What is the main somatostatin analogue?
What are the 2 major Dopamine D2 agonists?
What drugs work on the hypothalamus?
Octreotide, Bromocriptine, Cabergoline
What drugs work on the Anterior Pituitary?
The GH recombinant, antagonist, and Recombinant IGF-1
What is the main GH recombinant?
What is the main GH antagonist?
What is the main IGF-1 recombinant?
What drugs work on the Posterior Pituitary?
Vasopressin, Desmopressin, Conivaptan, Oxytocin
What are the parts of the Anterior Pituitary?
Pars Tuberalis, Pars Intermedia, and Pars Distalis
What are the parts of the Posterior Pituitary?
Infundibular stalk and Pars Nervosa
What are the 3 major "hormone excess" disorders of the Pituitary Gland?
Prolactinoma, Acromegaly/Gigantism (GH), Cushing's Disease (ACTH)
Discuss Dynamic Biochemical tests:
If a deficiency is suspected, do a stimulation test. If an excess is suspected, do a suppression test.
Discuss the Pituitary Insufficiency test:
Administer GHRH, CRH, GnRH, and TRH IV and if there is a failure to respond to stimulation indicates lack of pituitary function.
Discuss testing for ACTH:
Giving insulin produces hypoglycemia. The appropriate response is an increase ACTH and cortisol.
Relate Bitemporal Hemianopia with Pituitary dysfunction:
Bitemporal Hemianopia could be caused by Pituitary enlargement in which there is pressure on the optic chiasma.
Relate weight gain and Pituitary dysfunction:
Pituitary enlargement may affect the central satiety center in the hypothalamus leading to weight gain.
Relate Cerebral Stroke with Pituitary dysfunction:
A Hemorrhagic Pituitary adenoma with supracellar extension through the diaphragma sellae and affect the Circle of Willis.
Basically the growth puts pressure on the Circle of Willis.
Identify A Reticulin Stain in the normal Anterior Pituitary
It highlights Acinar Clusters in NORMAL histology.
In ABNORMAL histology, there is reticulin breakdown due to disorganized Monomorphic Acinar Clusters in Adenoma.
Identify a Reticulin Stain in the abnormal anterior pituitary:
It shows Reticulin breakdown due to disorganized Monomorphic Acinar Clusters in a Anterior Pituitary Adenoma
What are the most common secreting adenomas of all age groups?
Prolactin Adenoma of the Anterior Pituitary
Which gain of function mutations can lead to a Pituitary Adenoma?
1. GsAlpha leads to GH adenoma
2. Protein kinase A leads to GH and prolactin adenomas
3. Cyclin D1 leads to aggressive adenomas
4. HRAS leads to pituitary carcinomas
Which loss of function mutations can lead to Pituitary Adenomas?
1. Menin leads to GH, prolactin, and ACTH adenomas
2. CDKN1B leads to ACTH adenomas
3. Aryl Hydrocarbon Receptor Interacting Protein leading to GH adenoma
4. Retinoblastoma Protein
How does a G Protein Mutation lead to Endocrine Neoplasia?
G Proteins transmit signals from cell-surface receptors (GHRH, TSH, PTH receptors) to intracellular effectors which generate second messengers. cAMP then leads to proliferation and hormone synthesis.
Gain of Function mutation!
What is Multiple Endocrine Neoplasia?
MEN1 gene mutation leads to "MEN1 syndrome." It normally codes of Menin, a tumor suppression gene. Alteration in this will prevent the prevention of cell proliferation.
What are the "3 Ps" that detail a MEN1 mutation in Multiple Endocrine Neoplasia?
2. Parathyroid Gland Adenoma / Hyperplasia
3. Islet Cell Adenoma of the Pancreas
What 4 clinical presentations are often associated with a MEN1 mutation leading to Multiple Endocrine Neoplasia?
3. Cushing Disease
4. Zollinger-Ellison Syndrome
Discuss the pathology of a Prolactinoma:
1. Composed of Chromophobe Cells
2. Its nuclei are spheroidal with prominent nucleolus
3. There are Psammoma Bodies
4. Note that Lactotropes stain for Prolactinoma in a dot like or "Golgi Pattern"
Outline the hormonal effects of a Proactinoma:
1. Prolactin is over secreted
2. This inhibits the release of GnRH
3. The inhibition of GnRH causes Amenorrhea by affecting the Follicular and Luteal Phase of the menstrual cycle
4. The increase in Prolactin also causes lactation from the breast
How is a Prolactinoma treated?
