Endocrinology 2 Flashcards
Pituitary Function
- Controls function of peripheral endocrine glands
- Regulated by stimulatory, inhibitory factors from hypothalamus, feedback from other hormones
- Hormones separately regulated (although gonadotropins have related regulatory factors)
Pituitary Regulation
- Prolactin:
stimulant: TRH, Dopamine antagonist
inhibitor: Dopamine - GH stimulant - GHRH, decrease glucose, exercise inhibitor - somatostatin, glucose - FSH, LH
stimulant - GnRH(pulsatile)
inhibitor - GnRH(stable), sex steroids, inhibit
- TSH
stimulant: TRH, decreased T4/T3 inhibitor - Dopamine, increased T4/T3 - ACTH stimulant - CRH, ADH, decreased cortisol, decreased glucose
inhibitor: glucose, increased cortisol, dexamethasone
Causes of increased prolactin
- Pituitary adenoma: 70-80%
- Pituitary stalk compression: 5-10%
- Drugs (phenothiazines, H2 blockers, others): 5%
- Other: 5-10% -Macroprolactin – high MW forms, sometimes with symptoms
Evaluation of high prolactin
Prolactin level most helpful:
Upper reference limit 20-25 ng/mL
> 200 ng/mL, almost all tumors
100-200 ng/mL, 80-90% tumors
< 100 ng/mL, consider other causes
Growth Hormone
Relatively common syndromes of over- underproduction:
Overproduction: gigantism (children), acromegaly (adults)
Underproduction - pituitary dwarfism (children), few symptoms in adults
GH Excess
Basal GH not useful; often normal or only slightly
Glucose inhibits GH; test 1 h after oral glucose load (GTT): failure to suppress in tumors IGF-1 best single test for diagnosis, follow-up
GH Deficiency
Rare cause of dwarfism
Usually defined as failure of GH to respond to at least 2 stimuli
IGF-1 can be used in children > 5, not as helpful in young children In adults, GH replacement being explored for osteoporosis, aging
Hypopituitarism
Presents end organ failure with low pituitary hormone levels
May affect one or more hormone
Prolactin may be high due to loss of dopamine inhibition GH, gonadotropins early loss, TSH later, ACTH last; not always this order
Male Gonadal Function
FSH stimulates spermatogenesis
LH stimulates testosterone
Sertoli cells make inhibin, decreasing FSH production
Testosterone converted to dihydrotestosterone (more potent) by 5a reductase at cell level (little circulates)
Female Gonadal Function
Slight fall in estrogen causes LH surge
Before ovulation, estrogen dominant After ovulation, progesterone dominant
Lack of fertilization: progesterone falls, menstruation Can tell adequate estrogen by Nl periods, bleeding after progesterone withdrawal
Menstrual Cycle
Cells involved in menstrual cycle
Gonadal Tests
- Clinical evaluation (for estrogen)
- Progesterone, testosterone levels
- Adrenal androgens (DHEA-S)
- Free testosterone level (or estimation)
- Gonadotropins
- HCG
Sex Steroids
- Estrogen usually evaluated clinically, rarely measured (precocious puberty)
- Testosterone mainly bound to SHBG, but inhibits production; as T falls,
- SHBG rises, causing greater fall in active free T than total T
- Most free T assays unreliable, however
Sex Steroids 2
- If total T near lower end of normal, free T can be measured by equilibrium dialysis or estimated from total T, SHBG, and albumin levels
- Alternative approach: precipitate SHBG and measure residual T (called “bioavailable” T)
Progesterone
- Used to evaluate function of corpus luteum; used in fertility problems
- Must be interpreted based on day of cycle
- Considerable variation from one person to next
Gonadotropins
- Released in episodic bursts; in males, single specimens uninterpretable; use pooled specimens
- Not needed if testosterone or menstrual periods normal
- With 2nd gen. assays, central disease causes low levels
HCG
- Serum assays use Ab to -subunit; urine Ab detects -core fragment
- In pregnancy, levels double q 2d during 1st 12 weeks; lower rate of rise with ectopic, miscarriage
- In GTN, ectopic, may have abnormal forms not detected by some assays
Erectile Dysfunction
- Only 15-20% hormonal
- Screen with total or free testosterone; some add prolactin if T abnormal
- In primary gonadal failure, FSH/LH often normal; low levels in central hypogonadism
Amenorrhea
- Menopause ( FSH), pregnancy (HCG) common physiologic causes
- High prolactin common cause if these ruled out
- High androgens may cause this, often along with hirsutism
Hirsuitism
- Abnormal androgen effect
- Often familial (increased peripheral conversion)
- Adrenal - DHEA-S
- Ovarian - testosterone
- If virilization also present, usually due to tumor
Hirsuitism 2
- Polycystic ovary: high LH:FSH ratio (> 3:1, lab tests not diagnostic)
- Cushing’s syndrome
