Accurate assessment of estrogen receptor profiles in non-functioning pituitary adenomas using RT-digital PCR and immunohistochemistry.

BACKGROUND: Non-functioning pituitary adenomas (NFPAs) are common pituitary tumors, and surgery is generally the only treatment option. Few attempts have been made to explore target molecules for the development of NFPA pharmacological treatments. METHOD: We quantitatively assessed the expression profiles of estrogen receptor (ER) transcripts and proteins in NFPA samples, using reverse transcription-digital polymerase chain reaction (RT-dPCR) and immunohistochemistry, and further investigated the correlations between the expression levels of ER and those of downstream responsive genes. All patients had undergone surgery at the same high-volume hospital. A total of 20 patients with NFPAs were included. All patients were new-onset, and none were diagnosed with intratumoral hemorrhages or cysts. RESULTS: NFPA samples exhibited a bimodal ESR1 expression pattern and were categorized into significantly different high- and low-ESR1 expression level groups (P < 0.05). In contrast, expression levels of ESR1 variants and ESR2 could barely be detected. Similar results were obtained through the immunohistochemical staining of NFPAs, using well-validated antibodies against ERs. The expression levels of ESR1 positively correlated with those of GREB1, an estrogen-responsive gene [correlation coefficient (r) = 0.623, P = 0.003]. CONCLUSIONS: ESR1 expression levels in NFPAs exhibited a bimodal pattern and were positively correlated with GREB1 expression levels. The accurate assessment of ER expression levels may further advance future NFPA-related research.

Study of Simple Immunohistochemical Cytocolorimetric Assay Application for More Accurate Assessment of Prognosis in Patients with Pituitary Adenomas.

BACKGROUND: Immunohistochemistry is a basic diagnostic technique. Immunohistochemical examination results reflect mainly qualitative and less quantitative characteristics of proteomic status of cells. A combined approach with complex quantitative evaluation of marker expression using colorimetric analysis and computer technologies can expand the diagnostic capabilities of immunohistochemistry. We studied such an approach developed by using expression of the proliferative marker Ki-67 in pituitary adenomas. METHODS: A retrospective, blind, randomized, comparative study was performed of Ki-67 expression activity in pituitary adenomas using the traditional Ki-67 labeling index and a simple immunohistochemical cytocolorimetric analysis developed by us with immunohistochemical cytocolorimetric index (ICI) estimation as predictors of relapse, assessing the relationships of these indicators with the time before relapse. RESULTS: Mean Ki-67 labeling index was 3.87% ± 0.29% in the relapse-free group and 4.01% ± 0.29% in the relapse group; the difference was not statistically significant. The average Ki-67 ICI was 24.16% ± 0.51% in the relapse-free group and 30.68% ± 0.64% in the relapse group; the difference was statistically significant. The correlation coefficient of ICI values and time before relapse was -0.302, indicating the presence of a weak negative correlation. CONCLUSIONS: We successfully tested an ICI estimation method developed by us to assess Ki-67 expression in pituitary adenomas. The ICI technique can be used both as a prognostic factor for relapse and, in combination with other modern proteomic and genetic methods, as the basis for creation of new multimodal analyzing systems for functional state assessment of cells and tissues.

MGMT assessment in pituitary adenomas: comparison of different immunohistochemistry fixation chemicals.

