This document provides information about acromegaly, a rare disorder caused by excess growth hormone in adults. It discusses the typical causes, signs and symptoms, and effects on organ systems. Pituitary adenomas that secrete growth hormone are responsible for over 95% of cases. Clinical features depend on when excess growth hormone begins, causing either gigantism in children or acromegaly in adults, characterized by enlarged extremities and soft tissues. Complications can include joint and cardiovascular problems, diabetes, and sleep apnea. Early diagnosis and treatment are important to prevent morbidity.
2. Famous Names in Endocrinology
Acromegaly
• Robert Wadlow, the “Alton Giant” 1918-1940
Robert Wadlow, the “Alton Giant” is said to be the tallest human in
history, stood at 8’11 ½” and died at age 22 from an infected leg
ulcer. He was very spiritual, was a Boy Scout, and briefly attended
college until his death.
• Lurch of the Original Addams Family
• Andre the Giant
• “Jaws” of the James Bond Movie Fame
3. Introduction
• Growth hormone is the principal hormone
responsible for growth during childhood and
adolescence.
• Secreted by acidophilic somatotrophs
• IGF-1 is the mediator of its growth promoting
and anabolic actions.
• GHRH stimulates release of GH
4. Epidemilogy
• Growth hormone excess states are relatively rare
• Prevalence of 38-69 cases per million
• Incidence of 3-4 cases /million/yr in westen
population.
• A series of 34 cases reported from mumbai
showed mean age at the time of diagnosis 36.1
yrs for males and females respectively with a
slight male preponderance.(56%vs44%)
• The male to female ratio was 3:2 in a series fom
vellore.mean age of presentation 35 yrs
5. 00
• Acromegaly develops when somatotrophs proliferate
and oversecrete the hormone.
• A cascade of interacting transcription factors and
genetic elements normally determines the ability of
somatotroph cells to synthesize and secrete growth
hormone
• The development and proliferation of somatotrophs
are largely determined by agene called the Prophet of
Pit-1 (PROP1), which controls the embryonic
development of cells of the Pit-1 (POU1F1)
transcription factor lineage, as well as gonadotroph
hormone secreting cells
6. • Pit-1 binds to the growth hormone promoter
within the cell nucleus, leads to the development
and proliferation of somatotrophs and growth
hormone transcription.
• Once translated, growth hormone is secreted as
a 191-amino-acid, and a less abundant 176-
amino-acid form, entering the circulation in
pulsatile fashion under dual hypothalamic control
through hypothalamic-releasing and
hypothalamic-inhibiting hormones
7. • Growth hormone–releasing hormone induces the
synthesis and secretion of growth hormone, and
somatostatin suppresses the secretion of growth
hormone.
• Growth hormone is also regulated by ghrelin, a growth
hormone secretagogue–receptor ligand that is
synthesized mainly in the gastrointestinal tract in
response to the availability of nutrients.
• Studies to date suggest that ghrelin acts as a growth
hormone–releasing hormone predominantly through
hypothalamic mechanisms
8. 0
• In 1886, Pierre Marie published the first clinical description
of disordered somatic growth and proportion and proposed
the name “acromegaly.”
• Benda showed in 1900 that these tumors comprise mainly
adenohypophyseal eosinophilic cells, which he proposed to
be hyperfunctioning.
• Cushing, Davidoff, and Bailey documented the
clinicopathologic features of acromegaly and demonstrated
clinical remission of soft tissue signs after adenoma
resection.
• Evans and Long induced gigantism in rats injected with
anterior pituitary extracts, confirming the association of a
pituitary factor with somatic growth.
9. Etio pathogenesis
• Acromegaly is caused by pituitary tumors that
secrete GH or, very rarely by extrapituitary
disorders
• Regardless of the etiology, the disease is
characterized by elevated levels of GH and
IGF1 with resultant signs and symptoms of
hypersomatotropism.
10. • Pituitary Acromegaly
• More than 95% of patients with acromegaly
harbor a GH-secreting pituitary adenoma
• Pure GH-cell adenomas contain either densely
or sparsely staining cytoplasmic GH granules,
• Mixed GH-cell and PRL-cell adenomas are
composed of distinct somatotrophs expressing
GH and lactotrophs expressing PRL.
11. • Monomorphous mammosomatotroph
adenomas express both GH and PRL from a
single cell, whereas plurihormonal tumors
may express GH with any combination of PRL,
TSH, ACTH, or α-subunit.
• These patients present with clinical features
of acromegaly as well as hyperprolactinemia,
Cushing’s disease, or, rarely
hyperthyroxinemia.
12. Disordered GHRH Secretion or Action.
• Adenomas express receptors for GHRH, ghrelin,
and SRIF, but no activating mutations of the
GHRH or SRIF receptor have been reported.
• GHRH directly stimulates GH gene expression
and also induces somatotroph mitotic activity
• Clinically, GHRH production by hypothalamic,
abdominal, or chest neuroendocrine tumors
causes somatotroph hyperplasia and, rarely,
adenoma, with resultant unrestrained GH
secretion and acromegaly
13. • Failure to downregulate GH secretion during prolonged
GHRH stimulation also points to a role for GHRH in
maintaining persistent GH hypersecretion.
• Furthermore, a GHRH antagonist was found to reduce
production of human growth hormone in 50 patients
with acromegaly, suggesting a role for endogenous
GHRH
• Expression of intra-adenomatous GHRH correlates
with tumor size and activity, implying a paracrine role
for GHRH in mediating adenoma pathogenesis
14. Disordered Somatotroph Cell Function
• . A somatotroph mutation may be a prerequisite
for the abnormal growth response to disordered
GHRH secretion or action
• The monoclonal origin of somatotroph adenomas
was determined by X-chromosome inactivation
analysis of somatotroph tumor DNA.
• An altered Gs(α) protein identified in a subset of
GH-secreting pituitary adenomas leads to high
levels of intracellular cAMP and GH
hypersecretion.
