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.