PURPOSE: Despite the established role of O6-methyl-guanine-DNA methyltransferase (MGMT) as a marker for temozolomide response, consensus of the most reliable method to assess MGMT expression in pituitary adenomas is still missing. Currently, immunohistochemistry (IHC) assessment of formaldehyde fixed tissue samples is most widely used in a semiquantitative description. As formaldehyde fails to completely preserve nucleic acids, RCL2, an alcohol-based formaldehyde-free fixative, has been proposed as a more reliable alternative in terms of cell stability. Furthermore, as the current method of IHC is semiquantitative and observer-dependent, pyrosequencing, an objective tool to evaluate the methylation status of the MGMT promoter, has emerged as a reliable and accurate alternative. The aim of this study was to validate the current IHC method for assessment of MGMT protein expression in pituitary adenomas. METHODS: The tissue samples of 8 macroadenomas with positive IHC MGMT expression (> 50%) were investigated: first, we compared the time dependent stability of MGMT protein expression after pituitary adenoma removal between formaldehyde vs. RCL2. Then, we compared positive IHC MGMT expression with methylated promoter status using pyrosequencing. RESULTS: In the first 12 h after adenoma removal, tissue samples remained MGMT positive in significantly more samples when fixated with formaldehyde than with RCL2, respectively (96 vs. 81%, p = 0.025). CONCLUSION: Our data confirm that the current method using formaldehyde tissue fixation and IHC reveals stable and reliable results of MGMT assessment in pituitary adenomas.

Apparent diffusion coefficient and pituitary macroadenomas: pre-operative assessment of tumor atypia.

RATIONALE AND OBJECTIVES: Pituitary macroadenomas are predominantly benign intracranial neoplasms that can be locally aggressive with invasion of adjacent structures. Biomarkers of aggressive behavior have been identified in the pathology literature, including the proliferative marker MIB-1. In the radiology literature, diffusion weighted imaging and low ADC values provide similar markers of aggressive behavior in brain tumors. The purpose of this study was to determine if there is a correlation between ADC and MIB-1 in pituitary macroadenomas. MATERIALS AND METHODS: A retrospective review of diffusion imaging and immunohistochemical characteristics of pituitary macroadenomas was performed. The ADC ratio and specimen Ki-67 (MIB-1) indices were measured. Linear regression analysis of normalized ADC values and MIB-1 indices was used to compare these parameters. RESULTS: There were 17 patients with available ADC maps and MIB-1 indices. Local invasion was confirmed by imaging and intraoperative visualization in 11 patients. The mean ADC ratio for the invasive group was 0.68, with a mean MIB-1 index of 2.21 %. In the noninvasive group, the mean ADC ratio was 1.05, with a mean MIB-1 index of 0.9 %. Linear regression analysis of normalized ADC values versus MIB-1 demonstrates a negative correlation, with a linear slope significantly different from zero (p = 0.003, correlation coefficient of 0.77, and r squared = 0.59). CONCLUSION: We determine a strong correlation of low ADC values and MIB-1, demonstrating the potential of diffusion imaging as a possible biomarker for atypical, proliferative adenomas, which may ultimately affect the surgical approach and postoperative management.

Thyrotropin-secreting pituitary adenomas: epidemiology, diagnosis, and management.

Inappropriate secretion of TSH was first described in 1960 in a patient with evidence of hyperthyroidism and expanded sella on imaging. It was later found that a type of pituitary adenoma that secretes TSH (thyrotropinoma) was the underlying cause. The objective of the present review article is to summarize data on the epidemiology, pathogenesis, diagnosis, and management of thyrotropinomas. The prevalence of thyrotropinomas is lower than that of other pituitary adenomas. Early diagnosis is now possible thanks to the availability of magnetic resonance imaging and sensitive laboratory assays. As a corollary, many patients now present earlier in the course of their disease and have smaller tumors at the time of diagnosis. Treatment also has evolved over time. Transsphenoidal surgery is still considered definitive therapy. Meanwhile, radiation therapy, including radiosurgery, is effective in achieving tumor control in the majority of patients. In the past, radiation therapy was used as second line treatment in patients with residual or recurrent tumor after surgery. However, the availability of somatostatin analogs, which can lead to normalization of thyroid function as well as shrink these tumors, has led to an increase in the role of medical therapy in patients who are not in remission after pituitary surgery. In addition, dopamine agonists have shown some efficacy in the management of these tumors. Better understanding of the molecular pathogenesis of thyrotropinomas may lead to rationally designed therapies for patients with thyrotropinomas.

