OBJECTIVE: Evaluation of the efficiency of somatostatin analogues in the treatment of a mixed luteinizing hormone (LH)-, alpha-subunit-, prolactin (PRL)-secreting pituitary adenoma. DESIGN: A 30-year-old woman, with amenorrhaea-galactorrhaea, presented with a pituitary macroadenoma. The endocrine evaluation showed high plasma levels of PRL, LH, and alpha-subunit inhibited by 65%, 65% and 33% respectively under octreotide test (200 microg, s.c.). Long-term treatment with slow release (SR) lanreotide (30 mg/10 days, i.m.) restored menstrual cycles and normalized PRL values. Due to persisting supranormal levels of LH and alpha-subunit, and to the absence of tumoral shrinkage, the adenoma was resected by the transsphenoidal route. METHODS: In vitro characterization of the somatostatin receptor subtypes (SSTR) expression and functionality. Real-time polymerase chain reaction was performed to quantify the expression of SSTR mRNAs and functionality of the SSTRs was assessed in cell culture studies with various concentrations of native somatostatin (SRIF-14) and of analogues preferential for SSTR2 or SSTR5. RESULTS: This adenoma presented with high levels of SSTR2, SSTR3 and SSTR5 mRNAs, as compared with a series of gonadotroph adenomas. In cell culture studies, PRL, LH and alpha-subunit were inhibited by 60%, 47% and 33% respectively by SRIF-14 at a concentration of 10 nmol/l. The SSTR2 (BIM-23197, lanreotide) and SSTR5 (BIM-23268) preferential analogues both produced a partial 21-38% inhibition of PRL, LH, and alpha-subunit release. DISCUSSION: In this plurihormonal-secreting adenoma, the high efficacy of somatostatin analogues to inhibit PRL, LH and alpha-subunit secretion in vivo may be explained by the unusually high level of expression and by the functionality of both SSTR2 and SSTR5 receptor subtypes.
A Saveanu, I Morange-Ramos, G Gunz, H Dufour, A Enjalbert and P Jaquet
F Castinetti, I Morange, H Dufour, P Jaquet, B Conte-Devolx, N Girard and T Brue
Corticotropin-releasing hormone (CRH)-stimulated petrosal sinus sampling is currently the gold standard method for the differential diagnosis between pituitary and ectopic ACTH-dependent Cushing’s syndrome. Our objective was to determine sensitivity and specificity of desmopressin test during petrosal sinus sampling.
Patients and methods: Forty-three patients had petrosal sinus sampling because of the lack of visible adenoma on magnetic resonance imaging (MRI) and/or because of discordant cortisol response to high-dose dexamethasone suppression test. ACTH sampling was performed in an antecubital vein, right and left petrosal sinuses, then at each location 5 and 10 min after injection of desmopressin. Diagnosis was based on the ACTH ratio between petrosal sinus and humeral vein ACTH after desmopressin test. Diagnosis was confirmed after surgery. A receiver operating characteristics curve was used to determine optimal sensitivity and specificity.
Results: Thirty-six patients had Cushing’s disease (CD) and seven had ectopic ACTH secretion. A ratio > 2 after desmopressin was found in 35 of the 36 cases of CD (sensitivity: 95%). A ratio ≤ 2 was found in the seven patients with ectopic ACTH secretion (specificity: 100%). Sinus sampling was ineffective in determining the left or right localization of the adenoma (sensitivity = 50%). No major adverse effects were observed during or after the procedure.
Conclusion: Desmopressin test during petrosal sinus sampling is a safe and effective diagnostic procedure in ACTH-dependent Cushing’s syndrome. It thus represents a valuable alternative to CRH.
F Castinetti, M Nagai, H Dufour, J-M Kuhn, I Morange, P Jaquet, B Conte-Devolx, J Regis and T Brue
Objective: Though transsphenoidal surgery remains the first-line treatment of Cushing’s disease, recurrence occurs frequently. Conventional radiotherapy and anticortisolic drugs both have adverse effects. Stereotactic radiosurgery needs to be evaluated more precisely. The aim of this study was to determine long-term hormonal effects and tolerance of gamma knife (GK) radiosurgery in Cushing’s disease.
