EGFR/ErbB2-Targeting Lapatinib Therapy for Aggressive Prolactinomas.

CONTEXT: Approximately 10% to 20% of prolactinomas are resistant to dopamine agonist therapy. The ErbB signaling pathway may drive aggressive prolactinoma behavior. OBJECTIVE: We evaluated lapatinib, an ErbB1-epidermal growth factor receptor (EGFR)/ErbB2 or human EGFR2 (HER2) tyrosine kinase inhibitor (TKI), in aggressive prolactinomas. DESIGN: A prospective, phase 2a multicenter trial was conducted. SETTING: This study took place at a tertiary referral pituitary center. PATIENTS: Study participants included adults with aggressive prolactinomas showing continued tumor growth despite maximally tolerated dopamine agonist therapy. INTERVENTION: Intervention included oral lapatinib 1250 mg/day for 6 months. MAIN OUTCOME MEASURES: The primary end point was 40% reduction in any tumor dimension assessed by magnetic resonance imaging at study end; tumor response was assessed by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included prolactin (PRL) reduction, correlation of response with EGFR/HER2 expression, and safety. RESULTS: Owing to rigorous inclusion criteria, of 24 planned participants, only 7 consented and 4 were treated. None achieved the primary end point but 3 showed stable disease, including 2 with a 6% increase and 1 with a 16.8% decrease in tumor diameter. PRL response was not always concordant with tumor response, as 2 showed 28% and 59% increases in PRL. The fourth participant had a PRL-secreting carcinoma and withdrew after 3 months of lapatinib because of imaging and PRL progression. EGFR/HER2 expression did not correlate with treatment response. Lapatinib was well tolerated overall, with reversible grade 1 transaminitis in 2 patients, grade 2 rash in 2 patients, and grade 1 asymptomatic bradycardia in 2 patients. CONCLUSIONS: An oral TKI such as lapatinib may be an effective option for a difficult-to-treat patient with an aggressive prolactinoma.

A structural and functional acromegaly classification.

CONTEXT: GH-secreting pituitary adenomas exhibit heterogeneous natural history ranging from small tumors to large aggressive adenomas. OBJECTIVE: To rigorously classify an acromegaly patient cohort defined by clinical, radiological, histopathological, and outcome characteristics. DESIGN: Cross-sectional study. SETTING: Tertiary referral pituitary center. PATIENTS: Subjects were selected from a pituitary tumor research registry that includes 1178 patients with pituitary disease. Cluster analysis was performed on 338 acromegaly patients. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Biochemically active disease with elevated IGF-1 levels at follow-up. RESULTS: Cluster analysis of all patients yielded 292 who were rigorously classified to three acromegaly types. Type 1 (50%) comprised older patients with the longest follow-up and most favorable outcomes, characterized by densely granulated, nonaggressive microadenomas and macroadenomas. Type 1 tumors extend to the sphenoid sinus more frequently than suprasellar extension (concave tumor image) and express abundant immunoreactive p21 and somatostatin receptor 2. Type 2 (19%) comprised noninvasive, densely or sparsely granulated macroadenomas, without significant extension (flat tumor image), with intermediate biochemical outcome. Type 3 (31%) was characterized by sparsely granulated aggressive macroadenomas and comprised patients with adverse therapeutic outcomes, despite receiving more treatments. These tumors extend to both the sphenoid sinus and suprasellar regions with commonly encountered optic chiasm compression ("peanut" magnetic resonance image), with low tumor p21 and somatostatin receptor 2 expression. CONCLUSIONS: After validation, this classification may be useful to accurately identify acromegaly patients with distinctive patterns of disease aggressiveness and outcome, as well as to provide an accurate tool for selection criteria in clinical studies.

Hyperprolactinemia due to spontaneous intracranial hypotension.

