10/5- Diseases of the Ant Pituitary 1 (Prolactinoma, Acromegaly) Flashcards
What does “primary” refer to in disorders?
Refers to a problem at the level of the target organ versus secondary (pituitary) and tertiary (hypothalamic)
- i.e. primary adrenal insufficiency
Describe pituitary development
- Transcription factors
- Cells
Anterior pituitary precursor
-> Prop-1: Pit-1 and GATA-2
- Pit-1: somatotropes (GH), lactotropes (Prolactin), thryotropes (TSH)
- GATA-2: Thyrotropes (TSH) and Gonadotropes (LH/FSH)
-> T-pit/Tbx-19: corticotropes (ACTH) and melanotropes
Somatotropes (GH) share a common precursor cell with what other cell type?
Lactotropes (prolactin)
Thyrotropes (TSH) share a common precursor cell with what other cell type?
Gonadotropes (LH/FSH)
What are the glycoprotein hormones?
- Structure?
TSH, LH, FSH, (beta-HCG)
- Glycoprotein heterodimers
- Common alpha subunit
- Unique beta subunit
Describe the genetics of ACTH and how it results in various hormone products
- ACTH is a 39 AA peptide product of the pro-opiomelanocortin gene
- Specific “prohormone convertases” or endopeptidases cleave the pro-peptide into multiple products
Possible products:
ACTH:
- aMSH
- CLIP
Beta-LPH:
- gamma-MSH
- beta-endorphin
What is the most common and clinically relevant lesion of the pituitary?
Pituitary adenomas
Epidemiology of pituitary adenomas
- Classification
- 10-15% of cranial neoplasms are pituitary adenomas
- 5-25% of adults have small pituitary tumors (MRI vs. autopsy series)
- Mainly monoclonal (from a single cell)
1 cm rule:
- Microadenoma: < 1 cm
- Macroadenoma: > 1 cm
Class is based on secreted hormone
- Non-functioning (alpha-subunit)
- Lactotrophic (prolactin)
- Somatotrophic (GH)
- Corticotrophic (ACTH)
- Mixed-function (GH and prolactin)
- Gonadotrophic
- Thyrotropic (really doesn’t happen much)
What is the anatomy surrounding the pituitary/what can result from expansion of pituitary tumors?
- Cavernous sinus invasion: wrap around carotid (never impinge it!) but do affect extraocular eye movements via CN III, IV, V1, V2, VI
- Optic chiasm
- CSF rhinorrhea
What are non-hormonal signs and symptoms of a pituitary mass?
- Headache
- CSF rhinorrhea
- Visual field defects:
- Superior temporal quadrantanopsia or hemianopsia
- Decreased peripheral vision or “tunnel” vision
- Detected on examination by confrontation
- Humphrey (automated) or Goldmann (manual) by optometrist or ophthalmologist
- Double vision/disconjugate gaze: CN III/IV/VI
What is seen here?
PItuitary adenoma causing the optic chiasm to be stretched over the mass
Describe the regulation of prolactin secretion
- Pulsatile episodic pattern
- Tonic INHIBITORY control by dopaminergic (DA) neurons from the hypothalamus
- Levels rise in pregnancy and with breast stimulation in post-partum women
- Estrogen is a very potent signal for prolactin production
How do people present with hyperprolactinemia?
Women:
- Galactorrhea
- Amenorrhea
Men:
- Decreased libido
- Impotence/hypogonadal symptoms
- Rare to have galactorrhea (need estrogenized breast tissue)
What causes hyperprolactinemia?
Pituitary disease:
- Prolactinoma
- Macroadenoma PRL > 200
- Microadenoma PRL: 100-200 usually
- Other pituitary masses causing “stalk effect”
- Typ < 100 due to decreased dopaminergic inhibition
- Co-secretion with GH in a small proportion
- Share a common precursor cell
Other causes of hyperprolactinemia: pituitary disease?
- Prolactinoma
- Acromegaly (co-secretion)
- Pituitary Stalk compression or section (i.e. adenoma)
- Empty sella syndrome
Other causes of hyperprolactinemia: neurogenic?
Chest wall or spinal cord lesions (i.e. herpes zoster)
Other causes of hyperprolactinemia: endocrine?
- Pregnancy
- Hypothyroidism
- High estrogen states
Other causes of hyperprolactinemia: hypothalamic disturbances?
