Prolactin gene expression in human growth hormone-secreting pituitary adenomas

To elucidate the mechanism of hyperprolactinemia often observed in patients with growth hormone (GH)-secreting pituitary adenomas, the presence of immunoreactive prolactin (ir-PRL) and prolactin (PRL) messenger ribonucleic acid (mRNA) in the tumor tissue was examined by immunohistochemistry and cytoplasmic dot hybridization. Hyperprolactinemia was observed in three of 18 patients with GH-secreting adenoma. The tumor tissue was demonstrated to contain ir-PRL in nine patients and PRL mRNA in 13. The presence of ir-PRL in the tumor tissue was always associated with positive PRL mRNA, indicating production of PRL in GH-secreting tumors. Among the three patients with hyperprolactinemia, both ir-PRL and PRL mRNA was revealed in the tumor tissue of one, PRL mRNA but not ir-PRL was detected in the adenoma tissue of another, and neither PRL mRNA nor ir-PRL was found in the tumor tissue of the third. The association of hyperprolactinemia with the presence of both ir-PRL and PRL mRNA or PRL mRNA alone is indicative of PRL production and secretion. However, the absence of ir-PRL and PRL mRNA in the tumor tissue may indicate that hyperprolactinemia is caused by the suppression of PRL inhibitory factor due to hypothalamic dysfunction by the tumor mass. Thus, the study of PRL gene expression and immunohistochemistry in GH-secreting adenomas is valuable to understanding the pathophysiology of pituitary tumors.     

Antisense oligonucleotide-induced inhibition of adrenocorticotropic hormone release from cultured human corticotrophs.

OBJECT: Available therapies for Cushing's disease are often inadequate or involve the risk of significant morbidity. Accordingly, the need arises for the development of novel treatments, especially for cases caused by corticotroph hyperplasia, a condition difficult to treat using standard therapies. In this study, the authors investigated the use of phosphorothioate antisense oligonucleotides as a potential treatment for Cushing's disease. METHODS: Corticotrophs, obtained from a patient with Cushing's disease in whom pathological findings showed multifocal areas of corticotroph adenoma and hyperplasia, were grown in tissue culture. By assessing cell viability and using immunoradiometric assay techniques, it was determined that these cells grew autonomously and secreted adrenocorticotropic hormone (ACTH) in vitro. A fully phosphorothioated antisense oligonucleotide was constructed to be complementary to the first 25 bp of the region coding for ACTH in exon 3 of the proopiomelanocortin precursor. After incubation of the corticotrophs with liposome-coated phosphorothioate antisense oligonucleotides, a greater than 90% decrease in ACTH release was noted on Days 3 and 6, compared with nonsense-treated controls (p < 0.05). CONCLUSIONS: Antisense oligonucleotides may prove to be a useful adjunct in treating Cushing's disease by targeting one of its fundamental problems, ACTH hypersecretion.     

Pituitary adenomas that produce adrenocorticotropic hormone and alpha-subunit: clinicopathological, immunohistochemical, ultrastructural, and immunoelectron microscopic studies in nine cases.

Eight surgical and one autopsy specimen of pituitary adenomas (six cases of Cushing's disease, two of Nelson's syndrome, and one of hypopituitarism) were studied by histochemical, immunohistocytological, and ultrastructural methods. Eight tumors showed the characteristic histochemical profile of corticotroph adenoma--amphophilic to basophilic, and periodic acid-Schiff-positive to some extent. In all tumors, immunohistochemical studies revealed adrenocorticotropic hormone (ACTH) and alpha-subunit in the cytoplasm of some adenoma cells. By electron microscopy, seven tumors were found to be monomorphous; six were typical corticotroph adenomas and one was a subtype II silent corticotroph adenoma. One unique lesion was bimorphous--i.e., composed of corticotrophs as well as cells resembling glycoprotein cells. Immunoelectron microscopy by the double-labeling immunogold technique, performed on one corticotroph adenoma, demonstrated the presence of ACTH and alpha-subunit not only within the same adenoma cells but also within the same secretory granules. The cytogenesis of ACTH alpha-subunit tumors, a rare form of plurihormonal adenoma, remains to be elucidated. The duration of disease associated with these tumors exceeded the duration in patients with ordinary corticotroph adenomas. Given the low frequency with which increases in serum alpha-subunit are detectable in patients with such tumors--13% in this series--hormone production is not recognized at preoperative evaluation.     

