Exam 1 DPT V (Shatnawi)

What is the hypothalamus responsible for controlling?

appetite and water intake

body temp

circadian rhythms

childbirth and milk ejection

Where is the hypothalamus gland located?

at the base of the brain

Together, the hypothalamus and the pituitary gland regulate...

metabolism, growth, and reproduction

What hormones are synthesized by the hypothalamus?

oxytocin

vasopressin (antidiuretic hormone)

hypothalamic-releasing hormones

MOA of hypothalamic releasing hormones

stimulate or inhibit pituitary hormone secretion

Which pituitary gland releases oxytocin and ADH (prolactin)?

posterior

What is the major difference between the anterior and posterior pituitary gland?

anterior: has blood supply and carries releasing hormones from the hypothalamus to the gland

posterior: neurons, are stimulated by neurohormones

Anterior Pituitary Axis

blood

What hormones have a negative effect on the anterior pituitary axis?

dopamine and somatostatin

What hormones have a positive effect on the anterior pituitary axis?

Growth Hormone Releasing Hormone (GHRH)

Thyrotropin Releasing Hormone (TRH)

Corticotropin Releasing Hormone (CRH)

Gonadotropin-Releasing Hormone (GnRH)

Which hormone secreted from the anteriori pituitary gland can directly stimulate target tissues?

prolactin

Characteristics of the hypothalamus releasing hormones

secreted in pulses

transduce signals via second messengers (GCPR or JAK/STAT)

stimulate release or synthesis of pituitary hormones

stimulates hyperplasia or hypertrophy of target cells

regulates its own receptor

What is the relationship between dopamine and prolactin?

inverse!!

high dopamine, low prolactin

Corticotropin Releasing Hormone (CRH)

+ ACTH secretion

Thyrotopin-releasing hormone (TRH)

+ TSH and Prolactin secretion

hypothalamic releasing hormone that stimulates TSH release

Growth Hormone Releasing Hormone (GHRH)

+ GH secretion

Gonadotropin-Releasing Hormone (GnRH)

+ LH and FSH secretion

Prolactin Inhibiting Hormone (Dopamine)

- PRL Secretion

Where are releasing hormones and neurohormones synthesized?

hypothalamus

Where do the releasing hormones travel to and via what?

ANTerior pituitary via portal hypophyseal blood vessels

Where do the releasing hormones act on?

anterior pituitary gland

Where do the neurohormones travel to and via what?

POSTerior pituitary via hypothalamo-hypophyseal tract

Where do the neurohormones act on?

distant target organs

Where are the neurohormones released from?

posterior pituitary into general circulation

Long Loop

peripheral gland hormones feedback onto the pituitary and hypothalamus

Short Loop

anterior pituitary hormones feedback onto the hypothalamus

Primary Hyposecretion

gland not functioning normally

damage due to infection, autoimmune or toxic chemicals, or lack of components needed for hormone syntehsis/secretion

Secondary Hyposecretion

tropic hormone deficiency

"upstream"

Tertiary Hyposecretion

rare; defect in 2 or more components of hormone secretion cascade

Primary Hypersecretion

gland secreting too much

ectopic sites of excess hormone production (cancer's producing hormones)

Secondary Hypersecretion

excessive stimulation by tropic hormone

Tertiary Hypersecretion

rare and involves multiple defects in the hormone secretion pathway

due to prescence of a hormone-secreting tumor

Hypo-responsiveness Disorder

due to deficiency of or an abnormal receptor, particularly in signaling

may also be due to lack of converting enzyme to activate hormone or increased metabolism or binding

Hyper-responsiveness Disorder

usually due to upregulation of receptor

Oxytocin

stored in posterior pituitary gland

receptors: GPCR that activates PLC-IP3-Ca2+ pathway

MOA of Oxytocin

contraction of uterine muscles

increases PGE1 production and augments uterine smooth muscle contraction

contraction of mammary myoepithelial cells (milk ejection)

What can inhibit secretion of vasopressin/ADH?

