Term
| Describe the basic anatomical organization of the pituitary gland. |
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Definition
1) Anterior (Adenohypophysis)- Protein secretion
1a. Main Pars distalis (Most distal to hypothalamus)
1b. Pars tuberalis (extension of glandular tissue up to infundibular stalk)
1c. Pars intermedia (along fold-line remnant of Rathke's pouch)
2) Posterior (Neurohypophysis)- bundle of hypothalamic axons)
- Main pars nervosa
- Infundibulum (pituitary stalk that connects hypothalamus to pituitary). |
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Term
Which of the following is FALSE regarding the embryonic developing of the pituitary gland?
1) The anterior lobe is derived from ectodermal dissue
2) The posterior lobe is derived from an out-pocketing of the diencephalon (Neuroectoderm).
3) The infundibulum is derived from Rathke's pouch
4) The pars distalis is derived from the primitive oral cavity |
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Definition
3- The infundibulum (pituitary stalk) is the portion of the Neurohypophysis that connects the hypothalamus to the pituitary.
The neurophyophysis is derived from the diencephalon (neuroectoderm), NOT the primmitive oral cavity (ectoderm), from which Rathke's pouch forms the adenohyphysis |
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Term
Which of the following would NOT occur in the case of lateral growth of the pituitary gland.
1) Opthalmoplegia
2) Blindness
3) Deafness
4) Loss of sensation in face above jawbone |
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Definition
3)
The lateral boarders of the pituitary are formed by the cavernous sinus, through which runs CN III, IV and VI, as well as V1 and V2 and the internal carotid artery. The optic chiasm is also present.
If you have lateral growth, you damage III, IV and VI (all eye movements), the chiasm (CN II-vision) and the sensory divisions of V1 and V2.
CN VIII is NOT present in the carotid sinus. |
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Term
| What are the superior, inferior and lateral boarders of the hypophysis? |
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Definition
1) Superior: thick dura with foramen for infundibular stalk
2) Inferior: Sella turcica depression in sphenoid bone
3) Laterally: cavernous sinus (Optic chiasm, CN III, IV, VI, V1 and V2 and internal carotid artery) |
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Term
| What is the basic blood supply of the pituitary gland and hypothalamus and how does it relate to hormonal release? |
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Definition
Concentrated hypothalamic hormones reach Adenohypophysis through superior hypothalamic/hypophysial portal circulation.
Neurohypophysis is supplied by inferior branches of hypophysial arteries.
1) Branch of superior hypophysial artery (from internal carotid) breaks into capillary bed in lower hypothalamus (median eminence), where hypothalamic hormones are released into.
2) Blood from hypophysial capillaries drains into portal veins (hypothalamic-hypophysial), which branch again into a capillary bed in the anterior pituitary
3) Capillaries in atnerior lobe coalesce into veins (cavernous sinus veins) that drain into systemic venous blood. |
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Term
True or False:
Infundibular section results in abnormalities in anterior lobe system only. |
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Definition
| False. Posterior lobe is also affected (this is connection between neurophypophysis and hypothalamus |
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Term
| What are the 6 major hormones synthesized and secreted by the anterior lobe of the pituitary? |
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Definition
Polypeptides:
1) GH
2) Prolactin
3) ACTH
Glycoproteins (common alpha and varying beta subunits):
1) FSH
2) LH
3) TSH
Remember, hypothalamus produces releasing (turn on) and inhibiting (turn off) hormones that travel through hypothalamic/hypophysial portal system to stimulation/inhibit the anterior pituitary. |
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Term
Secretory cells of the anterior pituitary are characterized by immunocytochemistry and in situ hybridization.
Which hormones are released by each of the following cell types?
1) Somatotropes
2) Lactotropes
3) Corticotropes (POMC-expression)
4) Gonadotropes
5) Thyrotropes |
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Definition
Somatotropes (GH) are most abundant and Thyrotropes are least abundant (TSH)
Except for Gonadotropes, each cell type releases 1 hormone only!
