophs

--

--

Melanocytes in
skin

Betaendorphins

Corticotrophs

--

--

Unknown

Reproductive
organs
Mammary
glands and
reproductive
organs

Effect
Stimulates IGF1 production
and opposes
insulin
Stimulates
thyroxine
release
Stimulates
glucocorticoid
and androgen
release
Release of sex
steroids
Promotes
growth of these
organs and
initiates
lactation
Stimulates
melanin
synthesis
May be
involved in pain
control

Families of AP Hormones:
1) TSH, FSH, and LH
a. All Glycoproteins
b. Sugar moieties covalently linked to asparagine residues
c. Consists of (same in all 3) and (different for each hormone) subunit
2) ACTH
3) GH and Prolactin

Normal Physiology:
Steroid Hormones
Diffuse across plasma membrane and form complexes with cytosolic or nuclear receptors
Complexes activate transcription of genes
Manifestation of effects takes hours to days b/c of gene expression and protein translation
Examples:

o Testosterone, estrogen, progesterone, cortisol and aldosterone

Cholesterol is precursor to all steroid hormones

Peptide Hormones
Binds to cell surface receptors
Effects:
o Activation or inhibition of enzymes
o Altering Membrane proteins
o Affecting Cellular Trafficking
Occur rapidly, seconds to minutes
Can ALSO stimulate gene expression (delayed just like hormone effects)
Examples:
o Insulin
o PTH
o Vasopressin
o Oxytocin
Classes of Membrane-Spanning Receptors
1) Tyrosine and serine kinase receptors
a. Peptide hormone binds to extracellular domain of receptor and initiates signal transduction
cascade
b. Autophosphorylation of kinase receptor and subsequent phosphyrlation of downstream
target protein
c. Activation or inhibition of protein
d. E.g. insulin, growth factors
2) Receptor-linked kinases
a. Receptor associated tyrosine kindase phosphorylation
b. E.g. GH, prolactin, cytokines
3) G-coupled receptors
a. Binding of hormone/agonist to G-protein-coupled receptors GTP replaces GDP
dissociation of subunits (alpha and beta-gamma subunit) dissociated subunits have
different effects
4) Ligand-gated ion channels
a. Activation of ligand0gate ion channels influx or efflux of ions into the cell
b. E.g. binding of ACh to receptor results in influx of Na+ into cell
Endocrine, Paractine, and Autocrine
1) Endocrine
a. Affect their target organs at considerable distance from site of secretion
2) Paracrine
a. Act locally on adjacent cells and tissues
3) Autocrine
a. Secretions from a cell that beind to receptors on same cell
b. Regulatory actions on that cell
4) Neuroendocrine
a. Specialized neurons secrete peptides into blood
Pituitary:
Located in sella turcica
Hormone
ADH

Synthesized by
Supraoptic
vasopressinergi
c neurons

Stimulated by
Raised
osmolarity; low
blood volume

Inhibited by
Lower
osmolarity

Target Organ
Kidney

Oxytocin

Paraventricular
oxytocinergic
neurons

Stretch
receptors in
nibble and
cervix;

Stress

Uterus and
mammary
glands

Effect
Increases
permeability of
collecting duct
to reabsorb
water
Smooth muscle
contraction
leading to birth
or milk ejection

estrogen

Sheehans Syndrome
Case:
38 y.o. woman
Massive postpartum hemorrhage stabilized with multiple transfusions
Inability to lactate
Lethargic and Weak and dizziness upon standing
Sparse axillary and pubic hair (less than before) and pulse rate increases by ~20bpm upon
standing
Injection of CRH blunted elevation of serum ACTH
Injection of GnRH analog blunted elevation of FSH and LH levels
Serum Prolactin low
Overview:
Sheehan syndrome is postpartum necrosis/infarction of the anterior pituitary
(adenohypohysis)
Posterior pituitary (neurohypophysis) is spared because it has a different embryonic origin
different blood supply
o Anterior pituitary from Rathkes Pouch (endodermal evagination of roof of mouth)
o Posterior pituitary is ventral
Pathophysiology:
During pregnancy hyperplasia of lactotrophs (produce prolactin) of anterior pituitary
minimal perfusion needed by tissue
Postpartum hemorrhage blood supply to anterior pituitary can become sufficiently inadequate
infarction
o Blood supply is sufficient but inadequate for the hyperplasia that occurred during pregnancy

Prolactinoma and Hyperprolactinemia

Case:
32 y.o. woman
Recent visual problems and slight breast discharge (galactorrhea)
No period ~6 months (secondary amenorrhea)
Unable to become pregnant
Denies schizophrenia or treatment with neuroleptics (antipsychotics)
Labs:
o Negative for pregnancy
o Normal TSH
o Significantly elevated levels of prolactin
MRI: enlargement of structure in sella turcica
Pathophysiology:
Prolactinoma = pituitary adenoma, most common type of pituitary adenoma
Abnormal proliferation of lactotrophs abnormal production of prolactin
o In women galactorrhea
o Inhibition of hypothalamic release of GnRH decreases FSH and LH secretion eliminates
ovulatory cycle infertility and amenorrhea
o In men inhibition of GnRH decreases testerone impotence & loss of libido
ANOTHER MECHANISM head trauma causes damage to the tuberoinfundibular tract (from
hypothalamus through pituitary stalk) source of dopamine that inhibits prolactin release

ONE MORE MECH Hypothyroidism no feedback inhibition of TRH increased TRH released
increased secretion of prolactin
Breast Feeding or excessive nipple stimulation

Prolactin Physiology Related to Pregnancy (image below)

1) Preceding pregnancy:
a. Low levels of prolactin due to low estrogen and tonic hypothalamic inhibition
2) During Pregnancy:
a. Prolactin levels are high due to high estrogen levels (secreted by placenta) breast
maturation and lactogenesis
b. Lactation however is prevented high estrogen and progesterone
c. Basically estrogen high prolactin high but lactation is inhibited by high estrogen and
progesterone during pregnancy
3) Following Pregnancy:
a. Estrogen levels drop prolactin levels drop unless stimulation by suckling
b. Suckling levels of prolactin increase and lactation occurs
Prolactin has several effects:
1) Inhibition of GnRH anovulatory infertility
2) Stimulation of Breast Maturation
3) Stimulation of milk production (lactogenesis)
a. Lactation (normal milk production)
b. Galactorrhea (pathological milk secretion)
Control of Prolactin Secretion
1) Inhibition
a. Inhibited by dopamine
b. Dopamine Agonist eg bromocriptine
2) Stimulation
a. TRH
b. Dopamine Antagonists (e.g. antipsychotics)

Acromegaly + GH Physiology
Case:
38 y.o. male
CC: gradually enlarging hands and feet over last several years
Coarsened facial features
LABS:
o Elevated plasma glucose levels
MRI:
o Enlarged mass in sella turcica
Diagnostic test:
o GH levels measured after administration of oral glucose load
o After admin, no measurable decrease in GH suspected GH-secreting stumor
Diagnosis:
Acromegaly caused by GH-secreting tumor of anterior pituitary
Often can be diagnosed by looking at older pictures of patient and comparing it to current appearance
GH Physiology:
Secreted primarily at night in response to stressors such as starvation and hypoglycemia
Promotes conservation of carbohydrate and protein stores
Pathophysiology:
Pituitary adenoma composed of proliferating somatotrophs
Increased levels of GH elevated levels of serum glucose cause frank diabetes

Normally GH release leading to increase serum glucose is to prevent hypoglycemia

Increased GH and IGF-1 acting on bonds enlarged hands and feet (anabolic effects)