Typing of inflammatory lesions of the pituitary.

Inflammatory pituitary lesions account for 1.8% of all specimens from the German Pituitary Tumor Registry. They occure in 0.5% of the autoptical specimens and in 2.2% of the surgical cases. Women are significantly more often affected than men and are often younger when first diagnosed. In general, primary and secondary inflammation can be distinguished, with secondary types occurring more frequently (75.1%) than idiopathic inflammatory lesions (15.4%). In primary inflammation, the lymphocytic type is more common (88.5%) than the granulomatous type of hypophysitis (11.5%). The most common causes of secondary inflammation are Rathke's cleft cysts (48.6%), followed by tumors (17.4%) such as the craniopharyngioma (9.1%), adenoma (5.5%) or germinoma (2.0%). More causes are tumor-like lesions (7.1%) such as xanthogranuloma (3.5%) or Langerhans histiocytosis (3.5%), abscesses (5.5%), generalized infections (5.1%), spreaded inflammations (4.7%) and previous surgeries (4.0%). In 1.6% of all specimens the reason for the inflammation remains unclear. The described classification of hypophysitis is important for specific treatment planning after surgery.

[Acromegaly-associated lesions of the nasal mucosa. Case report]. / Mit Akromegalie assoziierte Veränderungen der Nasenschleimhäute. Fallbericht.

Acromegaly is a rare disease caused by a growth-hormone-secreting pituitary adenoma. Symptoms include enlargement of the hands, feet, and jaw with growing dental interspaces, as well as hypertrophy of the tongue and nasal and sinusoidal mucosa. The two latter symptoms are mostly responsible for the accompanying obstructive sleep apnea syndrome. Besides these "cosmetic" symptoms, the disease is associated with hypertension and diabetes mellitus, as well as with an increased risk for adenomas and carcinomas of the colon. The average time span from first symptom to diagnosis is well over 6 years; a single determination of insulin-like growth factor 1 in serum can confirm the disease. The treatment of choice remains surgical resection of the adenoma in suitable patients, whereas in extensive disease with invasion of surrounding tissue, drug therapy and/or radiotherapy may be necessary.

Clinical tumor growth and comparison with proliferation markers in non-functioning (inactive) pituitary adenomas.

BACKGROUND: As the development of clinically silent pituitary adenomas is not yet fully understood, the radiologically measured growth of inactive pituitary adenomas should be compared with adenoma classification and immunostainings for proliferation markers. MATERIAL AND METHODS: In 32 patients with non-functioning adenomas (NFA) from 45 operations with retrospectively available preoperative series of magnetic resonance imaging (MRI) we measured the largest growing diameter (LGD) in mm/ year. The adenomas were immunostained for Ki-67 (MiB-1), PCNA, p53 protein, IGF- and PTH-related protein. The positive nuclei for MiB-1, PCNA, and p53 protein were counted and their labelling indices (LI) were calculated. The clinical measurements were compared with these data and were statistically analysed (Spearman test, Whitney-U-test). The growth rate per year was available in 28 cases. We chosed three grades of LGD: less than 1.5 mm in diameter in 9 patients (32%), between 1.5 and 3.0 mm in 11 patients (39%) and more than 3.0 mm in 8 patients (29%). RESULTS: MiB-1 positive nuclei were found in 42% of adenomas, PCNA positive nuclei in 58% and p53 positive nuclei in 16%. IGF 1 was immuno-stained in 84% of adenomas. The mean LI for MiB-1 was 0.12 in adenomas growing less than 1.5 mm and 0.34 in adenomas growing more than 1.5 mm per year. For non-invasive adenomas, the MiB-1 LI was 0.03, for invasive adenomas it was 0.126 and for strongly invasive adenomas 0.212. The MiB-1 LI was lower in null cell adenomas than in FSH/LH adenomas. All these data for MiB-1 showed no statistically significant differences (p<0.05). PCNA LI in adenomas growing less than 1.5 mm per year was 0.51 in contrast to LI of 1.12 for those growing more than 1.5 mm. In non-invasive adenomas the PCNA LI was 0.796, in invasive adenomas 0.655 and in diffuse strongly invasive ones 1.011. Null cell adenomas had a lower PCNA LI than FSH/LH cell adenomas. CONCLUSIONS: Statistically significant differences were measured for the growth rate und the PCNA expression. P53 was immunostained in invasive adenomas only. There were no correlations to the clinical growth rate, but p53 expression correlated significantly to numbers of MiB-1 positive nuclei and PCNA positive nuclei. IGF-I expression was found to correlate inversely with age of patients. We recommend the use of PCNA if correlations to progression of tumor growth are wanted.