Stereotactic radiosurgery in Cushing's syndrome: acute radiation effects

Stereotactic radiosurgery was used for selective destruction of adrenocorticotropic hormone (ACTH)-producing adenomas in 18 patients with Cushing's syndrome. A radiation-induced lesion in the most anterior part of the sella turcica caused remission of the disease. The acute increase in ACTH and cortisol secretion that occurred in the majority of patients had no predictable relationship to the final outcome. Decreased cortisol excretion during the first three weeks after treatment was positively correlated to favourable long-term results. The treatment is a therapeutic alternative to open selective excision of the adenoma.     

Long term results of transsphenoidal adenomectomy in patients with Cushing's disease

As part of an ongoing series, 100 patients with Cushing's disease underwent transsphenoidal operations. Pituitary adenomas were confirmed in 93 patients, and initial remission was achieved in 86 (92%) of them. Hypercortisolemia was not corrected in 7 patients, and in 4 this was due to invasive adenomas. These patients were subjected to irradiation, medical treatment, or both after operation. Only 7 of the 100 patients had no pituitary adenoma found at operation, and they obtained no clinical remission even after partial or subtotal hypophysectomy. Follow-up review, with an emphasis on endocrinological studies, was performed on these patients for a mean period of 38 months. Seventy-eight patients were in long term remission after operation and had restoration of noncorticotropic hormone secretion as well as pituitary-adrenal function. Recurrence was noted in 8 patients after 19 to 82 months in remission. In all of these patients, pituitary adenomas were verified by reoperation and no case of corticotrophic cell hyperplasia was noted. We conclude that late recurrence of Cushing's disease may occur after adenoma removal and is due to the regrowth of adenoma cells left behind in the peritumoral tissue at the first operation. In view of the overall remission rate, transsphenoidal adenomectomy is considered a highly effective treatment for Cushing's disease.     

Tumors of the adrenal cortex and Cushing''s syndrome.

Fifty-nine patients with Cushing's syndrome, due to adrenocortical tumor, were studied and treated during the period 1953 through 1983 at Vanderbilt University Medical Center. Cushing's syndrome is caused by hypercortisolism that can be due to (1) medicinal use of steroids, (2) excess pituitary secretion of adrenocorticotropin (ACTH) (Cushing's disease), (3) adrenocortical tumor, benign or malignant, and (4) the ectopic ACTH syndrome. Clinical and endocrinologic features of Cushing's syndrome are described, and differential diagnosis of adrenocortical tumor by precise endocrinologic studies is detailed. Computerized axial tomographic (CAT) scan is currently the most accurate imaging modality for preoperative localization of tumors. Preoperative differential diagnosis between adrenocortical adenoma and carcinoma has become fairly accurate. Operative approaches in each category are described. Follow-up from 1 to 30 years has been completed for all patients, except for one who was lost after 7 years. Results of surgical treatment of adrenocortical adenomas are excellent, but the salvage from adrenocortical carcinomas is poor.     

Usefulness of multiple-site venous sampling in the treatment of adrenocorticotropic hormone-producing pituitary adenomas

BACKGROUND: While venous sampling for adrenocorticotropic hormone (ACTH) may be the most accurate way to establish a diagnosis of Cushing's disease, its usefulness for lateralization of adenomas is limited even in combination with simultaneous bilateral sampling methods. Therefore, to increase accuracy in predicting the lateralization of adenomas, we performed a trial in which we carried out simultaneous venous sampling from multiple sites of the cavernous sinus (CS) and inferior petrosal sinus (IPS). Here we report on the usefulness of our method in the correct tumor lateralization in patients with Cushing's disease. METHODS: Eighteen patients with Cushing's disease underwent simultaneous bilateral ACTH sampling. The samples were obtained from the anterior, middle, and posterior CS and the IPS. CS sampling after stimulation with corticotropin-releasing hormone (CRH) was also performed. The central-to-peripheral ACTH ratio (c/p ratio) was calculated using sampling data from each site; the lateralizing gradients (right versus left) were calculated using the c/p ratio. Instead of the conventional method where the lateralization gradient is based on sampling data from a single site, we used the distribution of the c/p ratio determined from multiple-site data. RESULTS: There was no significant difference in the mean lateralization gradient obtained from each set of sampling data (p > 0.05). With the conventional method, correct tumor lateralization was obtained in 50% of tumors in the IPS; 72.2 to 77.8% of tumors in the CS; and 77.8% of tumors in the middle CS after CRH. Our method using ACTH contour analysis based on multiple sites produced correct results in all 18 of the patients examined. The difference in correct calls between the conventional method and our method was significant (p < 0.05). CONCLUSIONS: Multiple-site sampling of ACTH is valuable for lateralizing the adenoma in patients with Cushing's disease; it produces more correct results than does single venous sampling.     

