S. Cannavò

Cabergoline: a first-choice treatment in patients with previously untreated prolactin-secreting pituitary adenoma.

Cabergoline (CAB) treatment is an effective, safe and well tolerated approach for hyperprolactinemia. We investigated the efficacy of 24-month treatment with CAB in 37 patients with previously untreated PRL-secreting pituitary adenoma and evaluated the hormonal and neuroradiological changes after the discontinuation of long-term therapy. Eleven patients with macroprolactinoma (1M/10F) and 26 with microprolactinoma (4M/22F) started treatment taking 0.25 mg CAB twice a week for 4 weeks. The dose was increased stepwise in 0.5 mg increments until reaching lowest maximally effective and tolerated dose. CAB was withdrawn before the end of the study in 6 women who became pregnant and in one patient who showed a slight increase of the macroadenoma at MRI. During treatment, PRL levels decreased significantly in macro (11.1±1.1 vs 407.8±98.3 μg/l, p<0.001) and microprolactinomas (11.1±1.6 vs 193.8±23.4 μg/l, p<0.05) and normalized in all macro and in 23/26 microprolactinomas. In 3 cases PRL levels decreased but did not normalize because the appearance of side effects, such as nausea or hypotension, prevented the increase of the dose of CAB. The effective dose of drug correlated significantly with basal serum PRL levels (p<0.05) and with the pituitary tumor size (p<0.05). A significant decrease of the mean adenoma size was evident for macro (6.9±1.8 vs 16.0±1.8 mm, p<0.001) and microprolactinomas (3.0±0.5 vs 6.5±0.4 mm, p<0.001) at MRI. The tumor disappeared in 4 macroadenomas and in 11 microadenomas after 12 months of treatment. CAB withdrawal was followed by serum PRL increase in 13 cases after 3 months, in 6 after 6 months, in 2 after 9 months, and in one patient at the 12th month. Five patients showed normo-prolactinemia with negative MRI after one year. Regular menses were restored in 7/10 macro-prolactinomas and in all oligo-amenorrhoic patients with microadenoma; serum testosterone levels normalized in 2/3 hypogonadic men. Five out of 6 women become pregnant and had uneventful pregnancies which resulted in deliveries of normal babies. In conclusion, this study confirms the effectiveness and safety of CAB for patients with PRL-secreting pituitary adenoma and suggests that it can be considered a first choice treatment.

Predictors of morbidity and mortality in acromegaly: an Italian survey

OBJECTIVE To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey of Italian acromegalic patients. DESIGN Retrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months. RESULTS A total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 μg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87-1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34-2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality. CONCLUSIONS Pretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.

Clinical presentation and outcome of pituitary adenomas in teenagers

objective Pituitary adenomas rarely occur in childhood and adolescence, but their mass effect and endocrine abnormalities can compromise both quality and length of life. In this study we evaluated the symptoms at onset and the long‐term consequences induced in teenagers by functioning or nonfunctioning pituitary adenomas.

Hypopituitarism induced by traumatic brain injury in the transition phase

Traumatic brain injury (TBI) has been associated with hypopituitarism in general and GH deficiency (GHD) in particular; the consequences of this on growth and development are likely to be critical in children and adolescents in the so-called “transition phase”. In order to verify the consequences of TBI on pituitary function in the transition phase, we studied a population of adolescents and young adults 3 and 12 months after brain injury [no.=23, 9 females, 14 males; age: 16-25 yr; body mass index (BMI): 21.9±0.6 kg/m2]. At 3 months, hypopituitarism was present in 34.6%. Total, multiple and isolated deficits were present in 8.6, 4.3 and 21.7%, respectively. Diabetes insipidus (DI) was present in 8.6% patients and mild hyperprolactinemia in 4.3%. At 12 months, hypopituitarism was present in 30.3%. Total, multiple and isolated deficits were present in 8.6, 4.3 and 17.4%, respectively. DI was present in 4.3% of patients and mild hyperprolactinemia in 4.3%. Total hypopituitarism was always confirmed at retesting. Multiple and isolated hypopituitarism were confirmed in 0/1 and 2/5, respectively. Two/23 patients showed isolated hypopituitarism at 12 months only; 1 patient with isolated at 3 months showed multiple hypopituitarism at retesting. GHD and secondary hypogonadism were the most common acquired pituitary deficits. These results show the high risk of TBI-induced hypopituitarism also in the transition age. Thus it is recommended that pediatric endocrinologists follow-up pituitary function of children and adolescents after brain injuries.