Salivary cortisol measurement--a reliable method for the diagnosis of Cushing's syndrome.

The measurement of cortisol in saliva is becoming more widely accepted as a screening test for the diagnosis of hypercortisolism. Since 1986, cortisol measurement in saliva has been continuously used in our department. In this study we compared salivary cortisol profiles from proven Cushing's disease patients with profiles from healthy subjects and obese children. The purpose was to evaluate the predictive value of the method for the diagnosis of hypercortisolism and to define cut-off levels to exclude or identify hypercortisolism. Cortisol in saliva was measured in 150 Cushing's disease patients (30 children, 120 adults, ranging from age 4-70), 100 healthy subjects (55 children, 45 adults, ranging from age 6-60), and 31 children (age 7-15) with an age-related body-mass-index above the 90th percentile. Generally, five saliva samples were taken over the day at 6:00-8:00 a.m., 11:00-12:00 a.m., 4:00-6:00 p.m., 7:00-8:00 p.m., and 10:00 p.m. The samples were measured using a radioimmuno-assay (INCSTAR Corporation, Stillwater, Minnesota, USA). For healthy subjects, morning levels of cortisol in saliva between 3-19 microg/l were found. These levels dropped to levels in between <1-11 microg/l at 11:00-12:00 a.m., <1-6 microg/l at 4:00-6:00 p.m., <1-4.5 microg/l at 7:00-8:00 p.m., and <1-2.9 microg/l at 10:00 p.m. The measured values showed a correlation with age, height, and weight. In Cushing's disease patients, the circadian salivary cortisol rhythm was missing, compared to healthy subjects. There was no significant difference in salivary cortisol levels or circadian rhythm between healthy or obese children. We found a high sensitivity for the detection of hypercortisolism at the 10:00 p.m. salivary cortisol measurement. The following, age dependent cut-off levels for salivary cortisol at 10:00 p.m. were calculated for the exclusion of hypercortisolism. Age 6-10: 1.0 microg/l (specificity 100%, sensitivity 87.5%); age 11-15: 1.7 microg/l (specificity 100%, sensitivity 100%); age 16-20: 1.6 microg/l (specificity 100%, sensitivity 76.2%); age 21-60: 1.6 microg/l (specificity 100%, sensitivity 90.9%) [corrected] For the proof of Cushing's syndrome, the following age-dependent cut-off levels at 10:00 p.m. were found: age 6-10: 1.9 microg/l (specificity 100%, sensitivity 80%); age 11-15: 1.7 microg/l (specificity 100%, sensitivity 100%); age 16-20: 2.5 microg/l (specificity 100%, sensitivity 84.2%); age 21-60: 1.9 microg/l (specificity 100%, sensitivity 97.6 %) [corrected] The cortisol assessment in saliva is a sensitive and reliable method to discriminate normocortisolemic from hypercortisolemic patients. From our view, the major advantages of this method are the reliability, non-invasiveness, and use in ambulatory patients.

Stimulation of spermatogenesis in stalk-sectioned rhesus monkeys by testosterone alone.

