Pituitary Gland Disorders 1
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(GH-RH) (CRH) (TRH) (TRH) (GTRH) (GTRH) 3
Classification of pituitary disorders: 1. Hypersecretory diseases: a. Acromegaly and gigantism: Usually caused by (GH)-secreting pituitary adenoma GH b. Hyperprolactinemia: prolactin i. Most common cause is prolactinomas (prolactin-secreting pituitary tumor). ii. Drug induced (e.g., (SSRIs) and some antipsychotics) iii. CNS lesions 4
2. Hyposecretory disease a. GH deficiency GH All hormones b. Pan-hypopituitarism : Result of partial or complete loss of anterior and posterior pituitary function. Can be caused by primary pituitary tumor, ischemic necrosis of the pituitary, trauma from surgery, or irradiation. This results in (ACTH) deficiency, GH deficiency, hypothyroidism, gonadotropins (FSH + LH) deficiency 5
Diagnosis/Clinical Presentations 6
1. Acromegaly Failure of an (OGTT) to suppress GH serum conc but with elevated (IGF-1) (GH serum conc alone are not reliable given the pulsatile pattern of release in the body.) i. Excessive sweating ii. OA, joint pain, paresthesias, or neuropathies iii. Coarsening of facial features iv. Increased hand volume/ring size, increased shoe size v. Hypertension, heart disease, and cardiomyopathy vi. Sleep apnea vii. Type 2 DM 7
Gigantism Acromegaly 8
2. Hyperprolactinemia Elevated serum prolactin concentrations i. Amenorrhea, anovulation, infertility ii. hirsutism, and acne in women iii. Erectile dysfunction, decreased libido, gynecomastia, and reduced muscle mass in men iii. Headache, visual disturbances 9
3. GH deficiency Decreased GH conc after provocative pharmacologic challenge (e.g., insulin, GH-releasing hormone) i. Delayed growth velocity/short stature ii. Central obesity iii. Immaturity of the face or prominence of the forehead 10
Pharmacotherapy Treatment of choice is surgical resection of tumor if causative for hypo & hyperpituitarism. Pharmacotherapy usually reserved for: a. Control before surgery or irradiation. b. When surgery is not possible (usually requires lifelong pharmacotherapy) c. Surgical failures or relapses after period of remission post-surgery. 11
Pharmacotherapy of Acromegaly a. GH receptor antagonist (e.g: pegvisomant) i. Efficacy: More than 95% of pts attain normal IGF-1 concentrations, and most have improved symptoms ii. Adverse effects. (a) Nausea, vomiting (b) Flulike symptoms (c) Reversible elevations in hepatic transaminases 12
b. Somatostatin analog (e.g.octreotide) i. M of A : (Blocks GH secretion) ii. Adverse effects : (a) Diarrhea, nausea, cramps, flatulence, fat mal-absorption. (b) Arrhythmias (c) Hypothyroidism (d) Biliary tract disorders (e) Changes in serum glucose concentrations (usually reduces) Efficacy: 50% 60% of pts experience normalization of IGF-1 conc with good symptomatic relief as well. 13
c. Dopamine agonists (e.g. bromocriptine, cabergoline) i. Mechanism of action: Dopamine agonist that, in acromegaly, causes paradoxical decrease in GH production (acts on the pituitary gland to block the production and release of growth hormone ) ii. Efficacy: Normalization of IGF-1 concentrations in about 10% of patients. More than 50% of patients will experience symptomatic relief. 14
Pharmacotherapy of Hyperprolactinemia a. Discontinue causative agent if drug induced. (SSRIs and some antipsychotics) b. Dopamine agonists i. Cabergoline (long-acting oral agent, ADR similar to bromocriptine) ii. Bromocriptine. Efficacy: May restore fertility in > 90% of women. Cabergoline may be easier for pts to take, given weekly administration. 15
Pharmacotherapy of GH deficiency a. Recombinant GH (Somatropin) i. Adverse effects (a) Arthralgias, injection site pain (b) Rare but serious cases of idiopathic intracranial hypertension have been reported. 16
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Adrenal Gland Disorders
Hypothalamic pituitary adrenal axis
Adrenal Gland physiology