Abnormalities of hypothalamic-pituitary-thyroid axis in patients with primary empty sella

Primary empty sella (PES) is a very frequent neuroradiological finding in the general population, that can induce hypopituitarism. Some studies focused on the association of PES with GH deficiency (GHD) or hypogonadotropic hypogonadism (HH), while data regarding the involvement of hypothalamic-pituitary-thyroid (HPT) axis, despite sporadic reports of central hypothyroidism, or the occurrence of hypoadrenalism (HA) are scanty. In this study, thyroid function and TSH response to exogenous TRH injection (TRH/TSH) were investigated in 43 patients [10 men and 33 women; aged (mean ±SD), 48±12 yr] with PES: 22 patients had total and 21 partial PES. Forty healthy subjects (9 men and 31 women; aged 46±12 yr) were enrolled as a control group. Central hypothyroidism was found only in 2/43 cases, whereas one patient showed primary hypothyroidism. In euthyroid patients, mean serum TSH levels were significantly lower than controls (TSH: 1.0±0.7 vs 1.4±0.6 mU/l, p<0.01) and 79% of them showed abnormal TRH/TSH responses (TRH test was performed in 34 euthyroid patients: 17 cases with total and 17 cases with partial PES), but mean serum free T4 (FT4) and free T3 (FT3) values were not significantly lower than controls (FT4: 15.9±0.4 vs 15.0±2.1 pmol/l, p=NS; FT3: 5.3±1.2 vs 5.8±1.5 pmol/l, p=NS). Moreover, no significant differences were evident in mean serum TSH, FT4 and FT3 between patients with total and partial PES (TSH: 1.1±0.7 vs 0.9±0.8 mU/l, p=NS; FT4: 16.3±2.6 vs 15.7±2.2 pmol/l, p=NS; FT3: 5.4±1.3 vs 5.2±0.8 pmol/l, p=NS) and the TRH/TSH peak was impaired or exaggerated/delayed in 9 and 3 patients with total and in 12 and 3 cases with partial PES. No significant differences in the prevalence of abnormal TRH/TSH responsiveness were found between patients with partial or total PES (χ2=1.6, p=NS). Other impairment of pituitary function was detected in 23/43 patients: GHD was present in 15 cases, HH in 11 and central HA in 5 patients. Isolated or combined hypopituitarism was present in 17 and in 6 patients, respectively. In conclusion, pituitary dysfunction is very frequent in patients with PES, but central hypothyroidism occurs rarely. The entity of arachnoid herniation into the sellar fossa does not play a significant role on the degree of HPT axis dysfunction.

Growth Hormone Receptor Variants and Response to Pegvisomant in Monotherapy or in Combination with Somatostatin Analogs in Acromegalic Patients: A Multicenter Study

CONTEXT The influence of full-length GH receptor (GHR) and exon 3-deleted GHR (d3GHR) on responsiveness to pegvisomant (PEG-V) in acromegalic patients is uncertain. OBJECTIVE The aim of the study was to assess the distribution of GHR genotypes in a large series of patients on PEG-V therapy and their influence on treatment efficacy and adverse effects. DESIGN AND SETTING A cross-sectional multicenter pharmacogenetic study was conducted in 16 Italian endocrinology centers of major universities and tertiary care hospitals. PATIENTS The study included 127 acromegalic patients enrolled from 2009 to 2010 not cured by previous surgery, radiotherapy, and long-acting somatostatin (SST) analogs, treated with PEG-V. INTERVENTION AND MAIN OUTCOME MEASURE Sixty-three of 127 patients received combined PEG-V + SST analog therapy. Clinical and hormonal data at diagnosis and before and during PEG-V therapy were inserted in a database. GHR exon 3 deletion and other polymorphisms were genotyped by the coordinator center. Differences in PEG-V dosage required for IGF-I normalization and occurrence of adverse effects between carriers and noncarriers of GHR variants were evaluated. RESULTS d3GHR variants were not in Hardy-Weinberg equilibrium (P = 0.008). No association of these variants with PEG-V dose required for IGF-I normalization, adverse effects occurrence, and tumor regrowth was found in patients on PEG-V and on PEG-V + SST analog treatment. Similar data were obtained considering the GHR variant rs6180. CONCLUSIONS This study did not confirm a better response of d3GHR to PEG-V treatment in acromegaly. Other studies are needed to determine whether deviation from Hardy-Weinberg equilibrium may indicate an association of d3GHR genotype with poor response to usual treatments.