1) 50% of cells- Growth Hormone (peptide)
2) 15%- Prolactin (peptide)
3) 15-25%- ACTH (peptide)
4) 10%- LTH and FSH (glycoprotein)
5) 5%- TSH (glycoprotein) |
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Term
What is the primary physiological effect of hormonal release from each of the following cell types and what is the primary target tissue?
1) Gonatotopes
2) POMC-containing Corticotropes
3) Thyrotropes
4) Lactotropes
5) Somatotropes
6) Neurohyophysis |
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Definition
All are secretory cells in anterior pituitary
1) LH/FSH control reproductive function in the gonads (ovary/testes)
2) ACTH acts on adrenal cortex to stimulate glucocorticoid release
3) TSH stimulates TH secretion from thyroid
4) Prolactin stimulates milk production in mammary glands
5) GH controls protein, lipid and carb metabolism in liver/adipose tissue
6a) PVN/ADH inserts aquaporins in cortical collecting duct for water preservation
6b) Supraoptic/Oxytocin Milk-ejection/uterine contractility from mammary glands. |
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Term
| What are direct and indirect mechanisms of GH action? |
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Definition
peptide hormone released from somatotropes in anterior pituitary.
1) Direct: binding to receptor on target cells
- Adipose cells increase TGA breakdown and decrease uptake of circulating lipids
2) Indirect: through intermediate
- Act on liver to increase IGF-1 (stimulates proliferation of chondrocytes and myoblasts, and stimulates amino acid uptake and protein synthesis) |
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Term
| What are the major effects of Growth hormone on protein, fat and carbohydrate metabolism? |
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Definition
1) Protein
- Increased AA uptake and synthesis and decreased oxidation (IGF-1 mediated)
2) Fat
- Enhanced utilization and decreased uptake (direct)
3) Carbohydrate
- Anti-insulin activity |
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Term
Which of the following is FALSE regarding regulation of growth hormone secretion?
1. Stimulated by hypothalamic peptide, GHRH
2. Inhibited by Somatostatin
3. Inhibited by gastric peptide, Ghrelin
4. Inhibited directly and indirectly by IGF-1
5. Pulsatile secretion is higher during sleep and declines in middle age |
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Definition
3- It is stimulated by stomach peptide.
GH is secreted more during puberty, sleep, stress and exercise.
Levels are lower in older, obese individuals.
- GH is stimulated by GHRH and Ghrelin
- GH is inhibited by somatostatin and IGF-1 (both directly on somatotropes and indirectly through somatostatin release) |
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Term
Which of the following is not a typical clinical presentation associated growth hormone deficiency?
1) Short stature
2) Increased muscle mass
3) Obesity
4) Osteopenia
5) Elevated cholesterol |
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Definition
Treat with recombinant hGH
2- DECREASED muscle mass |
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Term
True or False:
GH deficiency in adults is diagnosed by measuring IGF-1 levels. |
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Definition
False- these levels are low in normal elderly folks.
**re-test kids in adulthood before continuing hGH treatment**
1) Lack of increase in plasma GH to insulin-induced hypoglycemia to >5 ng/ml in adults or >10 ng/ml in children
2) Lack of increase in plasma GH to >4.1 to two pharmacological stimulation tests (GHRH plus arginine) |
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Term
| What are the 2 major roles of prolactin in milk production? |
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Definition
Synthesis in Lactotrophs increases during sleep and in response to nipple stimulation during nursing.
1) Induction of lobuloalveolar growth of mammary gland (secretory units)
2) Stimulation of milk production after giving birth (Prolactin + Cortisol + Insulin stimulate milk protein gene transcription) |
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Term
Secretion of this hormone increases following infundibular stalk sectioning.
1) Growth hormone
2) Prolactin
3) LH
4) ACTH
5) TSH
6) FSH |
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Definition
2- Prolactin secretion is under tonic inhibition by hypothalamic factors (dopamine)
This is why tumors of hypothalamus can sometimes cause hyperprolactinemia |
|
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Term
| How does hypothalamic activity inhibit prolactin release? |
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Definition
Dopamine secreted into portal blood by hypothalamic neurons, where it binds to receptors on lactotrophs and inhibits synthesis AND secretiotion of prolactin.