Testosterone alone stimulated spermatogenesis in four adult, pituitary stalk-sectioned rhesus monkeys. Ten to 14 weeks after transection of the pituitary stalk, testicular volumes declined to about one fifth of the presurgical values. Serum LH levels declined precipitously, being undetectable 1 week postsurgery, and serum testosterone levels were indistinguishable from those of castrated male monkeys by the 5th week postsurgery. After a transient decline, serum PRL levels increased to high values in all four monkeys throughout the rest of the postsurgery period. Twelve weekly injections of 250 mg testosterone enanthate resulted in peak testosterone levels around 25-fold higher than presurgical levels. Estradiol levels increased about 4-fold over presurgical levels, and PRL also increased further during the treatment phase. Small ejaculates were produced by electrostimulation by the 5th week of treatment. Thereafter, the ejaculate weight increased. Sperm were found from the 10th week in all four monkeys. By the 13th week of treatment, sperm counts in three monkeys ranged from 17-60 X 10(6) sperm/ejaculate. The sperm counts continued to increase for the first 4 weeks after the cessation of the testosterone enanthate injections. Thereafter, the sperm counts declined, and all four animals produced azoospermic ejaculates between 10 and 31 weeks posttreatment. Moreover, testosterone levels declined slowly and nonuniformly among the four animals. Testicular volumes declined and were at the lowest levels 14 weeks posttreatment. Estradiol and PRL levels also declined posttreatment. It is concluded that testosterone alone can stimulate spermatogenesis in stalk-sectioned rhesus monkeys even in the face of high serum PRL and estradiol levels.

Mutation and expression analysis of corticotropin-releasing factor 1 receptor in adrenocorticotropin-secreting pituitary adenomas.

The present study was designed to investigate a possible role of CRF1 receptors (CRF1-R) in the pathogenesis of Cushing's disease. ACTH-secreting pituitary adenomas and nonsecreting pituitary adenomas have been analyzed for mutations in the CRF1-R gene by PCR and sequencing and been compared with the sequences of normal anterior pituitaries. No mutations affecting the CRF1-R protein have been found in all tumors analyzed. However, we found a significant overexpression of the CRF1-R messenger RNA in ACTH-secreting pituitary adenomas vs. inactive adenomas and normal pituitaries. We conclude that mutations of the CRF1-R are unlikely to be involved in Cushing's disease. We suggest that the overexpression of the CRF1-R messenger RNA may be related to a disturbed receptor regulation in ACTH-secreting pituitary adenomas.

Analysis of thyrotropin-releasing hormone-signaling components in pituitary adenomas of patients with acromegaly.

In many acromegalic patients the paradoxical release of GH in response to TRH has been well documented, but the mechanisms underlying this phenomenon are not understood. It has been suggested that aberrant GH secretion may result from TRH endogenously synthesized by the adenoma. In 32 adenomas from acromegalic patients, TRH-like immunoreactivity (TRH-LI) was measured using 2 well characterized antisera. TRH-LI was not detectable in 10 samples, and in 19 samples, TRH-LI was measured only by the less specific antibody. With the TRH-specific antibody, TRH-LI was identified only in 3 samples, 2 of which contained exceedingly high concentrations (40 and 96 pg/mg tissue). In the latter 2 samples, prepro-TRH messenger ribonucleic acid was identified by Northern blot analysis, but not in the control tissue sample of a patient without pituitary disease and also not in the other adenomas analyzed by this technique. Transcripts of the TRH receptor were almost undetectable in all adenomas analyzed. For the TRH-degrading ectoenzyme, a potential regulator of TRH signals at adenohypophyseal target sites, transcripts were significantly expressed only in the TRH-producing adenomas. We conclude that the TRH-signaling elements examined are, in general, not directly involved in the mechanisms causing paradoxical GH secretion in acromegalic patients.

In vitro secretion of pro-opiomelanocortin (POMC) derived peptides in human ACTH-producing pituitary adenomas: evaluation of hormone ratios in different functional states.

