Hypothalamic and Pituitary Disorders
PRL elevating drugs
1st Generation Antipsychotics- Haldol 2nd Generation Antipsychotics- Aripiprazole, olanzapine Tricyclic antidepressants- Amytriptaline SSRI antidepressants- Fluoxetine, sertraline Gastrointestinal- Metaclopromide Anti-hypertensive- Calcium channel blockers, methyl dopa Opioid analgesics- Methadone, morphine, heroin
secondary/tertiary vs primary ACTH deficiency symptoms
ACTH deficiency does not cause salt wasting, volume contraction, and hyperkalemia because there is no significant reduction of aldosterone ACTH deficiency does not result in hyperpigmentation The above symptoms are seen in Addison's disease which is caused by a primary adrenal insufficiency
what is primary polydipsia? who is it seen in?
AKA psychogenic polydipsia Increase in water intake Most commonly seen in middle aged women
A patient with frontal bossing, tall stature, and macroglossia has what disorder? MCC is?
Acromegaly MCC is a Somatotropinoma
What is pituitary apoplexy? symptoms?
Acute hemorrhage or infarction of pituitary Sudden onset headache, visual symptoms, altered mental status, and hormonal dysfunction Often sequela of known tumor (pituitary adenoma)
clinical features of acromegaly related to?
Attributable to high serum concentrations of both pituitary-derived GH and liver-derived insulin-like growth factor Both somatic and metabolic effects and may have sx's of the somatotroph adenoma (compression effects)
optic chiasm compression symptoms
Bitemporal hemianopsia*, Loss of red perception, scotoma, blindness
adult presentation growth hormone deficiency
Changes in body composition --increased fat mass/central obesity --decreased muscle mass Dyslipidemia/increased inflammatory markers/decreased endothelial function Decreased bone mineral density Increased Cardiovascular Risk factors (high LDL, decreased cardiac output w/ exercise) Decreased psychological function/quality of life/well-being Increased mortality
what is acromegaly? what does it do and who does it affect?
Clinical syndrome of excessive secretion of GH production after closure of epiphyseal plates Stimulates release of IGF-1 from liver and kidneys Annual incidence: 3-6/million people. Mean age at diagnosis is 40 to 45 years, typically 12 years* after onset of sx's
presentation TSH deficiency
Cold intolerance Decreased appetite Bradycardia Facial puffiness Weight gain Depression Fatigue Dry skin Constipation Delayed DTRs Anemia hyperlipidemia
how to perform the cosyntropin stimulation test? iinterpretation?
Cosyntropin is synthetic ACTH Measure cortisol level before and after administration of Cosyntropin If cortisol level rises the problem is secondary If not, it is primary
central DI causes (neurogenic DI)
Deficient secretion of antidiuretic hormone (ADH)* Idiopathic - autoimmune injury to ADH-producing cells Primary or secondary tumors Infiltrative dz (histiocytosis, sarcoidosis) Trauma/TBI Infection (TB, syphilis) Pituitary surgery/neurosurgery Hypoxic or ischemic encephalopathy Granuloma (sarcoidosis)
what iis gonatropin deficiency
Deficient secretion of the gonadotropins FSH and LH result is hypogonadotropic hypogonadism
gigantism evaluation? interpretation? definitive test?
Determination of bone age, thyroid function tests, sex steroid hormone concentrations Measure TSH, IGF-1, and PRL levels GH suppression test - gold standard for making a definitive diagnosis Measures the serum GH response to an oral glucose load Normal GH response to elevated BG is reduction in secretion IF GH not <1 ng/mL within 2 hours - GH excess confirmed
posterior pituitary disorders
Diabetes Insipidus SIADH
causes primary polydipsia
Drugs - Phenothiazine (sensation of dry mouth) Hypothalamic lesions affecting thirst center Infiltrative lesions (i.e. sarcoidosis)
soft tissue and skin clinical features acromegaly
Enlarged jaw (macrognathia)( Enlarged, swollen hands and feet - increased shoe, glove and ring size* Coarsened facial features become coarse - enlargement of the nose, frontal bones, jaw, and the teeth become spread apart (enlarged hat size) Soft tissue overgrowth - macroglossia, enlargement of pharynx/larynx resulting in deepening of the voice and OSA (about 50%) and paresthesias of the hands causing CTS (about 20%) Hyperhidrosis is common - moist handshake Some women have hirsutism
what is gigantism? who is it seen in?
