Endocrinology

Pancreas

Hypothalamus

Hormone Intracellular Pathways

The Thyroid

Adrenal Medulla

Contraception

Graves (thyroid stimulating autoantibodies against the TSH receptor as opposed to Hashimoto's autoantibodies against TBG and thyroid peroxidase TPO, shows high radioactive iodine uptake, treat Hashimoto by levothyroxine), Multinodar Goiter (multiple areas of high radioactive iodine uptake), Thyroiditis

Hypothyroidism

Pregnancy

Alcohol

Hashimoto's Thyroiditis (most common cause of non-diet related hypothyroidism, diffuse radioactive iodine uptake low uptake)

Hyperthyroidism

Amiodarone

Decrease T3 (drug inhibits T4 to T3 conversion by blocking the action of 5' deiodinase)

Increase CO2 Production, Increase T4 Levels, Decrease LDL Levels

Metabolic Effects: Increase Glycogenolysis and Gluconeogenesis (Hyperglycemia), Increase Lipolysis, Decrease Cholesterol (Increases Cholesterol Secretion in Bile) and LDL (Increase LDL receptors in the liver). Increase Na/K ATPase pumps, Increase Oxygen Demand, Increase Respiratory Rate, Increase Body Temperature

Other Possible Symptoms: Weight Loss (Increase Metabolic Rate), Tachycardia, Warm Skin

Liver Disease

Increase TSH (high TSH think thyroid hyperplasia)

TBG produced by the liver decreases

T4 levels decrease since TBG carries T4

high estrogen levels increases TBG (estrogen increases TBG by slowing TBG clearance from the plasma) and total T4 increase but TSH normalizes

high estrogen levels increases TBG (estrogen increases TBG by slowing TBG clearance from the plasma) and total T4 but TSH normalizes

central hypothyroidism (or hyperthyroidism)

Decreased Cardiac Output

Symptoms: Lethargy, Weakness, Dysnea on Exertion, Cold Intolerance, Weight Gain with Loss of Appetite, Constipation, Hyporeflexia, Dry, Cold Skin, Coarse,Brittle Hair, Bradycardia, Depression, Poor Exercise Tolerance

Abnormal muscle metabolism (low T4 slows muscle cell metabolism)

congenital hypothyroidism (cretinism)

pneumonia

ADH release

Hyponatremia

myalgias and weakness

increased levels of serum creatine kinase

Lymphocytes inflitrate the thyroid

decreased T4, decreased rT3, and increased anti-TPO

antibodies produced against TBG and TPO

low T3

decreased LDL receptor density since T3 upregulates LDL receptor gene activation

(could) result in reduced TSH

(could) result in decreased T4

both TSH/T3/T4 low (or TSH/T3/T4 are high)

a pituitary tumor pressing on the pituitary gland could cause this

stunted growth, mental retardation, coarse facial features, umbilical hernia, enlarged tongue (cretinism is caused by low maternal iodine levels during pregnancy)

Thyroid Storm (a severe life-threatening) form of hyperthyroidism)

associated with a surge of catecholamines

typically precipitated by an acute event like illness surgery or trauma

Myxedema (severe form of hyperthyroidism)

cancers

papillary carcinoma most common

follicular carcinoma second most common (cannot be distinguished through fine needle aspiration)

follicular carcinoma (typically present with a single enlarged nodule)

"hot" nodules indicating an uptake of iodine to create T3/T4 are usually non-cancerous

"cold" nodules indicating low radioactive iodine uptake are possibly cancer because most cancers do not make hormone

medullary carcinoma are cancers of the parafollicular cells (amyloid deposits can be seen in the thyroid)

anaplastic thyroid cancer typically presents in the elderly and histology involves undifferentiated cells and enlargement is usually asymmetrical

The Adrenal Gland

17 alpha hydroxylase deficiency

3 beta hydroxysteroid dehydrogenase deficiency

11 beta hydroxylase deficiency

21 alpha hydroxylase deficiency

low cortisol production -----> high levels of ACTH

excess androgens ---------> ambiguous genitalia in females (enlarged clitoris and labial fusion)

accumulation of 17 hydroxyprogesterone

[in males testicular enlargement entails activity of the HPA axis while small testicular size indicates HPA axis inhibition] but in the case of 21 alpha hydroxylase deficiency males have normal appearing genitalia at birth and present with failure to thrive, vomiting, dehydration, hyponatremia and hyperkalemia

salt-wasting

males have premature adrenarche [pubic hair and axillary hair]

these patients unlike patients with 21 alpha hydroxylase activity will have increased amounts of 11-deoxycorticosterone which has some mineralocorticoid activity thus we will see some hypertension as well as hypokalemia

patients develop hypertension and hypokalemia due to mineralocorticoid accumulation

female patients have primary amenorrhea at puberty due to lack of androgen synthesis which in turn leads to lack of estrogens

male patients present with female or ambiguous external genitalia and undescended testicles secondary to androgen deficiency

males develop ambiguous genitalia [for androgen issue think of the female more affected when there is excess and male more affected when there is lack]

aldosterone deficiency

patients deficient in all steroid hormones

with androgen deficiency females at first appear normal then during puberty experience amenorrhea [androgens are required at puberty to normalize estrogen levels]

