Endo final

How does the posterior pituitary release hormones?

Synthesis in hypothalamus nuclei

Hormones travel down *Hypothalamopituitary Tract*

Stored in distended PP terminal axons

what are the Posterior Pituitary Hormones

-Vasopressin (Anti-Diuretic Hormone, ADH)
-Oxytocin

What stimulates the release of Vasopressin (ADH)

-Hyperosmolarity
-hypovolemia
-Volume depletion

What stimulates the release of oxytocin

parturition
suckling

What are Vasopressin releasing factors

Hyperosmolarity/Hypovolemia
Shock; Angiotensin II
Sympathetic Activity

What are the two vasopressin receptors and where are they located

V1 - blood vessel, liver, platelets
V2 - kidneys, Endothelial cells

What are the effects of vasopressin at the two receptors

blood vessels - constriction - increased systemic vascular resistance
kidney - increase fluid resorption - increased blood volume
Liver - Glycogenolysis
Endothelial cells - vWF release
Platelets - Aggregation

what is avp

arginine vasopressin

explain the effect of ADH on kidneys (where they affect, and how they affect)

V2R vasopressin receptors expressed on basolateral membranes of collecting duct cells

Receptor activation (GPCR, Ga-s cascade (increased cAMP, increased PKA activation)) increases aquaporin (AQP2) apical membrane expression

Increased H2O reabsorption

What is diabetes insipidus?

lack of ADH, or response to ADH

what is the difference between neurogenic and nephrogenic diabetes insipidus

neurogenic - Insufficient Vasopressin secretion
nephrogenic - Vasopressin Resistance

how do you tell if a patient has neurogenic and nephrogenic diabetes insipidus

administer desmopressin and
if the don't respond - nephrogenic
if the do - neurogenic

how do you treat neurogenic diabetes insipidus

Replacement ADH (desmopressin)

how do you treat nephrogenic diabetes insipidus

Reduce osmotic load; thiazide diuretic and/or prostaglandin inhibitor

what is SIADH

Syndrome of Inappropriate ADH
Hyper-ADH secretion

how do you diagnose SIADH

rule out everything else

I'm so sorry. I am not typing out all this shit

what are the symptoms of diabetes insipidus

polyuria, polydipsia

How do you diagnose diabetes insipidus (not differentiating between neurogenic and nephrogenic)

fluid restrict them for a certain amount of time
if they continue to urinate, and become hypovolemic - they have

what is the treatment of choice for SIADH

ADH Antagonist

what are some treatment options for SIADH

ADH Antagonist
Loop diuretics
Urea
​Demecocycline
Lithium
Hemodialysis

How do loop diuretics treat SIADH

they trap water in flitrate

How does Demecocycline treat SIADH

they decrease aquaporin expression

How does Lithium treat SIADH

degrades aquaporin

What are the physiological effects that Oxytocin can induce

Contraction of uterine myometrium
Myoepithelial contraction of mammary ducts
Prostaglandin synthesis in THE PLACENTA

WHAT IS THE SINGLE EXAPLE OF POSITIVE FEEDBACK

OXYTOCIN STIMULATES UTERUS TO CONTRACT
UTERUS CONTRACTING CAUSES MORE OXYTOCIN TO BE RELEASED

What initiates parturition

fetal lung development

what is oxytocin used for in pregnancy

inducing birth

when is oxytocin used to indnuce labor

-Pre-eclampsia
-Fetal distress
-Uncontrolled gestational diabetes
-Intrauterine infection
-Ruptured membranes
-Augmentation of contractions

What is tocolytic therapy?

Pharmaceutical intervention to slow down labor

Example: Oxytocin Receptor Antagonist (ORA)

how effective is Oxytocin Receptor Antagonist therapy at suppressing uterine contractions

did not demonstrate superiority

ORA was associated with less maternal adverse effects than treatment with the CCB or betamimetics.

Explain the HPA axis: Hypothalamus Pituitary Adrenal axis

Hypothalamus secretes CRH
CRH stimulates anterior Pituitary to release ACTH

what are the physiologic effects of Cortisol

Anti-inflammatory ​
"Stress" hormone
Plasma Glucose regulation​
Bone demineralization​

What zone makes aldosterone

zona glomerulosa

What zone makes cortisol

Zona Fasciculata

What zone makes testosterone

Zona Reticularis

where is cortisone activated

in the liver

what enzyme activates cortisone into cortisol

11b-HSD

How glucocorticoids work

-Soluble ligand, intracellular receptors ​
-Steroid binds receptor in the cytosol and forms complex​
-Ligand-receptor complex moves to the nucleus
-Effect: inhibit genes for pro-inflammatory cytokines​

What are the four forms of Cushing syndrome?