NUTRITIONAL AND METABOLIC ASSESSMENT IN OVERWEIGHT PATIENTS WITH AND WITHOUT HYPERPROLACTINEMIA CAUSED BY PROLACTINOMA.

INTRODUCTION: prolactinomas are pituitary adenomas that express and secrete prolactin. These patients are overweight and the mechanisms are being studied. GOALS: assess nutritional and metabolic status of overweight patients with and without hyperprolactinemia caused by prolactinoma and compare them. MATERIALS AND METHODS: cross-sectional study, patients with body mass index (BMI) ≥ 25 kg/m2 with and without prolactinoma: 1) 20 normoprolactinemic (NPrl) with prolactinoma; 2) 23 hyperprolactinemic (HPrl) with prolactinoma; 3) 28 controls without prolactinoma or alterations in prolactin levels. Evaluated through anthropometric, dietetics, and biochemical assessment. RESULTS: of the 71 patients evaluated, most were obese women with macroprolactinomas. All three groups had diets with low caloric and monounsaturated fatty acid (MUFA) intake, the NPrl group had low carbohydrate (CHO) intake and high lipid (LIP) and saturated fatty acid (SFA) intake, and the NPrl and HPrl groups had appropriate intake of polyunsaturated fatty acids (PUFA). The HPrl group had elevated total cholesterol. HDL cholesterol was below the recommended threshold for most patients. No statistically significant differences were found in anthropometric and biochemical variables among the groups. CONCLUSIONS: most patients with prolactinomas and controls are obese and metabolically similar regardless of prolactin levels. All groups presented low caloric and MUFA intake. Protein, LIP, SFA, and cholesterol were significantly different among the groups, the NPrl group ingested less amount of protein and greater of fat. Snacking between meals and changes of food consumption on weekends was reported by most patients. This is the first study comparing patients with prolactinomas and controls, both with overweight, regarding food consumption and feeding behavior.

Introducción: los prolactinomas son adenomas hipofisarios que expresan y secretan prolactina. Estos pacientes tienen sobrepeso y el mecanismo está en estudio. Objetivos: evaluar el estado nutricional y metabólico de los pacientes con sobrepeso con y sin hiperprolactinemia causada por prolactinoma y compararlos. Materiales y métodos: es un estudio transversal con pacientes con índice de masa corporal (IMC) ≥ 25 kg/m2 con y sin prolactinoma: 1) 20 normoprolactinémicos (NPrl) con prolactinoma; 2) 23 hiperprolactinémicos (HPrl) con prolactinoma; 3) 28 controles sin prolactinoma o alteraciones en los niveles de prolactina. Evaluados a través de estudios antropométricos evaluación dietética y bioquímica. Resultados: de los 71 pacientes evaluados, la mayoría eran mujeres obesas con macroprolactinomas. Los tres grupos tenían dietas con baja ingesta de calorías y ácidos grasos monoinsaturados (MUFA), el grupo NPrl tenía ingesta baja en carbohidratos (CHO) y alta en lípidos (LIP) y ácidos grasos saturados (SFA), y los grupos NPrl y HPrl tenían ingesta apropiada de ácidos grasos poliinsaturados (PUFA). El grupo HPrl tenía el colesterol sérico por encima del valor recomendado, mientras el colesterol HDL estaba por debajo del valor recomendado en la mayoría de los pacientes. No se encontraron diferencias estadísticamente significativas en las variables antropométricas y bioquímicas entre los grupos. Conclusiones: la mayoría de los pacientes con prolactinomas y los controles son obesos y metabólicamente similares, independientemente de los niveles de prolactina. Todos los grupos presentaron baja ingesta de calorías y de ácidos grasos monoinsaturados. Proteínas, LIP, SFA y colesterol fueron significativamente diferentes entre los grupos, el grupo de NPrl ingiere menos cantidad de proteína y mayor de grasa. La mayoría de los pacientes manifiestan picar entre las comidas y cambios en el consumo de alimentos los fines de semana. Este es el primer estudio que compara a pacientes con prolactinomas y controles, ambos con sobrepeso, en cuanto a consumo de alimentos y comportamiento alimentario.

