Dwarfism & Acromegaly

GROWTH HORMONE
ABNOMALITIES
 Introduction
• Dwarfism & Acromegaly

– Disorders of skeletal maturation and

somatic growth
Skeletal Maturation and Somatic Growth

• The growth plate is dependent on a variety

of hormonal stimuli

• GH, IGF-I

• Sex steroids

• Thyroid hormones

• Paracrine growth factors

• Cytokines
• The growth-promoting process also requires
caloric energy, amino acids, vitamins, and trace
metals
– and consumes about 10% of normal energy production

• Malnutrition impairs chondrocyte activity and

reduces circulating IGF-I and IGFBP3 levels
• Bone age is delayed by thyroid hormone
deficiency

• Hence, congenital or acquired

hypothyroidism is associated with stunted
growth, which is partially reversed by
thyroid hormone replacement
• Elevated pubertal sex steroid levels (esp estrogen)
– induce the GHRH-GH-IGF-I axis

– also directly stimulate epiphyseal growth

• High doses of estrogen → epiphyseal closure

– Animal experiment: a mutation of the estrogen receptor
prevented epiphyseal closure
• Several pathologic conditions along with increased
sex steroids are a/c accelerated bone maturation
– i.e. precocious puberty, androgen exposure (exogenous
or endogenous), congenital adrenal hyperplasia, &
obesity

• Thus, children with these conditions have

accelerated early growth, but end up with reduced
final height

• Contrary to sex steroids, glucocorticoid excess

inhibits linear growth
• Linear bone growth rates are very high in infancy
and are pituitary-dependent

• Mean growth velocity is ~ 6 cm/year in later

childhood

• Peak growth rates occur during midpuberty when

bone age is 12 (girls) or 13 (boys)
– secondary sexual devpt is a/c elevated sex steroids that
cause progressive epiphyseal growth plate closure
• Bone age is delayed in patients with all forms of
true GH deficiency or GH receptor defects that
result in attenuated GH action
• Short stature may occur due to
– constitutive intrinsic growth defects, or
– acquired extrinsic factors

• Delayed bone age in a child with short stature is

suggestive of a hormonal or systemic disorder

whereas normal bone age in a short child is more

likely to be due to a genetic cartilage dysplasia or
growth plate disorder
 Limb shortening terminology
• Rhizomelic: proximal shortening
(humerus or femur)

• Mesomelic: middle shortening

(tibia/fibula or radius/ulna)

• Acromelic: distal shortening (hand)

• Micromelic: entire limb shortened

 Dwarfism
• Also known as skeletal dysplasias

• a commonly used term for disproportionately short stature

• Height: >3 std deviations below the mean height for age

• Overall, pts with disproportionately short stature have

skeletal dysplasia (osteochondrodysplasia)
• If short stature is proportional, the aetiology is
• endocrine
• metabolic disorders
• chromosomal or
• nonskeletal dysplasia genetic defects
• Skeletal dysplasias are a heterogeneous group
of > 200 disorders characterized by
– anomaly cartilage & bone growth → abnormal shape
+ size of the skeleton & disproportion of the long
bones, spine, and head
 Skeletal dysplasias: Classification
• Epiphyseal Dysplasias
– Epiphyseal hypoplasia
– Epiphyseal hyperplasias

• Physeal Dysplasia
– Cartilage hypoplasias
– Cartilage hyperplasia
Skeletal dysplasias….

• Metaphyseal Dysplasia
– metaphyseal hypoplasias
– metaphyseal hyperplasia

• Diaphyseal Dysplasia
– Diaphyseal hypoplasia
– Diaphyseal hyperplas
• Dwarfism differs in
– natural histories
– prognoses
– inheritance patterns
– aetiopathogenetic mechanisms
– clinical manifestations
– radiographic findings
– morphology of the growth plate
 GH DEFICIENCY

Isolated GH deficiency is characterized by short

stature, micropenis, increased fat, high-pitched
voice, and a propensity to hypoglycemia