OBJECT Spontaneous intracranial hypotension is an increasingly recognized cause of headaches. Pituitary enlargement and brain sagging are common findings on MRI in patients with this disorder. The authors therefore investigated pituitary function in patients with spontaneous intracranial hypotension. METHODS Pituitary hormones were measured in a group of 42 consecutive patients with spontaneous intracranial hypotension. For patients with hyperprolactinemia, prolactin levels also were measured following treatment. Magnetic resonance imaging was performed prior to and following treatment. RESULTS The study group consisted of 27 women and 15 men with a mean age at onset of symptoms of 52.2 ± 10.7 years (mean ± SD; range 17-72 years). Hyperprolactinemia was detected in 10 patients (24%), ranging from 16 ng/ml to 96.6 ng/ml in men (normal range 3-14.7 ng/ml) and from 31.3 ng/ml to 102.5 ng/ml in women (normal range 3.8-23.2 ng/ml). In a multivariate analysis, only brain sagging on MRI was associated with hyperprolactinemia. Brain sagging was present in 60% of patients with hyperprolactinemia and in 19% of patients with normal prolactin levels (p = 0.02). Following successful treatment of the spontaneous intracranial hypotension, hyperprolactinemia resolved, along with normalization of brain MRI findings in all 10 patients. CONCLUSIONS Spontaneous intracranial hypotension is a previously undescribed cause of hyperprolactinemia. Brain sagging causing distortion of the pituitary stalk (stalk effect) may be responsible for the hyperprolactinemia.

Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis.

INTRODUCTION: Biochemical efficacy of somatostatin receptor ligand (SRL) treatment in acromegaly is defined by metrics for GH and IGF-1 control. Since the earliest therapeutic trials, biochemical control criteria, medical formulations, and assay techniques have evolved. MATERIALS AND METHODS: We searched PubMed for English-language trials published from 1974 to 2012 evaluating 10 or more patients, with a duration of more than 3 months and biochemical control as a key objective. We used a random-effects model to compare biochemical outcomes for octreotide and lanreotide trials according to study design characteristics. RESULTS: A total of 4464 patients were enrolled in the analyzed trials; 4125 were treated, and 3787 completed study treatment. Overall achieved control rates were 56% for mean GH and 55% for IGF-1 normalization. Treatment duration was significantly related to both GH (P < .001) and IGF-1 control (P = .02). Prior SRL therapy (P = .01), and year of study publication (P = .03) were related to biochemical control for GH but not IGF-1. No statistically significant differences in GH or IGF-1 response rates were observed for multicenter vs single center, retrospective vs prospective, study drug, and preselection for SRL responsiveness. Dosing scheme, GH response criterion, or switch study design were also not statistically significant in determining GH or IGF-1 response rate. CONCLUSIONS: Clinical design characteristics anticipated to impart efficacy bias including switching, preselection for SRL responsiveness, and retrospective design had no statistically significant impact on efficacy determination. Later year of publication, study duration, and prior SRL use are significant efficacy determinants for acromegaly trial outcomes.

Prolactinomas, Cushing's disease and acromegaly: debating the role of medical therapy for secretory pituitary adenomas.

Pituitary adenomas are associated with a variety of clinical manifestations resulting from excessive hormone secretion and tumor mass effects, and require a multidisciplinary management approach. This article discusses the treatment modalities for the management of patients with a prolactinoma, Cushing's disease and acromegaly, and summarizes the options for medical therapy in these patients.First-line treatment of prolactinomas is pharmacotherapy with dopamine agonists; recent reports of cardiac valve abnormalities associated with this class of medication in Parkinson's disease has prompted study in hyperprolactinemic populations. Patients with resistance to dopamine agonists may require other treatment.First-line treatment of Cushing's disease is pituitary surgery by a surgeon with experience in this condition. Current medical options for Cushing's disease block adrenal cortisol production, but do not treat the underlying disease. Pituitary-directed medical therapies are now being explored. In several small studies, the dopamine agonist cabergoline normalized urinary free cortisol in some patients. The multi-receptor targeted somatostatin analogue pasireotide (SOM230) shows promise as a pituitary-directed medical therapy in Cushing's disease; further studies will determine its efficacy and safety. Radiation therapy, with medical adrenal blockade while awaiting the effects of radiation, and bilateral adrenalectomy remain standard treatment options for patients not cured with pituitary surgery.In patients with acromegaly, surgery remains the first-line treatment option when the tumor is likely to be completely resected, or for debulking, especially when the tumor is compressing neurovisual structures. Primary therapy with somatostatin analogues has been used in some patients with large extrasellar tumors not amenable to surgical cure, patients at high surgical risk and patients who decline surgery. Pegvisomant is indicated in patients who have not responded to surgery and other medical therapy, although there are regional differences in when it is prescribed.In conclusion, the treatment of patients with pituitary adenomas requires a multidisciplinary approach. Dopamine agonists are an effective first-line medical therapy in most patients with a prolactinoma, and somatostatin analogues can be used as first-line therapy in selected patients with acromegaly. Current medical therapies for Cushing's disease primarily focus on adrenal blockade of cortisol production, although pasireotide and cabergoline show promise as pituitary-directed medical therapy for Cushing's disease; further long-term evaluation of efficacy and safety is important.

