Intra-uterine growth
Factoids
- Acting hormones are: growth hormone, IGF-II (early in gestation), IGF-I (late in gestation), and insulin (large newborn in diabetic mother)
- Smoking decreases placental vascularity and decreases birth weight
- The worldwide leading cause of low birth weight is poor maternal nutrition
Post-natal growth (Pre-pubertal)
Factoids
- Acting hormones are: growth hormone, insulin and thyroid hormone
- Steroids have no role in growth in this period but their excess will slow growth
- Congenital hypothyroidism will cause cretinism, but does not decrease the birth weight (every newborn should be screened for thyroid hormones)
- Hypersecretion of growth hormone in this period will cause giantism, with delay in pubertal changes and subsequent hypogonadism
Growth Hormone deficiency (pre-pubertal)
Causes
- Congenital deficiency
- Idiopathic deficiency due decrease in GHRH secretion
- Acquired deficiency due to hypothalamic-pituitary tumor
Dwarfism
Cause
Growth Hormone deficiency (pre-pubertal)
Laron Dwarfism (Laron syndrome) (Cause)
Tissue resistance to growth hormone (Increased growth hormone, and decreased IGF-I)
Growth Hormone deficiency (pre-pubertal)
Stimulation test
Arginine infusion
Growth Hormone deficiency (pre-pubertal)
Treatment
Simple replacement of GH
Growth Hormone deficiency (post-pubertal)
Effects and Treatment
- Decrease in lean body mass
- Replacement therapy is now considered an acceptable treatment
Laron Dwarfism (Laron syndrome) (Treatment)
Mecasermin (recombinant IGF) or synthetic IGF
Growth Hormone
Factoids
- Released from the anterior pituitary
- Peptide hormone
- Anabolic and catabolic
- Tesamorelin is an analog that is used to treat HIV-associated lipodystrophy
Growth Hormone
Anabolic effects
- Direct: growth by Increasing amino acid uptake by the cells
- Indirect: growth via growth factors (especially IGF-I)
Growth Hormone
Catabolic effects
- Decreases uptake of glucose in fat and muscles (raises blood glucose)
- Mobilizes fats by by increasing the activity of hormone sensitive lipase (raises free fatty acids) [Not cAMP]
Insulin-like growth factor-I (IGF-I)
Factoids
- Peptide similar in structure to insulin
- Pulsatile secretion (more likely during the night in stages III and IV (non-REM) sleep
- Half-life is 15-20 minutes
- Circulates bound to plasma proteins (regulated by GH), thus long half-life (24 hr marker of growth hormone secretion)
- Decreases in catabolic states
Insulin-like growth factor-I (IGF-I)
Effects
- Increases cartilage growth (chondrogenesis) in bones
- Increases lean body mass
Growth Hormone
Regulation
- Secretion requires the presence of normal plasma levels of thyroid hormone
- Deep sleep, puberty, hypoglycemia, exercise and amino acids like arginine and leucine promote GH secretion
- IGF-I and elevated glucose inhibit GH release
- Secretion is through GHRH (hypothalamus)
- Inhibition is through Somatostatin (hypothalamus)
- IGF-I stimulates somatostatin
- GH inhibit GHRH and stimulates somatostatin
Puberty
Reproductive changes
- Hypothalamic pulse generator (LH) increases activity just before physical changes at puberty
- First noted sign in females is breast development; first by estrogen (promotes duct growth), then progesterone (promotes development of milk-producing alveolar cells)
- First noted sign in males is enlargement of testes (FSH stimulating seminiferous tubules)
- Pubic hair development in both sexes is dependent on androgens
Puberty
Physical changes
During puberty, androgens promote secretion in the following sequence:
- If T4 is normal, increased androgens (males from testes and females from adrenals [adrenarche] —> increased GH —> increased IGF-I
- Near the end of puberty, androgens promote mineralization (fusion or closure) of the epiphyseal plates of long bones. Estrogen can also promote this even in males
- Growth spurt in females begins early in puberty and is nearly complete by menarche. In males it begins near the end of puberty
Acromegaly
Causes
Excess growth hormone secretion post-puberty due to:
- Anterior pituitary macro-adenoma (> 1 cm) (almost always)
- Ectopic GHRH secretion (very rare)
Note: some tumors contain lactotrophs and elevated prolactin can cause hypogonadism and galactorrhea
Acromegaly
Diagnosis
- Elevated IGF-I level (somatomedin C)
- Failure of suppression of GH/IGH-I after giving glucose
- MRI shows lesion in the pituitary
Acromegaly
Treatment
- First surgical removal by trans-sphenoidal approach
- If surgery fails, use GH receptor antagonist (pegvisomant) or octreotide (synthetic somatostatin). If both failed then use Cabergoline (dopamine agonist)
- If all the above treatments failed then we use radiation
Hypothalamic-Anterior Pituitary Axis