Coexistence of growth hormone-secreting pituitary adenoma and intracranial meningioma: A case report and review of the literature

The simultaneous occurrence of a pituitary adenoma and an intracranial meningioma is a rare event. We report the coexistence of an eosinophilic pituitary adenoma and a endotheliomatous meningioma, in the sellar region, and evaluate their endocrine, neuro-radiological and immunohistochemical pattern. A 47-year-old woman affected by acromegaly was referred to us. Serum GH level was 82 ng/ml and remained unresponsive to both OGTT (75 g per os) and iv. GHRH 1–29 (100 ug); IGF-1 was 807 ng/ml. Eight hours after acute sc administration of octreotide (100 ug) GH returned to normal levels (2.3 ng/ml). CT scan showed a large intra- and suprasellar mass involving the right cavernous sinus, with a retrosellar extension along the tentorium. A slight and inhomogeneous enhancement, with a periferal rim of bright signal was apparent at MRI. Conversely, the retrosellar component showed a bright homogeneous enhancement. The patient, therefore, underwent neurosurgery. Histological examination revealed the coexistence of 2 types of tissue: areas of endotheliomatous meningioma were interspersed among sheets of acidophilic adenoma tissue. Immunohistochemical analysis was performed in order to determine the relationship between the two masses: a positive staining for GH was shown in the areas of adenoma, as against for GHRH, neither in the adenomatous tissue nor in the slices of meningioma. Although MRI showed a latero-sellar post-surgical residual of meningioma, serum GH value was <1 ng/ml. In conclusion, the relationship beetwen the GH-secreting adenoma and the meningioma is unclear; however the GH-hypersecretion is not induced by a hypothetic GHRH-activity from the meningioma.

Use of Pegvisomant in acromegaly. An Italian Society of Endocrinology guideline

Acromegaly management is a significant challenge for endocrinologists. The Acromegaly Consensus Group developed several statements on the management of acromegaly and specifically on its medical treatment [1–3]. Acromegaly is a quite rare condition generally caused by a growth hormone (GH)-secreting pituitary adenoma [4]. Delayed diagnosis leads to prevalent presentation of the disease at the stage of macroadenoma (two-thirds of patients) and frequent persistence of active disease after surgery which remains in many patients the primary treatment option [5]. However, active acromegaly is potentially a life threatening condition due its severe systemic complications [6, 7] Therefore, elevated GH and insulin-like growth factor (IGF)-1 levels need to be strictly controlled after failure of surgery with medical or radiation treatments [8]. Furthermore, criteria for disease control may not be fulfilled in a considerable proportion of patients undergoing medical treatment with somatostatin receptor ligands (SRLs) after unsuccessful surgery [9, 10]. Accordingly, some acromegaly patients require the administration of GH antagonist Pegvisomant [11]. Pegvisomant has been introduced in clinical practice more than a decade ago as a medical therapy of acromegaly. However, specific guidelines for Pegvisomant use in acromegaly are lacking. Therefore, the Italian Society of Endocrinology constituted a task force with the objective of assessing the published literature and the clinical experience with Pegvisomant. This group involved endocrinologists recognized experts in the field of acromegaly management and their understanding of the data reported so far worldwide as well as their recommendations for Pegvisomant use in clinical practice are presented here. Biochemical and clinical results of Pegvisomant, indications, treatment modalities, combination therapies, safety and regulatory and cost/efficacy issues were evaluated. Evidences were graded with GRADE system [1–3, 12, 13] based on the quality of evidence as very low quality (VLQ; expert opinion with one or a small number of small uncontrolled studies in support), low quality (LQ; large series of small uncontrolled studies), moderate quality (MQ; one or a small number of large uncontrolled studies or meta-analyses), or high quality (HQ; controlled studies or large series of large uncontrolled studies with sufficiently long follow-up). Recommendations were defined discretionary (DR) if based on VLQ-LQ evidence, or strong (SR) if supported by MQ-HQ evidence.

