Novel Molecular Insights into the Combination Treatment of Acromegaly

In chapter 2 of this thesis we have confirmed that LA-SSA in combination with PEGV as a treatment modality for acromegaly still appears to be highly effective, after almost a decade of experience in the Rotterdam cohort (n=112). Normalization of IGF-I levels occurred in 97% of the patients, provided that the required PEGV dose was used. The median PEGV dose to achieve this efficacy rate was 80 mg/week [interquartile range: 60 – 120 mg]. Side effects such as lipohypertrophy (2.8%) and elevated transaminases of more than three times the upper limit of normal (13.5%) were mild and transient (n=141). Tumor size control and even tumor shrinkage is observed in a vast majority of patients. Pituitary tumor size increase was observed in one patient. Normalization of IGF-I levels in acromegaly patients is associated with the expression of SSTR2 on somatotroph adenomas. In the Rotterdam cohort (n=39), the SSTR2 expression was lower in patients pre-treated with LA-SSA and PEGV compared to drug-naive acromegaly patients after transsphenoidal surgery, which is described in chapter 3. Moreover, a higher required PEGV dose in combination with LA-SSA was needed in patients with a lower SSTR2 expression on drug-naive somatotroph adenomas to achieve normalized IGF-I levels. (Partial) resistance for LA-SSA alone could be one of the reasons why these patients with a lower SSTR2 expression necessitate LA-SSA in combination with PEGV. Chapter 4 and 5 focus on the common growth hormone polymorphism lacking exon 3, which is associated with disease severity and has been reported to be more responsive to PEGV treatment in acromegaly patients. Clinical data from the Rotterdam cohort (n=112) does not support a role for GHR genotype in treatment response or PEGV dosing nor PEGV serum levels in patients treated with LA-SSA in combination with PEGV. A meta-analysis obtained from four separate study cohorts including the Rotterdam cohort (n=324), confirmed that the presence of the d3- GHR in acromegaly patients has no impact on clinical practice. The polymorphism was not of added value for either the determination of the required PEGV dose or the prediction of PEGV responsiveness. Finally, the last study of this thesis did identify predictors for PEGV dosing. IGF-I levels, weight, height and age are associated with the required PEGV dose in order to normalize IGF-I levels in addition to LASSA. The IGF-I normalization dosage during PEGV monotherapy is only associated with patients weight. A multivariate prediction model which can be used as a clinical guidance tool for PEGV dosing in addition to LASSA can be found in chapter 6

Novel Molecular Insights into the Combination Treatment of Acromegaly

In chapter 2 of this thesis we have confirmed that LA-SSA in combination with PEGV as a treatment modality for acromegaly still appears to be highly effective, after almost a decade of experience in the Rotterdam cohort (n=112). Normalization of IGF-I levels occurred in 97% of the patients, provided that the required PEGV dose was used. The median PEGV dose to achieve this efficacy rate was 80 mg/week [interquartile range: 60 – 120 mg]. Side effects such as lipohypertrophy (2.8%) and elevated transaminases of more than three times the upper limit of normal (13.5%) were mild and transient (n=141). Tumor size control and even tumor shrinkage is observed in a vast majority of patients. Pituitary tumor size increase was observed in one patient. Normalization of IGF-I levels in acromegaly patients is associated with the expression of SSTR2 on somatotroph adenomas. In the Rotterdam cohort (n=39), the SSTR2 expression was lower in patients pre-treated with LA-SSA and PEGV compared to drug-naive acromegaly patients after transsphenoidal surgery, which is described in chapter 3. Moreover, a higher required PEGV dose in combination with LA-SSA was needed in patients with a lower SSTR2 expression on drug-naive somatotroph adenomas to achieve normalized IGF-I levels. (Partial) resistance for LA-SSA alone could be one of the reasons why these patients with a lower SSTR2 expression necessitate LA-SSA in combination with PEGV. Chapter 4 and 5 focus on the common growth hormone polymorphism lacking exon 3, which is associated with disease severity and has been reported to be more responsive to PEGV treatment in acromegaly patients. Clinical data from the Rotterdam cohort (n=112) does not support a role for GHR genotype in treatment response or PEGV dosing nor PEGV serum levels in patients treated with LA-SSA in combination with PEGV. A meta-analysis obtained from four separate study cohorts including the Rotterdam cohort (n=324), confirmed that the presence of the d3- GHR in acromegaly patients has no impact on clinical practice. The polymorphism was not of added value for either the determination of the required PEGV dose or the prediction of PEGV responsiveness. Finally, the last study of this thesis did identify predictors for PEGV dosing. IGF-I levels, weight, height and age are associated with the required PEGV dose in order to normalize IGF-I levels in addition to LASSA. The IGF-I normalization dosage during PEGV monotherapy is only associated with patients weight. A multivariate prediction model which can be used as a clinical guidance tool for PEGV dosing in addition to LASSA can be found in chapter 6

