Endo: IE 1

What are causes of hyperprolactinemia?

Prolactin-secreting pituitary tumors (adenomas)

• Microadenoma <10 mm diameter

• Macroadenoma ≥10 mm diameter

Renal insufficiency

Long-term untreated hypothyroidism

Medication induced

• Dopamine antagonists

• Prolactin stimulators

What are examples of drug-induced hyperprolactinemia?

Dopamine antagonists

• Antipsychotics (risperidone/paliperidone)

• Metoclopramide (antiemetic)

• Promethazine/Prochlorperazine

• Methyldopa/reserpine

• Benzodiazepines

• Opioids

• H2 receptor antagonists

• Protease inhibitors

Prolactin stimulators

• SSRI, TCAs, MAOi

• Estrogens/progestin

• 5-HT1 agonists (Triptans)

Other

• Verapamil

What is hyperprolactinemia diagnosis?

Serum prolactin >25 mcg/L

What is hyperprolactinemia medical management?

Medical management

• Normalize prolactin level

• Restore gonadal function and decrease symptoms

• Decrease tumor size

What is drug-induced hyperprolactinemia treatment?

Remove offending agents

Lower risk of antipsychotic-induced hyperprolactinemia with []

Aripiprazole d/t partial D2 agonist effects

→ Switch antipsychotic to aripprazole or ADD aripiprazole

What are dopamine agonists for prolactinoma? What is the dosing?

Which dopamine agent for prolactinoma is preferred?

Cabergoline d/t

Better tolerated / fewer side effects

Better efficacy in normalizing prolactin level

Higher frequency of pituitary tumor shrinkage

Restoration of gonadal function / alleviating symptoms of hyperprolactinemia

What are dopamine agonists A.E?

Nausea, constipation, headache, orthostatic hypotension, drowsiness/fatigue

What is baseline monitoring for hyperprolactinemia?

• Serum prolactin

• Blood pressure (sitting/standing)

• Echocardiogram

What monitoring every 4 weeks if for hyperprolactinemia?

• Serum prolactin

• A.E of medication

• Improvement in clinical symptoms

Once there is normal serum prolactin, how often should prolactin be measured?

Every 6-12 months and repeat MRI to measure size of prolactinoma

After 2 years of treatment: normal prolactin; no visible tumor, what should you do?

Discontinue/taper

Repeat serum prolactin every 3 months

Dopamine agonists: Patient counseling

Take with food to reduce GI upset

Take initial dose (bromocriptine) at bedtime due to potential side effect of dizziness, fatigue

Rise slowly (orthostatic hypotension

Do not abruptly discontinue treatment as it may precipitate dopamine agonists withdrawal symptoms (DAWS)

• Anxiety/panic attack/insomnia

• Depression/fatigue

• Sweating

When is surgery indicated for hyperprolactinemia?

Refractory pts or cannot tolerate meds

Large tumors that cause compression of adjacent tissues

What is the most common cause of Cushing’s syndrome?

Exogenous causes

What are endogenous causes of Cushing’s Syndrome?

ACTH dependent → pituitary adenoma → excess ACTH

ACTH independent → adrenal adenomas/carcinomas

Cushing’s syndrome diagnosis

1. Determine excess cortisol

   1. 24 hr urinary free cortisol

   2. Midnight plasma cortisol

   3. Late night salivary cortisol

   4. Dexmethasone suppression test

2. Determine cause

   1. Serum ACTH lvl

   2. Imaging tests (CT/MRI) for pituitary or adrenal tumor

Preferred treatment for Cushing’s?

Surgical resection of tumor

Drug selection is determined according to []

The etiology of Cushing’s syndrome (ACTH independent or dependent?)

Individual patient factors (gender, ADR of drug, DDI)

Cost

What is the overview of medical management of cushing syndrome?

Steroidogenesis Inhibitors

• Ketoconazole

• Osilodrostat

• Metyrapone

Adrenolytic Agents

• Mitotane

Neuromodulator Agents

• Cabergoline

• Pasireotide

Glucocorticoid Receptor Antagonoists

• Mifepristone

Ketoconazole: BBW

Hepatotoxicity

QT prolongation (C/I W/ anti-arrhythmic)

Ketoconazole monitoring frequency

Weekly ALT monitoring

→ Consider discontinuing/decreasing dose if:

• ALT values increase above the upper limit of normal (7-56)

• ALT values increase 30% above baseline

• Patient develops symptoms of liver failure

Ketoconazole: Metabolism

Strong CYP3A4 Inhibitor

• DDIs!