In 14 cases of ACTH-producing pituitary adenomas (8 cases of Cushing's disease and 6 cases of Nelson's syndrome) dispersed cells prepared from adenoma tissue were incubated in a superfusion or static incubation system and investigated for ACTH, beta-endorphin (beta-EP) and beta-lipoprotein (beta-LPH) production. Effects of cortisol and lysine vasopressin (LVP) were evaluated. During the superfusion a qualitatively parallel secretory pattern is obtained for all hormones. Quantitatively, however, the response to LVP stimulation is more pronounced for beta-endorphin-like immunoreactivity (beta-LPH/beta-EP-IR) causing ACTH/beta-LPH/beta-EP-IR ratios to change throughout single experiments. beta-EP/beta-LPH ratios, however, which were estimated by means of Sephadex G-50 gel chromatography at various key points of the superfusion, were constant for each tumor, although variable between different adenomas, ranging from 0.68 to 2.0. The results suggest neither a differential control for the secretion of the peptides investigated within individual tumors nor a direct effect of cortisol or LVP on pro-opiomelanocortin processing. Summarizing clinical data and in vitro findings such as secretory behavior or hormone ratios, we can find no characteristic differences between Nelson's syndrome and Cushing's disease.

Autoradiographic demonstration of in vivo 125I-growth hormone-releasing hormone (GHRH) binding by human GH-secreting pituitary adenomas transplanted on athymic nude mice.

This study was designed for the purpose of investigating a method for in vivo tumor labelling of human GH (hGH) secreting pituitary adenomas. Pituitary adenoma tissue removed from four acromegalic patients was transplanted into 62 athymic nude mice. After positive GHRH stimulation tests 125I-GHRH(1-44) NH2 was injected intravenously (i.v.) in ten nude mice. 10 min after 125I-GHRH injection, the nude mice were sacrificed, the transplants excised and prepared for light microscopical autoradiography. The mouse pituitary and skeletal muscle specimens served as controls. After the i.v. injection of 125I-GHRH we observed a marked accumulation of silver grains within the adenoma tissue indicating tumor labelling. This study is a first step in investigating a new method for labelling small residues of hGH secreting pituitary adenomas intraoperatively.

Effects of preoperative octreotide treatment on different subtypes of 90 GH-secreting pituitary adenomas and outcome in one surgical centre.

OBJECTIVE: To investigate the possible impact of pretreatment with octreotide on different subtypes of GH-secreting pituitary adenomas and on the outcome of transnasal surgery. METHODS: We reviewed a consecutive series of 90 acromegalic patients treated with octreotide alone before transnasal surgery. On the basis of magnetic resonance imaging, the tumours were classified into four groups: group A, microadenoma (n=7); group B, transnasally resectable macroadenoma (n=21); group C, invasive, potentially transnasally resectable macroadenoma (n=43); group D, non-resectable grossly invasive macroadenoma (n=19). All patients were treated for at least 3 months before surgery, with a mean daily dose of 221+/-31 microg octreotide. The mean follow-up was 51.7+/-1.4 months. The comparative group included 57 acromegalic patients who were not receiving octreotide treatment. RESULTS: After pretreatment with octreotide, tumour shrinkage was clearly observed in 28 of the 90 patients (31%). At surgery, the tumours after octreotide treatment were more often white or grey in colour (91% compared with 75%) and were observed to be slightly more often fluid or soft in texture (86% compared with 79%) than those in the comparative series. Endocrinological remission was achieved in all patients in group A, 95.2% in group B, and 81.4% in group C. In only 10 of the 14 patients with tumour shrinkage in group C, endocrinological remission was also achieved (71.4%). In the comparative series, endocrinological remission was achieved in 92.9% of group A, 87.5% of group B, and 73.9% of group C. CONCLUSIONS: Octreotide treatment slightly improved the already relatively high rate of endocrinological remission in invasive, potentially transnasally resectable macroadenomas. The rate of tumour shrinkage was found to decrease with extrasellar size. With the exception of tumour growth in approximately 7% of invasive adenomas and pituitary apoplexy in one patient, there was no disadvantage associated with the octreotide pretreatment.