Classification of adrenal gland disorders 1. Hypersecretary cortisol a. Cushing s syndrome ( cortisol) i. ACTH-dependent: ACTH secretion (Pituitary corticotroph adenoma )(80% of cases) ii. ACTH-independent: Result of excessive cortisol secretion or exogenous steroids (20% of cases) b. Hyperaldosteronism Primary aldosteronism a. Bilateral adrenal hyperplasia (70% of cases) b. Aldosterone-producing adenoma (30% of cases) aldosterone
3. Hyposecretory cortisol, aldosterone, and androgen a. Primary adrenal insufficiency (a.k.a. Addison s disease) i. Caused by autoimmune disorder, infection, or infarction ii. Results in cortisol, aldosterone, and androgen deficiencies.. (all adrenal cortex hormones) b. Secondary adrenal insufficiency i. Exogenous steroid use ii. Results in impaired androgen and cortisol production
Clinical Presentation
1. Cushing s syndrome Presence of hypercortisolism through 24-hour urine-free cortisol concentration Plasma ACTH concentrations (normal or elevated in ACTH-dependent) Overnight dexamethasone suppression test i. Central obesity and facial rounding (moon face) ii. Myopathies iii. Osteoporosis, back pain, compression facture iv. Abnormal glucose tolerance/diabetes v. Amenorrhea and hirsutism in women vi. Lower abdominal pigmented striae (red to purple) vii. Hypertension (morbidity and mortality)
2. Hyperaldosteronism Elevated plasma aldosterone-to-renin ratio i. HTN ii. Muscle weakness/fatigue iii. Headache iv. Polydipsia v. Nocturnal polyuria ( volume overload causes polyuria, polydipsia, nocturia, HTN, alkalosis, hypernatremia)
3. Addison s disease (Primary failure of the adrenal gland ) Abnormal rapid cosyntropin (synthetic ACTH) stimulation test (blunted increase in cortisol concentrations) suggests adrenal insufficiency i. Hyperpigmentation (caused by ACTH concentrations) ii. Weight loss iii. Dehydration iv. Hyponatremia, hyperkalemia, elevated BUN
Pharmacotherapy of adrenal gland disorders
Pharmacotherapy of Cushing s syndrome Surgical resection tumor is usual treatment of choice. Pharmacotherapy usually reserved for the same criteria listed above for pituitary adenomas 1. Ketoconazole M of A : it hinders cortisol production by inhibition of 11- and 17-hydroxylase.(drug of choice) ADR : (a) Gynecomastia (b) Abdominal discomfort (c) Reversible hepatic transaminase elevations
2. Mitotane M of A : Inhibits 11-hydroxylase but also has some direct adrenolytic activity 3. Etomidate i. M of A : Similar to ketoconazole, inhibits 11-hydroxylase ii. It is Given by I.V route of administration is usually reserved for situations in which rapid control of cortisol levels is required or oral therapy is problematic. 30
4. Metyrapone i. Mechanism of action: Hinders secretion of cortisol by blocking final step in cortisol synthesis through inhibition of 11- hydroxylase activity ii. Adverse effects (a) Hypoadrenalism e. Efficacy is measured by control of symptoms and normalization of 24-hour urine-free cortisol concentrations. 31
5. Pasireotide Mechanism of action: Somatostatin analog blocks ACTH secretion from pituitary 6. Mifepristone approved in 2012 for hyperglycemia associated with endogenous Cushing s syndrome. Proposed to limit binding of cortisol. May reduce insulin requirements and improve clinical symptoms associated with hyperglycemia. 32
Pharmacotherapy of Hyperaldosteronism a. Spironolactone (drug of choice) b. Eplerenone and amiloride are alternatives to spironolactone. 33
Pharmacotherapy of Addison s disease a. Steroid replacement (replace cortisol loss) i. Oral administration is commonly dosed to mimic normal cortisol production circadian rhythm. ii. Two-thirds administered in the morning and one-third in the evening b. Hydrocortisone: 15 mg/day (may negate need for fludrocortisone compared with using cortisone or prednisone) i. Cortisone acetate: 20 mg/day ii. Prednisone: 2.5 mg/day iii. Dexamethasone: 0.25 0.75 mg/day 34
c. Fludrocortisone is basically mineralocorticoid, replaces loss of mineralocorticoid: 0.05 0.2 mg/day by mouth d. For women with decreased libido or low energy levels because of androgen deficiency: Give DHEA (dehydroepiandrosterone): 25 50 mg/day f. Note that, during times of stress/illness, corticosteroid doses will need to be increased. 35
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