hyperprolactinemia, prolactinomas, anterior, and postirior

what is the normal pituitary hormone secretion

post pituitary: ADH, Oxytocin

Ant pit: GH, ACTH, TSH, FSH and LH, ptolactin

patho phys of prolactin

it is rel from iactroph cells of the ant pit, its rel is regulated by inh signals (dopamine) from hypothalamus. It induced growth and differentiation of cells of the mammary gland and is essential for lactation

Elevated prolactin levels inh GnRH and sunseq sex hormone production (ovulation)

meaning of hyperprolactinemia

persistent levels >30, normal levels is 15-25

levels> 200 are mostly ass with prolactin-secreting pit tumor

causes of hyperprolactinemia

pregnancy/lactation

stress, hypothy, kidney failure, stalk effect, meds

tumors prolactinomas (microadenoma

what is drug induced hyperprolcatinemia

typ ass with prolactin levels less than 100

dopamine antagonist: dopamine inh prolactin so these drugs incr prolactin (risperidone, haloperidone, TCAs-amitripyline, metoclopramide)

prolactin stimulants: SSRIs-fluoxetine, estrogen/progesterone, benzos, opioids

methydopa, verapamin

GnRH analogs (leuprolide, goserelin, naferelin)

trt of drug induced hyperprolactemia

Aripiprazole can be considered in antipsychotic-induced hyperprolactemia

– Partial dopamine D

– May be considered as add-on therapy if patient responding well to initial antipsychotic

– May discontinue offending antipsychotic and trial aripiprazole if patient was not responding well to initial treatment

presentation of hyperprolactinemia

Manifestations of estrogen deficiency: Irregular menstrual periods or amenorrhea, Infertility, galactorrhea, Reduction in sex drive

Vision loss/Headache (if prolactinoma)

Osteoporosis (if long-term)

men: same as above but manifestation of loss of testosterone production (loss of libido and body hair, erectile dys, infertility)

trt of prolactinomas (tumor)

surgery (risk of ant. pit damage)

radiotherapy (takes yrs and not specific leads to pit damage)

Drug: bromocriptine (parlodel), Cabergoline (dostinex)

Both drugs are D2 receptor agonists; stimulate postsynaptic dopamine receptors in the hypothalamus to release dopamine; bind to D2 receptors on cell membrane of prolactin-secreting cells, inhibiting release and synthesis of prolactin.

what is the preferred first line for prolactinomas

Cabergoline (dostinex): has higher affinity for receptor, more efficacious in reducing tumor size and normalizing prolactin levels with better GI tolerance. many pts who do not respond to bromocriptine will respond to cabergoline

what is the preferred option in the trt of prolactinomas in pregnancy

Bromocriptine (parlodel)

adverse effects of Bromocriptine (Parlodel) and Cabergoline (Dostinex)

Nausea (take with food), vomiting, diarrhea, headache

Orthostatic hypotension, dizziness

Worsening of psychosis

Heart valve disorders (Parkinson’s doses)

contraindications of Bromocriptine (Parlodel) and Cabergoline (Dostinex)

lactation, uncontrolled HTN, orthostasis, heart valve dx

what are drug interactions to Bromocriptine (Parlodel) and Cabergoline (Dostinex)

dopamine antagonists, 3A4 metabolism

when should you D/C dopamine agonists

if received at least 2 yrs of trt and

serum prolactin levels normalized and

absence of visible tumor on imaging

what do you do with trt after pregnancy

breastfeeding incr serum prolactin

trt is typ witheld until breastfeeding is complete

If visual field impairment develops, restart treatment – Will have to stop breastfeeding

what is the adrenal physiology and endocrine feedback

hypotha rel CRH - ant pit rel ACTH - adrenal cortex rel cortisol - pheriphery

cortisol has negative feedback to ant. pit and hypothalamus

what is the physiologic effects of cortisols

anti-inflammatory

stress hormone, plasma glucose regulation and bone demineralization

what is the hepatic role in cortisone production

11B-HSD 1 in liver catalyzes convertion of cortisone (inactive) to cortisol (active)

Hepatic insufficiency can impair conversion (dec. cortisol effects)