Suprasellar adrenocorticotropic hormone-secreting ectopic pituitary adenoma: case report and literature Review

OBJECTIVE AND IMPORTANCE: Functional ectopic pituitary adenomas are rare and can be misdiagnosed as extensions of pituitary adenomas when they are located in the vicinity of the normal gland. In this report, we present a case of an ectopic adrenocorticotropic hormone-secreting suprasellar pituitary adenoma that caused Cushing's disease. A literature review of previously reported ectopic pituitary adenomas is included to illustrate the diverse clinical manifestations of this disease entity. CLINICAL PRESENTATION: An 11-year-old boy was noted to have hirsutism, a buffalo hump, and unexplained weight gain consistent with Cushing's syndrome. Laboratory investigations revealed that the boy had elevated adrenocorticotropic hormone and serum cortisol levels unsuppressed by dexamethasone. Magnetic resonance imaging scans were suggestive of a pituitary adenoma with suprasellar extension. INTERVENTION: The initial transsphenoidal approach failed to achieve complete surgical resection. A repeat operation in which the pterional approach was used revealed a suprasellar pituitary adenoma without association with intrasellar contents. The patient's cushingoid symptoms improved significantly 3 months after surgery. CONCLUSION: Ectopic pituitary adenomas should be considered in the differential diagnosis for all patients with Cushing's syndrome. Furthermore, surgical approaches should be chosen carefully once the diagnosis of ectopic pituitary adenoma is made.     

Role of perioperative biological tests during the performance and follow-up of corticotroph adenoma exeresis

ACTH assay in cavernous sinus samples during resection of pituitary adrenocorticotroph adenomas is a simple and safe technique providing an intraoperative assessment of adrenocorticotroph hormone gradients. Bilateral puncture of the cavernous sinus can be achieved vial the standard transsphenoidal approach to the sella turcica. ACTH is determined with IRMA at 37;C with an incubation time of less than one hour. Among 71 cases in our experience, the ACTH gradient accurately predicted the position of the adenoma in 93% of the cases. This rate is higher than the 61% accuracy reported for inferior petrosal sinus sampling. The technique reported is more precise than MRI which correctly identifies adenomas in only 50% of the cases. The remaining cases are either false positives or false negatives. We report an 82% cure rate either via direct resection of the microadenoma or via partial hypophysectomy guided by the ACTH gradient. In our series, 20 cases of Cushing's disease had a normal MRI and no surgically identifiable adenoma. In 10 of these cases however, cure was achieved by performing ACTH gradient guided partial hypophysectomy. This method produces no morbidity and is most helpful for the neurosurgeon allowing confirmation of the position of an MRI-visible adenoma or an adenoma identified intraoperatively. It does not however replace neurosurgical experience which remains the most important predictive factor for outcome in surgical treatment of Cushing's disease.     

A spectrum of behaviour in silent corticotroph pituitary adenomas

Silent corticotroph adenomas (SCA) are pituitary tumours positive on immunohistochemical staining for ACTH but without clinical evidence of Cushing's disease in the patient. Previous reports suggest that these tumours may behave in a more aggressive way then other pituitary adenomas. We have followed the natural history of SCA and assessed whether histopathological indices predict tumour behaviour. We identified 22 patients in whom trans-sphenoidal surgery was performed for a non-functioning adenoma (NFA) with positive immunostaining for ACTH between 1990 and 2000 and examined the history of their disease. Patients were followed up for a mean of 4.8 years. A total of 86.7% of patients had documented visual deficits at presentation. In four cases hypercortisolaemia was observed later in the course of the disease. Two patients died as a result of their SCA and 33.3% of tumours recurred. Recurrence was more frequent in patients treated with adjuvant radiotherapy. Pathological indices (increased mitotic range and Ki-67) did not predict recurrence or malignant transformation. We suggest that certain 'silent' corticotroph tumours may have the potential for ACTH secretion leading to hypercortisolaemia at a later stage in the disease. The possibility of transformation to a more aggressive tumour needs to be considered in all SCA.     