The utility of oral glucose tolerance testing for diagnosis and assessment of treatment outcomes in 166 patients with acromegaly.

CONTEXT: GH suppression after oral glucose load [oral glucose tolerance test (OGTT)] and normal age- and gender-matched IGF-I levels reflect biochemical control of acromegaly. The OGTT is the gold standard for determining control of GH secretion at diagnosis and after surgical treatment, but the usefulness of performing an OGTT in patients treated with medical therapy has not been determined. OBJECTIVE: Our objective was to assess relationships between basal GH levels (basal GH), GH responses to OGTT [GH nadir (GHn)], and IGF-I levels. DESIGN: This was a retrospective electronic database review. SETTING: This study was performed at a tertiary outpatient pituitary center. PATIENTS: A total of 166 patients with acromegaly (79 females, 87 males) were included in the study. Four categories of testing were performed: diagnosis, postoperative assessment without medication, testing during somatostatin analog (SA) therapy, and testing during dopamine agonist (DA) therapy. MAIN OUTCOME MEASURES: Basal serum GH and IGF-I levels and GH levels 2 h after 75 g OGTT were measured. RESULTS: A total of 482 simultaneous OGTT and IGF-I measurements were observed from 1985--2008. Discordant results of oral glucose tolerance testing (GHn and IGF-I) were observed 33, 48, and 18% in postoperative assessment without medication, SA, and DA categories, respectively. In the SA category, 42% of tests were discordant with normal IGF-I and nonsuppressed GHn. In contrast, 4% of tests were discordant with normal IGF-I and nonsuppressed GH in those treated with DA. No significant differences in discordance were observed when basal GH was used. CONCLUSIONS: Both basal and GHn levels are highly discordant with IGF-I levels during medical therapy with SAs. The OGTT is not useful in assessing biochemical control in these subjects.

Lipodystrophy in patients with acromegaly receiving pegvisomant.

CONTEXT: Pegvisomant, a GH receptor antagonist, suppresses serum IGF-I levels into the normal range in more than 95% of patients with acromegaly. Documented side effects in the initial registration studies included headache, injection-site reactions, flu-like syndrome, and reversible elevation of hepatic enzymes. OBJECTIVE: We report seven patients with acromegaly treated with pegvisomant who developed lipodystrophy at the site of injection (anterior abdominal wall, thigh, buttock, and upper arm). This side effect resulted in discontinuation of pegvisomant in four patients, with subsequent regression of lipohypertrophy. SUBJECTS: Six female and one male patient with acromegaly, aged 24-59 yr, are reported. All patients had undergone prior transsphenoidal surgery, and four received subsequent radiotherapy. Four patients had been treated with maximal doses of somatostatin analogs with partial suppression of IGF-I levels before initiation of pegvisomant therapy. Pegvisomant suppressed IGF-I levels into the normal range in five of seven subjects, before discontinuation of the drug. Two of seven patients received pegvisomant as first-line medical therapy, without prior somatostatin analog treatment, and one received combination therapy with a long-acting somatostatin analog and weekly pegvisomant injections. One patient experienced an erythematous superficial injection-site reaction that responded to application of steroid cream before the onset of lipohypertrophy. CONCLUSIONS: We report seven patients with acromegaly who developed lipohypertrophy at the pegvisomant injection site. Pegvisomant was discontinued due to dissatisfaction with lipohypertrophy by four patients. Lipohypertrophy regressed in all patients when the medication was discontinued. Lipohypertrophy recurred when two patients were rechallenged with pegvisomant. Patients receiving pegvisomant should undergo frequent examination of injection sites for lipohypertrophy.

