Hypothalamus Pituitary Axis

endocrine system 

a chemical messenger system compromising feedback loops of hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs 

thyroid gland and adrenal gland

in humans the major endocrine glands are 

major functions of endocrine system

• regulation of energy storage, production, and utilization

• adaptation to new environments and conditions of stress

• facilitation of growth and development

• maturation and function of reproductive system

endocrine pharmacology

the balance of 2 altered states of function

deficiency and excess

2 altered states of function

strategy of endocrine system in deficiency

increase release or add agonist

strategy of endocrine system in excess 

decrease release or add antagonist 

anterior pituitary hormones

growth hormone (GH), prolactin (PRL), thyroid stimulating hormone (TSH), adrenocorticotropin hormone (ACTH), lutenizing hormone (LH), and follicule stimulating hormone (FSH)

anterior pituitary

gonadotropins are in the

LH and FSH

gonadotropins

posterior pituitary hormones

oxytocin (OXY) and anti-diuretic hormone (ADH; vasopressin)

hypothalamus pituitary axis

• hypothalamus - anterior pituitary - organ/gland - tissues

• hypothalamus - posterior pituitary - tissues

nuclear receptors (MOA)

modulate transcription of genes in target cells (tyrosine kinase receptors)

membrane receptors (MOA)

exert rapid effects on signal transduction pathways (G-protein coupled receptors)

sensory stimuli, dilation of cervix and vagina, and suckling 

stimulating factors of oxytocin release 

pulsatile

oxytocin release has … secretion

oxytocin receptor (GPCR)

oxytocin binds to

Ca2+ release from SR

oxytocin activates

contractile proteins (muscle contractions) 

Ca2+ release from oxytocin activates 

induction of labor

uterus and oxytocin release

milk ejection

breast and oxytocin release

Oxytocin MOA

1. oxytocin binds to oxytocin receptor (GPCR)

2. activates Ca2+ release from SR

3. Ca2+ activates contractile proteins: muscle contraction

oxytocin agonist 

activates oxytocin receptors to increase calcium release and uterine contractions

oxytocin agonist

used for induction and augmentation of labor, control uterine hemorrhage after delivery

adverse affects of oxytocin agonists

fetal distress, placenta abruption, uterine rupture, fluid retention, hypertension when administered as IV bolus

neuromodulation

oxytocin has

neuromodulation of oxytocin

acts in the hippocampus to sharpen sensory signals by decreasing background noise and enhances bonding in the emotional circuits with positive experiences 

oxytocin

also called the cuddle hormone

vasopressin

also called arginine vasopressin (AVP) and antidiuretic hormone (ADH)

fall in blood pressure and rising plasma osmolarity

stimulating factors of vasopressin

vasoconstriction and fluid retention 

2 main effects of vasopressin

vasoconstriction

in vascular smooth muscle on V1 receptors vasopressin causes

increase water resorption/cause fluid retention

in kidneys and water resorption on V2 receptors vasopressin will

vasopressin effects in kidneys on water resorption (V2 receptors)

1. binds G protein coupled receptor (V2)

2. activates adenylyl cyclase pathway

3. phosphorylation aquaporin 2 (AQP2) which is then inserted into luminal cell membrane

4. increases water resorption (anti diuretic)

V2 receptors more than V1 receptors

vasopressin receptors agonists will activate

vasopressin receptor agonists

acts in kidney to increase water resorption

adverse effects of vasopressin receptor agonists

can cause GI upset, hypervolemic hyponatremia, and allergic reactions 

desmopressin and vasopressin

vasopressin receptor agonists agents

vasopressin receptor agonists

used to treat diabetes insipidus and polyuria

diabetes insipidus

deficiency in vasopressin that causes excretion of abnormally large volumes of dilute urine and excessive thirst

vasopressin receptro antagonists 

blocks V2 receptors and acts in kidneys to decrease water resorption 

vasopressin receptro antagonists

used to treat hypervolemic hyponatremia in hospitalized patients

conivaptan and tolvaptan

vasopressin receptor antagonists

Growth Hormone Releasing Hormone (GHRH) and Ghrelin

stimulatory factors of Growth Hormone release

somatotroph

target cell type in anterior pituitary for growth hormone 

liver, muscles, bone, kidney, etc.

major target organ for growth hormone

insulin like growth factor (IGF-1)

target gland hormone for growth hormone

somatostatin and feedback inhibition by GH and insulin like growth factor-1

inhibitory factors of growth hormone

growth hormone MOA

1. GH binds to 2 GHR monomers

2. recruits 2 JAK2 molecules (tyrosine kinases) 