Hepatic drug-drug interactions may play a role in therapy selection

what is the glucocorticoid anti-inflammatory effects

inh pro-inflammatory pathways at multiple points

decr hyperthermic response to inflammatory pathway activity

what is the glucocorticoid molecular activity

Soluble ligand, intracellular receptors bounded to plasma proteins

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 pharmacological targets in hypercortisol dx

\-glucocorticoid receptor antagonist (mifepristone)

\-inh steroidogenesis

\-inh ACTH rel (2’ hypersecretion)

\-surgical resection/ablation of adrenal gland (1’ hypersecretion)

Moa of glucocorticoid receptor antagonist (mifepristone - Mifeprex)

binds to and antagonizes corticoid receptor by stabilizing GCR-hsp 90 co-repressor interaction. displaces helix 12 from agonist position, enlarging the coregulator binding site and enabling the binding of NCoR (red helix).

use only in pt who are aren’t candidates for surgical resection. Effective reversal of physical manifestations in Cushing’s (hyper- glycemia, weight gain, etc.)

ADR of mifepristone

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

rule out pregnancy in women of child bearing potential prior to initiation. Monitor: glucose, A1C, BP, K+, TFT’s Do not monitor cortisol levels!

CI to mifepristone

pregnancy, CYP3A4 interactions

causes of cushing’s syndrome

excess levels of glucocorticoids from endogenous production or exogenous sources

ACTH dependent: cushing and ectopic

ACTH independent: adrenal adenomas and carcinomas

iatrogenic: exogenous steroids

clinical presentations of cushing’s syndrome

central obesity, HTN, facial plethora, striae, muopathy with or without proximal muscle weakness, hirsutism (women)

diagnosis of cushing syndrome

conform steroid excess

determine source of steroid excess

medications that cause cushing’s dx

glucocorticoids

depo-provera, depo-subQ

megestrol acetate (megace ES)

what is the trt of choice for cushing dx

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

pituitary tumors: transsphenoidal adenomectomy

adrenal tumor: adrenalectomy steroid replacement required postoperatively for 6–12 mnths. mitotane is drug of choice, some efficacy with ketoconazole

ectopic ACTH-producing lung tumor: Thoracotomy - postoperative meds necessary

trt of cushing syndrome dependent on the cause

Irradiation of the pituitary: 6- to 12-month lag time; high incidence of panhypopituitarism; typically reserved for surgical failures

• Medical therapy: typically used for patients with nonlocalized or unresectable tumors, for patients who are not surgical candidates, and for patients whose condition did not respond to surgery or who had relapse after surgery; can also be used in preparation of surgery.

• Drug induced: taper and discontinue GC as soon as possible

pharmacologic agents used in cushing’s syndrome

Steroidogenesis inhibitors: blocks the production of cortisol

Adrenolytic agents: mitotane

Neuromodulators of ACTH release: cabergoline, octreotide

Glucocorticoid-receptor blocker: mifepristone

MOA of steroidogenesis inh

inhibition of 11B and 17-hydroxylase - ketoconazole, levoketoconazole (recorlex)

inh of 11B-hydroxylase - osilodrostat (isturia), metyrapone (metopirone), etomidate (amidate)

adrenolytic; directly suppresses the adrenal cortex - mitotane (lysodren)

ADR of steroidogenesis inh

ketoconazole: hepatotox (BW), male hypogonadism, gynecomastia

levoketoconazole: hepatotox, QTc prolongation

osilodrostat, metyrapone: androgenic effects (hirsutism, acne), hypokalemia

etomidate: sedation

mitotane: N/V, lethargy, somnolence, CNS

possible trt options in cushing syndrome based on etiology

ectopic ACTH syndrome: metyrapone & ketoconazole

Pituitary-dependent: mitotane, metyrapone, mifepristone, cabergoline, pasireotide

Adrenal adenoma: ketoconazole

Adrenal carcinoma: mitotane

examples of steroidogenesis inh

they are synthetic inhibitors

Aminogluethimide (cytadren)

ketoconazole (Nizoral)

metyrapone (metopirone)

\*Risk of acute adrenal insufficiency

examples of inhibition of ACTH release

somatostatin analog: Pasireotide (signifor)

Dopamide agonist: Cabergoline (dostinex)

surgical resection or ablation therapy

Surgical resection in 1’ vs. 2’ Cushing : remove adrenals or pituitary?

