ABSTRACT: Dopamine agonist resistance in prolactinoma is an infrequent phenomenon. Doses of cabergoline (CAB) of up to 2.0 mg/week are usually effective in controlling prolactin (PRL) secretion and reducing tumor size in prolactinomas. The clinical presentation, management, and outcome of patients that are not well controlled by such commonly used doses of CAB-resistant patients are poorly understood.
A multicenter retrospective study was designed to collect a large series of resistant prolactinoma patients, defined by uncontrolled hyperprolactinemia on CAB ≥2.0 mg weekly.
Ninety-two patients (50 F, 42 M) were analyzed. At diagnosis, most had macroprolactinomas (82.6%); males were significantly older than females (P=0.0003) and presented with a more aggressive disease. A genetic basis was identified in 12 patients. Thirty-six patients (39.1%) received only medical therapy, most underwent surgery (60.9%, including multiple interventions in 10.9%), and 14.1% received postoperative radiotherapy. Eight patients developed late CAB resistance (8.7%). The median maximal weekly dose of CAB (CAB(max/w)) was 3.5 mg (2.0-10.5). Despite a higher CAB(max/w) in patients treated with multimodal therapy (P=0.003 vs exclusive pharmacological treatment), a debulking effect of surgery was shown in 14 patients, with a higher rate of PRL control (P=0.006) and a significant reduction in CAB(max/w) (P=0.001) postoperatively. At last follow-up (median 88 months), PRL normalization and tumor disappearance were achieved in 28 and 19.9% of the patients respectively, with no significant sex-related difference observed in CAB(max/w) or disease control. Mortality was 4.8%, with four patients developing aggressive tumors (4.3%) and three a pituitary carcinoma (3.3%).
CAB-resistant prolactinomas remain a serious concern. Surgical debulking, newer therapeutic strategies, and early diagnosis of genetic forms could help to improve their outcome.
European Journal of Endocrinology 08/2012; 167(5):651-62. · 3.42 Impact Factor
ABSTRACT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown.
The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA).
This was a multicenter, international, collaborative study.
The study was conducted in 34 university endocrinology and genetics departments in nine countries.
Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis.
Presence/absence and description of AIP gene mutations were the main outcome measures.
There was no intervention.
Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations.
AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.
Journal of Clinical Endocrinology & Metabolism 06/2007; 92(5):1891-6. · 6.50 Impact Factor
ABSTRACT: Somatostatin (SST) analogues play an important role in the medical management of somatotroph pituitary adenomas and new agonists have the potential to be effective in a wider group of pituitary and other tumours. The anti-proliferative effect of SST occurs through multiple mechanisms, one of which is cell-cycle arrest, where p27, a cyclin-dependent kinase inhibitor, is an important regulator. We hypothesised that SST may upregulate p27 protein levels and downregulate the MAP kinase pathway in these tumours.
Human pituitary adenoma cells and rat pituitary cell line (GH3) were cultured and treated in vitro with octreotide and the broad-spectrum SST agonist SOM230 (pasireotide). Immunoblotting for p27 and phospho-ERK (pERK) was performed and proliferation assessed by [3H]-thymidine incorporation. Histological samples from acromegalic patients treated with octreotide before surgery were immunostained for p27 and compared to samples from untreated patients matched for sex, age, tumour size, extension and invasiveness.
We detected upregulation of p27 protein levels with SST analogue treatment in vitro in human pituitary adenoma samples. pERK1/2 was inhibited by SST analogues in both the human samples and GH3 cells. SST and its analogues inhibited the proliferation of GH3 cells. p27 immunostaining was stronger in samples from patients with longer preoperative octreotide treatment (more than 6 months) than in samples from patients with shorter treatment periods.
This study demonstrates that SST-mediated growth inhibition is associated with the downregulation of pERK and upregulation of p27. More potent and broader-spectrum SST analogues are likely to play an increasing role in the treatment of tumours, where the MAP kinase pathway is overactivated.
European Journal of Endocrinology 09/2006; 155(2):371-9. · 3.42 Impact Factor
ABSTRACT: Data on bone mineral density (BMD) in acromegaly are conflicting as most previous studies collectively evaluated eugonadal and hypogonadal patients of both sexes, with or without active disease. We have evaluated BMD in 152 acromegalic patients of both sexes with varying disease activity and gonadal status.
We studied 152 acromegalic patients (99 women aged 26-72 years, and 53 men aged 21-75 years), 107 with active and 45 with controlled disease. Eighty-five patients had normal gonadal status and 67 were hypogonadal.
In all patients we measured serum GH levels by immunoenzimometric assay, and serum IGF-I levels by radioimmunoassay. BMD was assessed at spine L2-L4 (LS) and at femoral neck (FN) by dual energy X-ray absorptiometry; results are expressed as Z-values.
We evaluated the effect of GH excess on bone at different sites in relation to gonadal status, disease activity and gender. At LS, in respect to the reference population, BMD (mean +/- SE) values were higher in eugonadal patients (active: 0.71 +/- 0.29, P < 0.02; controlled: 0.65 +/- 0.28, P < 0.05) and lower in hypogonadal ones (active: -0.64 +/- 0.35, 0.1 < P < 0.05; controlled: -1.05 +/- 0.36, P < 0.01), regardless of disease activity. On the contrary, at FN, BMD was higher than in the reference population, both in eugonadal (1.01 +/- 0.22, P < 0.001) and hypogonadal (0.63 +/- 0.17, P < 0.001) patients only in subjects with active disease, but not in those in which the disease was controlled (eugonadal: 0.31 +/- 0.23, P = ns; hypogonadal 0.04 +/- 0.28, P = ns). We did not observe any difference in BMD values according to gender both at LS (males vs. females -0.02 +/- 0.30 vs. 0.01 +/- 0.24, P = ns) or at FN (0.77 +/- 0.19 vs. 0.63 +/- 0.15, P = ns).
The anabolic effect of GH excess on bone in acromegalic patients is: (i) gender-independent; (ii) evident at the spine only in eugonadal regardless of disease activity; (iii) evident at femoral neck only in the presence of active disease regardless of gonadal status.
Clinical Endocrinology 06/2003; 58(6):725-31. · 3.17 Impact Factor