• Familial modes of inheritance are seen in 1/3 of

these individuals
– may be autosomal dominant, recessive, or X-linked

• ~10%: have mutations in the GH-N gene

– gene deletions & point mutations
• Mutations in transcription factors Pit-1 & Prop-1,
controlling somatotrope development
– leads to GH deficiency in combination with other pituitary
hormone deficiencies, which may only become manifest
in adulthood

• The diagnosis of idiopathic GH deficiency should

be made only after known molecular defects have
been excluded
 GHRH RECEPTOR MUTATIONS
• Recessive mutations of the GHRH receptor gene
in subjects with severe proportionate dwarfism are
associated with low basal GH levels that can’t be
stimulated by
– exogenous GHRH, GHRP, or insulin-induced
hypoglycemia

• The syndrome exemplifies the importance of the

GHRH receptor for somatotrope cell proliferation
and hormonal responsiveness
 GROWTH HORMONE INSENSITIVITY

• This is caused by defects of GH receptor structure

or signaling

• Homozygous or heterozygous mutations of the GH

receptor are associated with partial or complete
GH insensitivity and growth failure (Laron
syndrome)

• The diagnosis is based on normal or high GH

levels, with decreased circulating GHBP, and low
IGF-I levels

• Very rarely, defective IGF-I, IGF-I receptor, or IGF-I

signaling defects are also encountered
 NUTRITIONAL SHORT STATURE
• Secondary causes of abrogated GH receptor
function
– caloric deprivation and malnutrition, uncontrolled
diabetes, and chronic renal failure

• They also stimulate production of proinflammatory

cytokines, which can block GH-mediated signal
transduction

• Typically these children have features of acquired

short stature with elevated GH and low IGF-I levels

• Circulating GH receptor antibodies may rarely

cause peripheral GH insensitivity
 PSYCHOSOCIAL SHORT STATURE

• Emotional and social deprivation lead to growth

retardation
– accompanied by delayed speech, discordant
hyperphagia, and attenuated response to administered
GH

• A nurturing environment restores growth rates

 Dwarfism: Presentation & Dx
• requires clinical judgement in association with auxologic
data

• family history

• comprehensive evaluation if a pt's Ht is > 3 SD below the

mean for age or if the growth rate has decelerated

• Skeletal maturation is best evaluated by measuring a

radiologic bone age (degree of growth plate fusion)
• Final height can be predicted using

– std scales (Bayley-Pinneau or Tanner-

Whitehouse), or

– estimated by adding 6.5 cm (boys) or

subtracting 6.5 cm (girls) from the midparental
height
 Laboratory Investigation
• Because GH secretion is pulsatile, GH deficiency is
best assessed by examining the response to
provocative stimuli
– exercise, insulin-induced hypoglycemia, and
– other pharmacologic tests which normally increase
GH to > 7 µg/L in children

• Random GH measurements don't distinguish normal

children from those with true GH deficiency

• Adequate adrenal & thyroid hormone replacement

should be assured before testing
• Age- & gender-matched IGF-I levels are
inadequately sensitive or specific to make the
diagnosis but can be useful to confirm GH
deficiency

• Pituitary MRI may reveal pituitary mass lesions or

structural defects
Dwarfism: TREATMENT

• replacement therapy with recombinant GH (0.02

to 0.05 mg/kg per day S/C) restores growth
velocity in GH-deficient children to ~10 cm/year

• If pituitary insufficiency is documented, other

associated hormone deficits should be corrected
(esp adrenal steroids)
• In patients with GH insensitivity & growth
retardation due to mutations of the GH receptor

– Treatment with IGF-I bypasses the dysfunctional GH

receptor

– Growth rates have been maintained for several years,

and this therapy now signifies
improved final adult stature
Queen Henrietta Maria &
the Dwarf Sir Jeffrey Hudson, 1633
pituitary dwarfism
-physically well proportioned
-but may be sexually underdeveloped
-normal intelligence
?? may be sexually underdeveloped
 ACROMEGALY
• a chronic, debilitating condition caused by GH
hypersecretion

• It is nearly always caused by a pituitary adenoma; >

90%

• Most are macroadenomas (>1cmr),

benign & < 1% are malignant

• The tumors produce excess GH

• Acromegaly is usually sporadic but may rarely be

familial
• The tumours may be locally invasive, particularly into the
cavernous sinus