Cytotoxic ablation: Mitotane (Lysodren®; structurally like insecticide DDT). Gross destruction of zona fasciculata and zona reticularis, BUT NOT zona glomerulosaà specific loss of steroid secretion that is dependent on adrenocorticotrophic hormone (ACTH); mitochondrial dysfunction to apoptosis

Mitotane activated in adrenal cortex by enzymes which are specific to these zones (few off-target organ effects)

But: 80% patients have significant ADR causing dose reduction: diarrhea, nausea, vomiting, depression, somnolence, skin rash; withdrawn from US market

what dx leads to hypo-adrenal/adrenal insufficiency

chrousos syndrome

addison’s dx (AI)

bilateral adrenalectomy

congenital adrenal hyperplasia (CAH)

what is chrousos syndrome

Familial glucocorticoid resistance syndrome

NR3C1 mutation inactivates glucocorticoid receptor: apparent deficiency in cortisol activity

Symptoms: Hypertension, Hypokalemia, Hirsutism, Precocious puberty, Menstrual irregularities

how is adrenal insufficiency diagnosed

ACTH stimulation with cosyntropin (ACTH analogue)

Patient given ACTH– does their body respond by producing cortisol? If Yes: Not adrenal insufficiency If No: confirm 1’ vs. 2’ cause by measuring endogenous ACTH

low/norma - sec or tertiary AI

elevated -primary AI

what is addison’s dx

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

symptoms may include - hyperpigmentation, low BP, weakness, N/V/D, vitilgo

differences btwn primary and secondary addison’s dx

primary: involves the destruction of all regions of the adrenal cortex

Secondary: Pituitary (lack of ACTH secretion) or Hypothalamic problem (lack of CRH) • Aldosterone and androgen secretion typically preserved; mineralocorticoid replacement usually unnecessary

• Abrupt discontinuation of exogenous corticosteroid therapy; can still occur up to 1 year after glucocorticoid taper and discontinuation • Immune checkpoint inhibitor therapy (e.g., nivolumab (Opdivo), and pembrolizumab (Keytruda) causing hypophysitis and adrenal insufficiency.

symptoms and signs of adrenal insufficiency

weakness, salt craving, hypotension

incr pigmentation

fever

vitiligo, amenorrhea and cold intolerance

clinical labs adrenal symptoms

low cosyntropin, cortisol less than 18 mcg/dL

hyponatremia

hyperkalemia

elevated BUN

trt of addison’s dx

GC replacement therapy

• Hydrocortisone to duplicate the normal circadian rhythm of cortisol production

• Fludrocortisone acetate

monitor postural BP

Side effects of glucocorticoids

gastric upset, edema, hyprtension, hypokalemia, insomnia, hyperglycemia, cataracts

prevention of adrenal crisis

Sick day rules – Fever or illness requiring bedrest, need for antibiotics for an infection, prior to small outpatient procedures (e.g., dental work) – Double or triple one’s dose until recovery

• Parenteral therapy – Appropriate when patient is fasting for a procedure (e.g., colonoscopy), persistent vomiting, severe illness, surgery or trauma – e.g., injectable hydrocortisone (Solu-Cortef), glucocorticoid suppositories (but not if patient has diarrhea) – Don’t forget prescription for injection kit for all

• Teach the patient how to use it!

how does the negative feedback mechanism of glucocorticoids affect the use

\-use local application if possible

\-shortest duration possible

\-taper withdrawal to avoid rebound effects

what is Conn syndrome (pri aldosteronism)

it is mineralocorticoid excess

´ 1’ dysfunction: excess aldosterone produced by adrenal zona glomerulosa. Increase Na+ reabsorption; increased blood volume, increased blood pressure, hypokalemia. Symptoms: fatigue, numbness, muscle cramps, muscle weakness (due to hypokalemia) Increased risk of arrhythmias, MI (due to solute gradient/RMP changes)

trt of Conn syndrome

* surgical resection/ablation of adrenal tumor
* aldosterone receptor antagonist

examples of corticosteroid agonists

glucocorticoids (prednisone)

mineralocorticoids (fludrocortisone)

example of corticosteriod antagonists

receptor antagonists: glucocorticoids antagonists (mifepristpne) mineralocorticoids antagonists (spironolactone)

synthsis inh (ketoconazole)

etiology of primary aldosteronism

Leading cause of secondary hypertension and treatment resistant hypertension.