Reduced expression levels of the cell-cycle inhibitor p27Kip1 in human pituitary adenomas.

The molecular mechanisms leading to increased cellular proliferation rates and, thus, tumor formation in the anterior pituitary gland are poorly understood. The cyclin-dependent kinase inhibitor p27Kip1 is a key molecule regulating the G1 phase of the cell cycle in many cell types. Furthermore, it was shown that p27 knock-out mice develop pro-opiomelanocortin-positive pituitary tumors. In an effort to clarify the role of p27 in the normal and tumorous human pituitary, we studied the expression of p27 by immunohistochemistry, using a highly specific mouse monoclonal anti-human p27 antibody. Normal pituitaries and 54 pituitary adenomas (twelve somatotrope adenomas, nine prolactinomas, twelve corticotrope adenomas, three TSH-producing tumors, six gonadotrope adenomas, six null cell adenomas, and six oncocytomas) were analyzed. p27 expression was determined semiquantitatively with regard to both the percentage of positive cells and the intensity of the staining. Normal human pituitaries showed strong expression of p27 in most nuclei. In contrast, the levels of p27 were reduced in the majority of the tumors analyzed. Twenty-two tumors (six somatotrope adenomas, five prolactinomas, four corticotrope adenomas, two TSH-producing tumors, two gonadotrope adenomas, and three null cell adenomas) were completely p27-negative. In 18 tumors, p27 expression was found in < or = 10% of the cells. In the other ten tumors, 11-80% of the cells were p27-positive. In summary, we were able to demonstrate reduced expression levels of the cell-cycle inhibitor p27 in tumors derived from all pituitary cell types. Our data indicate that p27 may be an important regulator of cellular proliferation in the anterior pituitary, the underexpression of which could play a role in pituitary tumorigenesis.

Light microscopical morphometry of prolactin secreting adenomas under treatment with dopamine agonists.

In order to study the light microscopical alterations of pituitary tumours under dopamine agonist treatment, three groups of a total of 18 large or small cell chromophobe adenomas were analysed by light microscopical, immunohistological and morphometrical methods. They were all removed by transsphenoidal surgery. 6 of them were treated preoperatively with dopamine agonists, bromocriptine and/or lisuride, for various periods of time. 8 adenomas remained preoperatively untreated. 4 additional untreated tumors were small cell inactive adenomas for comparison. One case was excluded from the final evaluation of the data because it appeared to be a typical non-responder, clinically as well as histologically. Immunohistological positivity for prolactin was to be found in all cases in various degrees. Clinically active adenomas contained many prolactin positive cells, whereas in inactive adenomas only scattered cells were prolactin positive. The morphometric analysis revealed a reduction of the cytoplasmic area in a statistically significant degree in the group of adenomas under treatment, which explains adequately the shrinkage of the entire adenoma and the reduction of prolactin plasma levels. The morphometric data of treated adenomas resembled those of untreated inactive adenomas.

Combined sellar gangliocytoma and pituitary adenoma in acromegaly or Cushing's disease. A report of 3 cases.

Three cases of a composite sellar tumour composed of a gangliocytoma and an adenoma are presented. Two patients who showed acromegaly and hyperprolactinaemia had a gangliocytoma and a growth hormone (GH)-prolactin cell adenoma in close proximity. The gangliocytoma contained growth hormone-releasing hormone (GHRH) by immunohistochemistry. At the electron microscopical level, the gangliocytoma was characterized by numerous synaptic vesicles. The third patient, a child with Cushing's disease, presented a corticotropin-releasing hormone (CRH)-positive gangliocytoma in close contact with an adrenocorticotropic hormone (ACTH) secreting adenoma, the latter a typical densely granulated ACTH cell adenoma. Ultrastructurally, the gangliocytoma revealed synaptic vesicles and sparse secretory granules. The results suggest that gangliocytomas may promote the development of pituitary adenomas by hypersecretion of releasing hormones. Whereas 20 cases of sellar GHRH producing gangliocytomas in acromegaly are reported in the literature, the combination of a CRH-positive gangliocytoma and an ACTH cell adenoma in Cushing's disease is apparently the first case.