- Congenital adrenal hyperplasia - high steroid precursors (17-OH progesterone with 21-hydroxylase, 11-deoxycortisol with 11-hydroxylase deficiency)
Calcium Locations
- Skeleton - 99% of total calcium; not regulated hormonally, depends on balance of intake, loss
- Extracellular fluid – 1.25 mmol/L, closely regulated hormonally
- Intracellular fluid - 0.7 mmol/L, closely regulated by active transport
Extracellular Calcium Forms
- Free (ionized) - 45-50%
- Protein bound (mainly albumin) – 40-45%
- Complexed (PO4, HCO3, other anions): 5- 10%
- Only free physiologically active and hormonally regulated
First National Bank of Calcium
Vitamin D
- Two forms, D2 (ergocalciferol) from plants, main dietary from, and D3 (cholecalciferol), made in skin from cholesterol metabolite
- Activation of both in liver by 25-OHase; 25-OH D reflects diet and production
- Final activation in kidney by 1-OHase, active form; enzyme increased by PTH or low phosphate. Usually normal with dietary deficiency or decreased sunlight
Vitamine D Production Image
Calcitonin
- Produced by parafollicular (C) cells in thyroid, lung, others
- Increased by high calcium
- Inhibits bone resorption
- Probably not important in calcium regulation in humans
PTH-Related Peptide
- 8 of first 13 amino acids identical to PTH, binds to PTH receptors, has similar actions
- Produced by fetal parathyroid (not PTH), causes transplacental Ca transport
- Produced by breast epithelial cells, ? important in Ca absorption by baby
- Necessary for fetal bone development
Bone Calcium Regulation Image
Total Calcium
- Most common assay, automated
- Measures all forms
- Colorimetric assays inhibited by chelators (EDTA), gadolinium
- Influenced by changes in proteins, complexes; often insensitive to changes in free calcium in hospitalized patients
Free Calcium
- Measures physiologic fraction
- Affected by changes in pH, so requires special handling (best done along with blood gases)
- Most appropriate test in acutely ill patients
- Can be estimated from total calcium, albumin in outpatients
PTH Metabolism
- Produced as 84 amino acid peptide from precursors
- In circulation, rapidly cleaved to release 35-84 fragment; 7-84 fragment may also accumulate in renal failure
- Hypercalcemia inhibits PTH release, favors catabolism to fragments
- “Inactive” fragments cleared by kidneys
Intact PTH
- Most intact assays measure 7-84 fragments as well, making results falsely high (average 20-30%)
- “Biointact” PTH assays do not measure 7-84 fragments; not clear that they correlate better in renal failure
- 7-84 fragments bind to different PTH receptor, have opposite effects to PTH
Vitamin D
- Remember that 25-OHD has two hydroxyl groups is shown structure
- Reference ranges no longer based on central 95%, as deficiency common; based on ability to absorb Ca and inhibit PTH
- Lower reference limits for 25-OHD now generally around 20-30 ng/mL (used to be 5- 7 ng/mL)
Hypercalcemia
Three etiologies responsible for 99% of cases
- Hemoconcentration
- Primary hyperparathyroidism
- Malignancy
Hyperparathyroidism
- Most common cause in outpatients
- Typically mild (< 12 mg/dL, 3 mmol/L), stable over long periods
- Associated with low/low nl PO4, high Cl (Cl/PO4 ratio > 33)
- PTH usually increased or “high normal”
- PTH < 50% basal in 10-15 min with successful adenomectomy
Malignancy
- Often severe hypercalcemia (> 13 mg/dL), rises rapidly, symptomatic (confusion, coma, polydipsia)
- 80% due to PTHrP production (squamous, breast, renal)
- May also be due to bone metastases (e.g., myeloma), ectopic calcitriol
- PTH typically undetectable
Rare Causes of hypercalcemia
- Calcium ingestion - common cause in renal failure due to dysregulation of PTH release
- Sarcoidosis - ectopic calcitriol production (also some lymphomas)
- Immobilization (mainly in young)
- FHH - inherited down-regulation of calcium receptors, low urine Ca (fractional excretion << 1%)
Hypocalcemia Causes
Common - 90% of cases
Low albumin, renal failure
Uncommon causes - 10% of cases
- Hypomagnesemia
- Malabsorption, vitamin D deficiency (common in older adults)
- Hypoparathyroidism or PTH resistance in sepsis, shock, pancreatitis
Secondary Hyperparathyroidism
- Due to chronic hypocalcemia
- PTH generally much higher than in primary hyperparathyroidism
- More severe bone disease
- Often associated with high phosphate when due to renal failure; may cause metastatic calcification in vessels, elsewhere
Erectile Dysfunction
- Only 15-20% hormonal
- Screen with total or free testosterone; some add prolactin if T abnormal
- In primary gonadal failure, FSH/LH often normal; low levels in central hypogonadism
