Acromegaly

General

Acromegaly is a chronic, disfiguring disease that leads to a poor quality of life and decreased survival as a result of multiple coexisting systemic conditions.

Diagnostic delay — even a delay of 10 years or more — is common and is a major determinant of disease severity.

The role of clinicians in reducing diagnostic delay is crucial, since specific findings occur in multiple organs and should trigger a suspicion of acromegaly early in the disease course.

Once acromegaly is suspected, the clinician evaluating the patient should order an insulin-like growth factor I assay.

Multimodal treatment is often needed to control acromegaly, and new medical agents may improve both therapeutic efficacy and treatment adherence.

Numbers

3/1-million persons/year.

Although men present at a younger age than do women, women may show both increased incidence and mortality risk

>75% of pituitary GH tumours are macroadenomas (> 1cm) with cavernous sinus invasion and/ or suprasellar extension at diagnosis.

25% of acromegalics have thyromegaly with normal thyroid studies.

25% of GH adenomas also secrete prolactin.

Screening: ACROSCORE

General

A clinical scoring system designed to help identify acromegaly by evaluating specific symptoms and signs.
The maximum score is 14 points.
Used by physicians as a screening tool to prompt earlier diagnosis and referral for biochemical testing in suspected acromegaly cases.
Prencipe 2015

Points Breakdown

Diabetes mellitus type 2: 1 point
Hyperhidrosis (excessive sweating): 2 points
Thyroid hyperplasia (enlarged thyroid): 3 points
Carpal tunnel syndrome: 1 point
Dental diastasis (spaced teeth): 4 points
Colon polyps: 3 points

Risk Categories

Score 0: Low risk (positive predictive value 0.6%)
Score 1–5: Moderate (grey area)
Score >5: High risk (positive predictive value 46.1%)

A score greater than 5 suggests that acromegaly cannot be excluded and further investigation is warranted.

Aetiology

>95% of cases of excess GH result from a pituitary somatotroph adenoma.

Growth hormone carcinoma is extremely rare.

Other rare causes of acromegaly-thru Ectopic GH secretion

Carcinoid tumour
Lymphoma
Pancreatic islet-cell tumour.

Rare syndromic associations:

Multiple endocrine neoplasia type 1 (MEN 1)
McCune-Albright syndrome
Familial acromegaly
Carney complex

Clinical presentation

Gigantism

Pre-pubertal children (before epiphyseal closure)

Acromegaly

> 50 yrs

Skeletal overgrowth

Hand and foot size
Frontal bossing
Prognathism

Risks of long-term exposure to excess growth hormone (GH)

Arthropathy

Unrelated to age of onset or GH levels

Usually with longstanding acromegaly

Reversibilityᵃ:

a) Rapid symptomatic improvement

b) Bone & cartilage lesions irreversible

Peripheral neuropathy

Intermittent anesthesias, paresthesias

Sensorimotor polyneuropathy

Impaired sensation

Reversibilityᵃ:

Symptoms may improve

Onion bulbs (whorls) do not regress

Cardiovascular disease

Cardiomyopathy

Reduced LV diastolic function
Increased LV mass and arrhythmias
Fibrous hyperplasia of connective tissue

HTN: exacerbates cardiomyopathic changes
Reversibilityᵃ: may progress even with normal GH

Respiratory disease

Upper airway obstruction: caused by soft tissue overgrowth and decreased pharyngeal muscle tone with sleep apnea in ≈ 50%
Reversibilityᵃ: generally improves

Neoplasia

Increased risk of malignancies (especially colon-Ca) & soft-tissue polyps
Reversibilityᵃ: unknown

Glucose intolerance

Occurs in 25% of acromegalics (more common with family history of DM)
Reversibilityᵃ: improves with normalization of GH levels

Carpal tunnel syndrome

Oedematous synovial tissues compress the median nerve because over secretion of growth hormone causes increase of sodium and water retention in the extracellular fluid.

Elevated GH has 2-3x mortality rate from:

HTN
DM
Pulmonary infection
Cancer
Cardiovascular diseases

Disfiguring changes are permanent

Radiographic orofacial findings in a representative patient with acromegaly.

