Endocrine control of growth - normal and abnormal

Question 1

Fetal growth hormones

Answer 1

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

Question 2

Psychosocial dwarfism

Answer 2

poor home environment
inadequate parenting
abnormal GH secretion but GH treatment not effective
remove from environment, demonstrate catch-up growth (diagnostic)

Question 3

Mid-parental height

Answer 3

boys: father + mother + 13, all divided by 2
girls: father + mother - 13, all divided by 2

Question 4

Genetic factors of growth

Answer 4

Stature of parents
race/ethnicity
sex chromosome

Question 5

Absence of primary bone abnormalities

Answer 5

Skeletal dysplasias: achondroplasia, hypochondroplasia
Metabolic bone disease: rickets
spinal:
- congenital: hemivertebrae, spondylodysplasias
- acquired: irradiation

Question 6

GH secretion

Answer 6

hypothalamus –> GHRH and SRIF (somatostatin) –> pit somatotroph cells –> GH –> IGF-1 (liver)

Question 7

GHRH

Answer 7

major physiologic stimulus for GH secretion and synthesis
powerful and largely specific secretagogue of GH
GHRH also stimulates somatotroph proliferation and GH synthesis

Question 8

SRIF

Answer 8

somatostatin
major hypothalamic peptide that inhibits pituitary release of GH
acts on pituitary to suppress basal and stimulated GH secretion

Question 9

IGF-1

Answer 9

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

Question 10

GH direct effects

Answer 10

lipolysis
increased aa transport into tissues (diaphragm and heart)
increased protein synthesis in the liver

Question 11

Other sites of GH/IGF1 action

Answer 11

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

Question 12

GH vs IGF effects on blood glucose

Answer 12

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)

Question 13

Other factors that promote GH secretion

Answer 13

sleep
stress
exercise
hypoglycemia/rapid fall in glucose
arginine (aa infusion)
alpha-adrenergic agonists (clonidine)
beta-adrenergic antagonsits
estrogen

Question 14

GH regulation

Answer 14

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

Question 15

4 potential sites causing hGH resistance

Answer 15

Abnormalities of GH receptor/binding protein
abnormal signal transduction
defect of IGF synthesis
defect of IGF secretion

Question 16

IGFBP-3

Answer 16

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

Question 17

GH-IGF1 pathway

Answer 17

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

Question 18

Hypothalamic Causes of GH deficiency

Answer 18

hypothalamic dysfunction

• congenital malformation
• molecular defects of GHRH/GHRH receptor
• acquired: trauma, inflammation, tumors, irradiation

Question 19

Pituitary causes of GH deficiency

Answer 19

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

Question 20

PIT-1

Answer 20

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??

Question 21

GH deficiency consequences

Answer 21

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

Question 22

Thyroid hormone - growth

Answer 22

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

Question 23

SSx of hypothyroidism

Answer 23

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

Question 24

Primary hypothyroidism labs

Answer 24

Low T4
elevated TSH
+ thyroid microsomal Ab

Question 25

Hypothalamic/pituitary hypothyroidism labs

Answer 25

Low T4 | Normal TSH

Question 26

ACTH deficiency symptoms

Answer 26

fatigue, weakness GI complaints: vomiting, diarrhea, abdominal pain circulatory collapse weight loss growth retardation hypoglycemia (usually with GH deficiency)

Question 27

Replacement therapy for hypothyroid + cortisol deficiency

Answer 27

must replace cortisol for several days before synthroid initiated to avoid adrenal crisis - thyroid therapy increases metabolic rate!

Question 28

Cushing's syndrome

Answer 28

``` 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 ```

Question 29

Pubertal growth spurt

Answer 29

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)

Question 30

Gonadotropin deficeincy

Answer 30

LH/FSH cryptorchidism micropenis delayed puberty

Question 31

Vasopressin deficiency

Answer 31

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)

Question 32

Short stature algorithm

Answer 32

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

Question 33

Assessment of child with short stature

Answer 33

``` Medical, social history Anthropometry: child's height/growth velocity, parental height physical exam bone age karyotype to exclude TUrner evaluate specific systems ```

Question 34

Failure to thrive

Answer 34

weight falls off before height

Question 35

Growth failure

Answer 35

height falls off first

Question 36

Family history for short stature

Answer 36

``` size, wt of parents, siblings growth patterns of family age of menarche when stopped growing other "late bloomers"? ```

Question 37

Social history for short stature

Answer 37

``` living environment ages and occupations of parents caregivers finances parent/child interaction - observe ```

Question 38

Physical examination for a child with short stature

Answer 38

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

Question 39

Short and obese DDx

Answer 39

``` hormone deficiency (exception: cortisol/vasopressin deficiency canbe short and thin) syndrome ```

Question 40

Tall and obese DDx

Answer 40

exogenous obesity

Question 41

Short and thin DDx

Answer 41

malnutrition malabsorption systemic disease constitutional

Question 42

Growth velocity

Answer 42

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

Question 43

Head Circumference

Answer 43

familial relatively independent of Ht/Wt %ile last to go in starvation measure x3 - need 2 points over time to assess abnormality

Question 44

Bone age

Answer 44

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

Question 45

Screening tests for short stature (esp low wt for height)

Answer 45

CBC-D ESR electrolytes, BUN, creatinine, glucose LFTs, Ca/Mg/PO4, protein/albumin, tTG (celiac disease) urinanalysis and first morning urine specific gravity

Question 46

Endocrine screening for short stature

Answer 46

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

Question 47

Constitutional delay of growth and adolescence

Answer 47

"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

Question 48

Turner syndrome

Answer 48

``` short stature gonadal failure osteoporosis (RR 10) Hashimoto's thyroiditis T1DM Obesity and T2DM ```

Question 49

Short stature in Turner syndrome

Answer 49

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

Question 50

Pituitary deficiencies due to pituitary mass

Answer 50

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

Question 51

Craniopharyngioma

Answer 51

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)