Intraoperative measurement of adrenocorticotropic hormone in peripituitary blood in Cushing's disease.

A new method of intraoperative measurement of adrenocorticotropic hormone for the localization of microadenomas in Cushing's disease is described and, in 21 cases, compared with preoperative bilateral sampling of the inferior petrosal sinus. By intraoperative measurement of adrenocorticotropic hormone in peripituitary venous blood, it was possible to determine a gradient for adrenocorticotropic hormone in 14 of 19 patients with surgically proven adenomas. In 4 of 6 patients in whom a false positive bilateral sample from the inferior petrosal sinus directed the surgeon to the wrong side of the pituitary, the localization could be correctly determined by intraoperative radioimmunoassay of adrenocorticotropic hormone.

Recent results of secondary transnasal surgery for residual or recurring acromegaly.

OBJECTIVE: The results of secondary surgery for either residual or recurring acromegaly have been reported to be unfavorable. To evaluate the effectiveness of recent techniques of secondary transnasal microsurgery, we analyzed the surgical results of remnant or recurring acromegaly in patients who underwent secondary transnasal surgery from 1990 to 1996. METHODS: Secondary transnasal explorations were performed in 28 acromegalic patients (mean age+/-standard error, 39+/-2.3 yr) who had been previously treated with microsurgery (patients at our institutions, n=5; patients at other institutions, n=23). For most of these patients, medical treatment after primary surgery was unsatisfactory. Magnetic resonance imaging demonstrated 18 transnasally resectable tumors (64.3%) and 10 nonresectable grossly invasive tumors (35.7%). Surgical indication was based on elevated plasma growth hormone (GH) levels and evidence of tumor revealed by magnetic resonance imaging. RESULTS: Intraoperative GH measurement was performed in all patients. In 13 of 18 patients with resectable tumors, the surgical assessment with sufficient GH decline intraoperatively was likewise judged as complete and was later proved. In three of five patients with inadequate GH decline, endocrinological remission was achieved by performing further surgery. Thus, an endocrinological remission was achieved in 16 of 18 patients (88.9%) with resectable tumors. In 10 patients with nonresectable tumors, the tumor mass was further reduced. Overall, the endocrinological remission rate was 57.1% (16 of 28 patients). There was no serious morbidity and there was no mortality in this series. CONCLUSION: We conclude that in patients with transnasally resectable tumor residuals or recurrences confirmed by magnetic resonance imaging, endocrinological remissions can be obtained with high probability, even in secondary surgery after an unsuccessful previous operation.

Transnasal surgery for infradiaphragmatic craniopharyngiomas in pediatric patients.

