HYPOTHALAMUS PITUITARY AXIS

what is the endocrine system

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

what are major endocrine glands

thyroid gland and adrenal glands

what are the major functions of the 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

what are the two altered states of function endocrine pharmacology is balancing

deficiency and excess

how does endocrine pharmacology control deficiency

increase release or add agonist

how does endocrine pharmacology control excess

decrease release or add antagonist

what are the endocrine hormones

anterior pituitary hormones and posterior pituitary hormones

what are the anterior pituitary hormones

• growth hormone (GH)

• prolactin (PRL)

• thyroid stimulating hormone (TSH)

• adrenocorticotropin hormone (ACTH)

• lutenizing hormone (LH)

• follicule stimulating hormone (FSH)

what are the posterior pituitary hormones

• oxytocin (OXY)

• anti-diuretic hormone (ADH; vasopressin)

which anterior pituitary hormones are gonadotropins

lutenizing hormones and follicule stimulating hormone

what is the pathway of anterior pituitary hormone secretion

hypothalamus → anterior pituitary → organ/gland → tissues

what is the pathway of posterior pituitary hormone release

hypothalamus → posterior pituitary → tissues

what are the two main MOAs of endocrine hormones

nuclear receptors and membrane receptors

what is the MOA of nuclear receptors

modulate transcription of genes in target cells

• ex: tyrosine kinase receptors

• takes longer

what is the MOA of membrane receptors

exert rapid effects of signal transduction pathways

• ex; GPCR

• much faster

what type os secretion is oxytocin release and what stimulates it

• pulsatile release

• stimulated by sensory stimuli

  • dilation of cervix and vagina

  • suckling

MOA of oxytocin

1. oxytocin binds to oxytocin receptor (GPCR)

2. activates CA²⁺ release from SR

3. Ca²⁺ activates contractile proteins: muscle contraction

how does oxytocin work in the uterus

induction of labor

how does oxytocin work in the breast

milk ejection

MOA of oxytocin agonist

activates oxytocin receptors to increase Ca²⁺ release and uterine contraction

uses of oxytocin agonist

induction and augmentation of labor, control uterine hemorrhage after delivery

adverse effects of oxytocin agonist

• fetal distress

• placental abruption

• uterine ruptute

• fluid retention

• hypotension - when administered as IV bolus

how does oxytocin act

neuromodulation

what is neuromodulation

• acts in the hippocampus to sharpen sensory signals by decreasing background “noise”

• enhances bonding in the emotional circuits with positive experiences

what is vasopressin also known as

• arginine vasopressin (AVP)

• anti-diuretic hormone (ADH)

what are stimulating factors of vasopressin release

• fall in blood pressure

• rising of plasma osmolarity (increased conc in blood → dehydration)

what are two main effects of vasopressin

vasoconstriction and fluid retention

what two locations does vasopressin effect and what receptors are used

• vascular smooth muscle: V1 receptor

• kidneys on water resorption: V2 receptor

explain vasopressin effects in kidneys

• binds GPCR (V2)

• activates adenylyl cyclase pathway

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

• increases water resorption (anti-diuretic)

MOA of vasopressin receptor agonists

activates V2 receptors > V1 receptors

• acts on kidney to increase water resorption

adverse effects of vasopressin receptor agonists

• GI upset

• hypervolemic hyponatremia

• allergic reactions

vasopressin receptor agonist agents

• demopressin

• vasopressin (arginine vasopressin)

uses of vasopressin receptors agonists

• diabetes insipidus

• polyuria

what is diabetes insipidus

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

MOA of vasopressin receptor antagonists

block V2 receptors

• acts in kidney to decrease water resorption

uses of vasopressin receptors antagonists

hypervolemic hyponatremia in hospitalized patients

vasopressin receptor antagonist agents

• conivaptan

• tolvaptan

stimulating factors of growth hormone release

• growth hormone releasing hormone (GHRH)

• ghrelin (produced when you eat)

inhibitory factors of growth hormone release

• somatostatin

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

MOA of growth hormone

1. GH binds to 2 GHR monomers

2. receipts two JAK2 molecules (tyrosine kinases)

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

what else does GHR activate

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

physiological effects of growth hormone

• increased longitudinal bone growth

• increased bone mineral density

• anabolic effects in muscle

• catabolic effects in fat

• mixed effects in carbohydrate metabolism

  • GH reduces insulin sensitivity → increased serum glucose

  • IGF-1 decreased serum glucose

therapeutic consideration of growth hormones effects on carbohydrate metabolism

monitor blood sugar until you know which effect predominates

what causes growth hormone deficiency

genetic, damage to hypothalamus or pituitary

effects of growth hormone deficiency

• short stature

• decreased BMD

• decreased muscle mass

• adiposity

what causes growth hormone excess

pituitary adenomas

effects in children of growth hormone excess

increased longitudinal growth (gigantism)

effects in adults of growth hormone excess

acromegaly

• abnormal growth of cartilage, bone and vital organs

• results in hypertension, glucose intolerance, carpal tunnel syndrome, sleep apnea, and cardiovascular disease

what is somatropin

recombinant human growth hormone (rhGH)

