Endocrine control of growth - normal and abnormal Flashcards
Fetal growth hormones
IGF-1 and IGF2
Insulin: hyperinsulinemia - big baby; hypo - small baby
EGF and TGF-alpha
- EGF downregulated in smokers
Little role for GH and no role for thyroid hormones
Psychosocial dwarfism
poor home environment
inadequate parenting
abnormal GH secretion but GH treatment not effective
remove from environment, demonstrate catch-up growth (diagnostic)
Mid-parental height
boys: father + mother + 13, all divided by 2
girls: father + mother - 13, all divided by 2
Genetic factors of growth
Stature of parents
race/ethnicity
sex chromosome
Absence of primary bone abnormalities
Skeletal dysplasias: achondroplasia, hypochondroplasia
Metabolic bone disease: rickets
spinal:
- congenital: hemivertebrae, spondylodysplasias
- acquired: irradiation
GH secretion
hypothalamus –> GHRH and SRIF (somatostatin) –> pit somatotroph cells –> GH –> IGF-1 (liver)
GHRH
major physiologic stimulus for GH secretion and synthesis
powerful and largely specific secretagogue of GH
GHRH also stimulates somatotroph proliferation and GH synthesis
SRIF
somatostatin
major hypothalamic peptide that inhibits pituitary release of GH
acts on pituitary to suppress basal and stimulated GH secretion
IGF-1
with or without GH, stimulates growth
with GH, believed to feedback at hypothalamus and pituitary –> modulate GH secretion
effects of GH mediated mainly by IGFs
GH direct effects
lipolysis
increased aa transport into tissues (diaphragm and heart)
increased protein synthesis in the liver
Other sites of GH/IGF1 action
epiphysis: stimulation of epiphyseal growth
bone: stimulate osteoclast/blast activity, increase bone mass by endochondral bone formation
Adipose tissue: acute insulin-like effects followed by increased lipolysis
Muscle: increased AA transport, increased nitrogen retention, increased lean tissue
GH vs IGF effects on blood glucose
variable among individauls
GH induces insulin resistance –> GH infusion can induce hyperglycemia
GH in physiological amounts administered to GH-deficient children: enhance anabolism
- promotes positive nitrogen balance and promotes improved lean body mass
- does NOT increase risk for DM
IGF-1 and IGF-2 have hypoglycemic effects (low affinity to insulin receptors)
Other factors that promote GH secretion
sleep stress exercise hypoglycemia/rapid fall in glucose arginine (aa infusion) alpha-adrenergic agonists (clonidine) beta-adrenergic antagonsits estrogen
GH regulation
pulsatile, so must do stimulation before measurement
Children and young adults: max GH secretion within 1 hr after onset of sleep
Changes in puberty: increase in GH production rate and greater mass of GH released per burst, but no change in frequency of pulse/half life
- sex steroids mediate pubertal changes in GH secretion
4 potential sites causing hGH resistance
Abnormalities of GH receptor/binding protein
abnormal signal transduction
defect of IGF synthesis
defect of IGF secretion
IGFBP-3
coordinates GH and IGF1 actions
regulates IGF1 delivery to growth plate
IGF1 has hypoglycemic effects; so regulated by binding to 150kDA complex (+IGFBP-3, acid labile substance) that is slowly degraded once at growth plate
GH-IGF1 pathway
1) GH stimulates IGF1 production, acts on growth plate
2) GH regulates hepatic production of IGFBP-3 and ALS
3) GH induces differentiation of prechondrocytes into chondrocytes directly at growth plate
4) GH also stimulates local IGF-1 production and IGF-1 acts via an autocrine and paracrine mechanism to stimulate cell division
Hypothalamic Causes of GH deficiency
hypothalamic dysfunction
- congenital malformation
- molecular defects of GHRH/GHRH receptor
- acquired: trauma, inflammation, tumors, irradiation
Pituitary causes of GH deficiency
Pituitary GH deficiency:
- genetic: pPIT-1, PROP1, HESX1 –> combined hormone deficiency
- genetic abnormalities of GH production/secretion resulting in isolated GH deficiency
- congenital absence/hypoplasia of pituitary (midline defects)
- Acquired: trauma, inflammation, tumors, irradiation
PIT-1
POU1F1 gene encodes a homeobox TF Pit1
Pituitary specific TF –> pituitary development/hormone expression
Mutation –> hypoplasia of GH, PRL, TSH secreting cells
20-44% of idiopathic GH deficiency??
GH deficiency consequences
severe postnatal decrease in height velocity with tendency to truncal obesity (length usually normal at birth)
- weight fall of not to same extent as height
hypoglycemia, micropenis, prolonged jaundice in infancy
high-pithced voice, thin hair, skin
delayed bone age and teeth eruption
delayed puberty
associated midline problems (cleft palate) +/- other pituitary deficiencies
Thyroid hormone - growth
T3 direct effect on osteoblasts by interaction with receptor (TR)
Hypothyroidism occurring postnatally can result in profound growth failure and virtual arrest of skeletal maturation
T3 also indirect effect by interacting with GH synthesis and action as well as affecting action of IGFs
- thyroid hormone: permissive effect on GH secretion
- hypothyroid –> blunted GH response to provocative testing
SSx of hypothyroidism
short stature +/- delayed puberty
obesity
low growth velocity; delayed bone age +/- goitre
decreased energy, increased sleep
dry skin
constipation, cold intolerance
developmental delay if onset of hypothyroidism prior to age 3
fall off curve for length, but wt increases
Primary hypothyroidism labs
Low T4
elevated TSH
+ thyroid microsomal Ab
Hypothalamic/pituitary hypothyroidism labs
Low T4
Normal TSH
ACTH deficiency symptoms
fatigue, weakness
GI complaints: vomiting, diarrhea, abdominal pain
circulatory collapse
weight loss
growth retardation
hypoglycemia (usually with GH deficiency)
Replacement therapy for hypothyroid + cortisol deficiency
must replace cortisol for several days before synthroid initiated to avoid adrenal crisis
- thyroid therapy increases metabolic rate!
