Changes in multi-modality management of acromegaly in a tertiary centre over 2 decades.

PURPOSE: Acromegaly is a rare disease associated with chronic multisystem complications. New therapeutic strategies have emerged in the last decades, combining pituitary transsphenoidal surgery (TSS), radiotherapy or radiosurgery (RXT) and medical treatments. METHODS: This retrospective monocentric study focused on presentation, management and outcome of acromegaly patients diagnosed between 2000 and 2020, still followed up in 2020, with a minimum follow-up of 1 year, and comparison of the first vs. second decade of the study. RESULTS: 275 patients were included, 50 diagnosed before 2010 and 225 after 2010. 95% of them had normal IGF-1 levels (with or without treatment) at the last follow-up. Transsphenoidal surgery was more successful after 2010 (75% vs. 54%; p < 0.01), while tumor characteristics remained the same over time. The time from first treatment to biochemical control was shorter after 2010 than before (8 vs. 16 months; p = 0.03). Since 2010, RT was used less frequently (10% vs. 32%; p < 0.01) but more rapidly after surgery (26 vs. 53 months; p = 0.03). In patients requiring anti-secretory drugs after TSS, the time from first therapy to biochemical control was shorter after 2010 (16 vs. 29 months; p < 0.01). Tumor size, tumor invasiveness, baseline IGF-1 levels and Trouillas classification were identified as predictors of remission. CONCLUSION: The vast majority of patients with acromegaly now have successful disease control with a multimodal approach. They reached biochemical control sooner in the most recent half of the study period. Future work should focus on those patients who are still uncontrolled and on the sequelae of the disease.

Meningiomas in patients with long-term exposition to progestins: Characteristics and outcome.

OBJECTIVE: The aim of this study was to describe progestin-associated meningiomas' characteristics, outcome and management. MATERIAL AND METHODS: We included 53 patients operated on and/or followed in the department for meningioma with progestin intake longer than one year and with recent drug discontinuation. RESULTS: Cyproterone acetate (CPA), nomegestrol acetate (NomA), and chlormadinone acetate (ChlA) were involved in most cases. Mean duration of progestin drugs intake was 17.5 years. Tumors were multiple in 66% of cases and were located in the anterior and the medial skull base in 71% of cases. Transitional subtype represented 16/25 tumors; 19 meningiomas were WHO grade I and 6 were grade II. The rate of transitional subtype and skull base location was significantly higher compared to matched operated meningioma general population. No difference was observed given WHO classification. But Ki67 proliferation index tends to be lower and 5/6 of the WHO grade II meningiomas were classified as WHO grade II because of brain invasion. Strong progesterone receptors expression was observed in most cases. After progestin discontinuation, a spontaneous visual recovery was observed in 6/10 patients. Under CPA (n=24) and ChlA/NomA (n=11), tumor volume decreased in 71% and 18% of patients, was stabilized in 25% and 64% of patients, and increased in 4% and 18% of patients, respectively. Volume outcome was related to meningioma location. CONCLUSIONS: Outcome at progestins discontinuation is favorable but different comparing CPA versus ChlA-NomA and comparing tumor location. Long-term follow-up is required. In most cases, simple observation is recommended and surgery should be avoided.

Acromegaly in Carney complex.

PURPOSE: Carney complex (CNC) is a rare autosomal dominant syndrome, characterized by mucocutaneous pigmentation, cardiac, cutaneous myxomas and endocrine overactivity. It is generally caused by inactivating mutations in the PRKAR1A (protein kinase cAMP-dependent type I regulatory subunit alpha) gene. Acromegaly is an infrequent manifestation of CNC, reportedly diagnosed in 10% of patients. METHODS: We here report the case of a patient who was concomitantly diagnosed with Carney complex, due to a new mutation in PRKAR1A ((NM_002734.3:c.80_83del, p.(Ile27Lysfs*101 in exon 2), and acromegaly. In parallel, we conducted an extensive review of published case reports of acromegaly in the setting of CNC. RESULTS: The 43-year-old patient was diagnosed with an acromegaly due to a GH-secreting pituitary microadenoma resistant to somatostatin analogs. He underwent transsphenoidal surgery in our tertiary referral center, which found a pure GH-secreting adenoma. In the literature, we identified 57 cases (24 men, 33 women) of acromegaly in CNC patients. The median age at diagnosis was 28.8 ± 12 year and there were 6 cases of gigantism. Acromegaly revealed CNC in only 4 patients. 24 patients had a microadenoma and two carried pituitary hyperplasia and/or multiple adenomas, suggesting that CNC may result in a higher proportion of microadenoma as compared to non-CNC acromegaly. CONCLUSIONS: Although it rarely reveals CNC, acromegaly is diagnosed at a younger age in this setting, with a higher proportion of microadenomas.