OBJECTIVE: Transnasal surgery has been performed in only a small number of cases of pediatric craniopharyngiomas, and its efficacy is still a matter of debate. METHODS: We analyzed the results of transnasal surgery performed in 11 pediatric patients (6 male and 5 female patients) with infradiaphragmatic craniopharyngiomas who were younger than 15 years at the time of surgery (age range, 7.7-14.9 yr) and who were treated between 1985 and 1996, when more refined diagnostic and surgical techniques were available. Two of the patients had undergone primary surgery elsewhere. The transnasal approach was chosen because of sellar enlargement and the presence of an infradiaphragmatic tumor. The duration of the clinical follow-up period was at least 1 year. RESULTS: Five patients required drilling of incompletely pneumatized sphenoid sinuses to reach the sella, but in no cases were the anatomic differences related to patient age or size thought to be a limiting factor in the transnasal procedure. The normal pituitary gland was incised to expose a dorsally located tumor in each of eight patients (72.7%). This surgical procedure has never provoked any major functional damage to the anterior pituitary gland. Complete tumor resection was achieved in three patients (27.3%) and subtotal removal in eight (72.7%). Twenty-two (95.7%) of 23 normal functions were preserved after subtotal tumor removal. In contrast, only one of four normal functions was maintained after complete tumor resection. Persistent diabetes insipidus occurred after total tumor resection in one patient. Tumor regrowth occurred in two patients. No tumor recurrence was observed during the follow-up period. CONCLUSION: Based on the present findings, transnasal surgery seems to be indicated for most infradiaphragmatic craniopharyngiomas occurring in pediatric patients. Transnasal surgery is as safe to perform in pediatric patients as it is in adult patients. The concept of subtotal tumor removal with preservation of pituitary function, avoiding damage to hypothalamic structures and excessive cerebrospinal fluid leakage, seems to be justified in pediatric patients.

Transnasal microsurgery in children and adolescents with Cushing's disease.

OBJECTIVE: Transnasal adenomectomy is the treatment of choice for Cushing's disease. We review the diagnostic peculiarities, specific surgical problems, and outcome of children and adolescents with Cushing's disease. METHODS: We report on our series of 55 consecutive children and adolescents (range, 4.2-18.9 yr [mean age, 14.4 yr]; female:male = 1.1:1.0; mean follow-up, 54.5 +/- 38.6 mo [standard deviation]) with Cushing's disease on whom we performed surgery since 1980. The indication for transsphenoidal surgery is based on endocrinological parameters and not on neuroradiological findings. RESULTS: Detection rate of the tumor site was 22% using computed tomography and 33% using magnetic resonance imaging. Only 7 of 13 interpetrosal adrenocorticotropic hormone gradients obtained during inferior petrosal sinus sampling correctly lateralized the tumor site preoperatively (53.8%). In cases of incomplete sphenoid pneumatization, adequate exposure is achieved by drilling. The tumor finding rate is 98%. The remission rate is 100% when two early subsequent operations are included. The recurrence rate for 45 primary operations with follow-up of at least 1 year is 15.5%. Seven of nine subsequent operations for recurrent hypercortisolism were successful. One patient needed three more operations until hypercortisolism subsided; one patient achieved remission after additional pituitary irradiation. The surgical morbidity was low in this series, which consisted of two cerebrospinal fluid fistulas. The incidence of hypopituitarism after primary operations (10.3%) is significantly lower than after subsequent operations (45.5%). CONCLUSION: Direct transnasal submucosal surgery for Cushing's disease is successful, and pituitary function can be preserved in most of these young patients.

In vitro secretion of adenoma and anterior lobe cells in two typical cases of Cushing's disease.

Fragments of adrenocorticotropic hormone (ACTH) cell adenomas and anterior lobes of two patients with Cushing's disease were obtained by transnasal operation. Both patients showed the typical clinical course, with postoperative ACTH deficit and all other pituitary functions intact. Equivalent specimens of tissue were investigated by immunocytology and in a superfusion system. The majority of adenoma cells were ACTH-positive, whereas ACTH-secreting cells of the anterior lobes were mostly inactive and were reduced in number. In vitro, adenomatous tissue showed high ACTH secretion into the superfusion medium, which was increased significantly after vasopressin application. Corticoid feedback was impaired Anterior lobe cells exhibited a significant spontaneous ACTH secretion that was reduced by cortisol, but not stimulated by vasopressin. These results support the concept of an impaired corticoid feedback at the adenoma level in the presence of suppressed ACTH secretion of the para-adenomatous anterior lobe.

Growth hormone-secreting pituitary adenomas in childhood and adolescence: features and results of transnasal surgery.