Excess of growth hormone (GH) before fusion of the epiphyseal growth plates Only seen in growing children - elevated levels of serum GH and IGF-I Causes rapid, excessive linear growth and potentially extremely tall adult stature Often with mild to moderate obesity Prevalence - Very rare
Growth hormone deficiency children presentation
Failure to thrive short stature (decreased fusion of epiphysis/ growth plate < age) Early fibrosis of growth plate but delayed closure Delayed puberty
diagnosis gonadotropin deficiency females
Females - premenopausal (no testing if normal menses) Low estradiol PLUS follicle-stimulating hormone (FSH) that is not elevated = secondary hypogonadism
How does the decreased growth hormone in pituitary dwarfism affect the growth plates?
Growth plates fibrose early but close
brain compression symptoms
HA*, hydrocephalus, psychosis*, dementia
known causes of hyperprolactinemia
HcG - pregnancy DRUGS TSH, FT4 - hypothyroidism BUN/Creatinine - CKD LFT - cirrhosis Calcium - hyperparathyroidism Sex hormones - testosterone/LH/FSH or estradiol/LH/FSH
what are tumor symptoms
Headache*, visual field defects (classically bitemporal hemianopsia)*, and cranial nerve palsies Macroadenomas can also cause decreased secretion of other pituitary hormones, most commonly gonadotropins
what is the MC symptom of an intrasellar tumor
Headaches
Growth hormone deficiency newborn presentation
Hypoglycemia Jaundice Small penis
pituitary compression symptoms
Hypogonadism, hypothyroidism, growth failure/hyposomatotropism, hypoadrenalism know all
how is the anterior pituitary controlled
Hypophysiotropic hormones also known as Hypothalamic Releasing/Inhibiting hormones --The hypothalamus synthesizes different peptides that stimulate pituitary hormone secretion
anterior pituitary disorders
Hypopituitarism Acromegaly Gigantism Prolactinoma
What is the response of the anterior pituitary to Dopamine?
INHIBIT prolactin release
PRL testing results
If mildly elevated 21-40, repeat test for confirmation PRL values > 200 ng/mL - likely lactotroph adenoma MRI of the head in all patients with elevated PRL unless taking a medication known to cause this or untreated hypothyroidism
decsribe prolactin deficiency
Inability to lactate after child birth Isolated prolactin deficiency is rare Most have evidence of other pituitary hormone deficiencies
acromegaly associated with increased risk for
Increased risk for colon polyps, colon cancer, and other tumors Increased mortality rate - primarily from cardiovascular disease
testicular hypofunction or decreased testosterone causes
Infertility Impotence Decreased libido Decreased energy Hot flashes (if severe) Decreased muscle mass/strength (after years) Decreased BMD (after years)
clinical presentation prolactinemia premenopausal women
Infertility oligomenorrhea or amenorrhea Galactorrhea (not always) PRL > 100 ng/mL is typically associated with overt hypogonadism and subnormal estradiol secretion - amenorrhea, hot flashes, vaginal dryness
What is the response of the anterior pituitary to Somatostatin?
Inhibit GH and TSH release
What hormone is most likely going to be elevated in a person with acromegaly?
Insulin-like Growth Factor -1 (IGF-1)
diagnosis gonadotropin deficiency males
Low total testosterone (or Free Testosterone if obese) on two or more occasions at 8 to 10 AM PLUS luteinizing hormone (LH) that is not elevated = secondary hypogonadism
Causes hypopituitarism? which is MCC
MCC - pit adenoma impaired blood flow, compression, blockage of transmission of hormones Empty sella syndrome (abbreviated ESS) is where the pituitary gland shrinks or becomes flattened, filling the sella turcica, or "Turkish Saddle", with cerebrospinal fluid on imaging instead of the normal pituitary Sarcoidosis - causes abnormal collections of inflammatory cells that form lumps known as granulomas
pathologic causes prolactinemia
MCC Prolactinoma Other hypothalamic and pituitary disorders/tumors Drug induced Idiopathic Hypothyroidism Chest wall injury Estrogen Chronic renal failure (on HD) Cirrhosis Familial hyperprolactinemia
MCC acromegaly
MCC somatotroph (GH-secreting) adenoma of the anterior pituitary (Somatotropinoma)
other causes of GH deficiency
Malnutrition CKD Opioid tx Nl aging
what test can you do to diagnose ACTH deficiency
Measure serum cortisol at 8 - 9 AM on two or more occasions -If <3 mcg/dL, then cortisol deficiency (if known cause for hypopituitarism - dx is done, otherwise...) -Measure ACTH, if high then cause is primary, if not then cause is secondary/tertiary -If >18 mcg/dL, then cortisol sufficiency (diagnosis disproved and sx's are related to another issue) -If intermediate (between 3-18 mcg/dL), can do a metyrapone suppression test or a cosyntropin stimulation test to confirm primary vs secondary cause
acromegaly diagnosis? intepretation?