Pre-surgical medical treatment, a major prognostic factor for long-term remission in acromegaly.

PURPOSE: To determine whether pre-surgical medical treatment (PSMT) using long-acting Somatostatin analogues in acromegaly may improve long-term surgical outcome and to determine decision making criteria. METHODS: This retrospective study included 110 consecutive patients newly diagnosed with acromegaly, who underwent surgery in a reference center (Marseille, France). The mean long-term follow-up period was 51.4 ± 36.5 (median 39.4) months. Sixty-four patients received PSMT during 3-18 (median 5) months before pituitary surgery. Remission was defined at early (3 months) evaluation and at last follow-up by GH nadir after oral glucose tolerance test < 0.4 µg/L and normal IGF-1. RESULTS: Pretreated and non-pretreated groups were comparable for the main confounding factors except for higher IGF-1 at diagnosis in PSMT patients. Remission rates were significantly different in pretreated or not pretreated groups (61.1% vs. 36.6%, respectively at long-term evaluation). In multivariate analysis, PSMT was significantly linked to 3 months (p < 0.01) and long-term remission (p < 0.01). Duration of PSMT was not significantly different in cured or non-cured patients, at both evaluation times. PSMT appeared to be more beneficial for patients with an invasive tumor. No patient with a tumor greater than 18 mm or mean GH level exceeding 35 ng/mL at diagnosis was cured by surgery alone (vs. 8 and 9 patients in the pretreated group, respectively). Patients with PSMT showed more transient mild hyponatremia after surgery. CONCLUSIONS: PSMT significantly improved short and long-term remission in patients with acromegaly, independent of its duration, especially in invasive adenomas.

[Once weekly L-thyroxine treatment in non-compliance: A case report]. / Prise hebdomadaire de L-thyroxine dans un cas de non-observance du traitement substitutif.

INTRODUCTION: The non-adherence to substitutive treatment by L-thyroxine is the main cause of the discordance between high thyrotropin values and high doses of the drug. OBSERVATION: In a 36-year-old patient with post-surgery hypothyroidism, thyrotropin values ranged between 100 and 400 mUI/L, although daily replacement therapy included 300 µg of L-thyroxine and 75 µg of L-triiodothyronine. The oral loading test with L-thyroxine was normal and thyrotropin serum level returned to normal values under weekly oral administration of 1000 µg L-thyroxine. CONCLUSION: The strategy of non-adherence treatment in hypothyroidism is well defined with oral testing of L-thyroxine, followed by oral or parenteral weekly administration of the drug. The L-thyroxine oral test is the gold standard for diagnosis after eliminating of the other conventional causes: drug interactions or digestive malabsorption. L-thyroxine treatment should be discussed on a case-by-case basis, either daily under surveillance or once weekly oral or parenteral high dose.