Combined treatment of somatostatin analogues with pegvisomant in acromegaly

Treatment of acromegaly with monotherapy long-acting somatostatin analogues (LA-SSA) as primary treatment or after neurosurgery can only achieve complete normalization of insulin-like growth factor I (IGF-I) in roughly 40 % of patients. Recently, one of the acromegaly consensus groups has recommended switching to combined treatment of LA-SSA and pegvisomant (PEGV) in patients with partial response to LA-SSAs. This combination of LA-SSA and PEGV, a growth hormone receptor antagonist, can normalize IGF-I levels in virtually all patients, requiring that the adequate dose of PEGV is used. The required PEGV dose varies significantly between individual acromegaly patients. One of the advantages of the combination therapy is that tumor size control or even tumor shrinkage can be observed in a vast majority of patients. The main side effects of the combination treatment are gastrointestinal symptoms, lipohypertrophy and transient elevated liver transaminases. In this review we provide an overview of the efficacy and safety of the combined treatment of LA-SSAs with PEGV

Somatostatin Receptor Expression in GH-Secreting Pituitary Adenomas Treated with Long-Acting Somatostatin Analogues in Combination with Pegvisomant

Background: Growth hormone secreting pituitary adenomas (somatotroph adenoma) predominantly express somatostatin receptors (SSTRs) subtypes 2 and 5. Higher SSTR2 expression on somatotroph adenomas results in a better response to somatostatin analogues (SSAs), which preferentially bind, but also down regulate, SSTR2. The effect of the combined treatment with SSAs and the GH receptor antagonist pegvisomant (PEGV) on SSTR expression in somatotroph adenomas is currently unknown. Aim of the Study: To assess SSTR2 and SSTR5 expression in three groups of somatotroph adenomas: drug-naive, treated with long-acting (LA) SSA monotherapy, or LA-SSA/PEGV combination therapy before surgery. Additionally, we evaluated the required PEGV dose to achieve IGF-I normalization in relation to the SSTR expression. Materials and Methods: At our Pituitary Center Rotterdam, we selected acromegalic patients who underwent transsphenoidal neurosurgery. All patients were eventually treated with LA-SSA/PEGV combination therapy during their medical history. SSTR2 and SSTR5 expression in somatotroph adenomas tissues was determined using immunohistochemistry. Results: Out of 39 somatotroph adenoma tissue samples, 23 were drug-naive, 9 received pre-treatment with LA-SSA and 7 LA-SSA/PEGV combined treatment. SSTR2 expression was significantly higher in treatment-naive compared to combined treatment somatotroph adenomas (p = 0.048), while SSTR5 expression did not differ. Noteworthy, SSTR2 expression in naive somatotroph adenoma tissues was inversely correlated to the required PEGV dose to achieve IGF-I normalization during post-surgical medical treatment (ρ = -0.538, p = 0.024). Conclusion: In our specific cohort, the SSTR2 expression is lower in patients pre-treated with LA-SSA/PEGV compared to the drug-naive acromegalic patients. Additionally, the SSTR2 expression in treatment naive somatotroph adenoma tissues was inversely correlated with the required PEGV dose to achieve IGF-I normalization