Measure serum insulin-like growth factor 1 (IGF-1) concentration If normal no acromegaly If high - serum GH should be measured after oral glucose administration Inadequate suppression of serum GH after a glucose load confirms the diagnosis of acromegaly Then pituitary magnetic resonance imaging (MRI) - 90% show tumor (pituitary adenoma)
what is a metyrapone suppression test, what do you do? how do you interpret the results?
Metyrapone inhibits adrenal gland's ability to make cortisol, when administered, AM cortisol levels drop --Administer Metyrapone then measure ACTH If ACTH is elevated - adrenal dysfunction, if not - pituitary/hypothalamic dysfunction
What is the effect of oxytocin?
Milk let-down during lactation and contraction of the uterine myometrium during labor
what are the types of pituitary adenomas? how should they be managed?
Most are microadenomas < 10 mm --If NOT hyperfunctional, monitor microadenomas w/ MRI - annually initially, then less often if no evidence of growth Macroadenoma > 10mm --Resection should be considered --Approx 1/3 become invasive or cause local pressure effects May also cause problems due to compression effects
what are the types of pituitary masses
Most are pituitary adenomas (incidentalomas) -Often incidental findings on MRI Can be: -Functional (hypersecretion of hormones) -Hypofunctional (hyposecretion of hormones) -Non-functional (low- normal hormone secretion w/o symptoms)
treatment ACTH deficiency
Most pt's: Oral hydrocortisone* --Some pt's: Oral prednisone or methylprednisolone Additional corticosteroid must be given during stress (infection, trauma, surgery) mild-moderate illness, surgery or stress - doses are doubled or tripled Severe illness, trauma, major surgery: hydrocortisone 100 mg is given intravenously, followed by 200 mg daily (IV or IM) and then reduced to usual doses as the stress subsides Caution: wear medical alert bracelet describing condition and treatment
what is nephrogenic DI
Normal ADH secretion but varying degrees of renal resistance to its water-retaining effect
prolactin deficiency diagnosis/treatment
Not tested Not treated other than resection of tumor if indicated
acute hypopituitarism often due to? what does it cause? examples?
Often due to iatrogenic causes, infection, or infarction Causes devastating symptoms -Hypotension -Shock -Coma Examples: Sheehan's or Apoplexy
cavernous sinus compression symptoms
Ophthalmoplegia* +/- ptosis/diplopia, Facial numbness
ovarian hypofunction causes
Ovarian hypofunction = decreased estradiol secretion Amenorrhea or irregular periods Anovulatory infertility Vaginal atrophy Hot flashes Decreased Breast tissue (after years) Decreased bone mineral density (after years)
TSH deficiency diagnosis
Paired Hormone Measurement --TSH - usually low --Low total thyroxine (T4), Free T4, & triiodothyronine (T3) (Must check to ensure cortisol is not suppressed if low TSH found) Cortisol decreases TSH - must ensure low TSH is not due to low cortisol 1st
What is the most common cause of acromegaly?
Pituitary Adenoma
how to diagnose hypopituitarism? what should PE include?
Pituitary function should be tested --When a patient has a disease that affects the hypothalamus or pituitary Physical exam Thyroid exam, genital inspection, ophthalmic exam (acuity, EOMs, bitemporal hemianopsia) Signs of hypersecretion (Cushing like, acromegaly, galactorrhea)
What do bitemporal hemianopsia and galactorrhea suggest?