This is why phenothiazines (dopamine antagonist) increases prolactin and Dopamine agonists (bromocriptine, pergolide and carbergline) decrease prolactin levels. |
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Term
| Why might a lady with PD receiving Bromocriptine to treat tremors exhibit inability to breast feed? |
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Definition
| Dopamine agonist inhibits prolactin release from lactotrophs in anterior pituitary |
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Term
| What are the positive and negative regulators of prolactin secretion from the pituitary? |
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Definition
1) Inhibited by dopamine from hypothalamic neurons
2) Stimulated by TRH (primary hyperthyroidism)
Stimulated by Estrogens (late pregnancy) |
|
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Term
| What are the major physiological consequences of hyperprolactinemia in men and women, respectively? |
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Definition
Can be caused by drugs (phenothiazine), estrogen or TRH elevations
1) Men- prevents gonadal releasing hormone from hypothalamus and directly inhibits hormone release from gonads
- Hypogonadism
- Impotency and reduced sex drive
2) Women
- Amenorrhea
- Galactorrhea (excessive secretions) |
|
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Term
| What is congenital PRL deficiency? |
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Definition
| Rare disorder with GH and TSH deficiency in patients with Pit-1 transcription factor mutations. |
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Term
| Why might a women with amenhorrea and galactorhea be asked to take a TRF test? |
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Definition
| Elevated levels of TRF and estrogen (as well as dopamine antagonizing drugs) cause hyperprolactinemia, which leads to amenhorrea and galactorrhea in women, and hypogonadism and impotence in males |
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Term
True or False:
ACTH induces adenohypophyseal secretion of cortisol, aldosterone and adrenal androgens from the adrenal gland. |
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Definition
False! ACTH stimulates release of cortisol and adrenal androgens, but NOT aldosterone.
CRH from hypothalamus stimulates ACTH release from anterior pituitary, which stimulates the adrenal gland to produce and release cortisol (negative feedback) and adrenal androgrens.
CRH and ACTH are inhibited by Cortisol feedback. |
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Term
| Which hormones other than ACTH are produced by corticotropes? |
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Definition
POMC is synthesized and proteolytically cleaved into ACTH and
1) Beta-endorphin and Met-enkephalin (opioid peptides)
2) Melanocyte-stimulating hormone (MSH: controls melanin pigmentation in skin)
3) |
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Term
True or False:
ACTH levels peak during sleep, closest to midnight. |
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Definition
False, they are at nadir at midnight. They peak at 4:00am and then decline during the day.
Similar to TSH, which peaks between 9pm and 5am |
|
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Term
Patient presents with fatigue, muscle weakness, anorexia and weight loss. They have mild hyponatremia and hypoglycemia.
You check hormone levels and discover low levels of cortisol and adrenal androgens in the serum, but normal aldosterone levels
What might be going on? |
|
Definition
Symptoms of ACTH deficiency (perhaps due to pituitary tumor).
Without ACTH, there is no adrenal stimulation to produce cortisol and adrenal androgens, but you still get aldosterone (RAAS system control). |
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Term
| How is an ACTH deficiency diagnosed? |
|
Definition
Low serum cortisol confirmed with ACTH stimulation test
1) Cortrosyn test: Cortisol level < 18 ug/dl indicates deficiency
**ACTH levels can distinguish between primary and secondary causes** |
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Term
| What is the basic structure and action of TSH? |
|
Definition
Release from adenohypophysis is regulated by TRH in hypothalamus.
**BOth TRH and TSH are inhibited by high levels of thyroid hormone in blood**
1) Glycoprotein hormone with 2, non-covalently linked subunits
- Alpha is shared by LH and FSH
- Beta is unique for receptor specificity
2) Binds receptor in thyroid epithelial cells, stimulating synthesis and release of thyroid hormones (T4 and T3) |
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Term
Which of the following would NOT occur following a major hypothalamic lesion.