15. Extrapituitary Acromegaly
• The source of excess GH secretion in acromegaly may not
necessarily be pituitary in origin.
• Because management of ectopic acromegaly differs from
that for pituitary GH hypersecretion, rigorous clinical and
biochemical criteria should be fulfilled to confirm the
diagnosis of ectopic acromegaly.
• These include demonstration of elevated circulating GHRH
or GH levels in the absence of a primary pituitary lesion, a
significant arteriovenous hormone gradient across the
ectopic tumor source
• , biochemical and clinical cure of acromegaly after resection
of the ectopic hormone-producing tumor,
• and normalization of the GHRH-GH-IGF1 axis.
16. GHRH Hypersecretion
• . Hypothalamic tumors, including
hamartomas, choristomas, gliomas, and
gangliocytomas, may produce GHRH with
subsequent somatotroph hyperplasia or even
a pituitary GH-cell adenoma and resultant
acromegaly
17. Ectopic Pituitary Adenomas.
• GH-secreting adenomas may arise from
ectopic pituitary remnants in the sphenoid
sinus, petrous temporal bone, or
nasopharyngeal cavity.
• Very rarely, pituitary carcinoma may spread to
the meninges, CSF, or cervical lymph nodes,
resulting in functional GH-secreting
metastases that may be diagnosed by
radiolabelled octreotide imaging (Octreoscan).
18. Acromegaloidism
• . Rarely, patients who exhibit soft tissue and
skin changes usually associated with
acromegaly but normal baseline and dynamic
GH and IGF1 with no demonstrable pituitary
or extrapituitary tumor have been termed
acromegaloid. Pachydermoperiostosis should
be considered in the differential diagnosis
19. McCune-Albright Syndrome
• . The rare hypersecretory syndrome known as
McCune-Albright syndrome consists of
polyostotic fibrous dysplasia, cutaneous
pigmentation, sexual precocity, hyperthyroidism,
hypercortisolism hyperprolactinemia, and
acromegaly due to somatotroph hyperplasia.
• Although few patients have definitive evidence
• for a pituitary adenoma, Gsα mutations have
been detected in both endocrine and
nonendocrine tissue
20. Multiple Endocrine Neoplasia
• GH-cell pituitary adenoma is a well-documented
component of the autosomal dominant multiple
endocrine neoplasia type 1 syndrome, which also
includes parathyroid and pancreatic tumors
• MEN1, associated with germ cell inactivation of
the MENIN tumor suppressor gene,appears to be
intact in sporadic GH-cell adenomas.
• Rarely, functional pancreatic tumors in patients
with MEN1 also express GHRH
21.
22.
23.
24. • In a immuno histo chemical study of 100 pituitary
tumors from new delhi 40% were pleurihormonal
and the commonest combination was GH with
prolactin
• In a series of 75 pituitary adenomas seen over a
decade at Srinagar somatotroph adenoma was
the commonest seen in 44 pts
• Five of 25 pts with fibrous dysplasia reported
from chandigarh had acromegaly.and a bronchial
carcinoid secreting GH is also reported.
25. Clinical features
• Clinical presentation depends on the age of onset of the
GH excess
• If there is GH excess in child hood or adolescence prior to
epiphyseal fusion gigantism results (extreme tall stature)
• Pituitary gigantism is very rare: in a total sample of 2367
children and adolescents with pituitary adenomas, only
0.6% had gigantism
• Should be suspected when children are >3 SD above the
mean height for age.
• A study from chandigarh showed that a third of 36 pts of
GH excess diagnosedbefore the age of 21 yrs had
gigantism.these pts had higher GH values and more
frequently had hypogonadotropic hypogonadism.
26. • If the GH excess occurs in adult hood or after
fusion of the epiphysis enlargement of acral
parts or tips of body (nose;lips;hands and feet)
in addition soft tissues &internal parts of the
body enlarge except brain
27.
28. Clinical Manifestations
Mass effects of tumor
• Headache
• Visual field defects
• Hyperprolactinemia
• Pituitary stalk section
• Hypopituitarism
• Hypothyroidism,
hypogonadism,
hypocortisolism
Systemic effects of GH/IGF-I
excess
• Visceromegaly
• Soft tissue and skin changes
• Thickening of acral parts
• Increased skin thickness and
soft tissue hypertrophy
• Hyperhidrosis/Oily texture
• Skin tags and acanthosis
nigricans
30. Metabolic features
• Impaired glucose tolerance
• Diabetes mellitus
• Insulin resistance
• Other endocrine
consequences
• Goiter
• Hypercalciuria
• Galactorrhea
• Decrease libido, impotence
• Menstrual abnormalities
Bone and joint manifestations
• Increased articular cartilage
thickness
• Arthralgias and arthritis
• Carpal tunnel syndrome
• Osteopenia
31. Jaw prognathism and mandibular
overbite, widened incisor tooth gap Dolicomegacolon in acromegaly
32. • A recent study found that excess GH in humans is associated
with increased activity of the epithelial sodium channel, and
this could contribute to the volume expansion and soft tissue
manifestations seen in acromegaly .
• The growth of the pituitary adenoma may compress local
structures and cause neurological symptomatology and visual
disturbances.
• Somatotroph adenomas grow slowly, and patients presenting
these adenomas are usually older than 50 years.
• Changes in appearance derive from skeletal growth and soft
tissue enlargement, which is subtle in the early stage of the
disease.
• Visceromegalies are common, in the form of goiter,
hepatomegaly, splenomegaly, and macroglossia
33. • The clinical manifestations of acromegaly include
skin changes such as hyperhidrosis, oily skin, and
unpleasant odor, which are due to the deposit of
glycosaminoglycans.
• Pigmented skin tags over the trunk are common
in patients with acromegaly;
• it is not clear whether GH/IGF-I excess causes
skin tags directly, or whether they arise as a
consequence of insulin resistance and
dyslipidemia
34. • Rare manifestations include cutis verticis gyrate
and psoriasis.
• These manifestations respond well to decreased
GH level;
• Osteoarticular Manifestations.