Cushing’s syndrome
GC excess pituitary origin most common in pediatrics Growth retardation Central obesity - buffalo hump HTN muscular weakness osteoporosis thinning of skin, purple striae, easy bruising, excessive hair growth
Pubertal growth spurt
Due to estrogen in both male and female
E vital for bone maturation and proportiona
Examples of conditions with delayed bone maturation secondary to low estradiol: Turner, constitutional delay of growth in adolescence (CDGA)
Gonadotropin deficeincy
LH/FSH
cryptorchidism
micropenis
delayed puberty
Vasopressin deficiency
Diabetes insipidus
polyuria, polydipsia
hypernatremia
high serum osmolality, low urine osmolality
severe cases: excessive thirst prevent adequate intake of calories, leading to failure to thrive
may not manifest in cortisol deficiency until cortisol replaced (cortisol necessary for free water excretion)
Short stature algorithm
Normal: constitutional, familial/genetic
Pathologic:
1) Increased Weight/height: endocrinopathy
2) decreased or N weight/height: inadequate calories, chronic disease: renal cardio resp hematologic
3) disproportionate: skeletal dysplasia, metabolic bone disease, spinal disorders
4) associated with dysmorphic features: chromosomal, syndromes
Assessment of child with short stature
Medical, social history Anthropometry: child's height/growth velocity, parental height physical exam bone age karyotype to exclude TUrner evaluate specific systems
Failure to thrive
weight falls off before height
Growth failure
height falls off first
Family history for short stature
size, wt of parents, siblings growth patterns of family age of menarche when stopped growing other "late bloomers"?
Social history for short stature
living environment ages and occupations of parents caregivers finances parent/child interaction - observe
Physical examination for a child with short stature
accurate measurement of length/height, wt, HC
arm span and upper:lower segment ratio or sitting height
obvious/subtle dysmorphologies
evidence of systemic disease
evidence of neglect, abuse
dental eruption
goiter, genitalia for pubertal staging
Short and obese DDx
hormone deficiency (exception: cortisol/vasopressin deficiency canbe short and thin) syndrome
Tall and obese DDx
exogenous obesity
Short and thin DDx
malnutrition
malabsorption
systemic disease
constitutional
Growth velocity
single most useful and reliable indicator to rule out a serious endocrinopathy
growth along a given percentile is good evidence that growth velocity is normal
grows fastest in 1st yr of life: ~24 cm
by age 4, 4.5-6 cm/y
Head Circumference
familial
relatively independent of Ht/Wt %ile
last to go in starvation
measure x3 - need 2 points over time to assess abnormality
Bone age
growth potential inherent in tubular bones of body can be assessed by evaluation of progression of ossification within epiphyses
Ossification centres of skeleton appear and progress in a predictable sequence in normal children, and skeletal maturation can be compared with age-matched normals
Use radiography of left hand + wrist
can be used to predict patient’s ultimate height potential
Screening tests for short stature (esp low wt for height)
CBC-D
ESR
electrolytes, BUN, creatinine, glucose
LFTs, Ca/Mg/PO4, protein/albumin, tTG (celiac disease)
urinanalysis and first morning urine specific gravity
Endocrine screening for short stature
TSH or fT4 if suspicion of central hypothyroidism (hypothalamus/pit)
GH secretion:
- IGF1
- GH stim test if further investigations necessary (should ensure that not cortisol/thyroid deficient befoerhand)
- newborns usually have very high GH
Gonadal function:
-boys: testosterone, FH, LSH
- girls: estradiol, LH, FSH, chromosomes
Adrenal
- cortisol excess: Cushing - 24 h urinary cortisol or overnight 1 mg dexamethasone suppression test
- cortisol deficiency: can start with am cortisol
–> primary (Addison): high dose ACTH stim
–> Secondary (Pit) low dose ACTH stim
Constitutional delay of growth and adolescence
“late” bloomer
short stature +/- delayed puberty, often thin
normal growth velocity
delayed bone age
more common in boys
may have considerable psychosocial burden
normal hormone studies
may benefit from exogenous gonadal steroids
eventually reach target height and weight, dropoffs initially
Turner syndrome
short stature gonadal failure osteoporosis (RR 10) Hashimoto's thyroiditis T1DM Obesity and T2DM
Short stature in Turner syndrome
due to generalized defect in endochondral boen formation
growth failure begins early in gestation, well-established by mid-pregnancy, continues into postnatal life
often profound growth failure in first 1-2 y
by age 11, ~19cm shorter than avg
14, 26cm shorter than avg
final adult statures in untreated patients: 143.1 (20cm shorter)
most girls with TS are not GH deficient, but GH does improve final height in these girls
in BC:
- GH therapy approved for girls with TS
- not Pharmacare covered; 20-30k/y
Pituitary deficiencies due to pituitary mass
GH deficiency
diabetes insipidus
TSH deficiency due to lack of TRH
Note: cortisol deficiency cannot be ruled out from history and should check with low dose ACTH stim
Craniopharyngioma
tumour originating from remnants of Rathke’s pouch
begins in pituitary area, slowly grows upwards
supracellular calcifications often present
treated with surgery
if cystic, may be treated with chemo through a shunt
most frequent tumour in this age group (young children)