1) Increased prolactin levels
2) Decreased thyroid hormone levels
3) Decreased TSH levels
4) Decreased ACTH
5) Increased Cortisol levels |
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Definition
| 5- Without CRH from hypothalamus, there is no ACT to stimulate cortisol release from adrenal gland. |
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Term
Patient presents with lack of energy, weight gain, cold intolerance and constipation.
Labs reveal a low free thyroxin level and a slightly lowered TSH level. TRH levels are elevated.
What is going on? |
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Definition
Secondary hypothyroidism.
Thyroid hormone level and TSH levels are both low, suggesting that the problem is not in the thyroid gland itself (primary), but in the adenohypophysis. It is not tertiary, because TRH is being made by the hypothalamus. |
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Term
| Describe the basic mechanisms of action of LH and FSH. |
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Definition
Glycoprotein hormones (like TSH) with alpha and beta (variable) subunits that are secreted from gonadotropes in the anterior pituitary.
1) LH: Sex hormone release
- Bind cells of Leydig in testes, stimulating testosterone
- Bind theca cells in ovary, which release testosterone that can then be converted to estrogen by granulosa cells
2) FSH: follicle maturation
- In males, supports Sertoli cell function, supporting sperm maturation
- In females, stimulates maturation of ovarian follicles |
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Term
| What is the role of LH in pregnancy? |
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Definition
1) LH burst induces ovulation of mature follicles in the ovary (mature with FSH).
2) Residual cells within ovulated follicles proliferate to form corpora lutea, which secrete Progesterone and Estradiol
3) Progesterone is necessary for maintenance of pregnancy, and LH is required for continued development and function of the corpora lutea. |
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Term
Which of the following is FALSE regarding regulation of Gonadotropin secretion?
1) GnRH binds gonadotroph receptors and stimulates production and release of LH and FSH
2) Testosterone and Progesterone inhibit GnRH release from hypothalamus
3) Estrogen inhibits FSH release from adenohypophysis
4) Inhibin secretion from gonads activates FSH secretion from the pituitary |
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Definition
4: Inhibit inhibits and Activin activates (both gonad hormones)
In general, GnRH from hypothalamus stimulates LH/FSH secretion from pituitary, which activates sex hormones (testosterone, progesterone, estrogen) from gonads, with a classical negative feedback look. |
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Term
| What are the indications of low and high gonatotropin levels in males and females, respectively? |
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Definition
1) Males
High: Gonad failure/damage
Low: Hypogonadism and Impotence
2) Women
High: Gonad failure
Low: Amenorrhea |
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Term
How do oral contraceptives work?
How does this relate to using GnRH and HCG therapeutically? |
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Definition
1) Progestin (progesterone-mimick with estrogen added) inhibits LH secretion: you don't get ovulation.
2) Opposite
- GnRH will stimulate pituitary production of LH/FSH in patient with hypothalamic dysfunction and normal pituitary.
- HCG is an LH-like molecule with a long half-life (opposed to 20-30 min for LH) |
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Term
| What is Kallmann's syndrome? |
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Definition
Presents with Anosmia, low plasma LH and testosterone.
X-linked form of isolated hypogonadotropic hypogonadism (IHH) from mutation in neural cell adhesion protein that guides axon growth and allows GnRH neurons to migrate from site of origin in cribriform plate to anterior hypothalamus.
