ENDOCRINOLOGY HORMONE
the chemical messengers produced by the endocrine cells that travel through the circulation to specific body cells body cells contain receptors for specific hormones called TARGET CELLS
only those cells containing receptors will bind hormones –very specific, conc’n dependent & reversible CLASSIFICATION OF HORMONES
A. PROTEIN HORMONES
composed of AA (peptides, chains of 8 AA or less, amines)
synthesized in the endocrine glands as a larger precursor molecules called PREPROHORMONES –contains a leader sequence of AA called SIGNAL SEQUENCE –cleaved from the molecules called PROHORMONES –enzymatically cleaved to smaller molecules –active hormones –packaged into secretory vesicles
does not attach to plasma CHONS & circulates in the blood as free hormone short half life
B. STEROID HORMONES
synthesized in the cytoplasm by multienzyme processes derived from CHOLESTEROL
separated into groups based on the no. of carbon presents: C 18 – estrogens
C 19 – androgens
C 21 – gluococorticoids, mineralocorticoids & progesterone freely diffuse across the plasma mem. & into the bloodstream
bind to specific plasma CHON w/c allows them to remain in circulation for longer than the unbound or free form of the hormone
take longer to initiate their action & once started, the action is sustained for a prolonged period longer half life –bec. of their binding to the plasma CHON carriers
GROWTH HORMONE (GH)
composed of AA & share many of the same charac. as the CHON hormones from indiv. cells or group of cells
has its own specific extracellular receptor since they cannot cross the plasma mem. NEUROTRANSMITTERS (NT)
epinephrine/norepinephrine –may serve as either a hormone or NT, the diff. is the site of synthesis & action REGULATION OF HORMONE SECRETION
A. NEGATIVE FEEDBACK
the final hormone produced regulates its own secretion by inhibiting the secretion of 1 or more of the precursor hormones TRH (Thyroid Releasing H) – by hypothalamus
↓
TSH (T Stimulating H) – by pituitary gland ↓
TH – by thyroid gland B. POSTIVE FEEDBACK
the final hormone produced actually enhances or induces the initial hormone & causes its own prodxn to be ↑ rare; final hormone enhances or induces initial hormone ↑ production
Oxytocin
MECHANISM OF ACTION
A. PROTEIN HORMONE ACTION bind to extracellular receptors
activates an intracellular CHON (G) to transducer the signal to an enzyme (adenyl cyclase) to produce 2nd messenger cAMP 2nd messenger will cause intracellular changes
Bind to EC receptors Hormone-receptor complex Activate IC protein (G) transduce signal to Adenyl cyclase (enzyme) produce 2nd messenger cAMP cause IC changes
B. STEROID HORMONES ACTION
a heat shock CHON dissociates from the receptor after binding
hormone-receptor complex migrates into the nucleus & binds w/ a specific region on the DNA mRNA is produced & a CHON is synthesized
DISORDERS OF THE ENDOCRINE SYS. 2 categories:
1. 1° DISORDERS
problem w/ the gland that produces the hormone (hyper/hyposecretion), the outside stimulating agents is N Hyper more difficult to correct than hypo
Hypo – not detected until 80-90% of gland is nonfunctional 2. 2° DISORDERS
the gland that produces the hormone is capable of N fxn, the outside stimulating agents are either in excess or deficient hypersecretion of a hormone is often more difficult to correct than hyposecretion
hyposecretion is often not detected until approx. 80%-90% of the gland is nonfunctional normal gland function, outside stimulating agents in excess or deficient
HYPOTHALAMUS
- part of brain; under 3rd ventricle & directly above pituitary gland
- secrete neuropeptides (hormones): inhibit/ stimulate hormones of Anterior Pituitary Gland (APG); regulatory hormones - neurosecretory cells secrete the neuropeptides
Hypothalamic Hormones: Corticotropin