Ketoconazole: C/I, Not recommended, Use w/ caution

Ketoconazole AE

Adverse effects:

• GI intolerance

• Dermatologic reactions (rash/pruritis)

• Fatigue; myalgias

• Reversible elevation of hepatic transaminases (LFTs)

• Anti-androgenic effects (Gynecomastia)

Ketoconazole Monitoring

• Cortisol levels (to guide treatment)

• Liver function tests

• Adverse effects

• DDI

Osilodrostat (Isturisa): Indication

Cushing disease treatment

Osilodrostat (Isturisa): ADEs

May cause hypocortisolis

Dose-dependent QTc prolongation

Increased cortisol/aldosterone precursors and androgens

• Edema / hypertension / hypokalemia (aldosterone)

• Hirsutism / acne (androgen)

Osilodrostat (Isturisa): Monitoring Follow Up

Cortisol (24-hr urinary free cortisol) every 2 weeks until clinical response achieved

Serum potassium and magnesium to prevent HYPOkalemia

EKG (1 week after initiating therapy, as needed afterward)

Blood pressure (may increase so montior!)

Edema

Signs/symptoms of adrenal insufficiency

Pasireotide (Signifor): AE

Hyperglycemia

Bradycardia & QT prolongation

Elevated liver function tests

Cholelithiasis (gallbladder stones)

HA, fatigue

N/V/D

Injection site reactions

Pasireotide: Monitoring at baseline

Blood sugar

Liver function

ECG

Which medications may worsen her elevated BP and lower potassium?

Mifepristone and Olisodrustat

Which medication options to treat Cushing’s Syndrome may increase her blood glucose?

Pasireotide (Signifor)

Pasireotide: Monitoring during treatment

• Blood sugar

• Liver function

• Urine cortisol

Mifepristone (Korlym): Indication

Approved to control hyperglycemia in patients with Cushing’s syndrome who have type 2 diabetes or glucose intolerance

Mifepristone (Korlym): Monitoring

Cushing symptoms

Glucose (is it getting too low?)

Serum potassium (hypoK+)

Pregnancy test

No monitoring of cortisol or ACTH

Mifepristone: DDI

Inhibitor of CYP3A4 > 2C9

Mifepristone: C/I

Lovastatin / simvastatin

Cyclosporine, tacrolimus

Wishing to become pregnant/pregnant

Mifepristone (Korlym): AEs

Adverse effects:

• Edema, hypertension, hypokalemia (aldosterone effects)

• GI effects

• Fatigue, headache, dizziness

• Arthralgia

• Vaginal bleeding (anti-progesterone effects)

Mifepristone: Counseling

• Avoid large amounts of grapefruit juice (due to CYP 3A4)

• Hormonal contraception will not work as well while taking this medication; use non-hormonal contraception

• Be aware of signs/symptoms of adverse effects:

  • Hypokalemia (muscle cramps/weakness; irregular heart beat)

  • Hypoglycemia

Hypofunction of adrenal gland

Primary insufficiency

• Addison’s disease

• Cortisol/aldosterone deficiency

Secondary insufficiency

• Decreased ACTH

• HPA-axis suppression from medications

What causes HPA Axis suppression?

Exogenous steroids (Oral, Inhaled, Topical, Intranasal)

Mirtazapine

Progestins (medroxyprogesterone, megestrol)

Adrenal Insufficiency: Diagnosis

Low AM serum cortisol

Elevated serum ACTH

Corticotropin (ACTH) stimulation test

• Not affected by diurnal variation

Adrenal insufficiency is when serum cortisol is <[] mcg/dL

18

Adrenal insufficiency treatment

Glucocorticoids

• 15-25 mg/day hydrocortisone

• 20-35 mg/day cortisone acetate

• 3-5 mg/day prednisolone

Mineralocorticoids

• Aldosterone deficiency → Fludrocortisione (Florinef)

• Once daily in the AM

What is the dosing schedule for adrenal insufficiency?

2 or 3 daily doses

2 doses

• 2/3 in AM; 1/3 six-eight hours later

  • 15 mg in AM

  • 10 mg in afternoon

3 doses

• Decreasing doses

  • 15 mg in AM

  • 5 mg in late AM

  • 2.5 mg in late afternoon

CONTINUE WITH JELENA

What are hormones? What are they secreted by?

Hormones are potent chemical substances secreted by

• Specialized organs (glands)

• Circulate in blood

• Act on specific target cells that are distant from their source of secretion

What are exocrine glands?

Glands that release their secretions into a duct

What are endocrine glands?

Glands that release their secretions directly into blood

T/F: Pancreas and liver mixed glands with both exocrine and endocrine functions

Both exocrine and endocrine functions

Label these glands, also name the hormones they secrete.

1. Pituitary gland → GH, ACTH, TSH, FSH, LH, prolactin

2. Thyroid gland → T3, T4, Calcitonin

3. Parathyroid gland → PTH

4. + 5 Adrenal gland → Cortisol, mineralocorticoid,

5. Ovaries → Estrogen and progesterone

6. Testes → Testosterone

[] serves as an interface between neuronal inputs in response to external and internal stimuli and endocrine system. It regulates []

Hypothalamus

Pituitary gland

What does pituitary gland regulate?