• The most prevalent manifestation was axial
osteoarthritis, affecting the cervical and lumbar
areas, even at young ages.
• The characteristic radiological changes observed
were wide joint spaces and severe osteophytosis.
35. • Approximately 50% of patients have axial arthropathy (disk
space widening, vertebral enlargement, and osteophyte
formation) mainly affecting the lumbar area.
• Affectation of the lumbar area can cause restricted range of
movement, joint instability, and deformity of joint.
• The radiological appearance of arthropathy in acromegaly
was studied in small noncontrolled groups of patients with
the disease treated or untreated, but active.
• These studies have suggested that more severe radiological
changes are associated with disease duration and activity.
• The most prevalent manifestation was axial osteoarthritis,
affecting the cervical and lumbar areas, even at young ages.
36. • The carpal tunnel syndrome occurs in
approximately 30% to 50% of acromegalic
patients and is frequently bilateral.
• The predominant pathology of median
neuropathy in acromegaly consisted of
increased edema of the median nerve in the
carpal tunnel
37. • Decreased bone mineral density has been
reported in acromegaly almost exclusively at the
lumbar spine, a site rich in trabecular bone,
• whereas increases in bone mineral disease may
be observed in the forearm, a site rich in cortical
bone
• excess GH and IGF-I induce an increase of the
cortical bone density, independently of gonadal
function, whereas hypogonadism seems to
counteract the anabolic effect of GH on the
trabecular bone
38. • Cardiovascular manifestations occur in 60% of patients.
• Elevated growth hormone,hypertension, and heart disease
are negative determinants for life expectancy in
acromegaly.
• Cardiac involvement in acromegaly, in the absence of other
contributing factors, is called acromegalic cardiomyopathy,
which is initially characterized by cardiac hypertrophy,
followed by diastolic dysfunction and ultimately failure of
systolic function
• The presence of arrhythmias (atrial fibrillation,
supraventricular tachycardia, and ventricular arrhythmias)
is also more common, especially during exercise
39. • In a more recent study, cardiovascular risk factors
were studied in patients with acromegaly.
• An increased rate of hypertension and diabetes
was found, triglyceride levels were elevated, and
high- and low-density lipoproteins were low.
• Cardiovascular risk calculation has shown that
patients with acromegaly are at greater risk,
particularly female patients, and that this risk
decreased with normalization of IGF-I
40. • hypertension is considered to be one of the most
important prognostic factors for mortality
• It is present in one third of acromegalic patients,
and different mechanisms are increased plasma
volume, alterations in renin-angiotensin, insulin
resistance, and increased vascular resistance
• Excess GH can cause insulin resistance, as it alters
the ability of insulin to suppress glucose
production and stimulates its use
41. • prevalence of diabetes mellitus in acromegaly is
estimated to be 19 to 56%, in different series
• Carbohydrate intolerance occurs with a prevalence of
31% in the study by Biering et al. ,46% in the study of
Kasayama et al. and 16% in the analysis carried out by
Kreze et al.
• The most characteristic predisposing factors for
diabetes were older age and longer duration of illness.
• In the study of Kreze et al.diabetes is influenced by a
family history of diabetes and the presence of
hypertension.
42. • Acromegaly alters the structure of the respiratory
apparatus and impairs respiratory function.
• range of abnormalities results in two main respiratory
dysfunctions, namely, sleep apnea and impaired respiratory
function.
• Sleep apnea, the phenomenon of recurrent cessation or
reduction of airflow to the lungs during sleep, is a common
cause of snoring and daytime sleepiness in acromegaly.
• Impaired respiratory function is less frequently investigated
in acromegaly and originates from multiple alterations
involving the bone and muscle structure of the chest as
well as lung elasticity.
43. • Patients with acromegaly develop a barrel chest
due to changes in their vertebral and costal
morphology.
• Obstruction of the upper airways is a result of
macroglossia, prognathism, thick lips, and
hypertrophy of the laryngeal mucosa and
cartilage;
• it can cause sleep apnea and excessive snoring
and can complicate tracheal intubation during
anesthesia
44. • Moreover, using polysomnography, Attal and
Chanson found an average rate of 69% for
obstructive sleep apnea in patients with active
disease in prospective or retrospective
studies.
• Sleep apnea occurs in more than 50% of
patients.
• In patients with acromegaly, obstructive sleep
apnea predominates over central sleep apnea
45. • Hyperprolactinemia with or without galactorrhea
develops in approximately 30% of patients due to of
pituitary stalk compression or mixed tumor secretion
of GH and PRL.
• Hypopituitarism, by mass compression of the normal
pituitary tissue, occurs in approximately 40% patients;
• amenorrhea, impotence, or secondary thyroid or
adrenal failure may develop.
• Goiter and thyroid abnormalities are common,
potentially as a result of the stimulating effects IGF-I on
thyrocyte growth.
46. • Hypercalcemia in acromegaly is reported in up to
8% of patients;
• it is usually secondary to coexistent
hyperparathyroidism and does not resolve after
treatment of excess GH.
• hypercalciuria and nephrolithiasis may occur in
6–77% of patients with acromegaly.
• Proposed mechanisms of hypercalciuria include
parathyroid hyperplasia, renal tubular acidosis,
increased calcium absorption, and
overproduction of 1, 25 (OH)2 D
47. • One study evaluated sleep characteristics in a
small group of acromegalics;
• an astonishingly high number of patients were
found to be affected by restless leg syndrome,
• a neurological disorder characterized by a
compelling urge to move the limbs during the
night, due to unpleasant paraesthetic sensory
symptoms, which may lead to severe insomnia,
consequent daytime sleepiness, and reduced
quality of life.
48. • The gastrointestinal manifestations associated
with acromegaly are colon carcinoma,
adenomatous polyps, and dolichocolon.
• In a recent study, colonic diverticular disease was
found to be higher in patients with acromegaly
when compared with controls, and diverticula
were present at a significantly younger age.