- No GhRH stimulation of anterior pituitary prevents LH and FSH release and cause hypogonadism (hot flashes, lack of libido, ect.) |
|
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Term
True or False:
More than 50% of secretory cells of one type in the pituitary gland must be lost to product detectable deficiency. |
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Definition
True
>80% must be lost for severe basal loss (50% will manifest as a stimulation defect) |
|
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Term
| What are the major causes of hypopituitarism? |
|
Definition
1) Sellar and parasellar lesions
- Adenomas, craniopharyngiomas, parasellar tumors and metastasis
2) Iatrogenic- Neurosurgical procedure or post-operative irradiation (hypothalamic damage)
3) Infiltrative- Granuloma (Sarcoid, TB, mycoses), Hemochromatosis, Histiocytosis
4) Brain damage/trauma
5) Infarction
6) Autoimmune (lymphocytic hypophysitis)
7) Structural defects |
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Term
What does each of the following laboratory results indicate in hypopituitarism?
1) Low free thyroxin
2) Low IGF-1
3) Low FSH and normal/low LH
4) Low PRL
5) Low AM plasma cortisol (<10 mcg/dl) |
|
Definition
GH is usually affected first
1) TSH axis- order a TSH level as well
2) GH axis- also order GRF plus L dopa
3) LH/FSH- look at estradiol and testosterone as well
4) PRL axis- use TRH stimulation test.
5) ACTH axis- Order ACTH level (not elevated) and ACTH stimulation test. |
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Term
| What is the basic management strategy for hypopituitarism? |
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Definition
1) Address life threatening tumor mass effects of CV instability
2) Establish etiology and replacement
- replacing target gland products is easier than pituitary peptides
- If multiple defects exist, start replacing cortisol first, followed by thyroxine (thyroid accelerates catabolism of cortisol) |
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Term
| What is Sheehan's Postpartum pituitary necrosis? How do you treat? |
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Definition
Acute viral illness during pregnancy precipitates adrenal insufficiency, with causes hypotension and ischemic damage to hypophysial vessels leading to hypopituitarism.
Often presents with fatigue (adrenal, thyroid, GH), Amenorrhea, hypoglycemia, hypotension, hypothermia
Give stress dose glucocorticoids and T3/T4 a few days later. |
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Term
| What is the primary cause of pituitary hypersecretion? |
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Definition
Pituitary adenoma (prolactinoma is most common) presenting with headache and often visual loss and/or diplopia (lateral growth).
Macroadenomas (>10 mm) are "invasive" but do NOT metastasize and almost never produce ectopic hormones (except for ACTH and alpha subunit of glycoprotein hormones). |
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Term
12 year old presents with headache and visual disturbances. They also admit to having joint aches.
On PE, you notice coarse facial features and enlarged hands and feat.
What lab findings would you expect and what is the associated mutation? |
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Definition
Acromegaly from Pituitary Adenoma that is secreting GH (20% also secrete PRL)
1) Labs: High GH (increased plasma level and a-pulsatile) and IGF-1 levels
2) 1/3 of tumors have mutation in alpha chain of Gs protein in GTP binding domain.
- Constitutive increase in cAMP production in somatotrophs resulting in hyperplasia and adenoma formation. |
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Term
| How do you diagnose/treat a patient with Acromegaly? |
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Definition
GH-secreting pituitary adenoma, often from constitutive activation of Gs in somatotrophs.
Patients die from CV disease, cerebrovascular disease and malignancy.
1) GH level, IGF-1 level and glucose-intolerance test (normally inhibits GH)
2) Treat
- Transphenoidal adenomectomy is first line
- Irradiation (gamma knife) and therapy with octreotide (somatostatin analog with prolonged half life) is second-line
- Pegvisomant (GH analog that decreases GH affinity for receptor) does not shrink tumor, but has better symptomatic release and less GI side effects
**Can be given with octreotide** |
|
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Term
| How are Pegvisomant and Octreotide used to treat Pituitary tumors? |
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Definition
Used to treat GH-adenomas producing acromegaly in patients that refuse or do not qualify for transphenoidal adenomectomy.
Give em' together!
1) Octreotide
- Somatostatin analog with greater half life
- Normalize IGF-1 to 70% and shrinks tumor 33-50%
2) Pegvisomant
- GH analog that decreases GH affinity for receptor
- Won't shrink tumor, but will improve symptoms and reduce GI side effects relative to Octreotide |
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Term
Young woman presents complaining of persistent lactation and irregular periods.