Investigation

Endocrine test

Initial biochemical evaluation

IGF-1 (somatomedin-C) level

An excellent integrative marker of average GH secretion because

It is not secreted in pulses like GH
IGF-I has a long half-life
Mediates most growth hormone actions

To assess for

High GH levels (acromegaly)

The recommended initial test (testing for elevated IGF-1 is extremely sensitive for acromegaly)

Low GH levels

Good test at post op to test for remission:

IGF-1 levels measured 6 weeks postoperatively can be used in most patients to assess remission
Although patients with mildly elevated IGF-I may yet normalize by 3–6 months

Normal levels depend on

Age (peaking during puberty) /2

Normal IGF-1 by age

Age (yrs)	Level (ng/ml)
1-5	49-327
6-8	52-345
9-11	74-551
12-15	143-996
16-20	141-903
21-39	109-358
40-54	87-267
>54	55-225

Gender

Oestrogen may suppress IGF-1 levels

Pubertal stage
Lab

Typical fasting levels by age are shown in

GGC normal values: 97-502 microG/L
A low IGF-1 in the presence of 3 or more other anterior pituitary hormone deficiencies in an otherwise healthy individual is a strong predictor of GH deficiency

Treatment should be considered without dynamic testing.

A low IGF-1 level may be present in 30% % of patients without GH deficiency → will need further dynamic tests of GH secretion.

Be aware

Assays may produce spurious or misleading results in patients with severe liver disease, uncontrolled diabetes, malnutrition, or those taking combined oral contraceptives

Checking a single random GH level

Growth hormone (GH):

Normal basal fasting level is <5ng/ml.
In patients with acromegaly, GH is usually> 10ng/ml but can be normal.
Not a good test because

Pulsatile secretion of GH,

Normal patients may have sporadic peaks up to 50ng/ml.
Occasionally acromegaly may be present even with GH levels as low as 37 pg/ml.

Can be affected by various factors

BMI
Sex
Ethinylestradiol-containing oral contraceptive use

Not reliable indicator and is therefore not recommended

Use OGTT

Confirmatory biochemical testing

Oral glucose tolerance test (OGTT)

Aka:

Oral glucose suppression test (OGST)
Growth hormone suppression test.

General

Best confirmatory test
High glucose will reduce IGF secretion

Indicated

Less precise and more expensive than measuring IGF-1
However, may be more useful than IGF-1 for monitoring initial response to therapy.

Method

Preparation

Fasting from midnight.
19g cannula.
6 Red top Vacutainers.
6 grey top fluoride oxalate tubes

Take blood sample for GH and IGF-1 (into a red top Vacutainer) and glucose (into grey top tube) at T = 0.
Administer 75 grams oral glucose in 300 ml water over about 10 minutes.
Take blood for GH and glucose at t=30, 60, 90 and 120 minutes.
A synacthen test can be carried out at the end of this test, with samples for cortisol taken at t=120, 150 and 180. Synacthen 250 mcg is administered at t=120.

Interpretation

Normal:

Glucose given → IGF 1 rises (IGF 1 not tested) → GH levels fall

At least one of the samples during the test should have undetectable GH levels.
IGF1 is stable (like HbA1c does not change acutely so not tested)

Acromegaly:

Failure of suppression or a paradoxical rise in GH suggests acromegaly.
If the GH nadir (lowest) is not < 1 ng/ml, the patient is acromegalic.
Following treatment, A "safe level" of GH has been thought to be

Less than 10mU/l (3.8 ng/ml).

A failure of GH to suppress to less than 0.4 μg per litre during this test is indicative of acromegaly

More recently, this has been revised to 5mU/l (1.9ng/ml).

Sensitivity and specificity

False positives sometimes occur in patients with anorexia nervosa, or other causes of chronic starvation, although the IGF-1 level is usually normal.
GH suppression may also be absent with liver disease, uncontrolled DM & renal failure.
✖ Relatively contraindicated in patients with DM and high glucose levels

Other tests used uncommonly

Growth-hormone releasing hormone (GHRH) levels

May help diagnose ectopic GH secretion in a patient with proven acromegaly with no evidence of pituitary tumour on imaging.

