Cortisol-producing Adenomas Research Articles

COUP-TFI expression in human adrenocortical adenomas: possible role in steroidogenesis.

Chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) is an orphan nuclear receptor essential for neurogenesis, organogenesis, and cell fate determination. CYP17 gene transcription has recently been shown to be activated by SF-1 (steroidogenic factor-1) binding to a cyclic AMP-responsive sequence within the promoter region of the gene, and inhibited by COUP-TF binding to the sequence. Thus, COUP-TF and SF-1 act as a transcriptional repressor and activator, respectively, of CYP17 gene expression. Transcriptional repression by COUP-TFI is mediated by corepressors, N-CoR (nuclear receptor-corepressor) and SMRT (silencing mediator for retinoid and thyroid hormone-receptor), whereas transcriptional activation by SF-1 is mediated by coactivator SRC-1 (steroid receptor coactivator-1). We therefore examined the expression of COUP-TFI, SF-1, SRC-1, N-CoR, and SMRT in a variety of adrenocortical adenomas and compared the results with CYP17 mRNA levels. We found significantly high COUP-TFI mRNA expression in nonfunctional adenomas (n=8: 220+/-16%; normal 96+/-4%), a deoxycorticosterone-producing adenoma (n=1: 200%), and a pre-clinical Cushing's adenoma (n=1: 280%), intermediate COUP-TFI expression in cortisol-producing adenomas (n=8: 63+/-5%), and low COUP-TFI expression in aldosterone-producing adenomas (n=8: 49+/-4%). In contrast to COUP-TFI, SF-1 mRNA expression did not vary significantly among adrenals. We did not detect the expected negative correlation between COUP-TFI and CYP17 mRNA levels in adrenocortical adenomas. High COUP-TFI expression was associatedwith a nonfunctioning phenotype. Interestingly, the pattern of COUP-TFI expression was similar to the profile of N-CoR expression, but not of SMRT expression. These results indicate that COUP-TFI and N-CoR may play a role in steroidogenesis by human adrenocortical adenomas.

DAX-1 expression in human adrenocortical neoplasms: implications for steroidogenesis.

The DAX-1 gene encodes an orphan nuclear hormone receptor essential for normal fetal development of the adrenal cortex. Recently, DAX-1 has been shown to act as a transcriptional repressor of steroidogenic acute regulatory protein gene expression (StAR), suppressing steroidogenesis. We, therefore, investigated the expression of DAX-1 in a variety of adrenocortical tumors and compared the results with StAR mRNA expression. We found low or absent DAX-1 expression in aldosterone-producing adenomas (n = 11: 35 +/- 11%; normal adrenals: 100 +/- 17%) and in aldosterone-producing adrenocortical carcinomas (n = 2: 24 and 36%). Cortisol-producing adenomas showed intermediate DAX-1 expression (n = 8; 92 +/- 16), as did 3 non-aldosterone-producing carcinomas (72, 132 and 132%). High DAX-1 expression was present in nonfunctional adenomas (n = 3; 160 +/- 17%). In contrast to DAX-1, StAR mRNA expression did not show significant variations between groups. We did not detect the expected negative correlation between DAX-1 and StAR in adrenocortical tumors. These data suggest that high DAX-1 expression in adrenocortical tumors is associated with a non-functional phenotype whereas low DAX-1 expression favors mineralocorticoid secretion. These effects on steroidogenesis are mediated by mechanisms other than repression of StAR gene expression. Our results indicate that DAX-1 may be one of the factors influencing the steroid biosynthesis of adrenocortical neoplasms.

DAX-1 Expression in Human Adrenocortical Neoplasms: Implications for Steroidogenesis