• Tumours expanding → compress

– surrounding brain tissues e.g. optic nerves or optic chiasm

– pituitary tissue can alter production of other hormones, leading to

changes in menstruation and breast discharge in women and
impotence in men

• Some adenomas grow slowly while other adenomas grow

rapidly
• Rarely, ectopic secretion of GHRH or GH
– hypothalamic tumour, pituitary tissue remnants
in the sphenoid or paranasopharynx

– bronchial carcinoid, pancreatic islet cell tumor,

small cell lung cancer, adrenal adenoma,
lymphoma, medullary thyroid carcinoma,
pheochromocytoma

– endocrine tumors of the parathyroids or

pancreas (MEN 1)
 Clinical presentation
• variable manifestations of GH and IGF-I
hypersecretion
– are idle and often are not clinically diagnosed >10 years

– Acral bony overgrowth → frontal bossing, increased

hand and foot size, mandibular enlargement with
prognathism, & widened space btwn the lower incisor
teeth

– soft tissue swelling → increased heel pad thickness,

increased shoe or glove size, ring tightening, typical
coarse facial features, and a large fleshy nose
Clinically…

• Other commonly clinical features

– hyperhidrosis
– deep & hollow-sounding voice
– oily skin
– arthropathy, kyphosis, carpal tunnel syndrome
– proximal muscle weakness and fatigue
– acanthosis nigricans & skin tags
• Generalized visceromegaly
– cardiomegaly
– macroglossia
– thyroid gland enlargement
• Children & adolescents
– GH hypersecretion before epiphyseal long
bone closure leads a extra proportional
increase in the size of all body parts
(gigantism)
• Excessive secretion of GH in adult results in
– skeletal overgrowth

– Hypertension

– soft tissue swelling and peripheral nerve

– entrapment syndromes

– debilitating headache

– palmar hyperhidrosis, oily skin

– joint pain
– fatigues
Asa SL. The pathology of pituitary tumors. Endocrinol Metab Clin North Am 1999; 28: 13-43
• CVS
– the most significant clinical impact of GH excess
~30% of pts: coronary heart disease, cardiomyopathy with
arrhythmias, LVH, decreased diastolic function, & HTN

• RS: ~60% of pts: upper airway obstruction with

sleep apnea
– associated with both soft tissue laryngeal airway
obstruction & central sleep dysfunction

• Diabetes mellitus in ~25% of pts with acromegaly

– mostly are glucose load intolerant (as GH counteracts the
insulin action)
• Acromegaly is associated with an increased risk of
colon polyps and colonic malignancy;
– ~ 33% of acromegalic pts have polyps

• Overall mortality is increased ~ 3-fold, mainly due

to:
– CVS
– cerebrovascular disorders
– Malignancy
– respiratory disease

• Overall survival is reduced by an average of 10

years compared with an age-matched control
population, unless GH levels are controlled
 Acromegaly: Diagnosis
• Diagnosis is based on
– the clinical features
– elevated levels of GH and IGF-I
– inability to sufficiently suppress serum GH levels after on
oral glucose tolerance test (OGTT)

• Up to 20% of GH-secreting pituitary adenomas co-

secrete prolactin  prolactin level may also be
elevated

• MRI is more sensitive than CT scan

– it provides information about the surrounding structures
 Laboratory Investigation

• elevated serum IGF-I levels (age- & gender-matched);

thus, an IGF-I level is a valuable laboratory screening
measure when clinical features suggest acromegaly

• Due to the GH secretion pulsatility, measuring a single

random GH level is not useful for the diagnosis or exclusion
of acromegaly and does not correlate with disease severity
• The diagnosis of acromegaly is confirmed by
demonstrating the failure of GH suppression to < 1
µg/L within 1 - 2 hr of oral glucose load (75g)

• ~20% of patients exhibit a paradoxical GH rise

after glucose

• ~60% of patients with GH-secreting tumors may

exhibit paradoxical GH responses to TRH
administration
 Lab…
• PRL should be measured as it is elevated in ~25%
of patients with acromegaly