Pathology and pathogenesis of pituitary corticotroph adenoma

Corticotroph adenoma is a benign tumor composed of adenohypophyseal cells; carcinoma with metastasis and ectopic adenoma have also been reported. In our pathological series, the frequency of this type of adenoma is 13% (250/1863 tumors removed between 1970 and 2001). Usually, corticotroph adenomas synthesize peptides derived from POMC maturation: ACTH, ss-endorphine, and ssLPH. In the great majority of cases, ACTH induces hypercorticism with clinical and biological signs of Cushing's disease. However, some tumors the pathologist identifies as corticotroph adenomas are not associated with clinical signs of hypercorticism (20% of the corticotroph adenomas in our series). Corticotroph adenoma is a basophilic or chromophobe tumor composed of cells which remain regulated by cortisol. This may explain the small size of this type of adenoma in 80% of the cases. In contrast, "silent" adenomas or macroadenonas which synthesize high-weight POMC are aggressive invasive tumors. Neurosurgery is indicated for the treatment of corticotroph adenoma. Recurrence is explained by incomplete removeal of the tumor. Peroperative studies may be necessary to find microadenomas. In some cases, the whole pituitary must be removed and cut in serial sections to find a tumor measuring<2 mm. In our opinion, the existence of corticotroph hyperplasia inducing Cushing's disease remains to be proven (we have never observed one). The pituitary origin of the tumor is based on its monoclonality. The general mechanism of tumorigenesis is known, but the specific factors involved and markers of aggressiveness remain to be discovered.     

The Value of Intraoperative Cytology During Transsphenoidal Surgery for ACTH-Secreting Microadenoma

Summary  Background. Microsurgical selective adenomectomy is the best established method available for the treatment of Cushing's disease. However, this surgical method warrants still more efforts to improve the results in minute microadenomas. In this paper the authors evaluate a method of intraoperative cytological investigations during transsphenoidal surgery.  Method. Between January 1997 and September 1999, transsphenoidal surgery was performed in 75 patients with the diagnosis of Cushing's disease. Fifty-one cases of proven microadenomas were reviewed.  Findings. Of 51 cases, 33 tumors were 3 mm or less in diameter, here after called minute adenomas. In 49 of 51 (96.1%) microadenomas, adenoma tissue was identified by intraoperative cytological techniques. Postoperatively, only 35 of 51 ACTH-secreting microadenomas (68.6%) were confirmed by immunostaining methods. This lower percentage was most probably due to the small amount of tissue obtained. Therefore, in 14 cases (including 12 minute adenomas) the presence of the adenoma was only proven by cytological preparation and clinical outcome. The sensitivity of cytological preparations in cases of confirmed Cushing's disease was 100%.  Interpretation. The method described here was particularly well suited for the intraoperative discrimination and documentation of minute adenomas. Cytological preparation appears to be effective in improving the adenoma finding rate and the surgical outcome in cases of Cushing's disease.     

Selective removal of hypersecreting pituitary adenomas?

Summary The aim of this study of 101 pre- and postoperatively controlled hypersecreting pituitary adenomas (80 acromegalies, 15 Cushing's diseases, 6 Nelson's syndromes) was to establish in what cases a selective adenoma extirpation by the transnasal route is possible and advisable.In primary operations on acromegalics with small and medium size tumours 92% were postoperatively GH normal. Eighty five per cent of these had intact pituitary function. The results with larger tumours were worse (72%). During a control period of 1.5–5.5 years a renewed elevation of GH levels was observed in three cases, all in the first year, but never after clearly selective adenomectomy. These results, and the anterior lobe biopsies, which showed no GH cell hyperplasia, favour selective adenoma extirpation.In contrast to acromegaly, nodular ACTH cell hyperplasia in the anterior lobe was found in most cases of Cushing's disease, and therefore complete hypophysectomy was performed. The cortisol levels became either normal or, in most cases, lower than normal. A selective operation was performed on 6 Nelson tumours. The ACTH values became normal in about 50% of the patients but there was a tendency towards recurrence. Our experiences with Cushing's disease and Nelson's syndrome lead us to recommend total hypophysectomy.Supported by Deutsche Forschungsgemeinschaft, SFB 34.     