Pituitary tumor
DI symptoms
Polyuria, increase in urine output > 3 L/day in adults and 2 L/m2 in children NOT frequency or nocturia (no overall increase in output) Three causes of polyuria Primary polydipsia Central DI Nephrogenic DI
what is sheehan syndrome? what does it typically follow? onset?
Postpartum pituitary necrosis Usually follows a severe postpartum uterine hemorrhage Usually insidious onset: failure to lactate, amenorrhea Worldwide: I>3 million women suffer from Sheehan syndrome Yearly mortality of about 100,000
physiologic causes of prolactinemia
Pregnancy — PRL increases throughout pregnancy; range 35 to 600 ng/mL Nipple stimulation, breast stimulation, breast implants — likely due to reflex oxytocin stimulation (PRL may be measured after a breast exam) Stress — but very slight - values rarely exceed 40 ng/mL
hypopituitarism clinical manifestations- presentation
Presentation depends on extent of deficiency of each hormone Presentation is Challenging and Variable Onset - can be sudden or insidious Severity - mild to severe (partial to complete) Scope - anywhere from 1 - 6 hormones Hypopituitarism will present with symptoms similar to the presentation of the primary gland deficiency (with some notable exceptions) Symptoms can be difficult to notice if insidious onset (which is most usual presentation) Symptoms may range from mild to moderate to severe and may only show up in 1 or a few hormones
when does gonadotropic deficiency occur
Serious Illness, malnutrition, anorexia nervosa, alcoholism, opioid tx, Cushing syndrome, hyperprolactinemia, tx w/GnRH agonists (i.e. Leuprolide)
ACTH presentatiion
Similar to cortisol deficiency (like Addison's - but not due to adrenal insufficiency) Cortisol: increases BS via gluconeogenesis; suppresses immune system; helps metabolize fat, protein, carbs; decreases bone formation; maintains peripheral vascular tone
What is the response of the anterior pituitary to GnRH?
Stimulate the release of LH and FSH
What is the effect of TRH release by the anterior pituitary?
Stimulates the release of TSH GH PRL
treatment GH deficiency
Subcutaneous recombinant human growth hormone injections --Children with GH deficiency --Adult patients that had childhood GH deficiency --Symptomatic adults with severe GH deficiency Multiple side effects Controversial in adults
treatment optiions gigantism
Surgery — Transsphenoidal surgery is the TOC for discrete pituitary microadenomas or macroadenomas and may be curative Radiation — Adjunctive therapy to surgery but usually causes panhypopituitarism that can lead to growth failure, learning disabilities, emotional changes, and obesity Pharmacologic treatment — Indicated when surgery does not fully control GH excess or when surgery is not an option TOC - Octreotide; second line - Bromocriptine (less effective)
hypothalamus compression symptoms
Temperature dysregulation, appetite/thirst disorders*, obesity, DI*, sleep d/o*, behavioral dysfunction, autonomic dysfunction
when should you test for growth hormone deficiency
Test if high suspicion of deficiency: Known Pituitary or hypothalamic disease Hx of GH deficiency as a child panhypopituitarism deficiencies of ACTH, TSH, and gonadotropins Low serum insulin-like growth factor 1 (IGF-1) concentration confirms dx
describe the anatomy of the pituitary gland- how much does it weigh? where is it located? what does it consist of? what is it contiguous with?
The pituitary gland weighs ~600 mg located within the Sella Turcica ventral to the diaphragma sella it consists of anatomically and functionally distinct anterior and posterior lobes. The bony sella is contiguous to vascular and neurologic structures, including the cavernous sinuses, cranial nerves, and optic chiasm. In the context of this lecture, consider that pathological processes that cause the pituitary to expand within the intrasellar area may have significant central mass effects in addition to their endocrinologic impact.
How will height be affected in a pt who develops acromegaly as an adult?
There is no change in height after growth plates close
visceral enlargement clinical features
Thyroid enlargement may be diffuse or multinodular Cardiovascular abnormalities include hypertension, left ventricular hypertrophy, and cardiomyopathy Heart failure occurs in 3 to 10 %
TSH deficiency treatment
Thyroid hormone replacement only after cortisol checked and replaced w/steroids if indicated Replace thyroid hormone - levothyroxine: weight-based T4 dose of 1.6 mcg/kg Monitor with symptoms and FT4 Goal: serum T4 level at or above ULN, based on the rationale that only T4 is being given
What is the primary response of the adrenal cortex to ACTH?