Releasing Hormone (CRH) ↑ACTH, ß-lipotropin, ß-endorphin
Thyrotropin
Releasing Hormone (TRH) ↑TSH
Gonadotropin Releasing Hormone (GnRH) ↑FSH, LH
Prolactin Inhibiting Factor (PIF=dopamine) ↓ prolactin (PRL)
Prolactin Releasing Factor (PRF/TRH) ↑ PRL
Growth HRH (GRH) / Somatocrinin ↑ GH
Growth HIH (GIH) / Somatostatin (SS) ↓ GH
Melanocyte Inhibiting Factor(MIF) ↓ Melanocyte-Stimulating H
ADH/ Arginine Vasopressin (AVP) ↑ reabsorption of H2O from glomerular filtrate & urine; Vasoconstriction of Smooth Muscles
Oxytocin stimulate uterine muscle contraction; cause contraction of the breast muscles for the ejection of milk
Pineal gland
- on the posterior wall of the 3rd ventricle of the cerebrum - small “pine-cone” shaped structure
- exact fxn unknown; but synthesizes MELATONIN (synthesized from serotonin; can inhibit gonadotropic hormone in lower vertebrates {may or may not in humans})
- “3rd eye”: regulates the circadian rhythm/ diurnal pattern
- ↑ production in dim light - sleepy, tired, depressed during nighttime - Bright light inhibits melatonin – active, awake during daytime
Pituitary Gland (Hypophysis)
- connected to the hypothalamus by infundibulum or pituitary stalk through w/c the neuropeptides migrate to pit. gland - contained in a depression of sphenoid bone: SELLA TURCICA; adjacent to chiasm of optic nerve
- “Master Gland” - secretes numerous hormones w/c triggers other glands to produce hormones - enlargement leads to loss of vision
- 2 main lobes:
a. Posterior Pituitary/ Neurohypophysis – smaller hypothalamic lobe; storage of Oxytocin (targets the breast and the uterus) &
ADH/AVP (target organ is the kidney); synthesized in Hypothalamus; neuroectodermal in origin
b. Anterior Pituitary/ Adenohypophysis –specialized secretory epith. cells: synthesize & stimulate numerous hormones
stimulates the secretion of other hormones except GH & PRL
- regulate their own secretion by a (-) Feedback to Hypothalamus “short loop (-) feedback” - TSH, ACTH, LH,FSH, except PRL & GH - others can stimulate other adrenal glands to produce H. - TSH (thyroid stimulating hormone) – T3(triiodothyronin) and T4 (thyroxin)
- ACTH (adenocorticotrophic hormone)- target organ is the adrenal cortex; end hormone produced is cortisol
- LH and FSH – target organs are the gonads (testes for males; ovaries for females); testosterone is produced in males, estrogen and progesterone for females
- Growth factor- stimulates tissues such as cartilage, bones, muscles but these do not produce hormones - Prolactin – target organ is the breast; increase the size of the breast to prepare it to produce milk
Secretory Cells of AP (staining property with H&E)
1. Acidophils - stains red; Somatotrophs (secrete GH) & lactotrophs/ mammotrophs (secrete PRL) 2. Basophils – stains blue; thyrotrophs (secrete TSH) and Gonadotrophs (secrete FSH and LH) 3. Chromophobe Cells – don’t stain; corticotrophs (secrete ACTH)
Pituitary hormones (based on chemical configuration):
1. Polypeptides – hormones with intramolecular disulfide bonds (GH & PRL)
2. Glycoproteins –TSH, FSH, LH; share common α-subunit, differ in ß-subunit; ex: human chorionic gonadotrophin (hCG) 3. Single-chain peptides –hormones w/o disulfide bonds (ACTH)
POSTERIOR PITUITARY HORMONES
- ADH & Oxytocin – nonapeptides: contain 9 amino acids - both are inhibited by alcohol 1. ADH or Arginine Vasopressin (AVP)
a. Maintain body’s H2O balance by promoting ↑ H2O reabsorption in the tubules of the nephrons of kidneys less H2O in the urine (concentrating effect); ↑osmolality in urine compared to plasma
b. Vasoconstriction of BV “vasopressin”: maintain BP in traumatic injuries
- Administration of ADH can help prevent von Willebrand’s disease because ADH can release the von Willebrand factor - 1º stimulus: ↑ plasma osmolality (↑ Na) detected by the osmoreceptors in the Hypothalamus