The DAX-1 gene encodes an orphan nuclear hormone receptor essential for normal fetal development of the adrenal cortex. Recently, DAX-1 has been shown to act as a transcriptional repressor of steroidogenic acute regulatory protein gene expression (StAR), suppressing steroidogenesis. We, therefore, investigated the expression of DAX-1 in a variety of adrenocortical tumors and compared the results with StAR mRNA expression. We found low or absent DAX-1 expression in aldosterone-producing adenomas (n=11: 35±11%; normal adrenals: 100±17%) and in aldosterone-producing adrenocortical carcinomas (n=2: 24 and 36%). Cortisol-producing adenomas showed intermediate DAX-1 expression (n=8; 92±16), as did 3 non-aldosterone-producing carcinomas (72, 132 and 132%). High DAX-1 expression was present in nonfunctional adenomas (n=3; 160±17%). In contrast to DAX-1, StAR mRNA expression did not show significant variations between groups. We did not detect the expected negative correlation between DAX-1 and StAR mRNA in adrenocortical tumors. These data suggest that high DAX-1 expression in adrenocortical tumors is associated with a non-functional phenotype whereas low DAX-1 expression favors mineralo-corticoid secretion. These effects on steroidogenesis are mediated by mechanisms other than repression of StAR gene expression. Our results indicate that DAX-1 may be one of the factors influencing the steroid biosynthesis of adrenocortical neoplasms.

Laparoscopic adrenalectomy: a report on 50 operations.

To investigate the feasibility, safety and results of laparoscopic transperitoneal adrenalectomies performed with the patient supine, in patients affected by secreting and silent adrenal lesions. Exclusion criteria were suspected adrenal primary malignancies. Fifty patients (33 women and 17 men; mean age 49.6 years, range 19-75 years) underwent 51 laparoscopic adrenalectomies (one bilateral). After complete endocrinological evaluation, computed tomography or magnetic resonance imaging, or a combination thereof, 14 non-secreting adenomas, 13 aldosterone-producing adenomas, 13 cortisol-producing adenomas, eight phaeochromocytomas (one bilateral), one androgen-secreting adenoma, and two metastases were considered eligible for adrenalectomy. In five patients, associated procedures were performed during surgery. The lesions ranged in size from 1.5 to 10 cm. There were no intraoperative complications and no blood transfusions were required. The postoperative course was uneventful and painless in all patients. Mean postoperative hospital stay was 2.5 days. In all hypertensive patients, significant improvement or cure of hypertension was observed at follow-up (mean 18 months). In patients with secreting adenomas, normalization of hormone concentrations was obtained after removal of the tumour. In six patients with incidentaloma, the exaggerated 17-hydroxyprogesterone response to ACTH disappeared after surgery. Secreting and non-secreting adrenal lesions were treated safely by laparoscopy. Relatively small incidentalomas and subclinical hormonally active tumours can be removed by laparoscopy. Early diagnosis enhances prevention and treatment.

Localization and expression of adrenocorticotropic hormone receptor mRNA in normal and neoplastic human adrenal cortex.

The recent cloning of the ACTH receptor (ACTH-R) gene allows investigation of the tissue localization and relative abundance of ACTH-R mRNA in normal and neoplastic adrenal cortex. Using in situ hybridization (ISH) we studied the expression of ACTH-R mRNA in four adult adrenals of brain-dead patients, two cortisol-producing adenomas (CPA), three aldosterone-producing adenomas (APA), one non-functional adenoma (NFA), and three carcinomas. The results were compared with the mRNA expression of key steroidogenic enzymes and of the glucocorticoid receptor (GR) mRNA using Northern blotting. In adult adrenals, messenger RNA encoding ACTH-R was localized in all three zones of the adrenal cortex, in accordance with the stimulatory role of ACTH on mineralocorticoid, glucocorticoid and adrenal androgen secretion. In comparison, expression of side-chain cleavage enzyme (P450scc) showed a similar tissue distribution with mRNA abundance in all three zones, whereas 17-hydroxylase/17-20 lyase (P450c17) mRNA expression was only detected in the zona fasciculata and zona reticularis. All CPAs and APAs expressed significant levels of ACTH-R mRNA whereas an NFA showed low expression of ACTH-R mRNA. Two of three adrenocortical carcinomas expressed ACTH-R mRNA. Northern analysis using dot blot was employed to quantify ACTH-R and GR mRNA expression and confirmed the ISH data: ACTH-R mRNA expression was high in CPAs (275 and 195% vs 100 +/- 25% in adult adrenals), APAs (127, 200 and 221%) and two carcinomas (99 and 132%), but low in the NFA (7%) and in an androgen secreting carcinoma (16%). GR mRNA expression was high in the NFA (195%) and in two of three carcinomas (93, 188, 227%). We conclude that ACTH-R mRNA is upregulated in functional adenomas by yet unidentified mechanisms. The tissue distribution of ACTH-R and P450 enzyme mRNA expression is highly variable in neoplastic adrenals and does not allow a clear differentiation between benign and malignant tumors.