(18)F-FDG uptake at initial staging of the adrenocortical cancers: a diagnostic tool but not of prognostic value.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare cancer for which little level evidence exists to guide management. (18)F-FDG PET ((18)F-fluorodeoxyglucose positron emission tomography) is an increasingly used diagnostic tool in patients with suspicious or indeterminate adrenal tumors. In some other solid tumors, (18)F-FDG PET may offer prognostic information that can guide optimal patient treatment. The aim of the present study was to evaluate whether preoperative (18)F-FDG PET based on SUVs assessments has a prognostic value in ACC patients. METHODS: A retrospective analysis was performed in patients who underwent (18)F-FDG PET/CT for the evaluation of ACC. Inclusion criteria were an unequivocal diagnosis of ACC; all data from primary diagnosis available; (18)F-FDG PET/CT performed prior to surgery or other treatment of the primary tumor; a minimum of 6-months follow-up for surviving patients. All (18)F-FDG PET/CT procedures were reinterpreted in a blind fashion. RESULTS: Thirty-seven patients (23 without metastasis [M0], 14 with metastasis [M1]) fulfilled the study criteria. Median uptake values were tumor standardized uptake values (SUV)(max) = 11 (range: 3-56) and a tumor/liver SUV(max) ratio = 4.2 (range: 1.3-15). Median follow-up was 20 months. Although classic risk factors (tumoral stage, Weiss score) were associated with poor outcome, there was no correlation between primary tumor FDG uptake with overall survival (OS) and disease free survival (DFS) in M0 patients and with overall survival in M1 patients. (18)F-FDG uptake correlated inconsistently with sinister histological features, such as atypical mitoses or necrosis. CONCLUSIONS: At initial staging, primary tumor FDG uptake in ACC patients does not correlate with OS and DFS at 2 years. Patient prognosis and treatment strategy should not be based on uptake values.

A conservative management is preferable in milder forms of pituitary tumor apoplexy.

AIM: Our objective was to report a single-center experience of the management of pituitary tumor apoplexy. PATIENTS AND METHODS: We retrospectively analyzed a series of 44 patients hospitalized for pituitary apoplexy between January 1996 and March 2008 at the Timone Hospital, Marseille, France. RESULTS: Most frequent presenting symptoms were headaches (93%), visual impairment (85%) and vomiting (59%). Hypopituitarism was present at diagnosis in 88% of patients, with a high incidence of corticotroph deficiency (70%). A risk factor was found in 52% of patients, mostly hypertension. Apoplexy occurred in a previously undiagnosed pituitary adenoma in 32/44 cases (73%). The apoplectic event concerned 12 secreting, 27 non-functioning, 4 uncharacterized adenomas and one Rathke's pouch cyst. Nineteen patients underwent surgery within the first month, and one patient had conventional radiotherapy. Twenty-four patients, who had no ophthalmic or neurological signs, were conservatively treated in first intention; among them, 6 received high dose corticosteroids. After a median follow-up of 21 months, there was no significant difference in terms of endocrine or visual recovery between the operated and the conservatively treated groups, nor between patients treated with corticosteroids or not. Panhypopituitarism was observed in 52% of patients, but partial or complete visual recovery was present in the majority of patients (91%), whatever the therapeutic approach. CONCLUSION: The outcome of patients treated with or without surgery for pituitary apoplexy without severe neuro-ophthalmic deficits seems to be identical, pleading for a conservative management of pituitary apoplexy in the absence of visual emergency.

Comparison of [¹¹¹In]pentetreotide-SPECT and [¹8F]FDOPA-PET in the localization of extra-adrenal paragangliomas: the case for a patient-tailored use of nuclear imaging modalities.

AIMS AND METHODS: The aim of this prospective study was to compare the diagnostic value of [¹8F]FDOPA-PET and [¹¹¹In]pentetreotide-SPECT somatostatin receptor scintigraphy (SRS) in patients with nonmetastatic extra-adrenal paragangliomas (PGLs). Twenty-five consecutive unrelated patients who were known or suspected of having nonmetastatic extra-adrenal PGLs were prospectively evaluated with SRS and [¹8F]FDOPA-PET. ¹³¹I-MIBG and [¹8F]FDG-PET were added to the work-up in patients with a personal or familial history of PGL, predisposing mutations, abdominal PGLs, metanephrine hypersecretion and abdominal foci on SRS and/or [¹8F]FDOPA-PET. RESULTS: SRS correctly detected 23/45 lesions of which 20 were head or neck lesions (H&N) and 3 were abdominal lesions. [¹8F]FDOPA-PET detected significantly more lesions than SRS (39/45, P < 0·001). Both SRS and ¹8F-DOPA-PET detected significantly more H&N than abdominal lesions (66·7% vs 20%, P = 0·003 and 96·7% vs 67%, P = 0·012, respectively). In two patients with the succinate dehydrogenase D (SDHD) mutation, [¹8F]FDOPA-PET missed five abdominal PGLs which were detected by the combination of SRS, [¹³¹I]MIBG and [¹8F]FDG-PET. A lesion-based analysis using a forward stepwise logistic regression model demonstrates that size ≤ 10 mm (P = 0·002) and abdominal lesions (P = 0·031) were independently associated with "[¹8F]FDOPA-PET diagnosis only". In turn, a previous history of surgery and/or the presence of germline mutation was associated with lower lesion size (P = 0·001). CONCLUSIONS: The sensitivity of SRS for localizing parasympathetic PGLs is lower than originally reported, and [¹8F]FDOPA-PET is better than SRS for localizing small lesions. SRS should be replaced by [¹8F]FDOPA-PET as the first-line imaging procedure in H&N PGL, especially in patients at risk of multifocal disease (predisposing mutations and or previous history of surgery).

