Table 2.

Key recommendations

Overall

Referral to a multidisciplinary pituitary center should be considered for patients with equivocal biochemical, pathology, or imaging findings at diagnosis, and for patients insufficiently responsive to standard treatment approaches.

Diagnostic assessment

For all biochemical assessments, clinicians should know which assay is being used, which factors influence its performance, how normal ranges are obtained, and how it has been calibrated and validated.

In a patient with typical clinical signs and symptoms of acromegaly, IGF-I > 1.3×ULN for age confirms the diagnosis. Random GH measured after overnight fasting may be useful for informing prognosis, but is not required for diagnosis. For patients with equivocal results, IGF-I measurements can be repeated using the same validated assay, and OGTT might additionally be useful.

IGF-I and GH Assays

Well-validated IGF-I assays should be calibrated to the current international standard (02/254). Age-stratified reference ranges should be based on adequate numbers of subjects; sex-stratified reference ranges are likely not required beyond puberty if the normative population is sufficiently large.

BMI might influence normal IGF-I ranges, such that patients with high BMI have lower IGF-I levels for their age group. Nutritional, genetic, metabolic, and hepatic factors can also impact IGF-I concentrations, often inducing states of GH resistance.

There is currently no evidence that IGF-I measurement by mass spectrometry is superior to measurement by immunoassay.

Calibration to the current international standard for GH (98/574) should be standard with immunoassays but has not been validated for mass spectrometry.

OGTT

If OGTT is performed, 75 g glucose should be administered after fasting, and GH nadir assessed after 30, 60, 90, and 120 min.

BMI-based GH nadir cutoffs of < 0.4 µg/L for BMI < 25 kg/m2 and < 0.2 µg/L for BMI ≥ 25 kg/m2 can be considered.

Cessation of oral estrogen therapy 4 weeks prior to OGTT may avoid its effects on the GH axis.

OGTT can be safely performed among patients with impaired glucose tolerance or type 2 diabetes mellitus. However, in patients with uncontrolled diabetes, both random and post-OGTT GH levels should be interpreted with caution.

Measurement of basal and 120-minute glucose levels during OGTT is useful for detecting disturbances in glucose homeostasis.

Clinical, Imaging, and Pathology Assessments

A careful history and physical exam is required as it will often reveal unequivocal signs and symptoms related to local mass effect or secondary features of GH and IGF-I hypersecretion.

Gadolinium-enhanced pituitary MRI should be performed in patients at diagnosis using high-quality, high-resolution equipment.

Reporting should include information on invasion into surrounding structures based on modified Knosp grade.

Equivocal diagnosis of acromegaly associated with pituitary microadenomas should be referred for review by an experienced neuroradiologist before considering further imaging studies.

Standard pathology reporting should include immunohistochemistry assessment for pituitary hormones. Transcription factors can be used to define adenoma lineage and further characterize adenoma cell type when not classifiable on hormone expression alone.

Clinical implications of the 2022 WHO classification suggesting that pituitary adenomas could also be called pituitary neuroendocrine tumors remain unclear and the ongoing ramifications for acromegaly patients are not apparent.

Diagnostic delay

Prolonged exposure to excess GH with diagnostic delay leads to increased comorbidity and mortality risks with decreased QOL, and could lead to reduced treatment success and increased need for additional therapy.

Strategies aimed at reducing diagnostic delay should be implemented worldwide as they may reduce short-term and long-term morbidity and positively impact QOL.

All patients with a newly diagnosed pituitary mass should undergo IGF-I measurement.

Although widespread screening in the general population is not warranted, IGF-I screening could be considered in individuals with classical signs, symptoms, and comorbidities of acromegaly including acral enlargement and orofacial changes, particularly if these occur in conjunction with unexplained systemic manifestations such as sleep apnea or ventricular hypertrophy.

A systematic approach should be implemented among healthcare practitioners to increase awareness about acromegaly. Outreach strategies in collaboration with patient advocacy groups such as for other rare diseases could also help promote earlier referral for diagnostic testing.

Criteria for remission

The term “remission” indicating that active disease cannot be detected even if it might still be present is the most accurate descriptor for biochemical treatment outcome goals in acromegaly.

Although biochemical remission is the primary assessment of treatment outcome, it is not the only goal of treatment in acromegaly. In all cases, biochemical findings should be interpreted within the clinical context of acromegaly signs and symptoms.

Maintaining serum IGF-I level in the mid to upper half of the age-related reference range could be considered in clinically controlled patients to avoid induction of GH deficiency.

Postoperative remission

There are no definitive studies on the optimal assessment for postoperative remission, nor of the timing of its evaluation.