If an extra-pituitary source is suspected, chest and abdominal CT and/or MRI should also be obtained

GHRH stimulation test

Results may be discordant in up to 50% of patients with acromegaly and is thus rarely used (as of this writing, pharmaceutical production of GHRH has been discontinued)

Insulin-like Growth Factor-Binding Protein 3 (IGFBP-3) measurement

Normal function

A 264-amino acid peptide produced by the liver.
It is the most abundant of a group of IGFBPs that transport and control the bioavailability and half-life of the insulin-like growth factors (IGF), particularly IGF-1,

Not a good test for IGF1

Last option for testing

Octreotide scan

SPECT imaging 4 and 24 hours after injection with 6.5 mCi of indium-111 OctreoScan, a somatostatin receptor imaging agent

Monitoring of associated conditions

Colonic cancer

Monitor with colonoscopy

To screen for and assess the presence of colonic polyps and colorectal cancer.

Influence of Disease Control and History

The overall risk of cancer is reported to decrease when the patient's acromegaly is effectively controlled and IGF-I levels are normalised.
Patients who experienced a diagnostic delay of more than 10 years require diligent monitoring, as they remain at a higher risk of death from oncologic causes.

Cardiac

General

Monitoring the cardiac system in patients with acromegaly is vital because cardiovascular disorders are a major contributor to mortality and are directly correlated with diagnostic delays.

Primary Monitoring Tools

Echocardiography:

Look for

Concentric left ventricular hypertrophy
Valvular dysfunctions such as: aortic, mitral, and tricuspid insufficiency.

Standard and 24-hour ECG:

Look for

Arrhythmias
Electrical disturbances, such as QT-interval prolongation.

24-hour Blood Pressure Measurement:

Continuous monitoring is used to manage hypertension
Has a prevalence of 30 to 60% in these patients and is a major driver of cardiovascular death.

Clinical importance

Acromegalic Cardiomyopathy:

Characterised by diastolic dysfunction and may progress to systolic dysfunction in later stages.

Aortic Dilatation:

Monitoring includes checking for aortic ectasia or dilatation, which can lead to aortic insufficiency.

Risk Factors:

Specialist assessment is particularly urgent for younger patients or those whose cardiac findings occur without other typical risk factors.

Reversibility: While soft tissue hypertrophy may resolve with treatment, left ventricular hypertrophy and hypertension rarely disappear and may even progress despite effective hormonal control.
Ongoing Surveillance: Even when IGF-I levels are normalised, patients require specific treatments for coexisting cardiac conditions that do not remit.
Pre-surgical Management: Patients with severe heart failure or uncontrolled hypertension must be managed medically before undergoing pituitary surgery.

Management

General

Biochemical control remains the strongest predictor of patient outcomes,

Reflecting improvements in glucose metabolism, OSA, cardiovascular disease, and VFs.
However, structural heart and joint changes are unlikely to resolve

Treatment Goals and Success Rates

The primary objectives of treatment are to remove or control the pituitary adenoma, normalise IGF-I and growth hormone (GH) levels, and prevent associated systemic conditions.
Secondary goals include the preservation of anterior pituitary function and the normalisation of life expectancy.

Conservative

Indication

Asymptomatic elderly patients

Do not require treatment since there is little evidence that intervention alters life expectancy in this group

Surgery (transsphenoidal)

Goal of surgery

GH level <1
IGF 1 normalize

Following surgery, an IGF-1 and a random GH should be measured at 12 weeks or later. An age normalised IGF-1 value within the reference range and a GH of 1mcg/L, an OGTT should be performed and a nadir GH should be measured

Primary treatment because

More rapid reduction in GH levels
More rapid decompression of neural structures (e.g. optic chiasm)
Improving the efficacy of subsequent somatostatin analogues.

Somatostatin help reduce tumour size (reduce knosp score)

Medical

Indication

Patients not biochemically cured by surgery

Reoperation doesn’t work very often for acromegaly
Surgery is still helpful for those “not cured” and improves efficacy of other therapies;
IGF-1 may take months to normalize after surgery

Patients cannot tolerate surgery

(e.g. due to cardiomyopathy, severe hypertension, airway obstruction…; these contraindications may improve with medical therapy and then surgery can be reconsidered)

Recurrence after surgery or XRT

The growth hormone (GH)-insulin-like growth factor (IGF) axis with therapeutic entry points for the treatment of acromegaly.