• Diverticulosis in acromegaly was primarily
associated with the duration of the active
disease, which became even stronger when
adjusted for excess GH and IGF-I
49. • Considering all the prospective colonoscopy
screening studies, an increased prevalence of
colorectal cancer has been found in
acromegaly when compared with controls.
• No increase was demonstrable if acromegaly
was controlled, but if the disease was active,
premalignant polyps were more frequent and
increased their tendency to become
malignant.
50. • Multiple skin tags, a positive family history or
any other genetic predisposition, or advancing
age are considered as predisposing features to
consider colon cancer.
• Screening will depend on the initial findings,
whether IGF-I is normal or high, and on the
patient’s age.
• Whether colonoscopy should be performed
every 3 or 5 years is not defined.
51. • Different studies on the risk of prostate, breast,
colorectal, lung, and thyroid cancer suggest that high
circulating IGF-I levels are related to an elevated risk of
cancer,
• whereas high levels of insulin like growth factor binding
protein type 3 (IGFBP-3) levels are associated with a
reduced risk.
• GH has a stimulatory effect on both IGF-I and IGFBP-3,
and therefore there should not be an increased risk of
malignancy.
• Excess GH causes an elevated IGF-I to IGFBP-3 ratio,
which is expected to increase cancer risk
52. • The cancers most frequently studied in
acromegaly are colon, breast, and prostate
carcinomas, although many others have been
described including hematological, bronchial,
gastric, esophageal, thyroid, osteosarcoma,
pancreas, melanoma, ovarian, renal, adrenal,
biliary
53. • Colao et al. investigated the relationship of GH, IGF-I, and
insulin levels to colonic lesions in a cohort of consecutive
newly diagnosed patients with acromegaly and found that
fasting insulin levels were associated with premalignant
and malignant colonic lesions.
• It was also found that glucose tolerance and insulin levels
were strongly associated with colonic adenomas and
carcinomas.
• Diabetes or impaired glucose tolerance was a risk factor for
the development of colonic lesions
• an increased prevalence of colorectal neoplasms in
acromegaly, regular screening and polypectomy if required
would seem advisable
54. Clinical presentation of acromegaly
reported in an indian series ;vellore
Clinical features
• Male to female ratio
• Mean age
• Duration of symptoms
• Head ache
• Visual impairement
• Prior apoplexy
• Hypertension
• Hypothyroidism
• Hypocortisolism
• Hyperprolactenemia
• Overt diabetes
Findings
• 3:2
• 35 yrs
• 2 months to 10 yrs
• 53%
• 22%
• 9%
• 28%
• 16%
• 15%
• 26%
• 28%
55. Endocrine Images: Acromegaly
Foot X-ray of Patient with Acromegaly.
Notice the unusually thick “pad” of soft tissue overlying the
calcaneus (double arrow). It is said that a good clinical sign of
acromegaly is the inability to feel the calcaneus when pressing on the
heel.
Amilcare Gentili, M.D.
56. Endocrine Images: Acromegaly
Picture of wrestling star Andre the Giant and Skull X-ray of
man with acromegaly. Notice the characteristic prominent
supraorbital ridge (“frontal bossing”), large jaw, and dental
malocclusion with underbite (x-ray).
Andre the Giant by EKavet (Flickr)
acromegaly.org.uk
59. • Acromegaly is an insidious disease, which is often
diagnosed late (between 4 and more than 10 years after
onset).
• The increase in morbidity and mortality associated with
acromegaly is the result of the oversecretion GH and IGF-I
and the direct mass effect of the pituitary tumor.
• An early diagnosis of the disease is mandatory, although
none of these symptoms is sufficiently sensitive,
• Growth of the acral parts is uncommon in adults without
acromegaly and can be objectively evaluated by an increase
in shoe and/or ring size
60. • Another possible method for early diagnosis
of patients with acromegaly is to use software
in order to detect the features of acromegaly,
using photographs of the face.
• This could be a promising system for
identifying the disease
• When there is clinical suspicion of the disease,
biochemical confirmation is required to
establish the diagnosis
61. Endocrine Images: Acromegaly
Individual with acromegaly photographed over a 37-year span. Ages
in years are in lower left corner of each photograph.
Note that the changes occurring with acromegaly may be very gradual and go
completely undetected by the patient or his or her family for many years. It is
often only thorough the comparison with old photographs or complaints
involving complications of acromegaly, such as sleep apnea, diabetes or dental
problems that acromegaly is suspected.
28 yrs 49 yrs 65 yrs55 yrs
62. • Normal GH production from the pituitary gland is
pulsatile;
• most GHvalues fall in the range of 0.1-0.2 μg/L in
normal subjects, with the maximum production
occurring at night
• best way to assess overall daily GH production is
to obtain a mean GH over 24 h by frequent GH
sampling, although this method is inconvenient
and 24-h mean GH values have been found to
overlap with those of healthy controls
63. • In different situations IGF-I serves as a biomarker of the
activity of acromegaly.
• IGF-I levels are relatively stable and correlate with clinical
acromegaly and elevated GH levels.
• In order to accurately assess IGF-I levels, age-matched
controls are required, as the levels of IGF-I decreased 14%
per decade.
• In order to monitor disease activity, levels of GH and IGFI
are complementary.
• It has been suggested that in the presence of discordant
serum IGF-I and GH levels, IGF-I is more predictive than GH
in terms of insulin sensitivity and clinical symptom score
64. • Magnetic resonance imaging (MRI) with contrast
administration is the best imaging technique to
pinpoint the pituitary source of excess GH.
• This technique makes it possible to visualize and locate,
in relation to surrounding structures, adenomas larger
than 2mm in diameter.
• At the time of diagnosis, over 75% show a
macroadenoma (>10mm in diameter), which grows
into the cavernous sinus or suprasellar region.
• In rare cases, in patients with acromegaly and
unremarkable pituitary MR imaging and
• no evidence of ectopic GH or GHRH production
65.