IGF-I should be measured at 12 weeks after surgery to determine postoperative biochemical remission. Early random GH assessment on day 1–14 and comparison with preoperative GH can inform the degree of adenoma removal and subsequent longer-term remission.

OGTT assessment may provide further predictive value.

In patients treated with preoperative SRL, assessment should be repeated at 3–6 months to confirm remission.

Remission With Adenoma-Directed Medical Therapy

For patients treated with injectable SRL, IGF-I level measurement in the last week before the next injection should be used to determine a need for dose titration or consideration of alternative treatment options if normalization is not achieved.

For patients treated with oral SRL administered daily, assessment of IGF-I for the purposes of dose titration should be done after at least 2 weeks of treatment.

Timing of IGF-I assessment is not critical for patients treated with cabergoline administered in more than once-weekly intervals.

With all of these agents, random GH assessment is not likely to provide additional information in all patients but could be considered for symptomatic patients with IGF-I levels at the higher end of the ULN.

Remission With Peripherally Directed Medical Therapy

For patients treated with medical therapy that targets the GH receptor or the estrogen receptor, efficacy assessment is limited to IGF-I normalization.

With these agents, GH assessment is not informative and should not be performed.

Follow up

Follow up assessments should consider biochemical evaluation of treatment effectiveness, imaging studies evaluating residual/recurrent adenoma mass, and clinical signs and symptoms of acromegaly and its complications and comorbidities.

Biochemical

Within the first postoperative year, IGF-I measurements every 3–6 months may be appropriate to confirm remission, and then every 6–12 months to monitor for potential recurrence. OGTT might be helpful in evaluating patients with borderline IGF-I levels and clinical signs of disease activity.

For patients who did not achieve postoperative remission and who are treated with adjuvant SRL, IGF-I should be assessed 3 months after initiation/dose adjustment of injectable SRL and 2–4 weeks after initiation/dose adjustment of oral SRL to establish an optimal dosing regimen, and then every 6–12 months thereafter once biochemical control is achieved. Random GH might be helpful in select cases where evaluation of adenoma behavior is a concern.

As pegvisomant and cabergoline have a shorter half-life than injectable SRL, IGF-I should be assessed every 1–3 months after initiation/dose adjustment to establish the dosing regimen, and then every 6–12 months thereafter.

In patients receiving medical therapy as a bridge until radiotherapy effect is seen, IGF-I should be assessed at the intervals appropriate for the medical therapy used. With sustained decline of IGF-I within the target range, treatment can be paused at least once each year depending on rapidity of the IGF-I decline to test for the onset of radiation-induced remission.

For all patients, ideally, the same well-validated IGF-I assay should be used for all assessments. New or persistent elevations in IGF-I levels should be interpreted within the context of the individual clinical scenario and account for factors that could affect results such as pregnancy, estrogen use, starvation, and metabolic changes.

Imaging

The same standards for imaging and results reporting should be used in follow up as in diagnosis.   MRI should be performed at 3–6 months postoperatively and used as baseline for further assessments.   MRI should be performed upon signs of biochemical or clinical disease progression, and when a change in therapeutic modality is considered, such as prior to a second surgery or radiotherapy.   An individualized approach to MRI is appropriate for patients treated with pegvisomant based on country-specific labeling requirements, as well as for those with genetic markers or prior imaging suggestive of highly aggressive disease.

Clinical assessment

This Workshop endorsed evaluation and treatment of disease comorbidities according to prior consensus recommendations. The need for assessment of common comorbidities, such as hypopituitarism, obstructive sleep apnea, and vertebral fractures depends on clinical symptoms and adenoma behavior, and follow up according to accepted guidelines was recommended.

There was no consensus at this Workshop on whether colonoscopy should be performed in all acromegaly patients at diagnosis regardless of age. For all other cancers with reported increased frequency in acromegaly, including thyroid cancer, there was consensus that screening be performed according to national/regional guidelines for the general population.

SAGIT and ACRODAT may be useful in current clinical practice for assessing changes in acromegaly disease severity and progression over time. A prospective study measuring a clinically beneficial effect of ACRODAT as a monitoring tool is underway.

Considerations for second- and third-line treatment selection

Follow up assessments identify patients more likely to show a favorable response to second- and third-line medical therapy options if needed.

Results of follow up assessments can also be used to identify patients who might benefit from treatment options that have an improved safety profile or more convenient dosing regimen.

BMI body mass index; GH growth hormone; IGF-I insulin-like growth factor I; MRI magnetic resonance imaging; OGTT oral glucose tolerance test; QOL quality of life; SRL somatostatin receptor ligand; WHO World Health Organization; ULN upper level of normal