- RR of Plasma osmolality = 275-295 mOsm/Kg (>295 secretion of ADH) ADH stimulation
a. ADH (binds) to
b. V2 receptor (vasopressin) in distal convoluted tubules & collecting ducts activates
c. Adenyl Cyclase that will cause generation of
d. cAMP (cyclic adenosine monophosphate); (serves as the 2nd messenger: responsible for intracellular changes) initiates phosphorylation of membrane CHON which causes
e. ↑ in membrane permeability to H2O
Symptoms of ADH Deficiency & Diabetes Insipidus: 1) Polydipsia (↑ thirst)
2) Polyuria (↑ urine output; typically >3L /24 hrs) *N=2L
Laboratory Analysis
A. RIA— Spec: plasma anticoagulated w/ EDTA in prechilled tubes - centrifuge blood ASAP & remove plasma from cells
- plasma frozen until used for analysis
- ADH levels deteriorate with prolonged storage
- NV (healthy adult)= 2.3 – 3.1 picogm/mL or nanogram/L of plasma - plasma ADH conc. report w/ Px plasma osmolality for EVERY test Reference Ranges for ADH:
B. B. B. B. Water Deprivation Test (Indirect ADH measure)
Procedure: a. Weigh Px
b. Withhold H2O for 8hrs (can be done either at night or day) c. Every 2 hrs
Weigh Px (stop test if weight falls by >5% of initial body weight)
Px empty bladder: measure urine vol & osmolality (N = 300-800 mOsm/kg H2O)
Obtain blood sample : measure plasma osmolality (stop if result is >300 mOsm/Kg dehydrated) d. After 8hrs allow Px to drink (no more than twice urine vol. obtained in test to avoid acute hyponatremia).
Patient should be closely observed while test is being performed.
Normal: Should not have weight losses >3% & Serum/plasma osmolality w/in RR; urine osmolality must not go beyond 800 mOsm/kg of water
ADH deficiency: ↑ serum/plasma osmolality & ↓ urine osmolality over time tested (concentrating effect on plasma and
diluting effect on urine)
- inversely prop: Plasma & urine osmolality - alcohol: inhibit ADH & oxytocin
- cold temp: inhibit ADH 2. Oxytocin (OT)
- most active in pregnant women
- At term stimulates contraction of smooth muscles in the wall of the uterus (induce labor) - Synthetic oxytocin can be used to induce labor
- induces lactation by stimulating contraction of the myoepethielial cells in the mammary glands (ejection of milk) - premature labor prevented by injecting alcohol intravenously
- Nonpregnant women and men have basal levels of OT – its role not been determined
2 Strongest Stimuli for Oxytocin release: a. Distention of the uterus
b. Neonatal suckling of the nipple
Lab Analysis
A. RIA – Plasma anticoagulated w/ EDTA in prechilled tube - plasma can be frozen until used for analysis
- Reference Range = 1-5 pg/mL sample
ANTERIOR PITUITARY HORMONES: 1. Prolactin (PRL)
- by lactotroph (mammotroph) cells in the anterior pituitary gland - helps stimulate dev’t. of breast tissue needed for lactation
- postpartum women: it induces synthesis of milk in the mammary gland
PRL Values
a. Nonlactating women, men & children= < 20ng/mL - actual function not fully understood
- Hypersecretion is associated with Hypogonadism (impaired gonads, incomplete fxn) in both men and women
Osmolality (mOSm/kg) ADH (pg/mL)
270-280 <1.5
280-285 <2.5
285-290 1-5
290-295 2-7
b. 1st Trimester = <80 ng/mL c. 2nd Trimester = <169 ng/mL d. 3rd Trimester = <400 ng/mL Secretion of PRL:
- under control of PIF/ Dopamine from hypothalamus - ↑dopamine: ↓PRL; ↓ dopamine: ↑ PRL - No specific PRL-releasing factor, but thyrotropin releasing hormone (TRH) induce ↑ in PRL levels - ↑PRL – stress
Lab Analysis:
A. RIA – method of choice, fresh nonhemolyzed serum (frozen ASAP) is used - time of collection noted (↑PRL in the morning)
B. IRMA (immuno-radiometric assay) – doesn’t recognize all forms of PRL in circulation 2. Growth Hormone (GH)
- synthesized by the somatotroph cells in the AP