17,20 lyase deficiency

rare deficiency leaves mineralocorticoid and glucocorticoid activity both in tact

Cushing Syndrome (syndrome is excess cortisol generally while cushing disease indicates a pituitary secreting tumor)

low dose dexamethasone suppression test and early morning cortisol are confirmatory for Cushing's Syndrome

excess cortisol alters GnRH release decreasing FSH and LH

up to 20 percent of SCLC tumors secrete ACTH

Pseudo-Cushing's Disease occurs when there is an elevated cortisol level without involvement of the HPA axis

osteroporosis is a common feature of Cushing's Syndrome

dexamethasone test (dexamethasone is a glucocorticoid that acts like cortisol)

low dose (1mg)

high dose (8mg)

(administer dexamethasone at night then check serum cortisol levels in the morning) this test distinguishes where the ACTH is coming from if the test comes back responding to high dose this suggests a pituitary tumor otherwise no response indicates an ectopic ACTH secreting tumor

(administer dexamethasone at night then check serum cortisol levels in the morning). In normal patients the low dose of dexamethasone will supress ACTH release. If a patient has an elevated cortisol level then this confirms Cushing's and if the ACTH levels are high after low-dose dexamethasone then this takes it as step further and specifies that the CAUSE of her Cushing's Syndrome is due to overproduction of ACTH

adrenal hyperplasia and adrenal adenomas are ACTH independent causes of cushing's syndrome

ketoconazole is an antifungal that blocks the first step of cortisol synthesis by inhibiting desmolase or the conversion from cholesterol to pregnenelone and can be used to treat Cushing's. this drug cause blockage of androgen production causing a relative increase in estrogen/testosterone which can cause breast enlargement (gynecomastia), decreased libido and impotence

adrenal insufficiency/Addison's disease

most commonly caused by autoimmune destruction of the adrenal gland

waterhouse friderichsen syndrome is a rare cause of adrenal insufficiency caused by acute hemorrhage into the adrenal glands. cosyntropin stilumation tst can be used to evaluate adrenal cortisol production as cosyntropin is a synthetuc form of ACTH

the most common cause of secondary adrenal insufficiency is glucocorticoid therapy this leads to adrenal atrophy over time

nearly 60 percent of patients in adrenal crisis/shock have some underlying bacterial or viral infection AND in such patients it is critical to treat the adrenal crisis first before dealing with the infection

primary aldosteronism

hypokalemia, increased serum bicarbonate levels and metabolic alkalosis

Pheochromocytoma us a catecholamine secreting tumor [classic triad is headaches, sweating, tachycardia/racing heart]

remember that the insulin receptor is a tyrosine kinase receptors that works through autophosphorylation keep in mind the distinction that insulin does not activate cAMP while anterior pituitary hormones like LH, FSH, TSH and glucagon have pathways involving cAMP while GnRH, TRH and the posterior pituitary hormones ADH and oxytocin increase Phospholipase C production in turn increasing IP3 production

insulin life growth factor is a hormone released by the liver in response to GH and so can be used as a screening test for growth hormone

ANP and NO --- cGMP

GnRH, TRH, ADH, oxytocin --- PLC/IP3 [this should make sense because GnRH and TRH is produced by hypothalamus neurons and the posterior pituitary is a continuation of the brain from ectoderm of floor of brain | note that leuprolide decreases IP3 production]

glucagon, TSH, LH and FSH ---- cAMP

Prolactin and GH ---- JAK/STAT [usually involved in cell division so growth hormone especially makes sense]

insulin --- autophosphrylation by way of tyrosine kinase receptor

insulin release is inhibited by epinephrine more specifically insulin works by alpha 2 receptor activation which acts to inhibit insulin release [epinephrine also activates the Na/K pump]. Both insulin and epinephrine activate the Na/K pump although epinephrine opposes insulin release.

a rash with polyuria and polydipsia is a tell-tale sign of a glucagonoma

insulin increases glycogen synthesis by activating glycogen synthase and increases fatty acid synthesis by activating acetyl-coA carboxylase

type II diabetes the pancreatic islets contain amyloid as amylin peptide is secreted with insulin (pramlintide is an analog of amylin used to decrease postprandial glucose surge)