Design: Forty patients with Cushing’s disease treated by GK were prospectively studied over a decade, with a mean follow-up of 54.7 months. Eleven of them were treated with GK as a primary treatment.
Methods: Radiosurgery was performed at the Department of Functional Neurosurgery of Marseille, France, using the Leksell Gamma Unit B and C models. Median margin dose was 29.5 Gy. Patients were considered in remission if they had normalized 24-h free urinary cortisol and suppression of plasma cortisol after low-dose dexamethasone suppression test.
Results: Seventeen patients (42.5%) were in remission after a mean of 22 months (range 12–48 months). The two groups did not differ in terms of initial hormonal levels. Target volume was significantly higher in uncured than in remission group (909.8 vs 443 mm3, P = 0.038). We found a significant difference between patients who were on or off anticortisolic drugs at the time of GK (20 vs 48% patients in remission respectively, P = 0.02).
Conclusion: With 42% of patients in remission after a median follow-up of 54 months, GK stereotactic radiosurgery, especially as an adjunctive treatment to surgery, may represent an alternative to other therapeutic options in view of their adverse effects.
S Vallette-Kasic, H Dufour, M Mugnier, J Trouillas, H Valdes-Socin, P Caron, S Morange, N Girard, F Grisoli, P Jaquet and T Brue
OBJECTIVE: To assess the postsurgical outcome of patients with corticotroph microadenomas and to define predictors of the long-term outcome, with special emphasis on markers of tumor extension. DESIGN: Prospective study of 53 corticotroph microadenomas treated by enlarged adenomectomy. Patients followed for at least 2 years were classified into two groups: those in long-term remission and uncured patients (immediate failures and recurrences). Pre-, per- and postoperative parameters were analyzed as predictors of the long-term outcome. METHODS: Baseline hormone assessments were performed preoperatively, 8 days after surgery and every 6-12 months thereafter. Pituitary magnetic resonance imaging (MRI) allowed analysis of possible tumor extension to adjacent structures. Apparent completeness of the surgical removal was determined, and fragments labeled either 'tumor' or 'surrounding pituitary tissue' were submitted to serial sectioning. RESULTS: Immediate control of hypercortisolism was achieved in 43/53 patients (81%). However, later recurrences were observed in five patients (9%). Preoperative MRI showed tumor extension into adjacent structures with good specificity (91%) for prediction of surgical failure. Evidence of local invasion at surgery was also significantly predictive of the long-term outcome. A corticotroph adenoma was found at histological examination in 96% of the patients, and 26% had irregular limits, a feature significantly correlated with a poor outcome. Immediate postoperative plasma cortisol did not allow discrimination between long-term remissions and recurrences. CONCLUSION: Surgical failure was best predicted by signs of tumor 'invasiveness' at MRI, confirmed by peroperative examination and histology.
P Jaquet, G Gunz, A Saveanu, H Dufour, J Taylor, J Dong, S Kim, J-P Moreau, A Enjalbert and M D Culler
Objective: This study compared the potency of a somatostatin receptor (sstr)2–sstr5 analog, BIM-23244, of an sstr2-dopamine D2 receptor (sstr2-DAD2) molecule, BIM-23A387 and of new somatostatin-dopamine chimeric molecules with differing, enhanced affinities for sstr2, sstr5 and DAD2, BIM-23A758, BIM-23A760 and BIM-23A761, to suppress GH and prolactin (PRL) from 18 human GH adenomas that are partially responsive to octreotide or lanreotide.
Materials and methods: The sstr2, sstr5 and DAD2 mRNA levels were determined by RT-PCR. The effect of drugs was tested in cell cultures at various concentrations.
Results: In all tumors, the sstr2, sstr5 and DAD2 mRNA levels were coexpressed (mean levels±s.e.m. 0.4±0.1, 5.3±1.9 and 2.0±0.4 copy/copy β-glucuronidase). In 13 tumors, the maximal suppression of GH secretion produced by BIM-23A387 (30±3%) and BIM-23244 (28±3%) was greater than that produced by octreotide (23±3%). In six out of 13 tumors, BIM-23A758, BIM-23A760 and BIM- 23A761 produced greater maximal suppression of GH secretion than octreotide (33±5, 38±2 and 41±2 vs 24±2%). Their EC50 values were 10, 2 and 4 pmol/l. BIM-23A761 was more effective than BIM-23A387 in GH suppression (41±2 vs 32±4%). The new chimeric molecules produced maximal PRL suppression greater than octreotide (62±8 to 74±5 vs 46±11%).