Comparison of energy expenditure, body composition, metabolic disorders, and energy intake between obese children with a history of craniopharyngioma and children with multifactorial obesity.

UNLABELLED: Craniopharyngioma is a histologically benign brain malformation with a fundamental role in satiety modulation, causing obesity in up to 52% of patients. AIM: To evaluate cardiovascular risk factors, body composition, resting energy expenditure (REE), and energy intake in craniopharyngioma patients and to compare the data with those from children with multifactorial obesity. POPULATION: All obese children and adolescents who underwent craniopharyngioma resection and a control group of children with multifactorial obesity in follow-up between May 2012 and April 2013. MATERIALS AND METHODS: Anthropometric measurements, bioelectrical impedance, indirect calorimetry, energy intake, homeostatic model assessment insulin resistance (HOMA-IR), and dyslipidemia were evaluated. RESULTS: Twenty-three patients with craniopharyngioma and 43 controls were included. Children with craniopharyngioma-related obesity had a lower fat-free mass percentage (62.4 vs. 67.5; p=0.01) and a higher fat mass percentage (37.5 vs. 32.5; p=0.01) compared to those with multifactorial obesity. A positive association was found between %REE and %fat-free mass in subjects with multifactorial obesity (68±1% in normal REE vs. 62.6±1% in low REE; p=0.04), but not in craniopharyngioma patients (62±2.7 in normal REE vs. 61.2±1.8% in low REE; p=0.8). No differences were found in metabolic involvement or energy intake. CONCLUSIONS: REE was lower in craniopharyngioma patients compared to children with multifactorial obesity regardless of the amount of fat-free mass, suggesting that other factors may be responsible for the lower REE.

Gasto energético, composición corporal, trastornos metabólicos e ingesta energética en pacientes con antecedentes de craneofaringioma / Energy expenditure, body composition, metabolic disorders, and energy intake in patients with a history of craniopharyngioma

Introducción: Los craneofaringiomas son malformaciones histológicamente benignas que se sitúan entre el hipotálamo y la hipófisis, zonas con un rol determinante en la modulación de la saciedad. Aun siendo tumores benignos, presentan una considerable morbilidad. La obesidad está presente hasta en un 52% de los pacientes. Objetivo: evaluar factores de riesgo cardiovascular, composición corporal y gasto energético en pacientes con craneofaringioma, y compararlos con un grupo de obesos multifactoriales. Material y métodos: Se incluyeron todos los pacientes con resección quirúrgica de craneofaringioma, menores de 21 años, en seguimiento en nuestro centro entre mayo 2012 hasta abril 2013 que aceptaron participar por medio del consentimiento informado. Se realizó valoración antropométrica, composición corporal con impedanciometría, gasto energético con calorimetría indirecta y valoración de ingesta energética y de macronutrientes. Se determinó resistencia a la insulina (HOMA-IR) y dislipemia. Se comparó a los pacientes con craneofaringioma con obesidad, con un grupo de pacientes con obesidad multifactorial. Resultados: se estudiaron 39 pacientes. El 59% era obeso y presentó significativamente menor% de masa magra (62.4 vs 67.5 p=0.01) y mayor% de masa grasa (37.5 vs 32.5 p=0.01) comparados con los obesos multifactoriales. No se encontró diferencias en el compromiso metabólico entre los obesos con y sin antecedente de craneofaringioma. Se dividieron los pacientes en tertilos según% de gasto energético para categorizar en gasto bajo vs normal. Se encontró asociación positiva entre% de gasto energético y% de masa magra en obesos multifactoriales (68±1%; en los gasto normal vs 62.6± 1% en los gasto bajo: p 0,04). Sin diferencias dentro de la población de obesos con antecedente de craneofaringioma (62±2.7 en los gasto normal/alto vs 61.2±1.8% en los gasto bajo: p 0,8). El gasto energético basal (REE) fue menor en los pacientes con antecedente de craneofaringioma vs obesos multifactoriales, independientemente de la masa magra, lo que sustenta que existirían otros factores que actuarían disminuyendo el gasto energético. No hubo diferencia con respecto a la ingesta en ambos grupos estudiados. Conclusiones: los pacientes con antecedente de craneofaringioma presentan menor gasto energético no relacionado a la masa magra y similar ingesta energética comparado con obesos multifactoriales. No hubo diferencias en el compromiso metabólico entre los obesos con y sin antecedentes de craneofaringioma (AU)