Pituitary-dependent (aka Cushing DISEASE)
Ectopic ACTH syndrome
Adrenal adenoma
Adrenal Carcinoma

Explain ACTH levels at for each of the four forms of Cushing syndrome?

Pituitary-dependent (aka Cushing DISEASE)
- ACTH high
Ectopic ACTH syndrome
- ACTH high
Adrenal adenoma
- ACTH low
Adrenal Carcinoma
- ACTH low


Drug induced high cortisol
- ACTH low

what are the pharmalogical targets in Hyper-cortisol Disease

´1. Glucocorticoid receptor antagonist (mifepristone)
´2. Inhibit steroidogenesis
´3. Inhibit ACTH release (2' hypersecretion)
´4. Surgical resection/ablation of adrenal gland (1' hypersecretion)

what is an example of a Glucocorticoid Receptor Antagonist

Mifepristone

Mifepristone MOA

Binds/Antagonizes corticoid receptor by stabilizing GCR-hsp90 co-repressor interaction

Mifepristone displaces helix 12 from agonist position

Mifepristone contraindications

pregnancy, CYP3A4 interactions

Mifepristone ADEs

Endometrial hypertrophy (inc. progesterone), inc. endogenous ACTH, cortisol, hypokalemia, hypertension, nausea, fatigue, peripheral edema

Mifepristone indications

-Use only in patients who aren't candidates for surgical resection
-Effective reversal of physical manifestations in Cushing's (hyper-glycemia, weight gain, etc.)

Mifepristone brand

Mifeprex

Steroidogenesis inhibitor examples

Aminogluethimide (Cytadren)
Ketoconazole (Nizoral)
Metyrapone (Metopirone)

Aminogluethimide brand

Cytadren

Ketoconazole brand

Nizoral

Metyrapone brand

Metopirone

What drug classes are used for Inhibition of ACTH release

Somatostatin analog
Dopamine agonist

Somatostatin analog example

Pasireotide (Signifor®)

Dopamine agonist

Cabergoline (Dostinex®)

Pasireotide brand

Signifor

Cabergoline brand

Dostinex

What is the anticipated outcome following surgical resection of a tumor causing Cushing Syndrome (either anterior pituitary or adrenal cortex)?

anterior pituitary - possible deficiencies in every anterior pituitary hormones

adrenal cortex - loss of cortisol, aldosterone, and testosterone

What are the different names of Hypo-Adrenal/ Adrenal Insufficiency

-Chrousos Syndrome
-Addison's Disease
-Bilateral adrenalectomy​
-Congenital adrenal hyperplasia (CAH)​

What is Chrousos Syndrome

-Familial glucocorticoid resistance syndrome
-NR3C1 mutation inactivates glucocorticoid receptor: apparent deficiency in cortisol activity

What are the symptoms of Chrousos Syndrome

Hypertension, Hypokalemia, Hirsutism, Precocious puberty, Menstrual irregularities

When should you test cortisol levels

in the morning
8AM

How do you diagnose Adrenal Insufficiency

8AM cortisol level
- above 15 ruled out
- below 3 AI confirmed
- Between 3 and 15
\-------30 min cortisol test after ACTH administration
\--------------above 18 - ruled out
\--------------below 18 - AI confirmed

For confirmed AI
-if ACTH low or normal - secondary or tertiary
-if ACTH elevated - primary

What is Adison's disease?

Adrenal glands do not make enough steroids

Patient may be deficient in BOTH corticosteroids (cortisol) AND mineralocorticoids (aldosterone); alterations in salt/water balance and blood pressure

Why would patients have hyperpigmentation with Hypo-Adrenal diseases

ACTH is made as a pro-peptide (POMC)
When POMC is cleaved to make ACTH it releases MSH
melanocyte-stimulating hormone
causes production of melanin

what is MSH

melanocyte-stimulating hormone
causes production of melanin

What are some important points in using Glucocorticoids

1. Use local application (ex: topical) if possible
2. Shortest duration possible
3. Taper withdrawal to avoid rebound effects

How do you treat Conn Syndrome

1. Surgical resection/ablation of adrenal tumor
2. Aldosterone receptor antagonist

What is Conn Syndrome

Mineralocorticoid Excess

1' dysfunction: excess aldosterone produced by adrenal zona glomerulosa

Increase Na+ reabsorption; increased blood volume, increased blood pressure, hypokalemia