The possible role of apoptosis-suppressing genes, BCL-2 and MCL-1/EAT in human adrenal tumors

The expression levels of bcl-2, mcl-1/EAT, and bax were examined by Northern blot analysis and semi-quantitative RT-PCR method in 25 adrenal tumors, including seven adrenal pheochromocytomas (PHE), seven aldosterone-producing adenomas (APA), four adrenal cortisol-producing adenomas (CS), one deoxycorticosterone-producing adenoma (DOC) and six non-hyperfunctioning adrenal cortical adenomas (NF). Northern blot analysis revealed both bcl-2 and mcl-1/EAT mRNAs in all of the adrenal tumors. The expression levels differed greatly among the tumor samples. Mc1-1/EAT mRNA levels were enhanced in APA and CS compared with those in NF. In contrast, bcl-2 levels in NF were higher than in other tumors. Our results suggest that deregulation of such apoptosis-suppressing genes may contribute to the multistep tumorigenesis of human adrenal tumors and that mcl-1/EAT, one of the bcl-2 family genes, has a different role from that of bcl-2 in such pathways.

Expression of adrenomedullin mRNA in adrenocortical tumors and secretion of adrenomedullin by cultured adrenocortical carcinoma cells

Immunoreactive-adrenomedullin concentrations and the expression of adrenomedullin mRNA were studied in the tumor tissues of adrenocortical tumors. Northern blot analysis showed the expression of adrenomedullin mRNA in tumor tissues of adrenocortical tumors, including aldosterone-producing adenomas, cortisol-producing adenomas, a non-functioning adenoma and adrenocortical carcinomas, as well as normal parts of adrenal glands and pheochromocytomas. On the other hand, immunoreactive-adrenomedullin was not detected in about 90% cases of adrenocortical tumors (<0.12 pmol/g wet weight (ww)). Immunoreactive-adrenomedullin concentrations ranged from 0.44 to 198.2 pmol/g ww in tumor tissues of pheochromocytomas and were 9.2 ± 1.2 pmol/g ww (mean ± SD, n = 4) in normal parts of adrenal glands. Adrenomedullin mRNA was expressed in an adrenocortical adenocarcinoma cell line, SW-13 and immunoreactive-adrenomedullin was detected in the culture medium of SW-13 (48.9 ± 1.8 fmol/10 5 cells/24h, mean ± SEM, n = 4). On the other hand, immunoreactive-adrenomedullin was not detectable in the extract of SW-13 cells (<0.09 fmol/10 5 cells), suggesting that adrenomedullin was actively secreted from SW-13 cells without long-term storage. These findings indicate that adrenomedullin is produced and secreted, not only by pheochromocytomas, but also by adrenocortical tumors. Undetectable or low levels of immunoreactive-adrenomedullin in the tumor tissues of adrenocortical tumors may be due to very rapid secretion of this peptide soon after the translation from these tumors.