Gonads, Thyroid, Mammary gland and Adrenals

GnRH releases []

Gonadotrophs (LH, FSH)

TRH releases []

Thyrotrophs (TSH)

PRH releases [] + GHRH releases []

PRL (Lactotrophs)

GH (Somatrotrophs)

CRH releases []

ACTH (Corticotrophs)

How are hormones categorized based on chemical structures?

1. Steroid hormones

   1. They contain steroidal nucleus in their structure (e.g. Estradiol, Progesterone, Testosterone, Cortisol, Aldosterone)

2. Peptides/Proteins hormones

   1. They are made up single or multiple chains of amino acids (e.g. Growth Hormone, FSH, LH, TSH, ACTH, Prolactin, Insulin, Glucagon, Calcitonin, PTH

   
   

   1. Amino Acid derivative hormones (e.g Thyroxine, Epinephrine (Tyrosine derivative), Melatonin (Tryptophan derivative))

State where they are hydrophillic or hydrophobic.

Peptides/Proteins hormones

Steroid hormones & Thyroxine

Amino acid derivative thyroxine

Hydrophillic

Hydrophobic

Hydrophobic

Hydrophobic Hormones are []cellular and act via []

Intra

Nuclear receptors → changes in gene expression

Binding of hydrophilic hormones to cell surface receptors can cause activation of:

G-protein, Tyrosine Kinases, Ion Channels thus causing changes in cell signaling to bring about physiological effects

Hydrophobic hormones are bound to []

Plasma proteins e.g steroid binding proteins (SBP), sex hormone-binding globulin (SHBG) thyroxine-binding globulin (TBG)

Only free hormones is available for:

1. []

2. []

1. Binding to receptor and initiating biological response

2. Undergoing metabolic inactivation

FINISH SOME SLIDES BEFORE L.O

DONT MEMORIZE ALL PITUITARY HYPOTHALAMUS HORMONES → will come later, not a L.O

Describe the cortex part of adrenal gland histology.

Cortex

1. Zona Fasciculata which (cells of) secrete…

Glucocorticoid hormones: Cortisol (Hydrocortisone)

2. Zona Glomerulosa which (cells of) secrete…

Mineralocorticoid hormones: Aldosterone

3. Zona Reticularis which (cells of) secrete…

DHEA

Describe the medulla part of adrenal gland histology.

Synthesizes and secretes

1. Epinephrine

2. Norepinephrine

Describe Physiological Regulation of Glucocorticoid Hormone Cortisol’s Secretion

Hypothalamic Pituitary Adrenal Axis:

Hypothalamus → CRH → ACTH → Acts on Zona fasiculata → Cortisol synthesis + releases

Describe Negative Feedback Loop in HPA Axis

As the plasma cortisol levels increase, cortisol inhibits the release of CRH & ACTH

When are peak plasma levels of ACTH & Cortisol?

In the morning

Lowest at midnight

What are sampling times for diagnostic tests of Cushing syndrome?

Midnight plasma cortisol

Late night salivary cortisol

Cortisol causes its physiological effects by binding to [] receptors. What happens as a result?

Glucocorticoid receptor → conformational change + change in gene expression → Metabolism of glucose, lipids, amino acids → increased blood glucose

Cushing’s Syndrome is [] overproduction

Cortisol + aldosterone

Addison’s Disease is deficiecy of [] + []

Cortisol and aldosterone

What is the etiology of Cushing’s Syndrome

1. ACTH (ACTH-dependent Cushing’s syndrome) secreting tumors (adenoma)

2. Cortisol (ACTH-independent Cushing’s syndrome) secreting tumors (adenoma)

   1. Iatrogenic cause of Cushing’s syndrome (caused by steroid intake)

Will the plasma levels of ACTH and cortisol in patients with ACTH-Iindependent Cushing’s syndrome be higher or lower than the normal physiological values?

ACTH: Lower d/t negative feedback loop

Cortisol: Higher

Cushing’s Syndrome: Signs & Symptoms

Cushing’s Syndrome Management

If resection is not possible

Preoperative treatment to decrease circulating cortisol levels

Postoperative treatment while waiting for the beneficial effects of surgery

What are the drugs for Cushing’s syndrome?

• Steroidogenesis Ihibitors

  • Osilodrostat, Ketoconazole

• Adrenolytics

  • Mitotane

• Glucocorticoid-RA

  • Mifepristone

• Neuromodulators of ACTH release

  • Cabergoline, Paeriotide

Olisodrostat increases or decreases cortisol?

Decreases

Mifepristone increases or decreases cortisol?

Stays the same

Only inhibits the effects of cortisol

Mitotane MOA

Mitotane → Acyl Chloride → Protein denaturation → Cell death → Less cortisol

Mifepristone AE

Mifepristone also acts as antagonist of progesterone receptors causes endometrial thickening with or without vaginal bleeding abortifacient at high doses (thus pregnancy test before starting) increases ACTH and cortisol levels