Direct intraoperative micromethod for hormone measurements of pituitary tissue in Cushing's disease

BACKGROUNDDuring transsphenoidal surgery (TSS) for Cushing’s disease, the surgeon depends on experience to find minute adenomas. Cytological slide preparations or frozen sections, even when successful, are not specific concerning the hormone activity. In an attempt to improve accurate localization of minute ACTH adenomas, we evaluated a new intraoperative method of ACTH measurements in adenoma and anterior lobe microsamples. As most ACTH adenomas are monohormonal, the possible benefit of a GH measurement was investigated.METHODSWe included pituitary tissue of 32 patients, 22 with Cushing’s disease and 10 endocrine inactive pituitary adenomas as control. All patients underwent TSS by one surgeon. Preoperative data, intraoperative and perioperative hormone measurements of homogenized, weighed pituitary tissue samples, and histological findings are presented.RESULTSIn ACTH adenomas, the median ACTH content was found to be 1,688 ng/mg, minimum 345 ng/mg. The median GH was measured at 36 ng/mg. Anterior lobe tissue contained median 80 ng ACTH/mg, maximum 279 ng/mg. Median GH was 2,200 ng/mg. In hormonally inactive adenomas ACTH was less than 0.1 ng/mg, median GH was 5.5 ng/mg. There was no overlap of ACTH content in the tissues investigated. Therefore, by adopting 300 ng ACTH/mg as a cutoff level, a clear discrimination is given. Additional GH measurements are not necessary.CONCLUSIONThis new intraoperative method permits a clear differentiation between adenoma and pituitary tissue. In addition to intraoperative cytology and histology, this method can serve as a specific proof that the ACTH adenoma has been identified during surgery. This may be valuable in difficult cases with unclear intraoperative findings, especially after previously negative exploration.     

Intra- and postoperative plasma ACTH concentrations in patients with Cushing's disease cured by transsphenoidal pituitary surgery

Summary.  Background: The optimal treatment of choice for ACTH-producing pituitary adenomas is their complete removal by the transsphenoidal surgical approach. ACTH-producing pituitary adrenomas are, however, often small in size not detectable with neuro-imaging techniques, which may result in difficulties during their surgical removal. With the advent of rapid methods for plasma ACTH measurement, a few neurosurgical centers introduced intra-operative plasma ACTH determinations in peripheral and central blood samples to help improve the outcome of pituitary surgery in patients with Cushing's disease.  Method: To evaluate the usefulness of this new method, we performed, under standardized conditions, intra-operative plasma ACTH measurements with a rapid immunochemiluminometric method at different stages of transsphenoidal pituitary surgery in 7 patients with Cushing's disease.  Findings: We found that from the beginning of anesthesia until the end of operation, ACTH concentrations in venous plasma were highly variable by both the rapid and the standard methods. In most cases the changes in venous plasma ACTH concentrations that occurred until the end of surgery failed to indicate the removal of the ACTH-producing pituitary adenoma. However, a more than 50% decrease of venous plasma ACTH concentrations by the rapid assay was observed 2 h after completion of the operation in all but one of the patients. As evidenced by a long-term hormonal and clinical remission, these changes in plasma ACTH levels in all patients were accompanied by a complete removal of the ACTH-producing pituitary adenoma.  Interpretation: These findings indicate a slow disappearance of ACTH from the circulation after a successful pituitary surgery in patients with Cushing's disease. Published online October 10, 2002 Correspondence: Dr. K. Rácz, 2nd Department of Medicine, Semmelweis University Medical School, 1088 Budapest, Hungary     