lithium

What stimulates the vasopressin/ADH secretion?

hyperosmolality

hypovolemia

hypotension and hypoxia

stress and emotional response

TCA, nicotine, NSAIDs

V1 receptors

located on vascular smooth muscles

mediate vasoCONSTRICTION

V2 receptors

located at the collecting ducts in kidney

regulates aquaporins water channels

reduces diuresis through increasing water permeability of collecting tubules (water retention)

What are the two physiological roles of vasopressin?

water retention and vasoconstriction of muscles smooth muscles

What is an effect of vasopressin stimulating V1 receptors?

leads to increase in arterial blood pressure

Desmopressin (DDAVP)

oral dosage form of vasopressin

synthetic analog

more selective for V2

contains D-arginine at position 8 and 1st aa is deaminated

Disease related to ADH signaling

Diabetes Insipidus

Syndrome of Inappropriate Anti Diuretic Hormone (SIADH)

Diabetes insipidus Neurogenic/Central

ADH insufficiency, can treat with supplement

dysregulation of vasopressin synthesis or release

due to brain injury, surgery, tumor, chronic edema

Diabetes Insipidus nephrogenic (loss of vasopressin sensitivity)

normal level of vasopressin

problem lies at the receptors

due to end-stage renal failure OR drugs (lithium)

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

excessive productive of ADH

could be due to tumor producing hormones (SCC), head injuries, infections, or drugs

What drugs can cause SIADH?

carbamazepine

morphine

chemotherapy

TCA and SSRIs

Effects of SIADH (Na, Serum Osm, and Urine Osm)

Na: ↓

Serum Osm: ↓

Urine Osm: ↑

Effects of DI (Na, Serum Osm, and Urine Osm)

Na: ↑

Serum Osm: ↑

Urine Osm: ↓

Indications of Vasopressin and Desmopressin

1. treatment of NEUROgenic/central DI

2. pediatric nocturnal enuresis

What are the vasopressin antagonists?

conivaptan and tolvaptan

What are conivaptan and tolvaptan used for?

hyponatremia

too much vasopressin

Which releasing hormones act through JAK/STAT receptors?

growth hormone and prolactin

Which releasing hormones act through GCPR?

ACTH

TSH

LH

FSH

Growth Hormone or Somatropin (recombinant human GH)

synthesized and secreted by somatotroph cells

secreted in pulsatile manner: short bursts at NIGHT controlled by GHRH

anti-insulin effect on lipid and carb metabolism

What cells produce GH?

somatotroph

When can you see an increase in GH secretion?

after exercise and physical stress

highest: during childhood

What can be dependent on or independent of GH that is primarily found in the liver?

IGF-1

Stimulators of GH secretion

hypothalamic GHRH

DA, 5-HT (serotonin)

HYPOglycemia, stress, exercise, sleep, ingestion of protein-rich foods

Inhibitors of GH secretion

GH- negative feedback

somastatin

IGF-1, FFAs

Physiological effects of GH

decreases utilization and uptake of glucose

decreases insulin receptor sensitivity

increases lipolysis, muscles mass

stimulates gluconeogenesis

mediated by stimulation of IGF-1

Transient GH insufficiency

due to various pharmacologic agents or poorly controlled diabetes and hypothyroidism

GH deficiency in children

caused from mutations in genes for GHRH, GH, or receptors (congenital)

born with average birth weight, but by age 3 health is below 3rd percentile

hypoglycemia

growth failure

GH deficiency in adults

mainly acquired

IGF-1 levels are reduced

ultimately see loss of other pituitary hormones

Somatotropin

recombinant form of GH

treatment of GH deficiency in children and adults

can be used in animals for milk production

well tolerated

Mecasermin

recombinant form of IGF-1

used in patients with primary severe IGF-1 deficiency due to severe GH resistance, or GH receptor mutations and GH antibodies

Acromegaly

excessive production of GH that typically occurs in middle age

increased production of IGF-1

What is the primary cause of acromegaly?