Labs come back and reveal PRL level of 240 ng/ml.
What is the pathophysiology/treatment of this condition? |
|
Definition
Prolactinoma (PRL >200 is always prolactinoma)
1) Path
- Lactation is from ectopic production of PRL
- Oligomenorrhea is from PRL-mediated suppression of GnRH gene expression, disrupting pulsatile LH secretion
2) Treatment
- Dopamine agonist like Bromocriptine or Cabergoline (90% effective) (Carbergolide has higher 1/2 life and better compliance)
- Transphenoidal surgery offer incomplete cure (unique among Pituitary adenomas) |
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Term
Which is the only pituitary adenoma where pharmacological manipulation is suggested prior to surgical intervention?
1) Prolactinoma
2) ACTH-producing adenoma
3) GH-producing adenoma
4) FSH/LH-secretion adenoma |
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Definition
| 1- Give D2 agonist like Bromocriptine, or preferably Cabergoline. |
|
|
Term
| What is the clinical manifestation of ACTH-producing adenomas? |
|
Definition
Cushing Syndrome from increased cortisol
1) Central weight gain and Moon face
2) Hyperhidrosis (excess sweating)
3) Telangiectasia (dilation of capillaries)
4) Thinning of the skin (bruising)
5) HTN
6) Insulin intolerance (DM-II) |
|
|
Term
What is the usual etiology of high plasma gonadotropin levels?
How can you tell if it is the result of an adenoma? |
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Definition
1) Gonadal failure (no negative feedback)
2) Headache and visual disturbance with rare (15%) isolated production of alpha subunit
- Treat surgically and post-operative radiation (no effective pharmacology) |
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Term
Patient presents with visual disturbances and difficulty concentrating
He explains that he has been fatigued, lost weight and had peristent bowel movements.
On PE, there is no evidence of tachycardia, hypertension, tremor or bulging eyes.
You run some labs and discover that TSH levels are normal
Whats going on and how do you treat? |
|
Definition
1) TSH Hypersecretion from a pituitary adenoma.
- Graves is most common cause of hyperthyroidism, but there are no extrathyroidal manifestations that fit this. Also, primary thyroid disease would exhibit suppressed TSH levels.
2) Surgery with adjuvent Octreotide |
|
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Term
| What are "Null cell" adenomas? What is the primary complications of these tumors? |
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Definition
| Also called "silent adenomas," these tumors are clinically "non-functioning" groups of cells that can exhibit aggressive growth and invasion of surrounding structures. |
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Term
| Where is vasopressin synthesized and released from and what is its major action? |
|
Definition
Anti-diuresis (increase urine osmolality and decrease serum osmolality)
Remember, kidney CAN excrete 10-20L a day, but only does 1-2L because of AVP
1) ADH (AVP) is synthesized in PVN of the hypothalamus and stored/released from magnocellular axon terminals in the posterior pituitary into capillary beds which coalesce into efferent venous vasculature.
2) Binds V2R (GPCR) in cortical collecting duct (principal cells) on basolateral membrane and leads to cAMP-mediated insertion of aquaporins (type 2) in apical membranes.
3) Water diffuses across basolateral type 3/4 aquaporins in basolateral membrane into blood stream. |
|
|
Term
| What happens systemically when ADH levels are abnormally high? |
|
Definition
| Increased blood pressure ("pressor" effect) |
|
|
Term
| How is ADH secretion regulated? |
|
Definition
1) Plasma osmolality (increases cause increased ADH)
- Sensed by hypothalamic osmo-sensing neurons and transmitted to magnocellular (PVN and SON) neurons
2) Decreased blood pressure/volume (Larger changes required for stimulation)
Thirst is a "late" response that following ADH release.
- Stretch receptors in heart and large arteries |
|
|
Term
Which of the following regarding Diabetes Insipidus (DI) is incorrect?