- essential for normal growth; hormone of highest conc. in the AP
- anabolic in action in most tissues; stimulate synthesis of new CHON & causing cells to divide & ↑ in size - induces Lipolysis (fat breakdown)
- cartilage & bone growth & development, but action is indirect because: a. GH stimulates Liver to produce
b. Somatomedin—C (insulin-like growth factor 1 or IGF -1) binds to receptors on
c. cartliage & bone cells that stimulate
d. DNA synthesis & cell growth
Secretion of GH:
o controlled by 2 hypothalamic hormones:
a. Growth hormone releasing hormone (GRH) or Somatocrinin b. Growth hormone inhibiting hormone (GHIH/GIH) or Somatostatin o Other stimuli that induce the release of GH
a. Hypoglycemia (low blood sugar) b. Exercise or stress
c. High protein diet d. Acute starvation
e. Oral contraceptives and other drugs o ↓GH in obesity & corticosteroid therapy
o Growth hormones increase the body size of athletes
o Prior to that, extracts from the pituitary glands of cadavers were used but it was stopped because some athletes developed diseases to this practice
Lab Analysis:
A. RIA – method of choice
- fresh serum/ heparinized plasma (EDTA: ↓value) - RR (female) = 0-18 ng/ml
(male) = 0-4 ng/ml
3. TSH - glycoCHON produced by thyrothrops in AP - stimulates thyroid gland to produce
a) T4 (Thyroxin) b) T3 (Triiodothyronine)
- secretion controlled by thyrotropin releasing hormone (TRH) from hypothalamus 4. Gonadotrophins:
FSH glycoproteins produced by gonadotroph LH cells in the AP; regulate the sex cells & sex
hormones from gonads of both sexes
Secretion of Gonadotropins (Major stimulus: Gonadotropin Releasing Hormone (GnRH) in hypothalamus o Women-↑ prior to ovulation(day 14 of menstruation)
a. FSH stimulate follicle growth and maturation of ovum ESTROGEN
b. After Ovulation: LH stimulate Follicle become Corpus Luteum produce PROGESTERONE o Men:
a. FSH – stimulates spermatogenesis in seminiferous tubules of testes b. LH – stimulates Leydig or interstitial cells to produce TESTOSTERONE
- both are not secreted in a cyclic pattern as in women
A. RIA– method of choice for FSH
B. IRMA(Immunoradiometric Assay) – method of choice for LH: high degree of x-reactivity with hCG in RIA *Women: interpretation is based on menstrual cycle of Px
5. Adenocorticotropic Hormone (ACTH) - produced by corticotrophs in the AP
- fragment of larger precursor: Proopiomellanocortin - stimulates Adrenal Cortex to secrete CORTISOL - target organ: adrenal cortex
Secretion of ACTH (1º regulated by:)
a. CRH (Corticotropin Releasing Hormone) of the Hypothalamus b. Negative feedback action of Cortisol
Lab analysis: (EDTA/heparinized plasma) A. RIA – method of choice
B. IRMA
- unstable in whole blood & adheres onto sides of glass tube
- blood should be spun 1st in a refrigerated centrifuge remove plasma centrifuge again to remove other formed elements (proteolytic enzymes) that can cause breakdown of ACTH during thawing and freezing process
- sample should be frozen if not analyzed immediately - Shows diurnal variation: ↑ 8 AM (morning); ↓midnight - note time of sample collection proper interpretation - RR: 8 AM (25-100 pg/mL); 6 PM (<50pg/mL) - Lowest level is at 12 midnight
PITUITARY GLAND Clinical Applications:
1. DIABETES INSIPIDUS (Most common) a) deficiency of ADH or
b) failure of the kidney to respond to ADH
-produce large amts of urine (polyuria) w/ low specific gravity and urine osmolality
a. function of ADH: reabsorption of H2O [DI: H2O not reabsorbed rather urine is excreted out] - symptoms: fatigue, severe dehydration, hypothermia and shock
2 types of DI Neurogenic DI
- cause of the ADH deficiency may be a pituitary tumor, traumatic, or surgical injury, genetic, autoimmune or idiopathic Nephrogenic DI
- normal to elevated plasma concentrations of ADH, kidney is unable to respond to the hormone.