[Acromegaly in the elderly]. / L'acromégalie du sujet âgé.

UNLABELLED: Multicentric registers such as The French Acromegaly Register provide data on rare disorders that are otherwise difficult to obtain, so avoiding extrapolation from limited data sets. This study focuses on clinical, hormonal and therapy characteristics of acromegaly in people over 70 years old. The objective was to compare this population with the youngest to disclose if the medical management was similar. PATIENTS AND METHODS: The data were obtained from the 30 centres that have registered patients in the Acromegaly Register since 1999. RESULTS: The register listed 644 acromegaly patients on 1st January 2005, of whom 68 (22 men and 46 women) were over 70 years old, independently of the diagnosis date of their disease. Their average age was 76.8 + or - 5 years (range: 70-95) and they had suffered from acromegaly for 11 + or - 6 years (compared to 7 years in those aged less than 70). Their BMI were similar. Diabetes and hypertension were more frequent than in younger acromegalic patients and in the general French population matched for age. Circulating GH and IGF-1 concentrations were lower than in the younger acromegalic patients on inclusion and 1 year after treatment. There was no significant difference in the tumor size. Only 44% of the patients over 70 underwent surgery, against 90% of patients under 70 years. However, the fractions of young and elderly patients with a controlled disease 1 year after inclusion were the same (51%). CONCLUSION: In the limits of the use of register, these data reveal a high prevalence of diabetes and hypertension in the eldest acromegalic patients. Despite much less frequent surgical intervention, patients' disease under control is equivalent to the younger population 1 year after the initial interview, confirming the effectiveness of the choices of treatment.

Lanreotide for the treatment of acromegaly.

Lanreotide is an eight-amino acid peptide, which is an analog of the native somatostatin peptide, physiological inhibitor of growth hormone (GH). The drug shows high binding affinity for somatostatin receptors, SSTR2 and SSTR5, which is the primary mechanism considered to be responsible for decreasing GH secretion and GH cell proliferation in acromegaly. Two different formulations of lanreotide are currently available: lanreotide slow release, which requires intramuscular injection every 7-14 days, and lanreotide autogel, which requires deep subcutaneous injection every 4-8 weeks. Several studies have been published to date on the use of lanreotide in acromegaly. Antisecretory efficacy has been reported in 35%-70% of cases; this huge variability is probably explained by different indications (eg, primary or adjunctive postsurgical treatment), or the fact that some studies were based on patients known to be responders to somatostatin analogs. As a primary treatment, antisecretory efficacy was very similar, confirming the possibility of lanreotide as an option in cases of unsuccessful surgery, contraindication, or surgery refusal. Lanreotide also has antitumoral effects as it induces a decrease in tumor volume of [Symbol: see text]25% in 30%-70% of patients. This could be beneficial before transsphenoidal surgery, as a pretreatment, to decrease tumor volume and ease surgery; however, to date, advantages in terms of final remission or uncured status remain a matter of debate. Side effects are rare; the most frequent being gastrointestinal discomfort and increased risk of gallstone formation, and glucose metabolism modifications. Comparison with the other somatostatin analog, octreotide, tends to show identical levels of efficacy between both drugs. Lanreotide thus seems to be an effective treatment in acromegaly. To date, however, lanreotide is still considered as only suspending GH secretion, thus requiring prolonged and costly treatment.