1) Central (neurogenic or hypothalamic) DI is caused by ADH deficiency
2) Nephrogenic DI involves ADH resistance
3) Gestational DI involves AVP suppression due to excessive fluid consumption
4) Primary polydypsia is an acquired form of DI |
|
Definition
3: Gestational DI involves AVP deficiency due to AVP destruction by placental vasopressinase. Placental vasopressinase is hyper-active, because of abnormal hepatic metabolism during pregnancy.
The AVP suppression due to excessive fluid consumption described Primary Polydypsia, another acquired form of DI
DI is inappropriate excretion of copious dilute (hypotonic) urine despite a stimulus that should produce anti-diuresis |
|
|
Term
Which form of Diabetes Insipidus is described by each of the following?
1) Low plasma osmolality and dilute urine and low ADH levels
2) High plasma osmolality, dilute urine and low ADH levels: reversed by ddAVP addition
3) High plasma osmolality, dilute urine and elevated ADH levels: no improvement with ddAVP |
|
Definition
If unrestricted access to fluids to confounding diagnosis, perform "water deprivation test."
1) Primary Polydypsia from excess water consumption.
- Plasma is dilute, as is urine, and ADH is suppressed by plasma osmolality.
2) Central (neurogenic/hypothalamic) DI
- Plasma is concentrated from water loss in dilute urine.
- ADH is low because of destruction of ADH-releasing magnocellular neurons.
3) Nephrogenic DI
- Plasma is concentrated because of water losses
- ADH is high, but it cannot activate VR2 and/or AQ2 channels
- ddAVP has no effect, because it is the receptors that are disturbed. |
|
|
Term
How does each form of Diabetes insipidus respond to water deprivation in terms of maximum urine concentration, AVP levels and change in urine osmolality following ddAVP addition.
1) Complete central
2) Partial central
3) Complete nephrogenic
4) Partial nephrogenic
5) Primary polydypsia |
|
Definition
AVP levels take 7 days but response to ddAVP is rapid!
1) Complete central DI
- Very low urine concentration with undetectable AVP
- Dramatic increase of >50%
2) Partial central DI
- Mid-normal urine concentration that is increased >10% with ddAVP
- Low, detectible levels of AVP
3) Complete nephrogenic
- Very Low urine osmolality that does not improve with ddAVP
- High levels of AVP
4) Partial nephrogenic
- Very low urine osmolality that has a <50% change with ddAVP
- High AVP
5) Primary Polydypsia
- Low/normal osmolality of urine with <10Q% response to AVP
- High AVP levels |
|
|
Term
| What are the common causes of central diabetes insipidus? |
|
Definition
1) Hypothalamus lesion above sella and around base of 34d ventricle
- Since there is redundancy, lesion must be large or bilateral.
2) Complete stalk lesion
- Left and Right SON and PVN nuclei converge to form supraopticohypophysial tract in infundibulum |
|
|
Term
| What is SIADH and how do you treat it? |
|
Definition
1) SIADH is caused by irreversible infundibular stalk injury (supraopticohypophysial tract), where damaged neurons release ADH all at once.
- Fluid retention, Hemodilution and Hyponatremia
- May manifest with transient DI, followed by 2-3 weeks of SIADH during degeneration, and then a permanent DI phase.
2) Treat with fluid restriction and infusion of hypertonic (3%) saline for severe hyponatremia |
|
|
Term
| What is the "triphasic response" of DI following severe damage to the infundibular stalk? |
|
Definition
High stalk transection makes Triphasic response more likely
1) Phase 1
- Transient DI (1-2 days)
2) Phase 2
- Wallerian degeneration of cells and release of ADH causing SIADH
- Fluid retention, hyponatremia and hemodilution (restrict fluids and give 3% hypertonic saline).
3) Late phase (prolonged)
- DI returns |
|
|
Term
| What is adypsogenic DI and why are they likely to develop hypernatremia? |
|
Definition
"without thirst-generating capcity"
1) Patients do not respond to thirst, usually because of hypothalamic lesion (central) that damages the thirst center that is near the magnocellular system.
