Based from Acromegaly: An Endocrine Society Clinical Practice Guideline 2014

1. ACROMEGALY
By Farah Adibah Kasmin
Post Graduate, Faculty of
Medicine, UITM, Malaysia

2. GH physiology and pathogenesis of acromegaly
Approaches to the diagnosis and management of acromegaly

3. GH PHYSIOLOGY

4. PATHOGENESIS OF ACROMEGALY

5. CLINICAL FEATURES
The clinical features of acromegaly are due to local effects of an
expanding pituitary mass, as well as to the direct and indirect effects
of excessive secretion of GH and IGF-1, which can lead to systemic
complications and impaired quality of life.

6. LOCAL TUMOUR EFFECT
Headache
-60% of patients and may be severe and disproportionate to the size of the tumour.
Visual disorder
-Due to compression to the optic chiasm, leading to visual field disturbances, which begin
in the mid-periphery of the superior temporal sectors, then progress to bitemporal
hemianopia.
Other manifestations
-In case huge pituitary adenoma, hydrocephalus, unilateral exophthalmos due to orbital
invasion and seizures can present.
-¾ of patient have some degree of hypopituitarism upon diagnosis.
-1/3 is found to have Hyperprolactinemia as a consequence of pituitary stalk compression.

7. SYSTEMIC MANIFESTATION
1. Acral growth.
-Excessive growth of hands and feet due to soft tissue swelling, which increases the width of
the fingers, hands (spade-like hands) and feet, leading do successive changes in shoe, glove
and ring size.
-Osteoarthritis and joint hyperlaxity can also contribute to hands deformities.

8. 2. Orofacial changes.
-Typical facial features include pronounced brow protrusion, furrowing of front head,
enlargement of the nose and the ears, thickening of the lips, skin wrinkles and nasolabial
folds, as well as mandibular prognathism that leads to dental malocclusion and increased
interdental spacing.
-Macroglossia contributes to the appearance of obstructive sleep apnea.
-Sonorous voice deepening often occurs due to laryngeal hypertrophy and enlarged
paranasal sinuses.

9. 3. Skin and appendices changes
-Glycosaminoglycan deposition, increased connective tissue collagen production, and edema
lead to skin puffiness, facial skin wrinkles, nasolabial folds and heel pads thicken as well as
thickened skin, especially on palms of hands or soles of feet.
-Enlargement of sebaceous glands leads to hyperhidrosis and malodorous oily skin. These
are common early signs, up to 70% of patients.
-Skin tags may be markers for the adenomatous colonic polyps.
-Acanthosis nigricans, due to insulin resistance is also encountered.
-Alteration in skin capillaries produce increased vasoconstriction causing Raynaud’s
phenomenon is reported in up to 1/3 of patients.
- Hirsutism and hypertrichosis may also be found, and body hair may become coarsened.

10. 4. Musculoskeletal features
-Acromegalic arthropathy can affect up to 84% of the cases, especially older patients or
females, and any joint may be involved.
-Patients exhibit joint swelling, hypermobility, and cartilaginous thickening.
-Debilitating osteoarthritis may result in bone remodeling, osteophyte formation,
subchondral cysts, narrowed joint spaces, and periarticular ligament laxity.
-Carpal tunnel syndrome found in 20–64% of patients due to neural enlargement and wrist
tissue swelling.

11. SYSTEMIC COMPLICATIONS
1. Metabolic
- Excess GH associated with insulin resistance (in the liver and in periphery),
increased gluconeogenesis and lipolysis, and decreased peripheral glucose uptake.
-40-52%: Impaired glucose tolerance
-28-46%: Diabetes Mellitus
-Others: Dyslipidemia (particularly HyperTG, elevated lipoprotein-a and an excess
LDL particles)

12. 2. Cardiovascular
-35% mean prevalence of Hypertension.
-Valvulopathies especially aortic or mitral regurgitation.
-Arrhythmias.
-Concentric hypertrophy predominantly affecting the left ventricle, diastolic dysfunction and
progressive systolic impairment eventually leading to heart failure.
-If heart disease is present at diagnosis there is a mortality rate of 100% within 15 years.