Introduction: Craniopharyngiomas are histologically benign malformations located between hypothalamus and the pituitary gland, areas that play an important role in satiety modulation. Although the tumors are benign, they may cause significant morbidity. Obesity is found in up to 52% of patients. Aim: To assess cardiovascular risk factors, body composition, and energy expenditure in patients with craniopharyngioma, and to compare them to results in a group of children with multifactorial obesity. Material and methods: All patients who underwent surgical resection of craniopharyngioma, younger than 21 years of age, who were being followed-up at our center between May 2012 and April 2013 who gave their informed consent to participate were enrolled in the study. Anthropometric measurements, body composition with impedanciometer, energy expenditure with indirect calorimetry, and energy and macronutrient intake were evaluated. Insulin resistance (HOMA-IR) and dyslipidemia were determined. Patients with craniopharyngioma associated with obesity were compared to patients with multifactorial obesity. Results: Of 39 patients studied, 59% were obese and a significantly lower percentage of lean mass (62.4 vs 67.5 p=0.01) and a higher percentage of fat mass (37.5 vs 32.5 p=0.01) compared to multifactorial obese subjects. No differences were found in metabolic involvement between obese subjects with and those without a history of craniopharyngioma. Patients were divided into tertiles according to percentage of energy expenditure to categorize low versus normal expenditure. A positive correlation was found between percentage of energy expenditure and lean mass percentage in subjects with multifactorial obesity (68±1%; in those with normal energy expenditure versus 62.6±1% in those with low energy expenditure: p 0.04). No difference was found within the group of obese patients with a history of craniopharyngioma (62±2.7 in those with normal/high expenditure versus 61.2±1.8% in those with low expenditure: p 0.8). Baseline energy expenditure (BEE) was lower in craniopharyngioma patients than in those with multifactorial obesity, regardless of lean mass percentage, supporting the hypothesis that other factors may be involved in the decrease of energy expenditure. There was no difference in the food intake between both groups. Conclusions: Patients with a history of craniopharyngioma had a lower energy expenditure unrelated to lean mass and a similar energy intake compared to subjects with multifactorial obesity. No differences were found in metabolic involvement between obese subject with and those without a history of craniopharyngioma (AU)

Gynecomastia: when is treatment indicated?

This algorithmic approach can simplify your clinical evaluation and help you decide whether intervention or watchful waiting is appropriate.

Aggressive pituitary tumours: the role of temozolomide and the assessment of MGMT status.

BACKGROUND: Aggressive pituitary tumours are associated with substantial morbidity and mortality. Treatment options are often limited, and chemotherapy has been reserved as salvage therapy although historically results have often been disappointing. However, temozolomide, an oral alkylating agent, has recently demonstrated significant activity against these tumours. A DNA repair protein, 06-methylguanine-DNA methyltransferase (MGMT) has been suggested as a biomarker to predict response to temozolomide in pituitary tumours. MATERIALS AND METHODS: This paper will review the current literature on temozolomide and pituitary tumours and discuss the recent controversy surrounding the value of determining the MGMT status in this tumour group. A PubMed search was performed to retrieve articles, using the terms 'pituitary tumour' and 'temozolomide'. RESULTS: Overall, 24/40 (60%) of the published cases demonstrated a response to temozolomide therapy. The highest response rates were seen amongst prolactinomas (73%) and ACTH-secreting tumours (60%), whilst nonfunctioning pituitary tumours exhibit lower response rates (40%). Responsivity is typically evident in the first 3 months of therapy and may be dramatic and sustained. Low MGMT expression, as determined by immunohistochemistry, is associated with a high response rate (76%), whilst high MGMT expression has not been associated with responses. MGMT promoter methylation does not correlate with temozolomide response. CONCLUSIONS: Temozolomide is the first chemotherapeutic agent to show substantial response rates in aggressive pituitary tumours. MGMT immunohistochemistry, but not MGMT methylation analysis, shows promise as a predictive tool. Prospective clinical trials are now necessary to more accurately determine the efficacy of this agent in this patient group.