2) Without fluid intake, they get hypertonic plasma and must be managed with fixed daily fluid intake and ddAVP. |
|
|
Term
Which of the following is LEAST likely to cause central diabetes insipidus?
1) Pituitary adenoma
2) Craniopharyngeoma
3) Optic glioma
4) Pineal tumor
5) Granulomatous disease
6) Tuberculosis |
|
Definition
1) Pituitary adenomas tend to be slow growin, encapsulated and non-infiltrative neoplasms (rarely can be aggressive)
All others commonly cause damage to pituitary stalk |
|
|
Term
How can each of the following cause acquired nephrogenic diabetes insipidus?
1) Hypokalemia
2) Hypercalcemia
3) Lithium
4) Demeclocycline |
|
Definition
Lithium is most common drug-induced cause
1) Decreases concentrations of AQ2
2) Diminishes synthesis and inserition of AQ2 and exacerbates DI by acting as osmotic diuretic
3) Down regulates AQ2 and renal V2 receptors (MOST COMMON)
4) V2 receptor antagonist
** Amphotericin B and Aminoglycoside can also cause it** |
|
|
Term
| Why must ACTH deficiency be addressed during a work-up of suspected Diabetes Insipidus? |
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Definition
Corticotrophs in adenohypophysis can be damaged by similar processes.
ACTH causes release of cortisol, which suppresses synthesis of hypothalamic AVP and production and mobilization of AQ2 in distal nephron.
Low cortisol can cause increased AVP and AQ2, which can MASK DI features. |
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Term
| What are the major genetic variants of central diabetes insipidus? |
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Definition
All respond to ddAVP, since problem is production of or potency of AVP.
1) AD (most common)- Neuron damage
- Mutations in single allele of AVP-NP2 (precursor protein)
- Develop DI in first few months/years
- Mutated protein does not fold and form AVP, but is toxic to normal AVP and causes neuron necrosis and loss of AVP secretion.
2) AR (rare)- Diminished potency
- Associated with WOlfram syndrome (DI, DM, optic atrophy, deafness and other neurological abnormalities)
**DIDMOAD**
- Heterozygous mutation in WFS1 gene, encoding wolframin protein impairs normal processing of VN-SC protein and leads to destruction of neurons
3) X-linked recessive
- Normal VN2C and V2R genes
- Unknown culprit gene |
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Term
Which form of diabetes insipidus is associated with Diabetes mellitus, optic atrophy and deafness?
1) X-linked recessive central diabetes insipidus
2) Autosomal dominant nephrogenic DI
3) AR central DI
4) X-linked recessive nephrogenic DI |
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Definition
3)
Wolfram Syndrome (heterozygous mutations in WFS1 gene) associated with AR central DI. |
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Term
| What are the major genetic variants of Nephrogenic diabetes insipidus? |
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Definition
1) X-linked recessive (most common)
- Mutations in V2R that cause receptor mis-folding.
- Presents at birth with normal/high levels of ADH in males
2) Autosomal recessive (10%)
- Mutations in AQ2 gene with misfolding (trapped in ER)
- Presents at birth with increased AVP in males and females
3) Autosomal dominant (RARE)
- Mutations in Q2 gene that DOES respond to ddAVP
- Mild and often sub-clinical |
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Term
True or False:
Autosomal dominant central DI is the most common heritable form of central DI, while AD nephrogenic DI is the least common form os heritable nDI |
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Definition
True!
ADcDI involves mutations in AVP-NP2 precursor protein with neuron apoptosis
AD nDI is subclinical, with preserved response to ddAVP (AQ2 mutations) |
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Term
| How are central and nephrogenic diabetes insipidus treated, respectively? |
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Definition
1) Central
- Water intake and ddAVP intra-nasally or as a tablet.
2) Nephrogenic
- Correct underlying metabolic disorder (remove Lithium, use Thiazide or K-sparing diuretics)
- Decrease sodium and protein intake
- If all else fails, try an NSAID |
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