OBJECTIVE: Pituitary tumors causing gigantism are rare in childhood and adolescence. In a review of 2367 patients with pituitary adenomas who were treated between 1970 and 1997, we found 15 cases (0.63%, 9 male and 6 female patients) of growth hormone-secreting pituitary adenomas in patients who were less than 20 years of age at the time of surgery, and we compared their characteristics with those of adenomas in an adult group. METHODS: Patients were grouped according to their ages at the first operation, with five patients (33.3%) in the prepubescent group (0-11 yr), eight (53.3%) in the pubescent group (12-17 yr), and two (13.3%) in the postpubescent group (18-19 yr). All 15 patients exhibited the typical symptoms of growth hormone oversecretion. The incidence of hyperprolactinemia among patients with prepubescent onset was 66.7%. Radiological examinations demonstrated microadenomas in 4 patients (26.7%) and macroadenomas in 11 patients (73.3%). The mean follow-up period was 73.5 months. RESULTS: Direct transnasal explorations were performed for all patients. Tumor invasion into the cavernous sinus was observed in six patients (40%). Radical tumor resection was performed for four patients (80%) in the prepubescent group, for five patients (62.5%) in the pubescent group, and for neither patient in the postpubescent group. Surgical morbidity was caused by permanent diabetes insipidus in three patients (20%). Rapid growth was postoperatively improved in 80% of the prepubescent age group. The recurrence rate was 13.3% (2 of 15 patients). CONCLUSION: Transnasal pituitary surgery was found to be as safe in pediatric patients with gigantism as in adults. Growth hormone-secreting pituitary adenomas in childhood and adolescence were more likely to be invasive or aggressive than were those in adulthood. The clinical biological characteristics for children were different from those for adults.

Clinically nonsecreting pituitary adenomas in childhood and adolescence.

OBJECTIVE AND PATIENTS: Clinically nonsecreting pituitary adenomas are rare in childhood and adolescence. We analyzed five cases of clinically nonsecreting pituitary adenomas in patients (4 male and 1 female patient) under 20 years of age at surgery (0.22%), identified by a review of 2288 patients with pituitary adenomas treated from 1970 to 1996 at the Hamburg University. CLINICAL PRESENTATION AND RESULTS: Patient age at the onset of symptoms ranged from 8 to 13 years (mean, 10.8 yr), and age at surgery ranged from 12.5 to 19.5 years (mean, 15.5 yr). Two patients presented with endocrine symptoms, two with headache only, and one with a visual field defect. Endocrinological examinations showed pituitary insufficiency in two patients with endocrine symptoms. The serum prolactin level was normal in all patients. Radiological investigations demonstrated resectable macroadenomas with ring enhancement in four patients and a nonresectable macroadenoma with parasellar extension in one. Transnasal explorations achieved radical tumor resection except in one patient. The latter underwent a transcranial resection and radiotherapy because of parasellar tumor rest. Surgical morbidity consisted of left oculomotor nerve palsy after transcranial exploration. In two patients, normal pituitary function was preserved by transnasal surgery. Follow-up duration was 2 to 23 years (mean, 10.9 yr). There was no recurrence except for one parasellar adenoma. Immunohistological diagnosis was null cell adenoma in two patients, silent prolactinoma in two, and silent gonadotroph adenoma in one. The proliferative activity measured by Ki-67 (as the antibody MIB-1) and p53 expression revealed a positive reaction in one adenoma with parasellar extension. CONCLUSION: Clinically nonsecreting pituitary adenomas in childhood and adolescence cause different endocrine symptoms from those in adults. They caused pubertal and growth delay and/or primary amenorrhea in the patients investigated in this study. Transnasal surgery in childhood and adolescence is as safe as in adults. The characteristics of nonsecreting pituitary adenomas in this age group, including 20 patients cited from the literature, do not differ from those in adults.