Does first-line surgery still have its place in the treatment of acromegaly?

Transsphenoidal surgery is currently the first-line treatment of acromegaly. Remission is observed in 80 to 90% microadenomas, 50 to 60% non-invasive macroadenomas, and less than 20% invasive macroadenomas. Predictive factors include age, maximal size of the adenoma, cavernous sinus invasion, initial hormone levels and neurosurgeon's experience. Complications are rare, with about 5% definitive diabetes insipidus and 10% of new anterior pituitary hormone deficits. Somatostatin agonist pretreatment can be proposed as it decreases tumor volume in about 25% cases and might reduce the rate of immediate postsurgical complications; however, there is no obvious difference in surgical remission rate whether patients are pretreated or not. Debulking surgery can also be proposed in very large macroadenomas incompletely controlled by somatostatin agonists or resistant to medical treatment, as it was shown to facilitate somatostatin agonist efficacy in more than 50% cases.

Merits and pitfalls of mifepristone in Cushing's syndrome.

OBJECTIVE: Mifepristone is the only available glucocorticoid receptor antagonist. Only few adult patients with hypercortisolism were treated to date by this drug. Our objective was to determine effectiveness and tolerability of mifepristone in Cushing's syndrome (CS). DESIGN: Retrospective study of patients treated in seven European centers. METHODS: Twenty patients with malignant (n=15, 12 with adrenocortical carcinoma, three with ectopic ACTH secretion) or benign (n=5, four with Cushing's disease, one with bilateral adrenal hyperplasia) CS were treated with mifepristone. Mifepristone was initiated with a median starting dose of 400 mg/day (200-1000). Median treatment duration was 2 months (0.25-21) for malignant CS, and 6 months (0.5-24) for benign CS. Clinical (signs of hypercortisolism, blood pressure, signs of adrenal insufficiency), and biochemical parameters (serum potassium and glucose) were evaluated. RESULTS: Treatment was stopped in one patient after 1 week due to severe uncontrolled hypokalemia. Improvement of clinical signs was observed in 11/15 patients with malignant CS (73%), and 4/5 patients with benign CS (80%). Psychiatric symptoms improved in 4/5 patients within the first week. Blood glucose levels improved in 4/7 patients. Signs of adrenal insufficiency were observed in 3/20 patients. Moderate to severe hypokalemia was observed in 11/20 patients and increased blood pressure levels in 3/20 patients. CONCLUSION: Mifepristone is a rapidly effective treatment of hypercortisolism, but requires close monitoring of potentially severe hypokalemia, hypertension, and clinical signs of adrenal insufficiency. Mifepristone provides a valuable treatment option in patients with severe CS when surgery is unsuccessful or impossible.

The role of 18F-FDOPA and 18F-FDG-PET in the management of malignant and multifocal phaeochromocytomas.

BACKGROUND: (18)F-DOPA has emerged as a promising tool in the localization of chromaffin-tissue-derived tumours. Interestingly, phaeochromocytomas (PHEO) are also FDG avid. AIM AND METHODS: The aim of this study was to retrospectively evaluate the results of (18)F-FDOPA and/or (18)F-FDG-PET in patients with PHEO and paragangliomas (PGLs) and to compare the outcome of this approach with the traditional therapeutic work-up. Nine patients with non-MEN2 related PHEO or PGL were evaluated. At the time of the PET studies, the patients were classified into three groups based on their clinical history, conventional and SPECT imaging. The groups were malignant disease (n = 5, 1 VHL), apparently unique tumour site in patients with previous surgery (n = 1, SDHB) and multifocal tumours (n = 3, 1 VHL, 1 SDHD). (18)F-FDOPA and (18)F-FDG-PET PET/CT were then performed in all patients. RESULTS: PET successfully identified additional tumour sites in five out of five patients with metastatic disease that had not been identified with SPECT + CI. Whilst tumour tracer uptake varied between patients it exhibited a consistently favourable residence time for delayed acquisitions. (18)F-FDOPA uptake (SUVmax) was superior to (18)F-FDG uptake in cases of neck PGL (three patients, four tumours). If only metastatic forms and abdominal PGLs were considered, (18)F-FDG provided additional information in three cases (two metastatic forms, one multifocal disease with SDHD mutation) compared to (18)F-FDOPA. CONCLUSIONS: Our results suggest that tumour staging can be improved by combining (18)F-FDOPA and (18)F-FDG in the preoperative work-up of patients with abdominal and malignant PHEOs. (18)F-FDOPA is also an effective localization tool for neck PGLs. MIBG however, still has a role in these patients as MIBG and FDOPA images did not completely overlap.