3. activate downstream signaling pathways, which increases IGF-1 expression

Growth hormone release

also activates IRS-1 which may mediate the increased expression of glucose transporters on the plasma membrane

IGF-1 expression

growth hormone release increase

growth hormone

will increase longitudinal bone growth and bone mineral density, has anabolic effects in muscle, and catabolic effects in fat

increases serum glucose 

in carbohydrate metabolism growth hormone reduces insulin sensitivity which 

decrease serum glucose

in carbohydrate metabolism IGf-1 will

monitor blood sugar until you know which effect of carbohydrate metabolism predominates (decreased or increased serum glucose)

therapeutic consideration of growth hormone

genetic or damage to hypothalamus or pituitary galnds

causes of growth hormone deficiency

effects of GH deficiency 

short stature, decreased BMD, decreased muscle mass, and adiposity 

pituitary adenomas

causes of growth hormone excess

increased longitudinal growth (giantism)

in children growth hormone excess with lead to

acromegaly

in adults growth hormone excess can cause

recombinant human growth hormone (rhGH)

somatropin is a 

somatropin

binds GHR and increases the production of IGF-1

somatropin

used in children of short stature with GH deficiency (Turners syndrome, Noonan syndrome, idiopathic)

somatropin

used in adults with demonstrated growth hormone deficiency and/or deficiencies in 3 other pituitary hormones

adverse effects of somatropin 

carpal tunnel, peripheral edema, arthralgias, myalgias (more common in adults/obese)

contraindications of somatropin

malignancy or other proliferative disorders and acute critical illness

mecasermin

a recombinant insulin like growth factor 1 that stimulates IGF-1 receptors in GH/IGF-1 deficiency

mecasermin rinfabate

a recombinant IGF-1 with IGFBP-3 (binding protein) that stimulates IGF-1 receptors

adverse effects of mecasermin 

hypoglycemia, lipohypertrophy, do not use malignancy 

a meal or snack

mecasermin should be taken with

macasermin

used in growth hormone deficiency due to mutations in GHR or IGF-1 or antibodies against GH

tesamorelin

a synthetic growth hormone releasing hormone that increases GH and IGF-1 but clinical effects primarily to reduce visceral fat accumulation

tesamorelin

has minimal effects on glucose regulation, not approved for GH deficiency, used for HIV associated lipodystrophy 

somatostain analogues

mimics somatostatin, inhibits GHRH and GH release to decrease GH and IGF-1

growth hormone excess

somatostatin analogues are used in acromegaly in

octreotide

immediate acting immediate release somatostatin analogue

octreotide LAR

long acting slow release somatostatin analogue that decreases tumor size 

pasireotide

long acting slow release somatostatin analogue that inhibits ACTH secretion used in Cushing syndrome

lanreotide

long acting slow release somatostatin analogue

decreased insulin secretion and resistance and inhibitory effects on TSH and ACTH secretion

somatostatin analogues can cause GI upset and

glucagon secretion = hyperglycemia 

pasireotide and inhibit effects on TSH and ACTH secretion and can also increase 

pegvisomant

a GHR antagonist that binds to GHR to block the action of GH in acromegaly

subq injection daily or weekly

pegvismoat should be taken

adverse effects of pegvisomant

may cause elevated liver enzymes, injection site reaction, and monitor for pituitary adenomas

Prolactin from the anterior pituitary

when TRH stimulates the hypothalamus it releases  

lactotroph

the target cell of TRH in anterior pituitary

mammary glands

major target organ of TRH/prolactin

none

target gland hormones of prolactin/TRH

no unique factor, thyrotropin releasing hormone (TRH), suckling 

stimulating factors of prolactin release

dopamine inhibits release via D2 receptor (no negative feedback control)

inhibitory factors of prolactin release

dopamine and somatostatin

inhibitory hypothalamic factor of prolactin/lactotroph

MOA of prolactin

binds to PRL receptors (structurally related to GHR)

serum PRL levels rise transiently 

after exercise, meals, sexual intercourse, general anesthesia, myocardial infarction, and acute stress

pregnancy and breastfeeding

PRL levels rise and are sustained during

physiological effects of prolactin release

induce and maintain lactation, decrease reproductive function, suppress sexual drive

functions from prolactin release

ensure maternal lactation is sustained and not interrupted by pregnancy

hyperprolactinemia 

lactation with decrease in reproductive function 

decreased reproductive function due to hyperprolactinemia

suppress hypothalamic GnRH and gonadotropin secretion and impairs sex hormone synthesis in women and men (menstrual irregularities, infertility, decreased libido)

activate D2 receptors

dopamine agonists (MOA)

decrease in PRL secretion, and decrease in CNS motor control and behavior

when dopamine agonists activate D2 receptors