• variety of preparations (DNA sequences match GH); SQ inj QD

MOA of somatropin

binds GHR and increases the production of IGF-1

uses of somatropin

• children short stature with GH deficiency

  • turner syndrome, noonan syndrome, Prader-Willi syndrome, idiopathic

• adults with demonstrate GH deficiency and/or deficiencies in 3 other pituitary hormones

adverse effects of somatropin

• rare in children

• more frequent in adults

  • carpal tunnel syndrome

  • peripheral edema

  • arthalgias

  • myalgias

contraindications with somatropin

• malignancy or other proliferative disorders (cancer)

• acute critical illness (cardiovascular or respiratory)

what is mecasermin

recombinant insulin-like growth factor-1

MOA of mecasermin

stimulates IGF-1 receptors

what is mecasermin rinfabate

recombinant IGF-1 with IGFBP-3 (binding protein)

MOA of mecasermin rinfabate

stimulates IGF-1 receptors

adverse effects of mecasermin

• hypoglycemia (take with a meal or snack)

• lipohypertrophy

• do not use malignancy

uses of mecasermin

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

what is tesamorelin

synthetic growth hormone releasing hormone (GHRH)

what does tesamorelin do

increaeses GH and IGF-1 but primarily used to reduce visceral fat accumulation

what is tesamorelin not approved for

GH deficiency

use of tesamorelin

HIV associated lipodystrophy

MOA of somatostatin analogues

• mimics SST

• inhibits GHRH and GH release to decrease GH and IGF-1

use of somatostatin analogues

acromegali

immediate-acting, immediate release somatostatin analogue agents

Octreotide

long-acting, slow release somatostatin analogue agents

• Octreotide LAR: decreases tumor size

• Lanreotide

• Pasireotide: inhibits ACTH secretion; used in Cushing’s syndrome

adverse effects of somatostatin analogues

• GI upset (50% pts)

  • diarrhea, nausea, abdominal pain

• inhibitory effects on TSH and ACTH (pasireotide) secretion

• decreased insulin secretion, decreased insulin resistance (variable effects on glucose tolerance)

  • pasireotide: also increases glucagon secretion

    • hyperglycemia

what is pegvisomant

GHR antagonist

MOA of pegvisomant

binds to GHR and blocks the action of GH

interval of dosing for pegvisomant

SQ inj daily or weekly

use of pegvisomant

acromegaly

adverse effects of pegvisomant

• elevated liver enzymes

• inj site reactions

• monitor for pituitary adenomas 

stimulating factors of prolactin release

• thyrotropin releasing hormone (TRH)

• suckling

inhibitory factors of prolactin release

dopamine inhibits release via D2 receptor

does prolactin release have feedback control

no

MOA of prolactin

binds to PRL receptors (which are structurally related to GHR)

how do serum PRL levels rise

transiently

serum PRL levels rise transiently after ___

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

PRL levels rise and are sustained during ___

pregnancy and breastfeeding

physiological effects of prolactin

• induce and maintain lactation

• decrease reproductive function

• suppress sexual drive

functions of prolactin ensure ____

maternal lactation is sustained and not interrupted by pregnancy

hyperprolactinemia

• lactation

• decrease in reproductive function

  • suppress hypothalamic GnRH and gonadotropin secretion

  • impairs sex hormone synthesis in women and men

    • menstrual irregularities, infertility, decreased libido

MOA of dopamine agonists

activate D2 receptors (>D1 receptors)

• decrease PRL secretion, CNS motor control and behavior

uses of dopamine agonists

• hyperprolactinemia

• inhibition of lactation postpartum

• parkinson’s disease

dopamine agonist agents

bromocriptine and cabergoline

adverse effects of dopamine agonists

• GI upset

• orthostatic hypotension

• psychiatric disturbances

• vasospasm and pulmonary infiltrates (high doses)

gonadotropins

lutenizing hormone (LH) and follicule stimulating hormone (FSH)

stimulating factors for gonadotropins

• GnRH (pulsatile)

  • continuous GnRH leads to desensitization and down regulation of GnRH receptors

inhibitory factors of gonadotropins

feedback inhibition by sex steroids and inhibition

human chorionic gonadotropin (hCG)

• produced by placenta

• urine pregnancy test

physiological effects of LH in men

stimulates de novo androgen synthesis in testicular Leydig cells

physiological effects of LH in women

triggers ovulation and development of corpus luteum

physiological effects of FSH in men

stimulates sperm maturation

physiological effects of FSH in women

• stimulates growth of follicules in the ovary

• induces expression of LH receptors on the theca and granulosa cells

• increases expression of aromatase in granulosa cells stimulating estradiol synthesis