13. 3. Neurologic disorders
-Intracranial aneurysms, herniation of cerebellar tonsils, hearing loss and pituitary apoplexy.
- Pituitary apoplexy may result in spontaneous remission of acromegaly due to complete
destruction of the tumour.
4. Neoplastic complications
-It happens presumably due to the stimulatory effect of the IGF-1 on tumourigenesis hence
increased risk of certain tumours.
-Colorectal neoplasia: Benign tumors > Adenomas and hyperplastic polyps, Malignant >
colon cancer.
-Thyroid neoplasia: Thyroid nodules (approximately 25% with toxic nodules, 18–20% with
diffuse goiter, and 1.2–7.2% with thyroid cancer particularly, papillary carcinomas.

15. PRESENTATION OF ACROMEGALY

16. DIAGNOSIS OF ACROMEGALY
Biochemical:
1. Measure insulin-like growth factor 1 (IGF-1)
- Patients with typical clinical manifestations of acromegaly, especially with acral and
facial features.
-Patients without the typical manifestations of acromegaly, but have several of these
associated conditions: sleep apnea syndrome, T2DM, debilitating arthritis, carpal tunnel
syndrome, hyperhidrosis, and hypertension.
-Patient need to rule out acromegaly in a patient with a pituitary mass.
2. Elevated or equivocal serum IGF-1 levels, recommend for confirmation of
the diagnosis by doing oral glucose load test.
3. Confirmation of the diagnosis by finding lack of suppression of GH to <1
microgram/L following documented hyperglycemia during an oral glucose
load test.

17. Radioimaging
Pituitary MRI as the imaging modality of choice
-To visualize tumour size and appearance, as well as parasellar extent.
Visual field
-Performing formal visual field testing when the tumour is found to abut the optic chiasm on an
imaging.
-Visual impairment due to optic nerve compression by the tumour dictates the choice and rapidity
of treatment.
Others
-Evaluate for associated comorbidities including Hypertension, DM, Dyslipidemia, CVD, OSA and
OA.
-Screening Colon neoplasia with Colonoscopy at diagnosis.
-USG Thyroid if there is palpable thyroid nodularity.
-Assessing for hypopituitarism.

18. MANAGEMENT
Goals of treatment are biochemical normalization, reduction of mortality
risk, attenuation of symptoms, control of tumour mass, and maintenance of
pituitary function. Hence, the targets are:
1. Biochemical target goal of an age normalized serum IGF-1 value.
2. Random GH <1.0 microgram/L as a therapeutic goal.
3. Maintaining the same GH and IGF-1 assay in the same patient throughout management.

19. SURGERY
1. Transsphenoidal surgery as the primary therapy in most patients.
- Successful surgery produces immediate lowering of GH levels and provides tumour
tissue for pathological characterization.
- With experienced pituitary surgeons, microscopic or endoscopic transsphenoidal
microsurgery results in an initial remission rate > 85% for microadenomas and 40-50% for
macroadenomas.
- Complications from surgery include bleeding, spinal fluid leak, meningitis, sodium and
water imbalance, and hypopituitarism.
- Five-year disease recurrence rates range from 2 to 8%.
- Patient with persistent disease after surgery, repeat surgery may be useful when the
tumor is accessible.
- Role of pre operative medical therapy: SRLs indicated for patients with severe pharyngeal
thickness, OSA or high-output heart failure, to reduce surgical risk from severe
comorbidities.

20. 2. Surgical debulking
-Patient with a macroadenoma with low likelihood of surgical cure due to extrasellar
extension and no evidence of local compressive mass effects, surgical debulking can be
done to enhance subsequent medical therapy.
-In a prospective study, there was improved GH and IGF-1 response to lanreotide from 31 to
69% and from 42 to 89%, respectively, before and after surgical debulking.

21. POST OPERATIVE
1. To measuring an IGF-1 level and a random GH at 12 weeks or later.
2. And measuring a nadir GH level after a glucose load test in a patient with a GH
greater than 1microgram/L.
3. A serum GH <0.14 microgram/L suggests “surgical remission,” and a level
<1microgram/L indicates “control” and normalization of the mortality risk.
4. Perform imaging study of Pituitary MRI at least 12 weeks after surgery to visualize
residual tumour and adjacent structures.