66. • The diagnosis of acromegaly requires measurement of
a GH during oral glucose tolerance testing that is
greater than 0.4 μg/L or 1 μg/L together with
elevation of age-adjusted IGF-1 levels.
• In healthy subjects, serum GH levels initially fall after
oral glucose administration and subsequently increase
as plasma glucose declines.
• However, in patients with acromegaly, oral glucose
fails to suppress GH, and GH levels are equally likely to
increase, remain unchanged
67. • Serum IGF1 levels are high and correlate with the log of
serum GH determinations.
• IGF1 elevations may persist for several months after
GH levels become biochemically controlled in response
to treatment.
• Increased IGF1 levels are also encountered during
pregnancy and late puberty.
• A high IGF1 level is therefore highly specific for
acromegaly and correlates with clinical indices of
disease activity.
• IGFBP3 levels are also elevated but provide little added
diagnostic value.
68. • Biochemical diagnosis is made by determining
of GH after OGTT with 75 g and determining
the levels of IGF-I.
• The current international consensus for the
diagnosis of acromegaly recommends a nadir
GH equal to or greater than 0.4 μg/L after an
OGTT, in conjunction with clinical suspicion
and high IGF-I levels
69. • GH cannot be suppressed in the presence of liver failure,
kidney failure, poorly controlled diabetes, malnutrition,
anorexia, pregnancy, estrogen therapy, or in late
adolescence .
• In contrast, a recent study , found that 7 adult patients with
newly diagnosed untreated acromegaly out of a total group
of 40 had a GH nadir after an OGTT of less than 0.4 μg/L.
• These data highlight the limited diagnostic value of OGTT in
patients with biochemically active acromegaly but only
mildly increased GH output and the limitations for the
applicability of consensus guidelines on diagnosis in clinical
practice
70. Differential Diagnosis
• Distinguishing pituitary from extrapituitary acromegaly is
important for planning effective management.
• Regardless of the cause of unrestrained GH secretion, IGF1
levels are invariably elevated and GH levels are not
suppressed (i.e., to <1 μg/L) after an oral glucose load.
• When clinical features of acromegaly are associated with
normal GH and IGF1 levels, “burned out” or “silent”
acromegaly associated with an infarcted pituitary
adenoma, often with a secondary empty sella, should be
considered.
• About 5% of consecutive patients with proven GH-cell
adenomas have normal GH and increased IGF1 levels.
71. • Plasma GHRH levels are invariably elevated in patients
with peripheral GHRH-secreting tumors but are normal
or low in patients with pituitary adenomas
• Peripheral GHRH levels are not elevated in patients
with hypothalamic GHRH-secreting tumors.
• The presence of wheezing or dyspnea, facial flushing,
peptic ulcers, or renal stones, sometimes indicates the
diagnosis of a nonpituitary endocrine tumor.
• Hypoglycemia,hyperinsulinemia, hypergastrinemia,
and, rarely, hypercortisolism—all not usually
encountered in pituitary acromegaly—should justify an
evaluation for an extrapituitary source of GH excess
72. • MRI and CT scanning may be employed to localize
pituitary or extrapituitary tumors.
• The presence of a normal or small-sized pituitary
gland, or of clinical and biochemical features of
other tumors known to be associated with
extrapituitary acromegaly and elevated
circulating GHRH levels is an indication for extra
pituitary imaging.
• The McCune-Albright syndrome should be
considered after definitive exclusion of pituitary
and extrapituitary tumors.
73. Treatment
• Aims
• A comprehensive strategy for treatment of acromegaly
should aim to manage the pituitary mass, suppress GH
and IGF1 hypersecretion, and prevent long-term
clinical sequelae of hypersomatotropism while
maintaining normal anterior pituitary function.
• An elevated GH level per se is associated with a
threefold increased morbidity rate and is the single
most important determinant of mortality.
• It is important to reverse the mortality rate to that of
age-matched healthy subjects by aiming for tight GH
control.
74. • Serum GH levels should be suppressed to at least
1 μg/L (or lower) after an oral glucose load, and
IGF1 levels should be normalized for age and
gender.
• With good control, there should also be a normal
24-hour integrated secretion of GH (<2.5 μg/L).
• GH may not be measurable for most of the day,
yet the tumor may still be hypersecreting, as
reflected by increased levels of IGF1
76. Surgical Management
• Well-circumscribed somatotroph-cell adenomas
should preferably be resected by transsphenoidal
surgery.
• Successful resection alleviates preoperative
compression effects and compromised trophic
hormone secretion &preservation of anterior
pituitary function.
• Within 2 hours after successful resection,
metabolic dysfunction and soft tissue swelling
start improving and GH levels are sometimes
controlled within 1 hour
77. • Surgical outcome correlates well with adenoma size,
with preoperative serum GH levels, and particularly
with the experience of the surgeon.
• Smaller tumors (<5 mm), tumor totally confined within
the sella, and preoperative serum GH levels lower than
40 μg/L portend a favorable surgical outcome.
• 90% of patients with microadenomas achieve
postoperative GH levels lower than 2.5 μg/L, whereas
fewer than 50% of patients with macroadenomas of
any size had postoperative GH levels lower than 2 μg/L
after glucose administration.
78. • Overall, in 17 studies of 1284 patients published
between 1995 and 1999, 82% of patients harboring
microadenomas had normalized IGF1 levels and 47% of
those with macroadenomas achieved control
• A study of 2665 patients from a single center showed
that 72% of patients with microadenomas and 50% of
those with macroadenomas achieved GH levels lower
than 1.0 μg/L during glucose loading and normal serum
IGF1 levels.
• Eight percent of these patients experienced a
recurrence after 10 years.
79. • Side Effects.
• Although they are often transient, surgical
complications may require lifelong pituitary hormone
replacement.
• New hypopituitarism develops in up to 20% of patients,
reflecting operative damage to the surrounding normal
pituitary tissue.
• Permanent diabetes insipidus, CSF leaks, hemorrhage,
and meningitis occur in up to 10% of patients
• The extent and prevalence of local complications
depend on tumor size and invasiveness.