• Bilateral adrenal hyperplasia

• Aldosterone-producing adenoma (Conn syndrome)

signs and symptoms of pri aldosteronism

muscle weakness, fatigue, paresthesias, H/A

HTN, tetany/paralysis, polydipsia/nocturnal polyuria

ARR >30, PAC>15, hypernatremia, hypokalemia, hypomag, elevated glucose

trt of primary aldosteronism

Bilateral adrenal hyperplasia • Aldosterone-receptor antagonists • Aldosterone-producing adenoma (Conn syndrome) • Surgery (adrenalectomy)

trt of hyperaldosteronism

• Aldosterone R antagonists (ARA)

\- Spironolactone (Aldactone): non-selective ARA. AE (dose-dep): GI, impotence, gynecomastia, menstrual irregularities, hyperkalemia. Salicylates (ASA) can increase renal excretion of canrenone, the active metabolite

\-Eplerenone (Inspra): selective ARA. Fewer sex-steroid SE; substrate of CYP3A4 – avoid w/ strong inhibitors

\-Alternate options • Amiloride (Midamor): K+ sparing diuretic. less effective vs ARA. AE: GI, hyperkalemia, HA, dizzines

Hypothalamic-pit anatomy and physiology of the posterior pit an

its is a straight flow from hypothalamus to post pit that rel vasopressin and Oxy

physiologocal effects of pot pit hormones

vasopressin (ADH): stim by hyperosmolarity, hypovolemia, vol depletion, angiotensin II, inhibited by hypervolemia, hyposmolarity and physiologic effects acts on renal collecting ducts to prevent diuresis vasoconstriction

Oxytocin stim by parturition and suckling and physiologic effects on uterine contraction, milk ejection

how many vasopressin receptors

V1R: incr Bp directly by causein blood vessel constriction and incr systemic vascular resistance

V2R: incr water reabsorption, incr blood vol

fnx of vasopressin is to regulate extracellular fluid vol, blood pressure by incr arterial pressure

physiological effects of vasopressin

AVP synthesized in hypothalamus, trafficked along magnocellular axons to posterior pituitary lobe

Released directly into systemic circulation

Effects at distal tissues: Liver: Glycogenolysis. Kidney: Na+/H2O reabsorption. Vascular smooth muscle: Vasoconstriction. Endothelial cells: vWF release. Platelets: Aggregation

renal effects of ADH

V2R vasopressin receptors expressed on basolateral membranes of collecting duct cells

Receptor activation (GPCR, G a-s cascade) increases aquaporin (AQP2) apical membrane expression

Increased H2O reabsorption

what is Diabetes Insipidus

Insufficient Vasopressin secretion OR Vasopressin Resistance

Net effect: Decreased water reabsorption

Clinical symptoms: Polyuria, Polydipsia, Hyperosmolarity

Nerogenic: problem with the brain decr ADH syn and secretion

nephrogenic: Kidney is not acknowledging vaso

trt of diabetes insipidus

neurogenic: replace vaso ADH

nephrogenic: redyce osmotic load; thiazide diuretic and or prostaglandin inh to trt symptoms

in adults usually sec to other condition and/or drug therapy - identify and correct

what is SIADH - hyper vaso ADH secretion

Syndrome of Inappropriate ADH (incr water reabs leading to decr serum osmolarity (incr serum vol) and incr urine osmolarity (decr urine vol))

1’- posterior pituitary secretion or 2’-ectopic (small cell lung cancer) secretion; drug therapy

Clinical Symptoms: High blood volume, blood pressure, hypo- osmolarity

trt options for SIADH

\-fluid restriction

ADH vaso antagonist -vaptans

less common: loop, urea, demecocycline, lithium, hemodialysis

comparison between diabetes insipidus and SIADH

plasma vol: hypovolemia, normovolemia

serum na: increased, decr

urinary na: decr, incr

urinary output: incr, normal (aldosterone compensation)

mechanism: H2O loss due to decr ADH, H2O retention due to elevated ADH

use of tocolytic therapy oxytocin receptor antagonist (ORA)

management of pre-term labor by suppressing uterine contractions