• Thyroid function, gonadotropins, & sex steroids

may be attenuated because of tumor mass effects

• Because most patients will undergo surgery with

glucocorticoid coverage, tests of ACTH reserve in
asymptomatic patients are more efficiently deferred
until after surgery
 Acromegaly: Treatment
Rx goal
• improving symptoms caused by the local effects of the tumor
and/or excess GH/IGF-I production

Rx objectives
• reducing tumor bulkness & symptomatic relief

• lowering circulating GH concns to below a critical level (2.5

µg/L, "safe" GH)

• normalizing serum IGF-I concns inline with age

• improving (or at least not worsening) comorbidities (DM,

HTN, cardiomyopathy, sleep-apnea)

• decreasing the risk of premature mortality

 Treatment modalities (TPR)
• in order to achieve the Rx objectives:
– Transsphenoidal surgery

– Pharmacotherapy

– Radiation , or

– multi-modality therapy (i.e. TPR)

 Treatment…
• Chiefly initial mnx: surgical resection of GH-
secreting adenomas

• Somatostatin analogues: as adjuvant Rx

– preoperative shrinkage of large invasive
macroadenomas
– immediate relief of debilitating symptoms
– reduction of GH hypersecretion
• elderly pts experiencing morbidity
• pts declining surgery, or, when surgery fails

• If adjunctive medical therapy fails

– irradiation or repeat surgery
• Irradiation: relatively ineffective in normalizing IGF-I levels
– main disadvantages: the high rate of late hypopituitarism & the slow
rate (5-15 yrs) of biochemical response

• Stereotactic ablation of GH-secreting adenomas by gamma-

knife radiotherapy
– potential advances
– long-term results are unclear

• Somatostatin analogues may be given while awaiting the

full effect of radiotherapy

• Aggressive mnx of systemic sequelae of acromegaly (CVS,

diabetes & arthritis)

• Maxillofacial surgery for mandibular repair may also be

indicated
 SURGERY
• Transsphenoidal surgical resection
– both microadenomas (cure rate ~70%) &
macroadenomas (cure rate <50%)
• Soft tissue swelling improves immediately after
tumor resection

• GH levels return to normal within an hour, & IGF-I

levels are normalized within 3-4 days

• In ~10% of pts, acromegaly may recur several yrs

post-surgery;
– hypopituitarism ~15% of patients
 SOMATOSTATIN ANALOGUES
• Mech. of action via SSTR2 and -5 receptors (expressed by
GH-secreting tumors)

• Octreotide acetate is an 8-amino-acid synthetic somatostatin

analogue

• In contrast to native somatostatin, the analogue is relatively

resistant to plasma degradation

• It has a 2-hr serum t1/2 & possesses 40-fold greater potency

than native somatostatin to suppress GH

• Octreotide is given S/C, beginning with 50 µg TID (increase

1500 µg/d)

• <10% of patients don't respond to the analogue

• Octreotide suppresses integrated GH levels to <5 µg/L in
~70% of pts and to <2 µg/L in up to 60% of pts

• It normalizes IGF-I levels in ~75% of treated patients

• Prolonged use of the analogue isn't associated with

desensitization, even ≥10 yrs Rx

• Rapid relief of headache & soft tissue swelling occurs in

~75% of pts within days to weeks of Rx initiation

• Subjective clinical benefits of octreotide therapy occur more

frequently than biochemical remission
– most report symptomatic improvement
(headache, perspiration, obstructive apnea, & cardiac failure)
– modest pituitary tumor size reduction occurs in ~40% (reversed on
Rx stop)
• Two long-acting somatostatin depot formulations
– octreotide & lanreotide, are becoming the preferred
medical treatment for acromegalic patients

• Sandostatin-LAR: a sustained-release, long-acting

formulation of octreotide incorporated into
microspheres that sustain drug levels for several
weeks after IM inj.
– GH suppression occurs for as long as 6/52 after a 30-mg
injection;
– long-term monthly treatment sustains GH and IGF-I
suppression & reduction of pituitary tumor size
• Lanreotide:
– a slow-release depot somatostatin preparation