Repeat transsphenoidal surgery for Cushing's disease

Transsphenoidal resection of adrenocorticotrophic hormone (ACTH)-producing pituitary adenomas has the potential of curing most patients with Cushing's disease. However, transsphenoidal exploration of the pituitary is not always curative, and patients who have remission of hypercortisolism following surgery occasionally develop a recurrence. Whether repeat pituitary surgery should be performed for recurrent or persistent Cushing's disease has not been evaluated previously. To determine the efficacy of transsphenoidal surgery in recurrent or persistent Cushing's disease, we performed transsphenoidal surgery in 31 patients (22 women and nine men) who had previously undergone a transsphenoidal operation and two female patients who had had previous pituitary irradiation only. In 24 (73%) of the 33 patients, remission of hypercortisolism was achieved by surgery. Although preoperative computerized tomography (CT) scanning identified an adenoma in only three of the 33 patients, in 20 patients a discrete adenoma was identified at pituitary exploration. The incidence of hypercortisolism was greatest if an adenoma was identified at surgery and the patient received selective adenomectomy (19, or 95% of 20 patients), if there was evidence at surgery or by preoperative CT scanning that the previous surgical exposure of the pituitary was incomplete (seven, or 78% of nine patients), if an adenoma was seen on preoperative CT scanning (three of three patients), or if the patient had had prior pituitary irradiation without surgery (two of two patients). In contrast, only five (42%) of 12 patients who received subtotal or total hypophysectomy had remission of hypercortisolim. Surgically induced hypopituitarism occurred in six (50%) of these 12 patients, but in only one (5%) of the 20 patients who underwent selective adenomectomy. Three (13%) of the 24 patients who were in remission from hypercortisolims following repeat surgery developed recurrent hypercortisolism 10 to 47 months postoperatively. Repeat transsphenoidal exploration of the pituitary and treatment limited to selective adenomectomy should be considered in patients with hypercortisolism despite previous pituitary treatment. If an adenoma is identified during surgery, the chance of remission of Cushing's disease is high and the risk of hypopituitarism is low; however, if no adenoma can be found and partial or complete hypophysectomy is performed, remission of hypercortisolism is less likely and the risk of hypopituitarism is about 50%.     

Endocrinological evaluation of ACTH-secreting pituitary microadenomas: their location and alpha-melanocyte stimulating hormone immunoreactivity.

It has been hypothesized by Lamberts and coworkers in their analysis of 15 cases that adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas may be derived from either the anterior lobe or the intermediate lobe. The intermediate lobe type of Cushing's disease is thought to be controlled through a hypothalamic pathway and is characterized by hyperprolactinemia; suppressibility of cortisol with bromocriptine, and lower sensitivity to dexamethasone. The authors investigated the validity of this hypothesis in 125 cases of ACTH-secreting pituitary microadenomas by analyzing the endocrine findings, the locations of the microadenomas, and alpha-melanocyte stimulating hormone (alpha-MSH) immunoreactivity in the adenoma cells. No significant differences in the basal hormone levels, cortisol suppressibility with bromocriptine, sensitivity to dexamethasone, and recurrence rate were observed between patients with the microadenoma adjacent to the posterior lobe (considered typical of the intermediate lobe-derived tumor) or those with the microadenoma located in the anterior lobe. The locations of the microadenoma were not correlated with alpha-MSH immunoreactivity in the adenoma cells. No significant differences in endocrine findings were noticed between adenomas positive or negative for alpha-MSH. Thus, Cushing's disease cannot be simply divided into either the anterior lobe type or the intermediate lobe type by endocrinological evaluation as described by Lamberts, et al.     

Early post-operative ACTH and cortisol as predictors of remission in Cushing's disease

AIM: To study the value of early (24 h) post-operative ACTH and serum cortisol as predictors of remission after transsphenoidal surgery in Cushing's disease. METHODS: We prospectively studied 44 patients who underwent transsphenoidal surgery for Cushing's disease between 1997 and 2005. The mean follow-up period of patients after surgery was 49 months (19-102 months). The predictive value of clinical characteristics, pre-operative hormonal studies, radiological, surgical and histological findings, and post-operative hormonal studies were analysed. For the post-operative hormonal study plasma ACTH and serum cortisol were determined at 8.00 a.m. the day after surgery. RESULTS: After surgery, Cushing's disease remitted in 39 patients (89%) and persisted in 5 patients (11%). Three patients relapsed during the follow-up period. Only three study variables were predictive of persistence of Cushing's disease after surgery: the non identification of the adenoma in histology (an adenoma was found in 87% of the patients in remission, and in 20% of treatment failures, p = 0.01), the early post-operative plasma ACTH (patients in remission: 2 pmol/L (1.1-10.8 pmol/L), treatment failures: 8.2 pmol/L (1.1-12 pmol/L), p = 0.019), and the early post-operative serum cortisol (patients in remission: 128.4 nmol/L (27.6-4644 nmol/L), treatment failures: 797 nmol/L (606-1037 nmol/L), p = 0.003). ROC curves indicated that plasma ACTH < or = 7.55 pmol/L distinguished patients in remission from treatment failures with 80% sensitivity and 97.4% specificity, and serum cortisol < or = 585 nmol/L with 100% sensitivity and 90% specificity. CONCLUSIONS: Twenty-four hours after transsesphenoidal surgery for Cushing's disease, and without glucocorticoids replacement, patients with serum cortisol concentrations higher than 585 nmol/L, and/or plasma ACTH higher than 7.55 pmol/L, and/or those in which an adenoma is not identified in the histological study, have a high risk of treatment failure.     