Ketoconazole revisited: a preoperative or postoperative treatment in Cushing's disease.

CONTEXT: Although transsphenoidal surgery remains the first-line treatment in Cushing's disease (CD), recurrence is observed in about 20% of cases. Adjunctive treatments each have specific drawbacks. Despite its inhibitory effects on steroidogenesis, the antifungal drug ketoconazole was only evaluated in series with few patients and/or short-term follow-up. OBJECTIVE: Analysis of long-term hormonal effects and tolerance of ketoconazole in CD. DESIGN: A total of 38 patients were retrospectively studied with a mean follow-up of 23 months (6-72). SETTING: All patients were treated at the same Department of Endocrinology in Marseille, France. PATIENTS: The 38 patients with CD, of whom 17 had previous transsphenoidal surgery. INTERVENTION: Ketoconazole was begun at 200-400 mg/day and titrated up to 1200 mg/day until biochemical remission. MAIN OUTCOME MEASURES: Patients were considered controlled if 24-h urinary free cortisol was normalized. RESULTS: Five patients stopped ketoconazole during the first week because of clinical or biological intolerance. On an intention to treat basis, 45% of the patients were controlled as were 51% of those treated long term. Initial hormonal levels were not statistically different between patients controlled or uncontrolled. Ketoconazole was similarly efficacious as a primary or postoperative treatment. Among 15 patients without visible adenoma at initial evaluation, subsequent follow-up allowed identification of the lesion in five cases. No adrenal insufficiency was observed. Adverse effects were rare in patients treated long term. CONCLUSIONS: Ketoconazole is a safe and efficacious treatment in CD, particularly in patients for whom surgery is contraindicated, or delayed because of the absence of image of adenoma on magnetic resonance imaging.

Desmopressin test during petrosal sinus sampling: a valuable tool to discriminate pituitary or ectopic ACTH-dependent Cushing's syndrome.

UNLABELLED: 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 < or = 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.

Gamma knife radiosurgery is a successful adjunctive treatment in Cushing's disease.

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 mm(3), 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.

Efficacy of quinagolide in resistance to dopamine agonists: results of a multicenter study. Club de l'Hypophyse.

OBJECTIVE: A retrospective French multicenter analysis was carried out to assess changes in tumor volume and plasma prolactin concentration in order to evaluate the efficacy of quinagolide (Norprolac) in patients with prolactinoma resistant to ergot dopamine agonists. PATIENTS AND METHODS: One hundred seven patients (46 men and 61 women) from 27 centers were included in the statistical analysis. All had previously been treated with a dopamine agonist (bromocriptine). Fifty-five patients had undergone surgery before being administered quinagolide: 17 of the patients had also received radiotherapy (before and after the initiation of treatment with quinagolide in 14 and 3 cases respectively). Quinagolide was given at doses ranging from 75 to 750 microg daily and continued for more than one year for 84 patients. RESULTS: The prolactin level returned to normal after a mean interval of 9.8 1.6 months (1-48) in 47 of the 107 patients (44%) using a mean dose of quinagolide of 259 32.7 microg/d (75-750). The plasma prolactin concentration had already been normalized using bromocriptine in three patients. The variation in tumor volume was assessed in 82 patients since 8 had no residual tumor post-operatively and 17 had received radiotherapy: at least partial regression of the tumor was noted in 25 (30.8%), including 16 (19.5%) with a more than 50% decrease in the remaining tumor. The mean time taken to observe the anti-tumoral effect was 16.8 3.1 months (3-78) using a mean dose of quinagolide of 255.4 37.8 microg/d d (75-750). The following predictive indicators were identified concerning the efficacy of quinagolide: a pre-quinagolide prolactin level of<300 ng/ml in the group of patients whose plasma prolactin concentration was normalized, and a mean decrease in prolactin of 619 ng/ml in the group of patients showing a reduction in tumor volume treated with quinagolide for 3 months. Side effects (nausea, vomiting, hypotension) were generally mild and were observed in 51 patients (47.6%). Only 11 (10.2%) of patients had to discontinue treatment because of adverse reactions. CONCLUSION: An anti-tumoral effect was noted in 30.8% of patients and occurred within an interval of less than 2 years in 80% of cases at a dose of 300 microg/d. Normalization of the plasma prolactin concentration was obtained in 44% of cases and occurred in less than one year in 80% of patients at a dose of 300 microg/d. Quinagolide is a useful drug and from now on should be prescribed as first-line treatment for patients presenting with bromocriptine-resistant prolactinoma.