To Secrete Glucocorticoids
What is the specific type of procedure used to surgically treat acromegaly from a pituitary adenoma?
Trans-sphenoidal resection of the pituitary
gonadotropic deficiency treatment
Transsphenoidal removal of tumor will sometimes reverse sx's Life-long hormone replacement
acromegaly treatment
Transsphenoidal surgery* for patients with adenomas that appear fully resectable or impair vision Primary therapy with a long-acting somatostatin analog if adenoma does not appear to be fully resectable or poor surgical candidate If transsphenoidal surgery results in normalization of IGF-1 - no further therapy If not - start long-acting somatostatin analog (octreotide*) and/or dopamine agonist (bromocriptine/cabergoline*) If adenoma size increases despite medical therapy - radiotherapy or repeat surgery
what is the rule for hypopituitarism
When hypopituitarism exists, it most commonly impacts the sex hormones 1st, followed by PRL and GH, followed by ACTH and TSH
who should we test PRL levels
Women with oligomenorrhea, amenorrhea, or galactorrhea Men with symptoms of hypogonadism, impotence, or gynecomastia
clinical presentation prolactinemia postmenopausal women
already hypogonadal If macroadenoma sufficient to cause other symptoms - HA, vision changes --Incidental finding
hypopituitarism caveat
cannot assume the status of any hormone by the status of another But you cannot assume this presentation and once you find that hypopituitarism is affecting one hormone, you need to actively screen for other Ant. Pit. hyposecretion and test accordingly.
men presentation prolactinemia
causes hypogonadotropic hypogonadism - rough correlation to degree of hyperprolactinemia Decreased libido Impotence Infertility Gynecomastia (sometimes) Galactorrhea (rarely) Visual Loss If long standing - will also demonstrate decreased bone mineral density, reduced muscle mass, and reduce growth of facial hair
IF serum prolactin decreases to low normal in response to dopamine agonist treatment, then what do you do
decrease dose gradually, monitoring PRL Idiopathic hyperprolactinemia that responded well to treatment may do trial of stopping medications after 2 years Measure prolactin after three months and yearly thereafter
If lactotroph macroadenomas, initial treatment is
dopamine agonist Transsphenoidal surgery when dopamine agonist treatment is unsuccessful or tumor size increases or symptoms persist Radiation therapy as last resort
bone and joint clinical features acromegaly
gigantism in children; adults do not become taller Synovial tissue and cartilage enlarge, causing hypertrophic arthropathy of the knees, ankles, hips, spine, and other joints, spinal stenosis due to vertebral thickening
metabolic effects acromegaly
hyperinsulinism, insulin resistance, overt diabetes in 10 to 15 percent of cases, and impaired glucose tolerance in a further 50 percent, some have hypertriglyceridemia or hypercalciuria
severe ACTH deficiency symptoms
hypotension, vascular collapse/shock and death
lateral mass invasion causes? symptoms?
invasion impinges cavernous sinus → palsies of CN III, IV, and VI & ophthalmic and maxillary branches of CN V --Present w/ diplopia, ptosis, ophthalmoplegia, and ↓'d facial sensation
mild ACTH deficiency symptoms
lethargy, fatigue, poor appetite, weight loss, decreased libido, hypoglycemia, hyponatremia
Direct hypothalamic compression →
metabolic sequelae, i.e. precocious puberty/hypogonadism, diabetes insipidus, sleep disturbances, dysthermia, & appetite disorders
in bitemporal hemianopia, where is the lesion
optic chiasm
less severe ACTH deficiency symotpms
orthostatic hypotension, tachycardia, hypoglycemia
frontal lobe compression symptoms
personality d/o, anosmia*
pituitary stalk compression by tumor can cause
portal vessel compression disrupting pituitary access to hypothalamic hormones and dopamine → early hyperprolactinemia and later concurrent loss of other pituitary hormones --May also be caused by trauma, whiplash, or skull base fractures
what if there is no cause found for hypopituitarism
screen for hemochromatosis (iron and transferrin saturation/ferritin)
temporal and frontal lobe involvement symptoms?
seizures, personality disorders, and anosmia
suprasellar extension can cause
visual disturbance by compression of optic chiasm, or direct invasion of optic nerves or obstruction of CSF flow