- chronic renal dss such as chronic pyelonephritis, protein starvation, hypokalemia, sickle cell anemia, congenital defects in the receptors in the kidney.
- other cause of excess ADH: propagene carcinoma Diagnostic tests: plasma and urine osmolality
a. urine osmolality: low <400mOsm/kg b. urine volume for 24hrs is ↑ (>3L)
c. normal plasma osmolality if the H2O intake has not been restricted 2. SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE (SIADH) - excess ADH
- hypersecretion of ADH: excess H2O retention dilutional effect on the plasma components
- Dilutional hyponatremia: can induce generalized weakness, mental confusion, coma and convulsions - cause: may be pituitary tumor (benign) / carcinoma (elaborates hormones)
- other cause: Bronchogenic CA 3. Growth Hormone DEFICIENCY
- may be caused by pituitary tumors, traumatic injury, congenital disorders or idiopathic - children affected will fail to grow & be short in stature
- children with true GH deficiency—will respond and grow following injections of GH
to prove GH deficiency:
a. exogenous insulin injection – dangerous: induce severe hypoglycemia ↑ plasma GH coma b. injection of CRH (Corticotropic Releasing Hormone)stimulate pituitary gland to secrete GH c. strenuous exercise (20mins)
4. GH HYPERSECRETION
- rapid ↑ in height w/o distortion of body proportions
- hypersecretion of GH in adults is most often caused by a pituitary adenoma: Acromegaly a. disfiguring physical features: caused by ↑ IFG-I (somatomedin C) from the liver b. ↑ growth of most body soft tissues
c. ↑ size of the hands & feet with coarsening of the facial features, especially development of bony ridges over the eyes, large tongue
d. ↑insulin, postprandial glucose, P & Ca
e. joint pain, weight gain, goiter, heat intolerance, increased sweating Dx: serial measurements of GH
o Why serial? -your GH secretion is episodic.
Rx: transphenoidal surgical removal of the pituitary adenoma, radiation therapy 5. PANHYPOPITUITARISM
- generalized hypofunction of the pituitary gland with resulting ↓ in all pituitary hormone levels - thryoid, adrenal insufficiency, absence of gonadal fxn
SIMMONDS’ DSS :
- Develops after destruction of the pituitary by surgery, infection, injury or tumor
- extreme weight loss, dry skin, bradycardia, atrophy of the genitalia & breasts and progress to premature senility
SHEEHAN’S SYNDROME: - insidious (gradual) onset
- caused by pituitary infarction following complications of postpartum hemorrhage (vascular spasms of the hypophyseal arteries resulting in decreased blood flow to the pituitary, tissue hypoxia & necrosis)
o During Pregnancy: pituitary enlarges due to ↑ demand for hormones, ↑need for nutrients and O2 to the pituitary cells - failure of lactation (↓ PRL/hypoPRL)
- Hypothyroidism (↓TSH)
- postpartum amenorrhea (↓ FSH and LH) 6. HYPERPROLACTINEMIA
- excess secretion of PRL from the pituitary often caused by a pituitary tumor - Women: ↓ concentrations of Gonadotropins & Estradiol
o Cause continuous milk flow (galactorrhea, amenorrhea) - Men: enlargement of the breast tissue (gynecomastia)
o ↓ testosterone production with atrophy of the testes
THYROID FUNCTION TESTS THYROID STIMULATING HORMONE (TSH)
Effects of TSH on the thyroid is to increase the production and release of T4 from thyroglobulin, which in turn is converted to T3 at the peripheral tissue
Elevated in primary hypothyroidism
If the TSH remains low or low normal in the presence of decreased TSH secondary hypothyroidism Lab management: RIA
o Non-isotopic immunoassay methods such as EIA and chemiluminescence sTSH test of choice for initial diagnosis of thyroid dysfunction
o sensitive TSH
useful for monitoring patients who are receiving