Hyperadrenalism in childhood and adolescence.

Hyperadrenalism in childhood and adolescence has unique features that influence diagnosis and management. We reviewed our experience with 18 patients, ranging in age from 18 months to 18 years. Nine had bilateral adrenal hyperplasia, eight had adrenal neoplasms, and one had micronodular hyperplasia. Patients with congenital adrenal hyperplasia and hyperaldosteronism were excluded. Six patients with Cushing's disease diagnosed in earlier years were treated by total adrenalectomy and recently two patients underwent transsphenoidal removal of pituitary tumors. Bilateral adrenalectomy was carried out in one patient with micronodular hyperplasia and in a second because of elevated adrenocorticotrophic hormone (ACTH) levels from an undefined source. Eight patients had adrenal neoplasms, including five adenomas and three carcinomas. We found no reliable criteria to differentiate before surgery between adrenal adenomas and adrenal carcinomas. The most recognizable characteristic of malignancy was tumor size, specifically weight greater than 75 gms. Of the three patients with adrenal carcinoma, one expired 20 months after adrenalectomy and 8 months after receiving palliative partial hepatectomy for liver metastasis. Two patients are well with normal growth and development at 11 and 20 years following adrenalectomy. With the exception of one patient who died 6 years after surgery from a glioblastoma multiforme, all patients with adrenal adenomas are well. Eight patients underwent bilateral adrenalectomy for hypercortisolism. Five of the six who have reached their adult stature are significantly stunted. Four of six patients with Cushing's disease, treated by total adrenalectomy, have developed Nelson's syndrome at 2, 6, 10, and 12 years after surgery. Of the two patients undergoing transsphenoidal surgery, one had recurrent disease at 2 years and was treated by pituitary irradiation with recovery. The patients undergoing adrenalectomy for micronodular hyperplasia and ectopic ACTH are well at 2 and 4 years, respectively. Cushing's disease in children and adolescents is best treated by transsphenoidal removal of the pituitary adenoma. Adrenalectomy, once the most accepted approach, plays a secondary role and is indicated primarily in micronodular adrenal hyperplasia, in patients with ectopic ACTH production of an undefined source, and in recurrent Cushing's disease following prior pituitary irradiation. The high incidence of Nelson's syndrome in children treated by adrenalectomy mandates that patients at risk be monitored lifelong for the progression of a pituitary tumor.(ABSTRACT TRUNCATED AT 400 WORDS)     

Cushing''s disease today. Late follow-up of 17 adrenalectomy patients with emphasis on eight with adrenal autotransplants.

Cushing's disease has come full cycle. As originally asserted more than 50 years ago, modern diagnostic techniques now demonstrate an adrenocorticotropic hormone (ACTH) secreting pituitary adenoma in approximately 80% of such patients. At this historical juncture, we report a long-term follow-up of our 17 patients who underwent adrenalectomy (8) or later adrenalectomy plus adrenal autotransplantation (9) between 1955 and 1976. Two patients died soon after surgery and five others died later of "natural" causes. Four others moved away but were stable when last contacted. Of the six patients who remain available for current follow-up, three have undergone hypophyseal surgery. Another patient has evidence of pituitary enlargement, and the remaining two are yet to undergo computerized tomography (CT) scan. Four illustrative cases are reviewed in some detail. One case presented with Nelson's syndrome and acute onset blindness. The second represented multiple endocrine adenomatosis with hyperparathyroidism in addition to Cushing's disease. The third exhibited Cushing's syndrome from the autotransplants, finally cured by hypophysectomy. The fourth exhibited huge ACTH levels from a large pituitary adenoma that could not be totally resected and recurrent Cushing's syndrome associated with large autotransplant "adenomas." The initial surgical treatment of choice is pituitary adenectomy. Bilateral adrenalectomy will remain useful where curative pituitary surgery is not feasible. Neither pituitary irradiation nor medical therapy has been truly effective in our patients. Adrenal autotransplants survive, to some extent, in virtually all patients. However, the degree of function is variable, and the full function may not be achieved for many months or even years. Functioning autotransplants have not prevented Nelson's syndrome, and they would appear to offer little practical benefit at this time.