Hormone synthesis
- Hypothalamic hormones are synthesized in neuron cell bodies, packaged in vesicles, and transported down the axons to be stored and released from nerve terminals (in median eminence region [the stalk])
- The hormones are then secreted into the hypophyseal-portal system and transported to the anterior pituitary
Hypothalamic-Anterior Pituitary Axis
Hormone types
All hormones in this system are water-soluble
Hypothalamic-Anterior Pituitary Axis
Anatomy
- Pituitary is located in the bony sella turcica at the base of skull
- It hangs from the hypothalamus by a stalk (infundibulum)
- Dura membrane (diaphragm sellae) separate the pituitary gland and prevents cerebrospinal fluid from entering sella turcica
- Optic chiasm is 5-10 mm above this diaphragm
Hypothalamic-Anterior Pituitary Axis
Hormone secretion type
All hormones are released in a pulsatile pattern except for TRH
Hypothalamic Arcuate Nucleus
Secreted Hormones
- Dopamine (prolactin inhibitory factor [PIF])
- Growth hormone releasing hormone (GHRH)
Hypothalamic Preobtic Nucleus
Secreted Hormones
Gonadotropin releasing hormone (GnRH)
Hypothalamic Paraventricular Nucleus
Secreted Hormones
- Thyrotropin releasing hormone (TRH)
- Corticotropin releasing hormone (CRH)
- Somatostatin
Thyrotropin releasing hormone (TRH)
Pituitary target, Target percentage of pituitary, Target hormone secretion
- Thyrotrophs
- 10%
- Stimulates TSH and prolactin secretion
Corticotropin releasing hormone (CRH)
Pituitary target, Target percentage of pituitary, Target hormone secretion
- Corticotrophs
- 10-25%
- ACTH
Gonadotropin releasing hormone (GnRH)
Pituitary target, Target percentage of pituitary, Target hormone secretion
- Gonadotrophs
- 10-15%
- LH and FSH
Growth hormone releasing hormone (GHRH)
Pituitary target, Target percentage of pituitary, Target hormone secretion
- Somatotrophs
- 50%
- GH
Dopamine (prolactin inhibitory factor [PIF])
Pituitary target, Target percentage of pituitary, Target hormone secretion
- Lactotrophs
- 10-15%
- Prolactin
Somatostatin
Pituitary target, Target percentage of pituitary, Target hormone secretion
- Somatotrophs
- 50%
- Inhibits GH secretion
Gonadotropin releasing hormone (GnRH)
High frequency vs. Low frequency pulses Effects
- High favors LH secretion
- Low favors FSH secretion
Hypothalamic-Anterior Pituitary Axis
Effect of severing the connection at the pituitary stalk
- All anterior pituitary hormones will be decreased
- Except for Prolactin which will increase because it was under chronic source of inhibition (dopamine [PIF])
Hypothalamus
Hormones
- TRH
- CRH
- GHRH
- GnRH
- Somatostatin
- Dopamine (PIF)
Anterior Pituitary
Hormones
- TSH
- ACTH
- GH
- LH
- FSH
- Prolactin
Hypopituitarism
Causes
- Inherited
- Acquired:
- Head trauma (most common)
- Tumors (mass effect)
- Inflammation
- Vascular damage
- Hydrocephalus can also affect the hypothalamus
- Isolated deficiency:
- GH: sporadic or familial
- GnRH: Kallman syndrome (low LH,FSH and sex steroids, anosmia, and renal agenesis [50%])
- ACTH, TSH and prolactin extremely rare (usually a sign of panhypopituitarism)
- Craniopharyngioma (most common tumor in children)
Hypopituitarism
Loss of function sequence
- GH and GnRH
- TSH
- ACTH
- Prolactin
Note: typically trophic hormones are in the normal range; but their level is inadequate to stimulate peripheral glands adequately
Hypopituitarism
Stimulation tests [Academic perspective]
- GnRH —> LH and FSH
- TRH —> TSH and Prolactin
- Insulin infusion (hypoglycemia) —> GH and ACTH
Sheehan syndrome
Cause
Severe post-partum hemorrhage —> shock —> arteriolar spasm of the already enlarged pituitary (due to pregnancy) —> ischemic necrosis
Pituitary Adenomas
Types and Presentation
- Microadenomas (< 1 cm in diameter): present as a hormonal excess like Cushing disease
- Macroadenomas (> 1 cm in diameter): mass effect that present as panhypopituitarism and visual loss
Pituitary Adenomas
Microadenomas Prevalence
- Hyperprolactinemia 60% (hypogonadism and galactorrhea)
- Acromegaly 20%
- Cushing disease (ACTH) 10%
Pituitary Adenomas
Association
MEN 1
Posterior Pituitary
Hormones
- Arginine vasopressin (ADH)
- Oxytocin
ADH
Synthesis and Secretion
- Synthesized in supraoptic and paraventricular nuclei of the hypothalamus
- Stored and released from the posterior pituitary
ADH
Release regulators
- Osmoreceptors in the hypothalamus (respond to 1% change in osmolarity)
- Volume receptors (stretch and baroreceptors) [respond to 10-15% change in volume). In conditions of weightlessness like space or water immersion to the neck, there will be net shift of blood from limbs to abdomen and chest which lead to greater stretch of baroreceptors, thus suppressing ADH release