Normal

Release of GH from the pituitary is regulated primarily by growth hormone releasing hormone (GHRH) and somatostatin.
A single GH molecule binds to a constitutively dimerized, yet inactive, GH receptor (GHR) homodimer through sites 1 and 2.
GH interaction with the GHR induces a conformational change and initiates downstream signal-transduction pathways, which promotes peripheral IGF-I secretion from the liver and other tissues.
IGF-I binding to the IGF-I receptor (IGF-IR) mediates growth and metabolic functions.
The IGF-IR binding is modulated by IGF-binding proteins (IGFBPs).

Growth Hormone Derivative - an overview | ScienceDirect Topics

General endocrinology - Knowledge @ AMBOSS

Medical treatment of acromegaly comprises three drug classes:

Dopamine agonists

Dopamine receptor agonists suppress GH hypersecretion through binding to D2 receptors on adenomas.

Has 20% responders so can give a try

Bromocriptine

Dose is higher than prolactinoma: 20-60mg/day in divided doses
Lowers GH levels to

< 10 ng/ml in 54% of cases
< 5 ng/ml in only ≈ 12%.

Tumour shrinkage occurs in only < 20%

Cabergoline

Not as effective as Bromocriptine

Somatostatin analogues (somatostatin receptor ligand)

Long-acting somatostatin analogues act on the somatostatin receptors in the pituitary gland to inhibit GH secretion by the somatotrophs.

Use preop to improve surgical success

As first line or after DA trial

Octreotide (sandostatin)

vs somatostatin

45x more potent in suppressing GH secretion
2x more potent in suppressing insulin secretion

Does not causes rebound GH hypersecretion
Outcomes

GH levels reduced in 71%
IGF-1 levels reduced in 93%
Tumour size reduces significantly in 30%
Many symptoms improve within first few weeks

GH secretion is suppression

Starts in 1st hr,
Peaks at 3 hrs,
And remains reduced for 6–8 hrs

Side effects

GI dysmotility (flatulence, diarrhoea, n/a) → resolves in 10 days
15% bradycardia
15% cholesterol cholelithiasis
Mild hypothyroidism
Worsening of glucose intolerance

Dose:

Short acting 50mcg s/c TDS → inc. 1500mcg/day as required

Long acting 20mg IM every 4 weeks → inc. 30mg

Oral octreotide capsules

Initiated at a dose of 60 mg/day, given as 20 mg capsules TDS taken 1 h before a meal or 2 h after a meal to maximize bioavailability
OPTIMAL study demonstrate that biochemically controlled patients (IGF-I≤1.0×ULN) on stable doses of injectable octreotide or lanreotide maintain response to OOC
There are no data on the use of OOC as primary medical therapy in SRL-naïve patients. However, it is reasonable to expect that patients who respond to injectable octreotide LAR or lanreotide in this setting would also respond to OOC

Lanreotide

Predictor of good response to Somatostatin analogues (primary lanreotide 120 mg therapy every 4 weeks) → this might be true for other somatostatin analogues

Older age
Female sex
Lower IGF-I levels
Lower tumor T2 MRI hypointensity at baseline

Pasireotide

Somatostatin receptors agonist
Several studies confirm efficacy of pasireotide LAR for some patients uncontrolled on lanreotide or octreotide LAR.
However, rates of treatment induced hyperglycaemia and DM are high, requiring careful monitoring for glycemic side effects.

GHR antagonists

The GH analogue Pegvisomant contains amino-acid substitutions in the GHR binding sites, which blocks GH-induced signalling.

Site 1 contains eight amino acid substitutions that improve receptor binding
Site 2 contains a single amino acid substitution that blocks the conformational rearrangement of the GHR.

Very expensive

Indicated

If IGF1 level not controlled with:

Somatostatin analogues
Dopamine agonist
Surgery
Radiotherapy

Sim is the normalization of IGF-1 levels

Treatment for >12 months

Normal IGF-1 levels in 97% of patients.
No change in pituitary tumour size has been observed.