– a cyclic somatostatin octapeptide analogue that

suppresses GH and IGF-I hypersecretion for 10-14/7
after a 30-mg IM inj

– long-term administration controls GH hypersecretion

in two-thirds of treated pts

– improves pts compliance bse of the long interval of

drug injections
SOMATOSTATIN: Side Effects

• Somatostatin analogues are well tolerated in

most pts

• Adverse effects are short-lived and mostly

relate to drug-induced suppression of GIT
motility and secretion
– nausea, abdominal discomfort, fat
malabsorption, diarrhea, and flatulence (1/3),
these symptoms usually remit within 2 weeks
• Octreotide suppresses postprandial gallbladder
contractility and delays gallbladder emptying
– ~30% of patients on long-term Rx  echogenic sludge or
asymptomatic cholesterol gallstones

• Other side effects

– mild glucose intolerance due to transient insulin
suppression
– asymptomatic bradycardia
– Hypothyroxinemia
– local pain at the injection site
 DOPAMINE AGONISTS
Bromocriptine may suppress GH secretion in some
acromegalic patients, esp. cosecretion of PRL
• high doses (≥20 mg/d), administered as 3-4 doses/day
• GH levels are suppressed to <5 µg/L in ~20% of pts
• IGF-I levels are normalized in only 10% of pts

Cabergoline also suppresses GH and decreases adenoma

size when given at a relatively high dose of 0.5 mg/d

Combined Rx (octreotide & bromocriptine)

– induces additive biochemical control compared to either drug alone
 GH antagonists

GH analogues (e.g. pegvisomant)

• antagonize endogenous GH action by blocking
peripheral GH binding to its receptor

• Thus, serum IGF-I levels are suppressed

– reducing the detrimental effects of excess endogenous
GH
– normalizes concentrations of IGF-I in > 90% pts
 Acromegaly: Radiation
• External radiation therapy or high-energy
stereotactic techniques are used as adjuvant
therapy

• Advantage: patient compliance not required

• Tumor mass is reduced, and GH levels are

attenuated over time
 Radiation…
• But, 50% of pts require at least 8 years for GH
levels to be suppressed to <5 µg/L;
– this level of GH reduction is achieved in ~90% of pts
after 18 yrs but represents suboptimal GH suppression

– pts may require interim medical therapy for several years

prior to attaining maximal radiation benefits

– most patients also experience hypothalamic-pituitary

damage gonadotropin, ACTH, and/or TSH deficiency
within 10 yrs of therapy
 Prognosis

• The mortality rate is at least twice that of the

normal population

• The major sequelae of acromegaly

– cardiorespiratory
– cerebrovascular diseases
– diabetes
– neoplasia, particularly colon cancer

Bates AS, Van't Hoff W, Jones JM. An audit of outcome of treatment in

acromegaly. QJM 1993; 86: 293-299
 Prognosis…
• Acromegaly Rx must be individualised

• Age, tumor size & invasiveness, GH concentrations, the

patient's general medical conditions, presence and severity
of co-morbidities, availability of resources (expert
neurosurgeon or gamma-knife radiosurgery), & pts informed
wishes

• Multimodal Rx for most patients, based on continuously

emerging data on mnx

• However, even combinations of currently all available therapies can't

achieve all the goals of therapy in many pts with acromegaly
– patient outcomes are still less than desirable, with 10-20% of pts with
uncontrolled disease
CASE #1
 CASE #1
• A 22 yrs man, with 8-year
– Hx progressive enlargement of the forehead, hands &
feet

– he had to change his shoes frequently

– 2 yrs prior to this Hx, he devped intermittent headache,

progressive weakness, decreasing vision, slurring of
speech & increase urinary frequency

– the headache became severe 2/12 before admission &

associated sleep apnoea

– He was found to have raised BP Rx anti-HTN

O/E:
• acromegalic features
• BP 120/80 mmHg
• right temporal visual field defect
• vision in Lt eye was reduced to finger counting at 2 metres
Case …
• MRI-brain
– pituitary macroadenoma with suprasella
extension
• Elevated Growth hormones & prolactin levels
• Dx: acromegaly 20 pituitary macroadenoma
• RX:
– oral bromocryptine 15mg 8 hourly
– S/C octreotide 100 μg 8 hourly
– his symptoms improved
– awaiting trans-sphenoidal resection of the
pituitary macroadenoma