Shrinkage of a PRL-secreting pituitary macroadenoma resistant to cabergoline

Cabergoline decreases both serum PRL levels and size of prolactinomas, including some tumors resistant to other dopamine-agonists. It is common observation that the shrinkage of the adenoma is preceded by suppression of PRL levels. A minority of patients, who do not show a significant decrease of PRL after a short trial with dopamine-agonists, undergoes neurosurgery or radiotherapy. We report on the case of a 14-year-old girl with a huge prolactinoma who showed, during cabergoline treatment (0.5 mg twice a week), a significant shrinkage of the pituitary mass but no decrease of the very high PRL values. She was referred to us after partial removal of the suprasellar extension of the pituitary tumor. The post-surgical evaluation showed very high PRL levels (9352 μg/l; 20941 μg/l before surgery), which did not decrease during the 2-year treatment with cabergoline (nadir value: 8735 μg/l). However, one month after the beginning of therapy, MRI showed a significant shrinkage of the tumor (tumor volume 5.7 ml, compared with 45.1 ml prior to surgery and 24.4 ml after surgery). Subsequently MRIs demon-strated a progressive reduction of the size with a complete disappearance of the suprasellar and parasellar tissue (tumor volume 1.8, 0.9 and 0.2 ml, at 3, 6 and 12 months, respectively). The MRI performed at the 24th month showed a secondary empty sella, with residual tumor tissue in the right sphenoidal sinus. Increasing cabergoline, up to 3 mg a week, failed to induce any decrease of PRL levels. In conclusion, in such macroprolactinomas the shrinkage of tumor is not strictly correlated with (or it is partially dissociated from) the inhibition of PRL hypersecretion. The choice of other therapeutic options in cabergoline-resistant macroprolacti-nomas needs careful neuroradiological evaluation after a short trial of pharmacological treatment.

Hypopituitarism findings in patients with primary brain tumors 1 year after neurosurgical treatment: preliminary report.

Hypopituitarism represents the consequence of many conditions, in both the adult and child population. It may occur after neurosurgical treatment of brain tumors arising near sella turcica. Much more attention has been focused on lesions far from the hypothalamicpituitary region as possible causes of pituitary impairment, validating the concept of the particular fragility of these structures. The aim of this study was to evaluate pituitary function in particular GH deficiency (GHD) in patients submitted to neurosurgery for benign tumors of the central nervous system (CNS) not involving hypothalamic-pituitary region. We observed 37 patients with benign brain tumors [13 males, 24 females, age: 54.6±13.9 yr; body mass index (BMI): 25.1 ±4.0 kg/m2] performing a basic evaluation of the pituitary function and a dynamic test of the GH/IGF-I axis [GHRH (1 pg/kg iv)+arginine (0.5 g/kg iv) test] for 3 and 12 months after the neurosurgical treatment. Some degree of hypopituitarism was shown in 16 patients (43.2%) at the 3-months follow-up. Hypogonadism was present in 4 patients, hypoadrenalism in another 4 and hypothyroidism in 2. Two patients showed mild hyperprolactinemia and no patients had diabetes insipidus. Seven patients (18.9%) were GH deficient (peak GH <16.5 µg/dl). At 12 months retesting, some degree of hypopituitarism was confirmed in 8 patients, hypogonadism in 2 and hypothyroidism in one; no patients showed hypoadrenalism and GHD was present in 5. This data suggests that hypopituitarism of various degree may develop in patients who are submitted to neurosurgery for primary brain tumors, even far from hypothalamic-pituitary region.