80. The Role of Radiation Therapy
• When radiation therapy for acromegaly is being
considered, it should be conducted by an experienced
pituitary radiotherapist in a specialized center.
• Radiation therapy should generally be reserved for
third-line treatment, occasionally as second-line
treatment, but rarely as first-line treatment.
• Patients who do not have tumor growth control or
normalization of hormone levels with surgery (for
example, after debulking of a nonresectable tumor)
and/or medical therapy are possible candidates for
radiation therapy
81. • If radiation therapy is deemed necessary, the choice of
technique is dependent upon the tumor characteristics:
• conventional radiotherapy is preferred for large tumor
remnants or tumors that are too close to optic pathways,
where as stereotactic radiotherapy is preferred when there
is a smaller tumor size or when improved patient
convenience is desired.
• Stereotactic radiotherapy may produce beneficial effects on
GH and IGF-I sooner than conventional radiotherapy, but
this is unproven and may be due to the aforementioned
selection bias in trials.
• At present, there is insufficient evidence to provide
definitive recommendations in favor of one particular
technique over another
82. • Primary or adjuvant irradiation of GH-secreting
tumors may be achieved by conventional external
deep x-ray therapy or by heavy-particle (proton
beam)or gamma knife radiosurgery.
• Maximal tumor irradiation should ideally be
attained with minimal soft tissue damage.
• Precise MRI localization, accurate simulation,
isocentral rotational techniques, and high-voltage
(6 to 15 MeV) delivery have improved the efficacy
of radiation therapy
83. • Up to 5000 rads is administered in split doses of
180-rad fractions divided over 6 weeks.
• Radiation arrests tumor growth, and most
pituitary adenomas ultimately shrink.
• GH levels fall gradually during the first year after
treatment, and levels are lower than 10 μg/L in
70% of patients after 10 years.
• Radiation therapy effectively shrinks GH-cell
adenomas and lowers GH levels over 20 years in
more than 90% of patients
84. • During the first 7 years after irradiation, IGF1
levels were normalized in fewer than 5% of
patients with acromegaly in one report,
• whereas in another study, approximately 70% of
patients exhibited normal levels when tested
during longer follow-up.
• Radiotherapy does not normalize GH secretory
patterns, and this probably accounts for
persistently elevated IGF1 levels in the face of
apparently controlled GH levels.
85. • Stereotactic pituitary tumor ablation by the
gamma knife has been reported,and 82% of
those treated had normal serum IGF1 levels;
• some of these patients were being treated
simultaneously with somatostatin analogues.
• About 50% of patients achieved glucose-
induced GH suppression to less than 1 ng/mL
and normal IGF1 levels within 66 months after
treatment
86. • Side Effects.
• After 10 years, about half of all patients receiving
radiotherapy have signs of pituitary trophic
hormone disruption
• hair loss, cranial nerve palsies, tumor necrosis
with hemorrhage, and, rarely, loss of vision or
pituitary apoplexy, have been documented in up
to 2% of patients.
• Lethargy, impaired memory, and personality
changes may also occur.
87. • In a 10-year follow-up study of 35 patients
treated with gamma knife radiosurgery, half of
the patients developed pituitary hormone
deficiencies (40% hypoadrenalism, 11%
hypothyroidism, 13% hypogonadism, and 6% GH
deficiency).
• Because of side effects, radiation therapy should
be employed as an adjuvant when control is not
achieved by surgery or medical management and
for patients who refuse these other therapies
88. • Many of the potential safety concerns with
radiation therapy for acromegaly remain
unresolved.
• The possible causative link between radiation
therapy and cerebrovascular mortality and
morbidity is still unclear .
• In addition, although second tumors have been
reported , data on the effects of newer focused
radiation therapy techniques on the development
of second tumors are not yet available.
90. Dopamine Agonists
• bromocriptine and cabergoline,have been used
as primary or adjuvant therapy for acromegaly.
• Usually, up to 20 mg/day of bromocriptine lowers
GH—a dose that is higher than that required to
suppress PRL in patients harboring
prolactinomas.
• Approximately 15% of patients worldwide have
been reported to have suppressed GH levels (<5
μg/L) when taking the medication (7.5 to 80
mg/day)
91. • Dopamine agonist efficacy appears to be independent
of PRL concentration.
• The drug causes minimal tumor shrinkage, but some
patients experience subjective clinical improvement
despite persistently elevated serum GH or IGF1 levels.
• Side effects of bromocriptine are more marked than
those of cabergoline, especially because high doses are
required.
• These side effects include gastrointestinal upset,
transient nausea and vomiting, headache, transient
postural hypotension with dizziness, nasal stuffiness,
and, rarely, cold-induced peripheral vasospasm
92. • Clinical situations in which cabergoline may be useful
include:
• When the patient prefers oral medication (DAs are the
only oral medication available for acromegaly) DR.
• After surgery (very occasionally as first-line therapy) in
selected patients, such as those with markedly
elevated prolactin and/or modestly elevated GH and
IGF-I levels DR.
• As additive therapy to SRL therapy in patients partially
responsive to a maximum SRL dose DR—approximately
50% of such patients may achieve control of GH and
IGF-I levels
93. SRIF Receptor Ligands
• The use of SRLs is most appropriate:
• As first-line therapy when there is a low
probability of a surgical, cure (for example, large
extrasellar tumors with no evidence of central
compressive effects) DR ( discretionary
recommendations )
• After surgery has failed to achieve biochemical
control SR.( strong recommendations)
—
94. • Before surgery to improve sever comorbidities that
prevent or could complicate immediate surgery (the
benefits of this are unproven) DR.
• To provide disease control, or partial control in the
time between administration of radiation therapy
and the onset of maximum benefit attained from
radiation therapy (radiation therapy can take several
years to produce disease control
95. .