[Macroprolactinemia, a variety of hyperprolactinemia. Apropos of 5 cases]. / Macroprolactinémie, une variété d'hyperprolactinémie. A propos de cinq observations.

Macroprolactinemia, due to increased circulating levels of large molecular weight forms of prolactin, results in elevated level of immuno-reactive prolactin. The big variants have only weak biological activity; thus macroprolactinemia appears as a case of hyperprolactinemia without clinical significance as demonstrated by the five patients described. The diagnosis is based upon chromatography which separates the hormone and its variants. This disorder produces a pitfall in the diagnostic evaluation of hyperprolactinemia.

Prolactinomas resistant to bromocriptine: long-term efficacy of quinagolide and outcome of pregnancy.

Resistance to bromocriptine, defined as the absence of normalization of prolactin (PRL) levels despite a 15-30 mg daily dose of bromocriptine during at least 6 months, has been observed in 5-17% of the prolactinomas according to the literature. The recent availability of a new potent dopamine agonist, quinagolide, prompted us to analyze its long-term therapeutic effects in 28 patients with prolactinomas resistant to bromocriptine. Before bromocriptine, their PRL levels were 520 +/- 185 micrograms/l (mean +/- SEM) and decreased to 291 +/- 154 micrograms/l after a 6-21 month period of bromocriptine treatment. All the women (N = 20) remained amenorrheic and hypogonadism was not improved in men (N = 8). Subsequently, after 1 year of 150-300 micrograms/day quinagolide, 12/28 patients of the present series recovered normal gonadal function and their initial mean baseline PRL value (404 +/- 180 micrograms/l) was 16 +/- 2 micrograms/l after 1 year of treatment. A significant tumor shrinkage was observed in 5/8 macroadenomas (62%). During the 3-year follow-up period under quinagolide, a similar good control was achieved in these patients, with the exception of one man presenting with a secondary rise of PRL under quinagolide. In contrast, 15 other patients (one patient interrupted quinagolide at 6 months because of poor tolerance) were not normalized under 150-450 micrograms/day quinagolide. Their initial PRL levels (606 +/- 298 micrograms/l) were reduced to 343 +/- 187 micrograms/l (versus 463 +/- 265 micrograms/l under bromocriptine after the same duration of treatment). Despite such a partial inhibitory effect of quinagolide, 7/12 women resumed menstrual cycles and three pregnancies occurred. In no case was any tumor shrinkage noticed during the 3-4-year follow-up. Three patients even presented, after 2 years of quinagolide treatment, with a secondary rise of PRL values associated with a further tumor growth in two patients. During the 3-year follow-up period, nine pregnancies occurred in seven women. In five women, after quinagolide withdrawal, the plasma PRL baseline values ranged from 52 to 158 micrograms/l and from 65 to 192 micrograms/l, respectively, at the first trimester and at the end of uneventful pregnancies. In contrast, in two women a rapid increase of PRL (240-400 micrograms/l) correlated with tumor growth during the first trimester. Such a tumor progression was blocked by quinagolide treatment but not by bromocriptine. These data, although observed in a limited series, justify the careful follow-up of pregnancies in this subclass of patients at risk. Finally, in the whole population, long-term control of hyperprolactinemia by quinagolide was obtained in 11/28 patients (39%) previously resistant to bromocriptine, and 15/20 women (75%) resumed normal gonadal function with a quinagolide daily dose of 300 micrograms in most of them.