1. Dopamine Agonist (Bromocriptine, Cabergoline)
2. Surgical Resection
3. Radiotherapy for macroadenoma
What is the normal response to hypoglycemia?
An increase in GH levels.
What would occur after Glucose Loading in a patient with Acromegaly?
1. Glucose levels remain higher after time
2. GH remains at a higher level
What are the clinical features of Gigantism and Acromegaly?
1. Enlarged head, Mental Disturbances
2. Large lower jaw which causes spaces in teeth. Large nose, large tongue, large hands
4. Enlarged Heart
Discuss the clinical outcomes of Acromegaly:
1. Early identification and treatment may limit this condition
2. Good Prognosis with appropriate therapy
3. Skeletal changes do NOT regress
What are the three main effects of IGF-1 that cause the main problems in Acromegaly?
1. Cartilage Growth
2. Increase in Blood Glucose
3. Bone and Tissue Growth
What do Estrogen, Testosterone, and Throxine do in regards to GH?
They work on the Hypothalamus to increase the release of GHRH. GHRH works on the Pituitary to release GH.
What are the effects of GH?
1. Adipose Tissues in which increased lipolysis FFAs are released
2. Liver in which IGF-1 is released and an increase of glycogenolysis and gluconeogenesis leads to Hyperglycemia.
3. Stomach in which Ghrelin is released
4. Synergizes with Cortisol and antagonizes Insulin. This is why it can lead to Insulin Resistance
5. Kidney in which there is an increase in GFR which leads to an increase in Sodium and Water retention leading to HTN and edema.
What down regulates the release of GHRH?
What are the 2 types of Somatotroph Adenomas? What is seen in them?
Densely vs Sparsely granulated Somatotroph Adenomas. They show Keratin-8 staining.
What is used to treat a Somatotroph Adenoma?
2. Octreotide (a somatostatin analogue)
What are the therapeutic uses of Somatostatin analgues?
Acromegaly, to prevent gigantism, carcinoid syndrome, gastrinoma, and esophageal varices
What are the main adverse drug reactions to Somatostatin Analogues?
GIT problems, Gall Stones, Vit B 12 deficiency, some cardiovascular problems (sinus bradycardia and conduction disturbances
What is the main GH antagonist?
Pegvisomant. It will keep GH high and decrease IGF-1
What is Sheehan Syndrome?
Postpartum Necrosis of the Anterior Pituitary. In this there is ischemic necrosis due to post-parturition hypotension. The posterior pituitary is not affected.
This occurs because there is no direct arterial blood supply to the naterior hypophysis, only a low-pressure portal vein system.
This leads to hypopituitarism.
What are the clinical symptoms of hypopituitarism?
1. Always tired, very muscularly weak
2. Hair loss, including pubic hair (LH, FSH)
3. Irregular, light periods
4. Weight loss
5. Libido loss (hypogonadism)
6. Loss of skin pigmentation (ACTH)
7. Gynecomastia in males
8. Cold Intolerance (TSH)
What 3 systems are affected in Adult hypopituitarism?
1. Reproductive system
What occurs in children with Hypopituitarism?
1. Mental Growth Retardation
2 "Symmetrical Dwarfism"
3. Delayed Puberty
Outline the order and symptoms associated of hormones lost in Hypopituitarism:
1. GH (patient doesn't feel good)
2. FSH/LH (my libido is gone)
3. TSH/ ACTH (life threatening)
Outline the hormone deficiency in hypopituitarism in children and the associated disorders:
1. Dwarfism (GH)
2. Cretinism (TSH)
3. Hypogonadism (FSH/LH)
4. Adrenocortical Deficiency Syndrome (ACTH)
What are some therapeutic uses of GH?
1. Short stature due to congenital/acquired GH deficiency
2. GH deficiency in adults
3. Turner's Syndrome
4. AIDS related muscle wasting
What is Rieger's Syndrome?