22. MEDICAL THERAPY
1. Patient with persistent disease following surgery.
2. Patient with significant disease (ie: moderate- to-severe signs and
symptoms of GH excess and without local mass effects), use of either
a SRL or pegvisomant as the initial adjuvant medical therapy.
3. Patient with only modest elevations of serum IGF-1 and mild signs
and symptoms of GH excess, for trial of a dopamine agonist, usually
cabergoline, as the initial adjuvant medical therapy.

23. 1. SOMATOSTATIN RECEPTOR
LIGANDS (SRLS)
- As primary therapy in a patient who cannot be cured by surgery,
has extensive cavernous sinus invasion, does not have chiasmal
compression or is a poor surgical candidate.
- First-generation SRLs (octreotide acetate, octreotide long-acting
release [LAR], lanreotide depot, oral octreotide) and a second
generation SRL (pasireotide LAR) activate distinct subsets of
somatostatin receptors (SSTRs), thereby inhibiting GH secretion while
promoting apoptosis and exerting anti proliferative effects.
- Effectiveness of treatment is based on measurement of serum IGF-1
and GH, which should be measured after 12 weeks just prior to the
next dose.

24. 2. PEGVISOMANT
- It is a human GH receptor antagonist, competes with endogenous
GH for binding at its receptor and blocks peripheral production of
IGF-1.
- It is administered SC as 10-, 15-, or 20-mg daily injections.
- Serial imaging with MRI scan is suggested to evaluate tumour size
in a patient receiving pegvisomant.

25. 3. DOPAMINE AGONIST
- Cabergoline is most likely to be useful in patients with just modest
elevations of GH and IGF-1 levels, with or without concomitant
hyperprolactinemia.
- Cabergoline doses administered to patients with acromegaly are
often above the usual dose range advised in hyperprolactinemic
patients (0.5 to 2.0 mg/week).
- Adverse effects: nausea, vomiting, orthostatic dizziness, headache,
nasal congestion, constipation, and digital vasospasm.

26. 4. COMBINATION THERAPY
Combining medical therapies may improve efficacy, reduce side
effects associated with an individual medication, decrease the
frequency of injections and total drug dose, and potentially offer a
cost benefit and improved compliance during long-term treatment.
SRL + pegvisomant: Normalization of IGF-1 in 95% of patients.
SRL + cabergoline: Normalization of IGF-1 in 42 - 60% of patients.
Pegvisomant + cabergoline: Normalization of IGF-1 in 68% of
patients.

27. RADIOTHERAPY (RT)/STEREOTACTIC
RADIOTHERAPY(SRT)
- Indicated for residual tumour mass following surgery as an adjuvant
therapy or if medical therapy is unavailable, unsuccessful, or not
tolerated.
- After RT, recommended for periodic withdrawal of medical therapy
1 to 3 months (depending on the specific drug) for reassessment of
GH and IGF-1 levels.
- Remission rates of 10–60% have been reported with SRT.
- SRT includes: Gamma knife, CyberKnife, and a linear accelerator.
- Although the overall efficacy of SRT may be similar to conventional
RT, time to remission may be shorter with SRT.
- Annual hormonal testing of patients recommended following RT for
hypopituitarism and other delayed radiation effects.

29. REFERENCES
1. Laurence Katznelson, Edward R. Laws, Jr, Shlomo Melmed, Mark E.
Molitch, Mohammad Hassan Murad, Andrea Utz, John A. H. Wass,
Acromegaly: An Endocrine Society Clinical Practice Guideline, The
Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 11,
1 November 2014, Pages 3933–3951,
https://doi.org/10.1210/jc.2014-2700
2. Vilar, L., Vilar, C.F., Lyra, R. et al. Acromegaly: clinical features at
diagnosis. Pituitary 20, 22–32 (2017).
https://doi.org/10.1007/s11102-016-0772-8
3. Nazanin Ershadinia, MD, Nicholas A. Tritos, MD, DSc , Diagnosis
and Treatment of Acromegaly: An Update, MayoClinic Proceeding,
VOLUME 97, ISSUE 2, P333-346, FEBRUARY 01, 2022,
https://doi.org/10.1016/j.mayocp.2021.11.007