Levothyroxine or levotriiodothyronine for hypothyroidism THYROXINE
total T4 (TT4) detect both the T4 bound to protein and the free biologically active T4
Assay for TT4 employ non-isotopic IA such as Fluorescense polarization immunoassay (FPIA) and chemilumiescence Free Thyroxin (free T4)
o Only 0.02%
o Much better indicator of thyroid status than total &4
o FT4: can enter cells and undergo conversion to the metabolically potent T3 o Elevated in approximately 95% of hyperthyroid patients
TRIIODOTHYROININE (T3)
Total T3 useful in evaluating suspected thyrotoxicosis in which the FT4 is normal
Useful in diagnosing mild hyperthyroidism because T3 rises earlier and more markedly than does T4 in all common forms of hyperthyroidism
Methods for measuring TT3: enzyme immunoassays (MEIA) and chemiluminescence THYROID HORMONE-BINDING RATIO (RESIN T3 UPTAKE)
THRYOGLOBULIN
Storage form of the TH precursors
Measured primarily in the monitoring of patients with follicular or papillary thyroid cancer Increased with stimulation by TSH, thyroid-simulating immunoglobulins (TSIg), TRH or hCG
The last parameter to normalize after thyrotoxicosis therefore useful in resolving thyroid history in the presence of normal T4 and T4 but with symptoms of thyrotoxicosis
Measures by chemiluminescence THYROID ANTIBODIES
Thyroid microsomal antibodies (TMAb)
o Present in about 85% of px with Hashimoto’s thyroiditis o In 85% of those with Grave’s dieases
Anti-thyroglobulin antibodies (TgAb)
o Found in 60% of patients with Hashimoto’s thyroditis o In 30% of patients with Graves’ diseases
o *TMAba and TgAb: predictor of outcome of antithyroid drug therapy in patients with Graves’ disease TSH receptor antibodies (TRAb) or Thyroid-Stimulating antibodies (TSIg)
o *TMAb and TgAb: hemagglutination tests in which erythrocytes that have been coated with either Tg or microsomes agglutinate when the respective antibody is present
o *thyroid peroxidase (TPO) antibodies: main autoantigenic component of microsomes TSH STIMULATION TEST:
Can detect abnormalities before TH concentrations are outside their reference ranges
Useful in distinguishing between pituitary and hypothalamic hypothyroidism, confirming mild hyperthyroidism in patients whose free T3 and T4 are equivocal and yet whose other clinical findings are suggestive of thyrotoxicosis
Injecting 200-500ug of synthetic TRH after determining a baseline TSH level 15, 30 and 60 minutes TSH determinations
Side effects: headache, nausea, chest tightness and mild hypotension CLINICAL APPLICATIONS:
HYPERTHYROIDISM
Increase in circulating TH both free and total Can be overt or subclinical
o Subclinical hyperthyroidism Asymptomatic
Normal TH levels, decreased sTSH At risk for atrial fibrillation, osteoporosis At risk are women older than 50 o Overt hyperthyroidism
Associated with elevated free and total T4 and T3, accompanied by a markedly decreased sTSH o Thyrotoxicosis
Condition that occurs when excessive amounts of TH in circulation affect peripheral tissue Manifestations:
Decreased weight with normal appetite Nervousness
Sweating Palpitations Heat intolerance Muscle weakness
Clinical signs: enlarged thyroid (goiter), eyelid retraction and tremor THYROID STORM:
State of thyroid crisis that requires emergency treatment
May occur following an infection, childbirth, diabetic ketoacidosis, withdrawal of antithyroid drugs or therapeutic use of radioiodine or surgical treatment in the thyrotoxic patients
Due to sudden increase in circulating TH
Symptoms: tachycardia, heart failure, high fever, nausea, vomiting and psychiatric disorders and coma Hyperthyroidism divided into 3 categories:
o Primary thyroid disease