Side effects:

Hypoglycemia Associated with GH Lowering in Patients with Diabetes Mellitus
Significant but reversible liver function abnormalities occur in < 1%.
Antibodies to GH occurred in 17%, but tachyphylaxis was not observed
Lipohypertrophy

A lump of fatty tissue under your skin caused by repeated injections in the same place

Cross-Reactivity with GH Assays
Serum GH typically increases for 5–6 months and then stabilizes, probably as a result of loss of negative feedback on IGF-1 production.

Dosage

5–40mg/d S/C

Dose must be titrated to keep IGF-1 in the normal range, to avoid GH deficiency conditions
Patients with DM and those with a higher BMI require higher doses of pegvisomant and more rapid up-titration to achieve IGF-I normalization

Evidence

Ten-year follow-up from ACROSTUDY shows a 73% biochemical control rate with very low rates of transient elevated transaminases and 6.8% exhibiting tumor growth visible on MRI.

Combination therapy

May be more effective than individual drugs.
GH antagonist + somatotrophic analogue

Low-dose octreotide LAR or lanreotide + weekly pegvisomant
Pasireotide + pegvisomant

Can yield biochemical control rates exceeding 70% even when pegvisomant doses are kept low.
However, the addition of pegvisomant does not ameliorate the high rates of pasireotide-induced hyperglycemia

Radiotherapy

Indication

Failure of medical therapy.

Not recommended as initial treatment.
GH levels decline very slowly after XRT
Evidence

Graffeo 2020 n102 retrospective: SRS

57% achieved biochemical control at a median of 19 months
22 patients persisted with active disease despite adjuvant medical treatment

German Acromegaly Registry:

RT type

Fractionated radiotherapy (FRT) (n=233)
SRS (n=119)

Follow up 45 years
Outcome

	FRT	SRS
Median time to achieve disease control	3.0 years	2.1 years
10-year remission rate	48%	52%

Side effects

Graffeo 2020 29% developed hypopituitarism at a median of 29.5 months with SRS
German Acromegaly Registry: adrenocorticotropin (ACTH) and thyrotropin (TSH) deficiencies were more common with FRT than with SRS

Outcome

The observed decline in reported mortality among acromegaly patients is likely due to more effective therapies, which, in turn, yield higher biochemical control rates and reduce the likelihood of developing respiratory and cardiovascular comorbidities that increase mortality

Surgical outcomes

Women, especially when postmenopausal, may exhibit lower surgical remission rates from TSS, as they tend to have

Larger and more invasive tumours that are less amenable to total resection.

Patient age is likely not a predictor of surgical outcomes, nor does it impact the favourable effects of postsurgical remission on alleviating disease comorbidities.
Surgery results in biochemical control for more than 75% of patients with microadenomas and approximately 50% of those with macroadenomas at experienced centres.

Medical outcomes

Medical treatments such as somatostatin receptor ligands maintain control in 30% to 50% of patients, while growth hormone antagonists like pegvisomant can lead to biochemical control in 70% to 90% of cases.

Radiotherapy outcomes

Long-term follow-up of patients treated with SRS and fractionated radiotherapy show that approximately 50% achieve and maintain biochemical control.

However, up to 1/3 of patients with normal pituitary function develop hypopituitarism, confirming the need for ongoing monitoring.

Reversibility of Systemic Complications

Resolvable Manifestations: Once hormonal control is achieved, hyperglycaemia, carpal tunnel syndrome, and soft tissue hypertrophy may resolve.
Persistent Manifestations: Conditions such as hypertension, left ventricular hypertrophy, sleep apnoea, and arthropathy can be ameliorated but rarely disappear and may even progress despite effective treatment.
Bone Health: Vertebral fractures remain a significant risk and can occur even in patients whose IGF-I levels have been successfully normalised.
Cancer Risk: The overall risk of cancer appears to decrease when the disease is effectively controlled.

Survival and Mortality

Improved Survival Factors: Prolonged survival is strongly associated with a shorter time to remission, the use of surgery, and treatment with somatostatin receptor ligands.
General Trends: Recent data shows lower mortality rates than in the past due to improved global guidelines and follow-up for coexisting conditions.
High-Risk Subpopulations: An increased standardized mortality rate persists for certain groups, particularly those with a diagnostic delay of more than 10 years, older patients, and women.