Any hypothalamic disturbance, including:
- Craniopharyngioma or other tumors
- Sarcoidosis
- Irradiation
- Stress (physical or psychological)
- Pseudocyesis
Other causes of hyperprolactinemia: drugs?
Drugs (anti-dopamine action)
- Dopamine antagonists
- Phenothiazines/anti-pyschotics
- Reserpine (depletes dopamine)
- Alpha methyldopa
Other causes of hyperprolactinemia: misc?
- Chronic renal failure (because prolactin is cleared by the kidney)
- Idiopathic
Prolactinoma pearls: diagnostic testing?
1. Rule out pregnancy (beta-HCG)
2. Rule out hypothyroidism with thryoid function tests (TSH, free T4)
3. Other hormone levels
- IGF-1, LH, FSH, AM cortisol
- Testosterone or estrogen
4. MRI pituitary with Gad enhancement (pituitary tumors are very common and prolactinomas are common among these)
5. Formal visual field testing
What is seen here?
Microprolactinoma
- Left: pre-contrast
- Right: gadolinium
What is seen here?
Macroprolactinoma
Why might GH/IGF-1 axis elevations be present with prolactinoma?
Common precursor cells secrete both (“somatomammotrophs”)
What should you do if presentation is prolactinoma but the level is low?
Why does it happen?
Do a 1:100 dilution of serum
(“Hook effect” due to too much antigen (prolactin) in fallible immunoassays leads to falsely low values)
Elevated prolactin with no clinical symptoms may be what?
Big prolactin” which is an aggregate held together by glycosylation or antibodies which is not hormonally active but is detected in the lab assays (Polyethylene glycol precipitation will solve this problem)
Treatment of prolactinomas and hyperprolactinemia?
The only pituitary adenoma where surgery is not considered first-line
Dopamine agonists (for Micro- and Macro- adenomas)
- Bromocriptine – nausea, orthostasis
- Cabergoline – longer acting, better tolerated
- (Pergolide – valve dysfunction)
Careful follow-up, especially for Macro (clinical, PRL levels, MRI, visual field exams)
What is cabergoline?
Used for micro/macroadenoma treatment:
- Able to bind the dopamine receptor on cells and nerves
- “Dopamine receptor agonist”
What surgery may be done for prolactinoma?
- When should it be considered?
Transsphenoidal resection; surgery done for prolactinomas when:
- Non-responders or intolerant of treatment
- Significant compressive effects
- Hemorrhagic
- Young reproductive age women with macroadenomas and years of fertility ahead
What is Growth hormone
- Secretion timing
- Stimuli
190 AA peptide hormone
- Secretion is diurnal; levels rise during deep sleep
- Physical activity and emotional stress stimulate GH secretion
Release is controlled by:
- GHRH: positive
- Somatostatin (used to be called Somatotropin release inhibitory factor, SRIF): negative
- analogues of these are used clinically
What mediates most of the GH effects on somatic growth?
Insulin-like growth factor I (IGF-I or somatostatin C)
- Skin
- Connective tissue
- Cartilage, bone
- Organs
What are other (non-growth) effects of IGF-1?
- Glucose hemeostasis: insulin resistance
- Ca metabolism: bone density
- Lipolysis: body composition
Causes of GH excess:
- Pituitary
- Ectopic GH (rare)
- GHRH secretion (rare): hypothalamus
- Ectopic neoplasms (usually NE)
Pituitary
- Sporadic adenoma
- Multiple Endocrine Neoplasia Type 1 (3 P’s – Pituitary, Parathyroid, Pancreatic Islet Tumors)
- McCune Albright (Gsa subunit mutation)
- Carney complex
Ectopic GH (rare)
- Pancreatic islet cell tumor
- non-Hodgkin’s lymphoma
GHRH secretion (rare): hypothalamus:
- hamartomas
- gliomas
- gangliocytomas
Ectopic neoplasms (usually neuroendocrine)
- carcinoid
- islet cell tumor
- small cell lung ca
- medullary thyroid carcinoma
Clinical manifestations of excess GH?
- Headache
- Weight gain
- Acral enlargement
- Prognathism and malocclusion
- Arthritis/arthralgias
- Hyperhidrosis
- Oily skin
- Skin tags
- Easy fatigability
- Muscle Weakness
- Hoarseness
- Cardiac disease
- Hypertension
- Dyslipidemia
- Glucose intolerance
- Galactorrhea
- Constipation
- Decreased libido/Impotence
Facial features of acromegaly?