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.

The GnRH test in the assessment of patients with pituitary and parapituitary lesions: results of a 5-year retrospective study.

OBJECTIVE: To examine the utility of the GnRH (gonadotrophin-releasing hormone) test in the management of patients with pituitary and parapituitary lesions. PATIENTS AND METHODS: A 5-year retrospective study of LH (luteinizing hormone) and FSH (follicle stimulating hormone) responses to GnRH test in patients with HP (hypothalamic-pituitary) disease in a regional endocrine centre. Serum LH and FSH concentrations were measured at baseline and at 20 and 60 min after an intravenous bolus of 100 mcg (micrograms) of GnRH. The GnRH responses were categorised by tumour size, tumour type, and gonadal status. RESULTS: Of the 104 patients studied, 46 were male and 58 were female. There were 50 normal, 38 subnormal and 16 exaggerated LH responses compared with 34 normal 67 subnormal and three exaggerated responses for FSH. Seventy-four patients (71.2%) were hypogonadal. Normal LH responses were achieved in half of the hypogonadal subjects and normal FSH responses in more than a third. Furthermore, the LH responses were exaggerated in nine hypogonadal patients compared with three for FSH. The GnRH test could not differentiate between pituitary or parapituitary lesions either by size or type of lesion. An exception was the male non-functioning adenoma (NFA) sub-group (10 patients, all were hypopituitary, seven were hypogonadal), which demonstrated significant subnormal LH and FSH responses compared with other male and female tumour type sub-groups. CONCLUSIONS: The data from this study indicate that the GnRH test is unhelpful in the clinical assessment of the HP axis in patients with HP disease.

Comparative immunohistochemical assessment of craniopharyngioma and related lesions.

Craniopharyngiomas (CP), Rathke's cleft cysts (RCC), and sellar xanthogranulomas (XG) are closely related lesions. As expression of cytokeratins 8 (CK8) and 20 (CK20) was reported in RCC but not in CP, the present study investigates the reproducibility of immunohistochemical distinction between CP and RCC, attempting to identify the relationship of XG to these lesions. A comparative study of 55 patient specimens (25 CP, 28 RCC, and 2 XG) was analyzed for the histological features of xanthomatous changes and squamous metaplasia, and expression of CK8 and CK20. In the 25 CP cases, xanthomatous changes were seen in 5 (20%), with CK8 reactivity demonstrated in all 25 cases. A prominent xanthomatous component was identified in 13 of 28 RCC (46%), and squamous metaplasia was seen in 11 (39%), 9 of which also contained xanthomatous features. CK8 reactivity was demonstrated in all 28 RCC cases, whereas CK20 was seen only in 9 cases (32%). Of the two cases diagnosed as XG, none contained epithelium, and immunohistochemistry for cytokeratins was not observed. Overall, differential expression of cytokeratins cannot reliably distinguish CP from RCC. Furthermore, expression of CK20 in RCC is generally seen within a background of prominent squamous metaplasia and reactive xanthomatous changes.

Assessment of long-term remission of acromegaly following surgery.