• The two analogs of somatostatin available for
clinical use are the cyclic octapeptides octreotide
and lanreotide
• octreotide is 45 times more potent at suppressing
pituitary GH secretion than native somatostatin-
14 and has a half-life of 2 h when given sc
• Somatostatin analogs and native somatostatin
elicit their biological effects by activating
somatostatin receptors.
• There are five distinct somatostatin receptors,
types 1–5 .
96. • Octreotide and lanreotide have greatest affinity for
receptor subtypes 2 and 5, with their affinity for
subtype 2 being about 10-fold higher than for
subtype 5 .
• Receptor subtypes 2 and 5 are those through which
endogenous somatostatin suppression of GH occurs
and are also the predominant types of somatostatin
receptors found in GH-secreting pituitary tumors
97. • The first preparation of somatostatin analog available for
clinical use was sc-administered octreotide.
• After sc injection, serum octreotide levels rise within 30
min and then fall over the next few hours.
• The maximal suppressive effect of octreotide on GH levels
occurs between 2 and 6 h after the injection
• Octreotide is also available in a long-acting release (LA dose
of octreotide in its sc form is 100–250 g thrice daily, but
doses up to 1500 g over a 24-h period can be given )
• The usual starting dose of octreotide LAR is 20 mg with
titration down to 10 mg or up to 30 or 40 mg, based on the
response of GH and IGF-I levels.
.
98. • A number of studies have drawn comparisons among
the efficacy of short-acting octreotide, octreotide LAR,
and lanreotide SR.
• Most studies comparing lanreotide and longacting
octreotide report somewhat greater efficacy with
octreotide LAR
• One study from Jenkins et al. , a short-term,
prospective randomized study in unselected patients,
reported that IGF-I levels were normalized in 56% of 11
patients 14 d after lanreotide injection and in 67% of
18 patients 4 wk after octreotide LAR injection
99. • A number of studies have compared the efficacy of
sc octreotide and octreotide LAR.
• These studies, for the most part retrospective, have
reported a similar efficacy for the two preparations
. J Clin Endocrinol Metab 85:4099–4103
100. • The efficacy of somatostatin analogs in combination
with the dopamine agonists bromocriptine or
cabergoline has been examined in a few small studies.
• Overall, most studies, although not all, have shown
that 10–20% of somatostatin analog-resistant patients
have some further suppression of GH and/or IGF-I
levels with the addition of a dopamine agonist to
somatostatin analog therapy
• The comparative efficacy of a somatostatin analog
combined with bromocriptine vs. cabergoline has not
been assessed.
101. • An improvement in the signs and symptoms of acromegaly
occurs overall in 64–74% of patients treated with depot
analog therapy
• Studies have reported improvements to varying degrees in
headache, soft tissue swelling, arthralgia, carpal tunnel
syndrome, snoring, hyperhidrosis, fatigue, and malaise.
• With depot somatostatin analog therapy, as has been
shown for sc octreotide, more patients subjectively report
improvement in the signs and symptoms of acromegaly
than the number of patients whose GH/IGF-I levels
normalize.
• Symptomatic improvement is likely due to lowering without
complete normalization of GH/IGF-I levels in such patients.
102. • Manifestations of cardiovascular disease, the leading
cause of mortality in these patients, can improve
with somatostatin analog therapy.
• A number of studies have shown improvements with
somatostatin analog therapy in cardiac structure and
function, including left ventricular mass index, left
ventricular hypertrophy, and ejection fraction .
• Normalization of IGF-I has also been associated with
improvement in cardiac performance on octreotide
• An improvement in sleep apnea can also occur in
some patients with acromegaly treated with
octreotide
103. • Another very important component of the efficacy of
somatostatin analog therapy for acromegaly is its
effect on tumor shrinkage
• Overall, in combined data from patients receiving
either the long-acting analogs or sc octreotide as
adjunctive therapy, about 30% of patients had tumor
shrinkage
104.
105.
106. Long-term efficacy and safety of subcutaneous pasireotide
in acromegaly: results from an open-ended, multicenter,
Phase II extension study
• Pasireotide (SOM230) is a multi receptor-targeted
somatostatin analogue with a unique receptor binding
profile, having high affinity for sst2 and sst5, as well as
sst1 and sst3
• Therefore, it has the potential to be a more effective
therapy for acromegaly than octreotide or lanreotide
• Phase II extension study showed that, following 9
months of pasireotide therapy (3 months in the core
study and 6 months in the extension study), 23 %
(6/26) of patients with acromegaly achieved
biochemical control
107. • pasireotide resulted in significant and ongoing
reductions in tumor volume throughout the extension
phase of the study.
• Fifty-nine percent of patients achieved a significant
(C20 %) reduction in tumor volume over the course of
the core and extension studies.
• A significant reduction in tumor volume was more
commonly observed in patients with biochemical
control than in uncontrolled patients.
• However, a reduction of at least 20 % in tumor volume
was seen in 5/13 (38.5 %) patients who did not achieve
biochemical control
108.
109. • In addition to biochemical control and reductions in
tumor volume, this study showed that long-term
pasireotide treatment is associated with long-term
improvements in the symptoms of acromegaly,
including headache, fatigue, perspiration and
osteoarthralgia
110.
111. GH receptor antagonist
• The indications for its use are:
• In patients who have persistently elevated IGF-I levels
despite maximal therapy with other treatment
modalities SR.
• Possibly as monotherapy or in combination with a SRL
in other patients DR.
• However, more data are required before firm
guidelines can be given on this.
• Pegvisomant is highly effective in acromegaly and
significantly improves the quality of life in patients
that require both SRLs and pegvisomant to achieve
biochemical control
112. Long-Term Safety of Pegvisomant in Patients with
Acromegaly: Comprehensive Review
in ACROSTUDY
,• Pegvisomant is a GH receptor antagonist. The ACROSTUDY is a global
safety surveillance study of long-term treatment of acromegaly with
pegvisomant.
• Objective: The objective of the study was to monitor long-term safety and
treatment outcome
• Subjects (n 1288) were treated with pegvisomant for a mean of 3.7 yr
and followed up in ACROSTUDY for a mean of 2.1 yr.