GH-secreting pituitary adenoma

What is the primary clinical manifestation seen in acromegaly?

increased production of IGF-1

Pituitary Gigantism

excess of GH in children

elevated levels of both GH and IGF-1

excess GHRH is primary cause

What is the primary cause of pituitary gigantism?

excess GHRH

What is the major difference between acromegaly and pituitary gigantism?

excess GHRH is RARE in acromegaly

excess GHRH is PRIMARY CAUSE in pituitary gigantism

What is the main goal of hormone hyper-secretions for GHRH?

reduce both GH and IGF-1 levels

somatostatin analogs, GH receptor antagonists, dopamine agonists

Somatostatin

inhibits release of: GH, TSH, glucagon, insulin, gastrin

half life: 1-3 min

Somatostatin Analogs

octreotide, lanreotide, pasireotide

What somatostatin analog has the highest affinity for SST5?

pasireotide

What is special of the somatostatin analogs?

NO loss of efficacy or desensitization with repeated administration

PEGvisomant (Somavert)

GH receptor ANTAgonist

prevents physiology effects of GH on target tissues and reduces IGF-1 levels

DOES NOT inhibit GH secretion, just effects the receptors

What are the dopamine agonists?

bromocriptine and cabergoline

Bromocriptine and Cabergoline

dopamine agonists

oral route is an advantage

not as effective as SST analogs

Which DA agonist is the most effective?

Cabergoline

Prolactin

synthesis and secretion from lactotroph cells

decreases reproductive function and suppress sex drive

mainly for milk production

What is prolactin negatively regulated by?

dopamine

What type of receptor does prolactin act through?

JAK/STAT

Hyperprolactinemia

state of persistent elevation in serum PRL - above 25 ug/L

What are some common causes of hyperprolactinemia?

prolactin-secreting pituitary adenoma: PRL elevation is proportional to tumor size

drug-induced: antipsychotics, increased 5HT, verapamil

What drugs can be used to treat hyperprolactinemia?

bromocriptine

pergolide

cabergoline

quinagolide

Bromocriptine

ergot derivative

first D2 agonist used to treat hyperprolactinemia

stimulates post-synaptic D2 GiPCRs in AP lactotrophs which inhibits AC resulting in decrease cAMP which blocks IP3

can activate voltage-sensitive K channels to inhibit voltage-sensitive Ca++ channels

normalizes PRL in most patients and reduces tumor size

Cabergoline (Dostinex)

higher affinity of selectivity for D2 receptors (same MOA of bromocriptine)

inhibits ACTH secretion

significant first pass metabolism

Panhypopituitarism

complex or partial loss of anterior and posterior pituitary function

complex disorder due to deficiencies in many pituitary hormones

requires life-long hormone replacement therapy and monitoring of homeostatic functions

Most common causes of panhypopituitarism

primary pituitary tumors

ischemic necrosis of the gland

surgical trauma

irradiation

CNS infections

Primary panhypopituitarism

abnormality of pituitary secretory cells

Secondary panhypopituitarism

loss of proper external stimuli required for normal release of hormones

What is the physiological action of the hypothalamus-pituitary-adrenal axis (HPA)?

digestion

metabolism

maintain fluids and electrolyte balance

preserve normal cardiovascular function

growth

immune system

mood

circadian rhythms

What is the short loop negative feedback of HPA?

anterior pituitary

What is the long loop negative feedback for HPA?

adrenal cortex and then anterior pituitary

Corticotropin-Releasing Hormone (CRH)

produced in hypothalamus, stored in anterior pituitary

stimulates secretion of ACTH

used for diagnostic purposes ONLY:

CRH stimulating test (adrenal insufficiency)

Differential diagnosis of Cushing's Syndrome

Adrenocorticotropic hormone (ACTH)

secreted from anterior pituitary in response to CRH

liberated with melanocyte-stimulating hormone

What kind of rhythm does ACTH release as?

diurnal

synchronized with day/night cycles