OBJECT: The criteria for remission of acromegaly following transsphenoidal adenoma resection are in evolution. In the present study the authors evaluate the utility of predicting long-term remission by reference to a single fasting growth hormone (GH) level on the 1st postoperative day. METHODS: A retrospective analysis was conducted on 181 patients with acromegaly who underwent transsphenoidal resection between 1973 and 1990 and completed a 5-year follow-up period. Fasting serum GH levels were obtained in all patients on the 1st postoperative day in the absence of exogenous glucocorticoids. All patients participated in a follow-up evaluation lasting at least 5 years, which included measurements of serum insulin-like growth factor-I (IGF-I) levels as an index of acromegalic activity. Among the 181 patients, GH levels ranged from 0 to 8 ng/ml in 131 (72%) on the 1st postoperative day, suggesting biochemical remission. This group included 107 (84%) of the 127 patients with microadenomas, but only 24 (44%) of the 54 with macroadenomas. Nevertheless, 15 (11%) of the 131 patients who initially had attenuated GH levels displayed recurrent acromegaly within the first 2 years (with elevated levels of IGF-I in all cases, and abnormalities appearing on magnetic resonance images in nine cases). Only one of 116 patients in whom the initial postoperative GH level was lower than 2 ng/ml experienced a recurrence, whereas 14 (93%) of the 15 patients with postoperative GH levels between 2.2 and 8 ng/ml subsequently displayed biochemical evidence of acromegaly. CONCLUSIONS: The findings indicate that a fasting morning serum GH level lower than 2 ng/ml on the 1st postoperative day portends long-term biochemical remission of acromegaly, whereas higher levels are a significant marker for recurrent disease.

Impaired estrogen-induced negative feedback on gonadotropin secretion in patients with gonadotropin-secreting and nonfunctioning pituitary adenomas.

BACKGROUND: Several in vitro studies suggest that gonadotropin-secreting pituitary adenomas (Gn-omas) and non functioning pituitary adenomas (NFPA) originate from gonadotroph cells. Patients with Gn-oma and NFPA frequently show abnormal gonadotropin response to TRH. The aim of the study was to investigate whether the estrogen-induced negative feedback is operating in either patients with Gn-oma or NFPA. MATERIALS AND METHODS: Serum gonadotropin levels were evaluated at 24 h after ethinylestradiol administration (1 mg per os; EE2 test) in seven patients with a diagnosis of Gn-oma, based on the presence of high follicle-stimulating hormone (FSH) and/or lutenising hormone (LH) levels with normal or high levels of sex steroids, in 22 patients with NFPA with normal or low levels of gonadotropin and sex steroids, and 30 sex- and age-matched healthy subjects. A normal response to EE2 test was arbitrarily defined as a serum LH and FSH decrease of at least 40 and 30% below basal levels. RESULTS: Among patients with Gn-oma, only one had a normal FSH inhibition and another, a normal LH inhibition. Among the 22 patients with NFPA, the EE2 test caused a normal FSH or LH reduction in 10 and 15, respectively, while a normal reduction of both FSH and LH was observed in nine. CONCLUSIONS: The study demonstrates that estrogen-induced negative feedback of gonadotropin secretion is disrupted in almost all patients with Gn-oma and in half of those with NFPA. This defective feedback is reminiscent of the resistance to thyroid hormones and glucocorticoids observed in patients with thyroid-stimulating hormone- (TSH-) and adrenocorticotropic hormone- (ACTH-)secreting adenomas, respectively.

Are markers of proliferation valuable in the histological assessment of pituitary tumours?

The prediction of tumour behaviour and response to treatment has led to interest in the assessment of the proliferative potential of tumours. Pituitary tumours are usually histologically benign but are capable of aggressive growth and local invasion, although distant metastasis is limited to the very rare pituitary carcinoma. These differences in tumour behaviour may determine both the prognosis and also the effectiveness of treatment whether it be surgery, drugs or radiotherapy. Immunohistochemistry using antibodies to Ki-67 and proliferating cell nuclear antigen (PCNA) which are expressed in cells that have entered the cell cycle, can be used to assess the proportion of the cells from a tumour that are proliferating. The percentage of positively stained nuclei (labelling index (LI)) may be helpful in predicting appropriate management, as there is a relationship in many tumours between labelling index, invasiveness and tumour recurrence. This has been shown to be true for pituitary tumours, although there may be significant overlap such that low LI may be seen in the rare, aggressive, metastatic pituitary carcinomas, and high LI in indolent tumours. Thus although assessment of proliferation may be helpful in arousing suspicion as to subsequent tumour recurrence or invasiveness, this technique also demonstrates that there are other important and as yet unidentified processes that determine pituitary tumour behaviour.