• A total of 1147 adverse events were recorded in 477 subjects (37%),
among which 192 AE in 124 subjects(9.6%)were considered to be related
to pegvisomant.
• Serious AE were recorded in 159 subjects (12.3%), whereas pegvisomant-
related Serious AE were recorded in 26 subjects (2%).
• No deaths (15 subjects; 1.2%) were attributed to pegvisomant use.
113. • Data entered and evaluated in ACROSTUDY indicate
that pegvisomant is an effective and safe medical
treatment in patients with acromegaly.
• The reported low incidence of pituitary tumor size
increase, liver enzyme elevations, and lipodystrophy at
the injection site are reassuring.
• J Clin Endocrinol Metab 97: 0000–0000, 2012
114. • The incidence of increase in pituitary tumor size in the
subset with confirmed MRI increases on central
reading represented 3.2%of the overall cohort with at
least two available MRI (n936).
• Injection-site reactions were reported in 28 cases
(2.2%).
• In 30 patients (2.5%),an elevated aspartate amino
transferase or alanine amino transferase of more than
3 times the upper level of normality was reported.
• There were no reports of liver failure.
• After 5 yr of pegvisomant treatment, 63.2% of subjects
had normal IGF-I levels at a mean dose of 18 mg/d.
115. Acromegaly and Pregnancy: A Retrospective
Multicenter Study of 59 Pregnancies in 46 Women
• Study Design: This was a retrospective multicenter study.
• Patients: The study included 46 women with GH-secreting
pituitary microadenomas (n 7) or macroadenomas (n 39).
• Their mean age was 31.7 yr (4.5 yr).
• Incomplete trans sphenoidal surgical resection (n 39) and
pituitary radiation (n 14) had been performed, respectively,
2.9 +_2.6 and 7.3 +_ 4.2 yr before pregnancy.
• The patients were receiving dopamine agonists (n 25) and/or
somatostatin analogs (n 14), and GH/IGF hypersecretion was
controlled and uncontrolled in,respectively, 23 and 34 cases.
• Five pregnancies followed the fertility treatment.
116. • Fifty-nine pregnancies resulted in 64 healthy babies.
• Gestational diabetes and gravid hypertension occurred in four
(6.8%) and eight (13.6%) pregnancies, respectively, and both
were more frequentwhenGH/IGF-I hypersecretion was not
controlled before pregnancy.
• Visual field defects were diagnosed during pregnancy in four
women, three of whom were diagnosed with acromegaly
during the pregnancy.
• Seven women had isolated headache.
• Magnetic resonance imaging performed 3.9 0.3 months after
delivery showed that the size of the adenoma had increased
in three cases, decreased in two cases,and remained stable
in22cases.
• Seventeen women breast-fed with no complications
117. conclusions
• 1) pregnancy in women with active or uncontrolled
acromegaly may be associated with an increased risk of
gestational diabetes and gravid hypertension;
• 2) pregnancy is occasionally associated with symptomatic
enlargement of GH-secreting pituitary macroadenomas;
• 3) changes in serum GH and IGF-I concentrations are
variable during pregnancy, indicating that routine
monitoring is not mandatory if the pregnancy is uneventful;
• 4) GH-suppressive treatment can be safely withdrawn after
conception in most acromegalic women. (J Clin Endocrinol
Metab 95: 4680–4687, 2010)
118. • Four women gave birth to a small-for-gestational-age
infant;
• all had received somatostatin analogs, alone or in
combination with dopamine agonists, during
pregnancy.
• The mean IGF-I level fell significantly during the first
trimester in 12 cases(before conception 588
+_207ng/ml,first trimester 319 +_126ng/ml,P 0.002),
• whereas the GH concentration did not change
significantly
119. Ongoing challenges
• There are certain areas where more data are needed
on the use of medical therapies in acromegaly. Firstly,
there are no head to- head studies of the different SRLs
of adequate design and power to recommend one drug
over the other.
• Secondly, data on the potential use of GHRA as a first-
line treatment or in combination with SRLs are needed.
• And thirdly, the relative cost-effectiveness of all
medical therapies as monotherapy, or in the various
combination options discussed above, requires
evaluation
120.
121. Goals of Treatment
• Mortality reduction
• Tumor shrinkage
• Treatment of comorbidities
122. Monitoring the Patient with Acromegaly
• Biochemical markers of response
• MRI
• Pituitary function
• Echocardiography
• Sleep disturbance
• Colonoscopy
123. • Significant progress has been made in the management of
acromegaly in recent years.
• If managed appropriately by a multimodality team with
specific experience in managing pituitary tumors, there is no
reason for patients to have reduced life expectancy or
frequent morbidity.
• However, unresolved issues exist:
• the aim of ensuring that patients are managed by
appropriately experienced healthcare professional teams is
not yet a reality
• little is known about the cost-effectiveness of the various
management options for acromegaly; and combining
treatments may improve patient morbidity and QoL, but more
data are needed
127. • The standardized mortality rate for acromegaly is 1.72.
• Mortality is related to GH levels of over 2–2.5 μg/L and
less clearly with elevated IGF-I .
• Treatment with radiotherapy may be associated with
increased mortality .
• A meta-analysis of mortality ratios in patients with
acromegaly found all-cause mortality increased in
comparison to the general population.
• Although the mortality risk has decreased due to
modern treatment strategies, including
transsphenoidal surgery, there is still a 32% increased
all-cause mortality risk in acromegaly.
128. • The standardized mortality rate for acromegaly is 1.72.
Mortality is related to GH levels of over 2–2.5 μg/L and
less clearly with elevated IGF-I
• Treatment with radiotherapy may be associated with
increased mortality .
• A meta-analysis of mortality ratios in patients with
acromegaly found all-cause mortality increased in
comparison to the general population.
• Although the mortality risk has decreased due to
modern treatment strategies, including
transsphenoidal surgery, there is still a 32% increased
all-cause mortality risk in acromegaly.