Medical therapy: options and uses.

Since the initial use of medical treatment for acromegaly, several advances have been made in the understanding of the pathophysiology of growth hormone producing tumors, resulting in the development of multiple medical options and novel treatments. Currently there are three major classes of medication available for the treatment of acromegaly: somatostatin receptor ligands, growth hormone receptor antagonists, and dopamine agonists. Somatostatin receptor ligands are the treatment of choice for acromegaly due to their effectiveness in controlling growth hormone excess in approximately 60% of patients and their beneficial effects on tumor volume. Clinical trials have demonstrated efficacy of pegvisomant in up to 97% of patients, but long term data and safety have yet to be established. Dopamine agonists are inexpensive, but their use is hampered by their lack of efficacy compared to other medications. Medical therapy has an established role as adjuvant therapy after non-curative surgery, as well as primary therapy for selected patients unsuitable for surgical resection. Medical treatment to control growth hormone hypersecretion is often needed after radiation therapy until the effects are evident. Preliminary data suggest a potential role for medical treatment prior to surgical resection, surgical debulking to improve medical efficacy, and combination therapy with multiple medications from the three classes. More studies are required, however, to validate the utility of these approaches in treating acromegaly. With the available therapies, disease control can be achieved in nearly all patients with acromegaly.

Acromegaly with moderate hyperprolactinemia caused by an intrasellar macroadenoma.

BACKGROUND: A 31-year-old woman presented 12 months after discontinuing the oral contraceptive pill with progressive headache to her primary-care physician. She had previously presented with irregular menses to her obstetrician-gynecologist 4 months after discontinuing the oral contraceptive pill. Her serum prolactin levels were 153 microg/l and a pituitary MRI revealed a 13 mm intrasellar mass consistent with an adenoma. The patient was given 0.5 mg cabergoline twice weekly, and after 6 weeks her prolactin levels fell to 31 microg/l. After 6 months, however, she complained of persistent frontal headache and a repeat MRI revealed that the adenoma had increased in size to 16 mm. The patient was referred to an endocrinologist for further evaluation. INVESTIGATIONS: Serum insulin-like growth factor 1 levels and growth hormone levels measured 2 h after ingestion of 75 g of oral glucose. DIAGNOSIS: Acromegaly and hyperprolactinemia caused by a mixed-cell adenoma, secreting growth hormone and prolactin. MANAGEMENT: Trans-sphenoidal surgery followed by medical therapy with 20 mg intramuscular octreotide-LAR monthly.

Body mass index determines evoked growth hormone (GH) responsiveness in normal healthy male subjects: diagnostic caveat for adult GH deficiency.

GH secretion is decreased in obese subjects, whereas age-adjusted IGF-I concentrations are normal. This study was undertaken to rigorously delineate the extent of obesity [elevated body mass index (BMI)] associated with decreased somatotrope secretory function resulting in apparent adult GH deficiency. The peak GH response evoked by combined arginine (0.5 g/kg infused iv over 30 min) and GHRH (1 microg/kg iv bolus) was measured in 59 healthy male subjects with BMIs ranging from normal to obese. BMI correlated with the peak evoked GH response (Pearson r = -0.59; P < 0.01), and the percentage of subjects exhibiting an abnormal evoked GH response, i.e. less than 9 ng/ml, increased from 5% for those with a BMI less than 25 (normal), to 13% for those with a BMI of 25-26.9 (mildly overweight), to 33% for those with a BMI of 27-29.9 (moderately overweight), and to 64% for those with a BMI of 30 or more (obese). BMI is a major determinant of evoked adult GH response to provocative testing. The diagnosis of adult GH deficiency using the evoked GH response in patients with even mild BMI elevation does not accurately distinguish normal from deficient responses and may result in the erroneous classification of obese subjects as GH deficient and thus unnecessarily requiring GH replacement.