Biochemical assessment of Cushing's disease in patients with corticotroph macroadenomas.

The majority of cases of Cushing's disease are due to an underlying pituitary corticotroph microadenoma (< or = 10 mm). Corticotroph macroadenomas (> 10 mm) are a less common cause of Cushing's disease, and little is known about specific clinical and biochemical findings in such patients. To define further the clinical characteristics of patients with corticotroph macroadenomas, we performed a retrospective review of Cushing's disease due to macroadenomas seen at Massachusetts General Hospital between 1979 and 1995. Of 531 patients identified with a diagnostic code of Cushing's syndrome, 20 were determined to have Cushing's disease due to a macroadenoma based on radiographic evidence of pituitary adenoma greater than 10 mm and pathological confirmation of a pituitary adenoma. A comparison review of charts of 24 patients with Cushing's disease due to corticotroph microadenomas identified on the basis of radiographic evidence of a normal pituitary gland or a pituitary adenoma 10 mm or less in diameter was also performed. The mean ages of the patients (+/- SD) with macroadenomas and microadenomas were similar (39 +/- 12 and 38 +/- 14 yr, respectively). The baseline median 24-h urine free cortisol (UFC) excretion was 1341 nmol/day (range, 304-69,033 nmol/day) and 877 nmol/day (range, 293-2,558 nmol/day) for macroadenoma and microadenoma patients, respectively (P = 0.058). After the 48-h high dose dexamethasone suppression test, UFC decreased by 77 +/- 19% (mean +/- SD) and 91 +/- 7% in macroadenoma and microadenoma subjects, respectively (P = 0.04). Fifty-six percent of macroadenoma patients and 92% of microadenoma patients had greater than 80% suppression of UFC after high dose dexamethasone administration (P = 0.03). The baseline median 24-h urinary 17-hydroxysteroid (17-OHCS) excretion was 52 mumol/day (range, 25-786 mumol/day) and 44 mumol/day (range, 17-86 mumol/day) for macroadenoma and microadenoma subjects, respectively (P = 0.09). After the standard high dose dexamethasone suppression test, 17-OHCS excretion decreased by 46 +/- 33% and 72 +/- 22% for macroadenoma and microadenoma subjects, respectively (P = 0.02). Fifty-three percent of patients with macroadenomas and 86% of patients with microadenomas had greater than 50% suppression of 17-OHCS after high dose dexamethasone administration (P = 0.02). Baseline plasma ACTH values were above the normal range in 83.3% of macroadenoma patients and in 45% of microadenoma subjects (P = 0.05). Tumors were immunostained with the MIB-1 antibody for Ki-67 to investigate proliferation in the adenomas. There was a trend for a higher Ki-67 labeling index in corticotroph macroadenomas, and seven (44%) macroadenomas vs. three (18%) microadenomas had labeling indexes greater than 3%, but this was not statistically significant. In summary, corticotroph macroadenomas are often associated with less glucocorticoid suppressibility than the more frequently occurring microadenomas. Therefore, the lack of suppression of UFC or 17-OHCS after the administration of high dose dexamethasone in a patient with Cushing's disease does not necessarily imply the presence of ACTH-independent Cushing's syndrome and is more commonly seen in patients with corticotroph macroadenomas than in those with microadenomas. Increased plasma ACTH concentrations are typical of patients with corticotroph macroadenomas and may be a more sensitive indicator of neoplastic corticotrophs than the UFC or 17-OHCS response to standard high dose dexamethasone testing.