Conclusions: Novel dopamine-somatostatin chimeric molecules with differing, enhanced activity at sstr2, sstr5 and DAD2, consistently produced significatly greater suppression of GH and PRL than either octreotide or single-receptor-interacting ligands in tumors from patients classified as only partially responsive to octreotide therapy. The higher efficacy of the chimeric compounds was, at least partially, linked to their high affinity for sstr2 (IC50 1–10 pmol/l). The other mechanisms by which such molecules produce an enhanced inhibition of GH remain to be elucidated.
J Eroukhmanoff, I Tejedor, I Potorac, T Cuny, J F Bonneville, H Dufour, G Weryha, A Beckers, P Touraine, T Brue and F Castinetti
Both antitumor and antisecretory efficacies of dopamine agonists (DA) make them the first-line treatment of macroprolactinomas. However, there is no guideline for MRI follow-up once prolactin is controlled. The aim of our study was to determine whether a regular MRI follow-up was necessary in patients with long-term normal prolactin levels under DA.
Patients and methods
We conducted a retrospective multicenter study (Marseille, Paris La Pitie Salpetriere and Nancy, France; Liege, Belgium) including patients with macroprolactinomas (largest diameter: >10 mm and baseline prolactin level: >100 ng/mL) treated by dopamine agonists, and regularly followed (pituitary MRI and prolactin levels) during at least 48 months once normal prolactin level was obtained.
In total, 115 patients were included (63 men and 52 women; mean age at diagnosis: 36.3 years). Mean baseline prolactin level was 2224 ± 6839 ng/mL. No significant increase of tumor volume was observed during the follow-up. Of the 21 patients (18%) who presented asymptomatic hemorrhagic changes of the macroprolactinoma on MRI, 2 had a tumor increase (2 and 7 mm in the largest size). Both were treated by cabergoline (1 mg/week) with normal prolactin levels obtained for 6 and 24 months. For both patients, no further growth was observed on MRI during follow-up at the same dose of cabergoline.
No significant increase of tumor size was observed in our patients with controlled prolactin levels on DA. MRI follow-up thus appears unnecessary in patients with biologically controlled macroprolactinomas.
F Maurice, A Dutour, C Vincentelli, I Abdesselam, M Bernard, H Dufour, Y Lefur, T Graillon, F Kober, P Cristofari, E Jouve, L Pini, R Fernandez, C Chagnaud, T Brue, F Castinetti and B Gaborit
Glucocorticoid excess is one of the most important causes of bone disorders. Bone marrow fat (BMF) has been identified as a new mediator of bone metabolism. Cushing syndrome (CS) is a main regulator of adipose tissue distribution but its impact on BMF is unknown. The objective of the study was to evaluate the effect of chronic hypercortisolism on BMF.
This was a cross-sectional study. Seventeen active and 17 cured ACTH-dependent CS patients along with 17 controls (matched with the active group for age and sex) were included.
The BMF content of the femoral neck and L3 vertebrae were measured by 1H-MRS on a 3-Tesla wide-bore magnet. Bone mineral density (BMD) was evaluated in patients using dual-energy X-ray absorptiometry.
Active CS patients had higher BMF content both in the femur (82.5 ± 2.6%) and vertebrae (70.1 ± 5.1%) compared to the controls (70.8 ± 3.6%, P = 0.013 and 49.0 ± 3.7% P = 0.005, respectively). In cured CS patients (average remission time of 43 months), BMF content was not different from controls at both sites (72.3 ± 2.9% (femur) and 46.7% ± 5.3% (L3)). BMF content was positively correlated with age, fasting plasma glucose, HbA1c, triglycerides and visceral adipose tissue in the whole cohort and negatively correlated with BMD values in the CS patients.
Accumulation of BMF is induced by hypercortisolism. In remission patients, BMF reached values of controls. Further studies are needed to determine whether this increase in marrow adiposity in CS is associated with bone loss.