Due to a mutation in PITX2, it leads to unique symptoms:
1. Iris Hypoplasia
2. Eccentric Pupils and/or Iris Holes
3. Dental Hypoplasia
4. Craniofacial Dysmorphism
5. Redundant Umbilical Skin
6. Cardiac Defects
7. Limb Abnomalies
9. Sensory Hearing Loss
10. Mental Defects
What are the signs and symptoms of Craniopharyngioma?
1. Hypopituitarism (unlike adults, presents as growth retardation)
2. Delayed Puberty
3. May present with: Central Diabetes Insipidus, Hyperphagia/Obesity, Loss of Thirst Sensation, Loss of Temperature Regulation
What test would you use for Craniopharyngioma or Hypopituitarism?
Insulin-Induced GH Stimulation Test. The idea is to give insulin to induce a hypoglycemic state. Normally hypoglycemia would induce GH release. In hypopituitarism, GH response does not increase.
Outline the important points of embryology of the Pituitary Gland:
It develops from 2 separate epithelia extending towards each other.
The boundary epithelial ectoderm in the roof of the pharynx forms a pocket (Rathke's pouch) that comes into contact with the Neuro ectoderm of the developing brain.
How does a Craniopharyngioma form?
During development, epithelial rests due to imperfect closure of the hypophysis (craniopharyngeal duct).
Discuss the pathology of a Craniopharyngioma:
Grossly, the tumor is filled with little cysts that contain a yellow-brown, cholesterol rich fluid (machine oil)
There are also cholesterol crystals.
Outline the pathogenesis leading from Craniopharyngioma to Central Diabetes Insipidus:
1. The posterior pituitary releases vasopressin/ ADH and Oxytocin is produced by the hypothalamic nuclei
2. If damage prevents the release of Vasopressin, there is decreased renal water reabsorption.
3. Inappropriately dilute urine
4. Diabetes Insipidus (polyuria, polydipsia)
What is used to diagnose Diabetes Insipidus?
1. "Clean Catch" Urine
2. Osmolality is measured to determine any abnormalities
3. Water Deprivation test
4. ADH administration
How can one use lab values to determine the difference between Diabetes Insipidus Central vs. Nephrogenic vs Psychogenic?
1. Central DI has Absent ADH. Nephrogenic has normal.
2. Central DI has a plasma osmo at 280 while nephrogenic has a normal-high osmo. Psychogenic has a osmo < 270.
3. Psychogenic DI has low sodium
What are the Vasopressin Receptors?
V1- On vascular smooth muscles and has a "pressor" effect causing an increase in IP3/DAG calcium (constriction)
V2- Renal- antidiuretic effect. Extra-Renal- releases VIIIc ad VWF coagulation factors
What are the therapeutic uses of vasopressin?
1. Advanced Cardiac Life Support
2. Bleeding Esophageal Varices
What are the therapeutic uses of Desmopressin?
1. Neurogenic DI
2. VWF Disease
How does Oxytocin work?
Actions are mediated through IP3/DAG to increase Calcium
What are the uses of Oxytocin?
1. Induce and augment labor after cervix has ripened
2. Control post-partum hemorrhage
3. Improve milk ejection (nasal)
What are the adverse reactions to Oxytoxin?
Cardiac Arrhythmia, CNS stimulation, excessive uterine contractions, and hyponatremia
What are the contraindications of Oxytocin?
1. Fetal Distress
2. Abnormal Fetal Presentation
4. CPD (cephalo-pelvic disproportion)
What is the clinical presentation of SIADH?
5. Stupor, coma, and seizures
6. Delirium and Dementia may occur
What are the lab findings of SIADH?
2. Decrease in Serum Osmolality
3. Inappropriately Concentrated Urine
4. Decrease in BUN
Discuss the pathogenesis that can lead to SIADH from a small cell lung cancer:
1. Small Cell Lung Cancer
2. Leads to release of ADH
3. Pituitary release of ADH
4. Both lead to Kidney causing water retention
How likely is it that Pituitary Pathology will lead to SIADH?
Almost never happens
What drugs can induce SIADH?
2. Vinca Alkaloids
What drugs are used to manage SIADH?
2. Conivaptan which has an affinity for V1a and V 2
Which receptors does Conivaptan work on?
V1a and V2