What are the symptoms of Conn Syndrome

fatigue, numbness, muscle cramps, muscle weakness (due to hypokalemia)

What are some complications of Conn Syndrome

Increased risk of arrhythmias, MI (due to solute gradient/RMP changes)

What are the effects of glucocorticoids on metabolism

Protein catabolism; hepatic glycogenesis and gluconeogenesis

What are the effects of glucocorticoids on the CV system

-Increased cardiac output/peripheral vascular tone

What are the effects of glucocorticoids on the renal system

-Water metabolism by increasing glomerular filtration rate

What are the effects of glucocorticoids on the immune system

-Decrease eosinophils, basophils, cytokines, and lymphocytes; increase neutrophils, platelets, and red blood cells

what are some Features that discriminate Cushing's Syndrome

Easy bruising
Facial plethora
Proximal myopathy
Striae (reddish-purple)
Weight gain with decreasing growth velocity in children

who should be screened for Cushing's Syndrome

1.Patients with unusual features for age (e.g. osteoporosis, HTN)
2.Patients with multiple and progressive features, particularly those that are more predictive of Cushing's Syndrome (e.g. myopathy, plethora, red striae, easy bruising)
3.Children with decreasing height percentile and increasing weight
4.Patients with adrenal incidentaloma compatible with adenoma

What effect does Cushing's syndrome have on 24-hour UFC test, and what result indicates Cushing's syndrome

Increased excretion of cortisol
\>60 mcg/24-hour period

What effect does Cushing's syndrome have on Late-night salivary cortisol, and what result indicates Cushing's syndrome

Loss of late-night nadir
\>145 ng/dL

What effect does Cushing's syndrome have on DST, and what result indicates Cushing's syndrome

Failure of suppression of ACTH and cortisol release
\>1.8 mcg/dL

describe Inferior petrosal sinus sampling (IPSS)

requires catheterization of both petrosal sinuses with serial measurements of ACTH in each sinus and peripheral vein after administration of CRH

describe Jugular venous sampling (JVS)

uses same concept as IPSS with lower sensitivity

what is the treatment of choice for cushings syndrome

transsphenoidal surgical resection by an experienced surgeon, unless surgery is not possible or unlikely to significantly reduce glucocorticoid excess

what does the Post-operative Management look like for Transsphenoidal Surgery

Remission: generally defined as morning serum cortisol values

How do you discontiue glucocorticoids

Assess morning cortisol level every 3 months, followed by an ACTH stimulation test starting when the level of cortisol is \>7.4 mcg/dL

Recovery can be confirmed if baseline or stimulated ACTH \> 18 mcg/dL

Need to taper GC when discontinuing!!

what drugs should be used for Ectopic ACTH Syndrome (EAS)

Metyrapone
Ketoconazole

what drugs should be used for Pituitary-dependent

Mitotane
Metyrapone
Mifepristone
Cabergoline
Pasireotide
Osilodrostat
Levoketoconazole

what drugs should be used for Adrenal Adenoma

Ketoconazole

what drugs should be used for Adrenal carcinoma

Mitotane

what is a Adrenolytic agent/steroidogenesis inhibitor

Mitotane

what are examples of Steroidogenesis inhibitors

Etomidate, ketoconazole, metyrapone, osilodrostat, levoketoconazole

what are examples of Glucocorticoid-receptor blocking agent

Mifepristone
Relacorilant (undergoing clinical trials)

what are examples of Neuromodulators of ACTH release

Cabergoline, pasireotide, octreotide

which Steroidogenesis Inhibitors is preferable in pregnant women

Metyrapone (Metopirone)

which Steroidogenesis Inhibitors is preferable in women

Ketoconazole (Nizoral)

which Steroidogenesis Inhibitors is preferable in men

Metyrapone (Metopirone)
Osilodrostat (Isturisa)

which Steroidogenesis Inhibitors are oral

Ketoconazole (Nizoral)
Metyrapone (Metopirone)
Osilodrostat (Isturisa)
Mitotane (Lysodren)

which Steroidogenesis Inhibitors are IV

Etomidate (Amidate)

Ketoconazole ADEs

GI upset, hepatotoxicity & QT prolongation (BW), male hypogonadism, dermatologic reactions

Osilodrostat brand

Isturisa

Etomidate brand

Amidate