Types of Drugs Glucose Control

Long Acting --- these insulin type drugs are long acting because they precipitate out at body pH then dissolve back into the blood from crystals

Short Acting --- Aspart, Lispro, Glulisine [reduced hexamer and polymer formation allows quicker absorption]

Regular Insulin

Detemir --- an added fatty acid side chain causes it to aggregate in subcutaneous tissue and bind reversibly to albumin allowing it to dissolve slowly

thiazolidinediones (TZDs) work by binding to PPAR-gamma receptors in adipose tissue and to retinoid X-receptors leading to decreased insulin resistance

Glargine --- human insulin with an amino acid substitution that makes the molecule soluble in an acidic liquid for storage

Sulfonylureas close potassium channels in beta cells making them more sensitive to glucose-induced insulin release [chlorpropamide is a sulfonylureas that causes flushing with alcohol consumption this drug can also cause hyponatremia secondary to increased ADH activity]

biguanides including metformin decrease production of glucose by the liver and increase insulin sensitivity

canagliflozin is an example of a SGLT2 recdptor that would act on the luminal side of PCT cells

Amylin analogues include pramlinitide given subcutaneously along with insulin to allow insulin to work more effectively (amylin is normally released by the body with insulin)

metformin works by shunting glucose pathways it will decrease serum free triglycerides thus decreasing the triglycerides that can participate in gluconeogenesis it shunts glucose into lactate thus increasing blood lactate levels as well as decrease TAG levels and LDL cholesterol levels

Glucosidase Inhibitors [acarbose, miglitol, voglibose] --- block intestinal glucosidase thus decreasing the conversion of complex carbohydrates into monosaccharides

alcoholic cirrhosis is associated with a decrease in serum testosterone, cirrhosis is a cause of male hypogonadism with associated testicular atrophy and infertility, estrogen levels increase in cirrhosis stimulate Sertoli cells to release SHBG thus raising serum SHBG (this protein binds both testosterone and estrogen but binds testosterone to a greater degree), the increased estrogen levels leads to gynecomastia in men

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Kallman Syndrome --- absence of GnRH secretion from the hypothalamus due to impaired migration of GnRH neurons from origin in olfactory bulb to hypothalamus resulting in low GnRH, FH, LH, and Testosterone [boys present with undescended testicles while girls present with delayed breast development

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Sex Hormone Binding Globulins [since SHBG binds stronger to testosterone then less SHBG means more circulating free testosterone]

Increase SHBG --- estrogens and hyperthyroidism [increases estrogen effects and causes gynecomastia in men]

Decrease SHBG --- androgens, hypothyroidism, nephrotic syndrome [increases androgen effects causes hirsuitism in women]

Breast

spironolactone not only binds to mineralocorticoid receptors in the distal tubule and collecting duct but also binds to androgen reeptors and increases the aromatization of testosterone to estradiol leading to gynecomastia in about 10 percent of patietns [thus spironolactone can be used to treat hirsuitism, acne and alopecia in women because of its anti-androgen activity]

anabolic steroid abuse [erythrocytosis is a side effect] can lead to gynecomastia

Tamoxifen is a selective estrogen receptor modular (SERM) that competitively binds to estrogen receptors decreasing estrogen-induced DNA synthesis [note that estrogen receptors can be found inside or outside the nucleus]

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5-alpha reductase deficiency

infant assigned female gender and experiences masculinization and phallic growth at puberty [this is different than Androgen Insensitivity Syndrome where estrogen effects dominate at puberty]

inability to convert testosterone into DHT which plays a crucial role in development of external genitalia

finasteride inhibits 5 alpha reductase thus blocking the conversion of testosterone to DHT THUS can be used to treat hair loss in men

normal internal genitalia but external genitalia predeominately female

Oral Contraception Pills (OCPs)

history of DVT and PE

combination OCPs include estrogen and progestin [combination OCPs increase risk of cervical cancer especially HPV positive patients]

smokers over 35 years of age have increased risk of CV events so women who smoke over 35 is an absolute contraindication with OCPs

progestin only [levonrogestrel an example] pills cause endometrial atrophy thus combination pills lead to less breakthrough bleeding but estrogen increases clotting factor production may lead to resistance to protein C | progestin only pills will act on the cervix by thickening the cervical mucus and thinning the endometrial lining [progestin only pills do not effect the production of androgens in theca cells nor do they affect the production of estrodial by granulosa cells

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PCOS

high estrone

high insulin

low FSH or LH:FSH ratio above 3

low progesterone

Dopamine Antagonists [cause increase in prolactin levels]---- Haloperidol [antipsychotic], Risperidone, [antipsychotic], Metoclopramide [antiemetics] but tricyclic antidepressants, SSRI, metoclopramide and verapamil also cause prolactin excess

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