- Thickened scalp with deep folds
- Thickened calvarium of skull
- Frontal bossing
- Oily skin
- Skin Tags
- Thick lips
- Exaggeration of nasolabial folds
- Prognathism with increased interdental spacing
Limb features of acromegaly?
- Increased soft tissue padding on hands and feet
- Oily skin
- Hyperhidrosis
Musculoskeletal manifestations of acromegaly?
Bone growth
- Prognathia (enlarged jaw) with wide-spaced teeth (diastema), temporomandibular
- Thickening of shafts of metacarpals, metatarsals, phalanges
- Tufting of terminal phalanges
- Exostoses in bones of hands and feet - Knee, shoulder, spine
Joint:
- Cartilage growth:
- Proliferation of chondrocytes
- Thickened joint cartilage and widened joint spaces
- Osteoarthritis with joint instability, wear-and-tear
Causes of symptoms in GH excess:
- Neuropathy
- Enlargement of visceral organs
- Glucose intolerance/overt diabetes
Neuropathy
- Demyelination, also secondary to DM
- Carpal tunnel syndrome with soft tissue expansion and compression of the median nerve (edema and enlarged tendons)
Enlargement of visceral organs
- Heart
- Thyroid
- Liver
- Kidneys
- Prostate
Glucose intolerance/overt diabetes:
- Insulin resistance
What is the biochemical confirmation of excess GH?
Single serum GH > 100 ng/mL (very high)
- Rarely do “spot” hormone levels
- Diurnal and pulsatile rhythms
- Short half life (20-50 min)
Elevated IGF-1
- Longer half life (hours)
- What we really want to see!
“If it’s high, suppress it…“
- Oral glucose tolerance test (75 g glucose)
What is the management of acromegaly?
Surgical removal of adenoma (1st line)
- Transphenoidal resection
Medical therapy
- Somatostatin analogues (inject 1/month)
- Octreotide
- Sandostatin LAR
- Lanreotide LAR
- Pegvisomant
- GH-R antagonist
- Dopamine agonist (for mild elevation of GH)
- Bromocriptine/cabergoline
What are complications of acromegaly?
Patients with acromegaly have higher mortality rates (2 – 3 X)
Cardiovascular & Cerebrovascular 60%
Respiratory 25%
Malignancy 15%
- colonic polyps
- intestinal (colon, stomach, espophagus)
- depends on the study
- RR of death 1.3
- colon cancer 3.0
- breast 1.9
What complications should people with acromegaly be screened for?
Cardiovascular:
- BP monitoring
- ECG
- Echo
Respiratory
- Polysomnography (sleep study)
Glucose metabolism
- Fasting glucose
- OGTT
Osteoarthritis
- Xrays of clinically significant joint problems
Cancer
- Colonoscopy
T/F: if you reduce hormone levels, you normalize the risk of complications in people with acromegaly?
True
What are inherited causes of pituitary adenomas?
Inappropriate signal transduction
- McCune Albright (GH)
- G protein alpha subunit (Gsa1) mutation (somatic, post-zygotic)
- Café-au-lait spots
- Precocious puberty, acromegaly or gigantism, thyrotoxicosis
Inappropriate signal transduction
- Carney complex (GH)
- PKA type 1 regulatory subunit
- GH producing adenomas
- Spotty skin pigmentation and blue nevi
- Primary pigmented nodular adrenocortical disease (micronodular) >>> Cushing’s syndrome
- Cardiac myxomas, Shwanomas
- Testicular tumors, ovarian tumors
Multiple Endocrine Neoplasia (MEN 1)
What is Multiple Endocrine Neoplasia (MEN) 1
- Genetics
- Symptoms
- AD menin gene mutation (tumor suppressor)
3 Ps!
1. Pituitary adenoma (50-70%)
- Prolactinomas (60%)
- GH (10-25%)
- ACTH
2. Parathyroid hyperplasia (multiple glands) (80-90%)
- Hyperparathyroidism
- Hypercalcemia
3. Pancreatic neuroendocrine tumors (65-80%)
- Gastrinoma (50-80%) “ectopic”
- Insulinoma (10-30%)
- Glucagonoma
- Somatostatinoma
- Vasoactive intestinal polypeptide (VIPoma)
(Thymic carcinoid)