- Ethanol inhibits it
- Cortisol and thyroid hormones decrease its release
Osmolarity point (Resetting Conditions)
- Pregnancy
- Menstrual cycle
- Volume depletion
Note: in all these conditions there will be downward resetting
ADH
Action
- Reabsorption of water at renal collecting tubules (via V2 receptors) by placing aqua pores into the luminal membrane
- Increased urea reabsorption (with water)
- In severe hemorrhage, high levels of ADH via V1 receptors on vascular smooth muscle cause a vasoconstriction
Atrial Natriuretic Peptide (ANP)
Source
Hormone secreted by the heart as a whole but mainly right atrium
Atrial Natriuretic Peptide (ANP)
Release regulators
- Stretch of atria (independent of nervous involvement)
- Increased salt intake
- CHF and all fluid overload states
Atrial Natriuretic Peptide (ANP)
Action
- Causes loss of water and sodium from the kidneys by
- Increases GFR by causing dilatation of afferent arteriole and constriction of efferent arteriole
- Decreases water and sodium reabsorption in the collecting ducts
- Inhibits aldosterone
- It works through cGMP
Atrial Natriuretic Peptide (ANP)
Uses
Normal ANP level is used to exclude CHF as a cause of dyspnea
Brain Natriuretic Peptide (BNP)
Source
Hormone secreted from heart mainly from ventricles
Brain Natriuretic Peptide (BNP)
Release regulators
- Stretching of ventricles
- Normally very little but increased markedly in patients with dilated hearts
Free Water Clearance
Equation
- CH2O = V - ([Uosm * V)] / Posm)
- Uosm: urine osmolarity
- Posm: plasma osmolarity
- V: urine flow rate
Positive Water Clearance
Interpretation
- Uosm / Posm < 1
- Losing water
- Decreased ADH
Negative Water Clearance
Interpretation
- Uosm / Posm > 1
- Retaining water
- Increased ADH
Negative Water Clearance, High ADH, High Posm
Diagnosis
Dehydration
Negative Water Clearance, High ADH, Low Posm
Diagnosis
SIADH
Positive Water Clearance, High ADH, High Posm
Diagnosis
Nephrogenic DI
Positive Water Clearance, Low ADH, High Posm
Diagnosis
Neurogenic DI
Positive Water Clearance, Low ADH, Low Posm
Diagnosis
Primary Polydipsia
Sectioning of Pituitary stalk
Effects on ADH
Triphasic respones
- DI
- SIADH (release of ADH from dying cells)
- DI
Hyperprolactinemia
Presentation
- In females: galactorrhea, amenorrhea and infertility
- In males: decreased libido and impotence
Panhypopituitarism
Causes
Any pituitary tumor that destroys more than 75% of the gland like:
- Pituitary adenomas
- Sheehan syndrome
- Craniopharyngiomas
Visual field changes in hypothalamic disorders
Association
- Pituitary adenoma
- Craniopharyngioma
- Midline hamartoma
- Langerhans histiocytosis
- Inflammatory processes like sarcoidosis and meningitis
Pineal Gland
Diseases
- Dystrophic calcification
- Tumors:
- Seminomas (most common)
- Teratomas
Prolactin
Actions
- Stimulates milk production in breasts
- Inhibits ovulation in females and spermatogenesis in males by inhibiting GnRH synthesis and release
Prolactin
Secretion regulators
- It is tonically inhibited by dopamine from hypothalamus
- Prolactin inhibits its own secretion by increasing dopamine synthesis and secretion from hypothalamus
- TRH increases its secretion (like in primary and secondary hypothyroidism)
- Sight/cry of baby will inhibit the hypothalamic dopamine inhibition of prolactin, thereby increasing its secretion
- Dopamine inhibitors will cause increase in prolactin secretion like
- Medication: most antipsychotics, estrogens like OCPs and pregnancy, methyldopa and verapamil
- Chest wall injury (via ANS)
- Nipple stimulation
- Estrogen also directly stimulates pituitary release of prolactin
- Renal failure will increase prolactin (by reducing its elimination)
Prolactinoma
Treatment
- First line: Dopamine agonists like bromocriptine or cabergoline (more tolerable) after excluding pregnancy
- Second line: Transsphenoidal resection (if medical Rx failed or there is compressive effects)
Nelson Syndrome
Pathophysiology
Enlargement of existing ACTH-secreting pituitary adenoma after bilateral adrenalectomy for refractory Cushing disease (due to removal of cortisol feedback mechanism)
Nelson Syndrome
Presentation
- Hyperpigmentation
- Headaches
- Bitemporal hemianopia
Nelson Syndrome
Treatment
- Pituitary irradiation
- Surgical resection
Acromegaly
Associations
- Impaired glucose tolerance (insulin resistance)
- Increased risk of colorectal polyps and cancer
Empty Sella Syndrome
Description
- Atrophy or compression of pituitary
- Often idiopathic
- Common in obese women
Pituitary Apoplexy
Description
- Sudden hemorrhage of pituitary gland, often in presence of adenoma
- Presents as sudden severe headache, bitemporal hemianopia or diplopia, and features of hypopituitarism