Laparoscopic Adrenalectomy

One hundred consecutive laparoscopic adrenal procedures for a variety of endocrine disorders were reviewed. There was no mortality, morbidity was 12%, and conversions was 3%. During follow-up, none had recurrence of hormonal excess. Laparoscopic adrenalectomy is the procedure of choice for adrenal removal except in carcinoma or masses > 15 cm. The authors evaluate the effectiveness of laparoscopic adrenalectomy for a variety of endocrine disorders. Since the first laparoscopic adrenalectomy was performed in 1992, this approach quickly has been adopted, and increasing numbers are being reported. However, the follow-up period has been too short to evaluate the completeness of these operations. One hundred consecutive laparoscopic adrenal procedures from January 1992 until November 1996 were reviewed and followed for adequacy of resection. Eighty-eight patients underwent 97 adrenalectomies and biopsies. The mean age was 46 years (range, 17-84 years). Indications were pheochromocytomas (n = 25), aldosterone-producing adenomas (n = 21), nonfunctional adenomas (n = 20), cortisol-producing adenomas (n = 13), Cushing's disease (n = 8), and others (n = 13). Fifty-five patients had previous abdominal surgery. Mean operative time was 123 minutes (range, 80-360 minutes), and estimated blood loss was 70 mL (range, 20-1300 mL). There was no mortality, and morbidity was encountered in 12% of patients, including three patients in whom venous thrombosis developed with two sustaining pulmonary emboli. During pheochromocytoma removal, hypertension occurred in 56% of patients and hypotension in 52%. There were three conversions to open surgery. The average length of stay has decreased from 3 days (range, 2-19 days) in the first 3 years to 2.4 days (range, 1-6 days) over the past 16 months. During follow-up (range, 1-44 months), two patients had renovascular hypertension and none had recurrence of hormonal excess. Laparoscopic adrenalectomy is safe, effective, and decreases hospital stay and wound complications. Prior abdominal surgery is not a contraindication. Pheochromocytomas can be resected safely laparoscopically despite blood pressure variations. Venous thrombosis prophylaxis is mandatory. The laparoscopic approach is the procedure of choice for adrenalectomy except in the case of invasive carcinoma or masses > 15 cm.

Absence of angiotensin II type 1 receptor gene mutations in human adrenal tumors.

Regulatory actions of angiotensin II (AngII), which is involved in the pathophysiology of hypertension and also participates in cell proliferation and cell differentiation, are mainly mediated by AngII type 1 (AT1) receptor. Recently, activating mutations of receptors causing hyperfunctioning endocrine diseases have been described in the case of the TSH and LH receptors, implicating that such mutations might occur in other G-protein-coupled receptors. Furthermore it seems to be possible that genetic variations of AT1 receptor have an influence upon the action of AngII. Therefore, we searched by sequence analysis of the coding region of AT1 receptor gene for activating mutations and genetic polymorphisms in 56 human adrenal tumors (16 aldosterone-producing adenomas, 10 cortisol-producing adenomas, 1 aldosterone-producing carcinoma, and 29 incidentalomas). We were not able to identify any activating mutation in the coding region of AT1 receptor gene. We conclude that activating mutations of the AT1 receptor are not a major cause of the development of adrenal adenomas, if at all. In addition, polymorphic subtypes of AT1 receptor do not seem to play a major role in the pathogenesis of these tumors, even though a tendency towards a higher frequency of the polymorphic base substitution at position 573 (T573-->C) in cortisol-producing tumors needs to be further evaluated.

Plasma dehydroepiandrosterone sulfate levels in patients with hyperfunctioning and non-hyperfunctioning adrenal tumors before and after adrenal surgery.

To investigate the clinical significance of plasma dehydroepiandrosterone sulfate (DHEAS) measurements, 175 patients with histologically confirmed adrenal tumors, 10 cortisol-producing adenomas, 59 aldosterone-producing adenomas, 56 non-hyperfunctioning adenomas, 13 adrenocortical carcinomas, 13 adrenal cysts, and 24 adrenomedullary tumors were studied. Plasma DHEAS levels were expressed as percentage of the mean of sex- and age-matched groups of healthy, normal subjects (DHEAS %). We found that before adrenal surgery, DHEAS % values were significantly reduced in patients with cortisol-producing (mean, 15.2% of control; 95% confidence interval (CI), 9.4-24.7%), non-hyperfunctioning (28.4%; 22.4-36.0%) as well as aldosterone-producing adrenocortical adenomas (55.4%; 47.1-65.1%) compared with controls, while values were normal in patients with adrenal cysts and in those with adrenomedullary tumors. Plasma DHEAS % values exhibited a great variability in adrenocortical carcinomas (mean, 84.0%; 95% CI, 33.2-212.5%). Death from adrenocortical carcinoma was more frequent in patients with high plasma DHEAS % values compared with those with low DHEAS %. During long-term postoperative monitoring, we found that plasma DHEAS levels of patients with aldosterone-producing and non-hyperfunctioning adenomas returned to normal in the second and fourth postoperative year respectively. In patients with cortisol-producing adenomas, plasma DHEAS remained suppressed for as long as 8 years after the operation. These findings show that except in adrenocortical carcinomas and cysts, plasma DHEAS levels are significantly decreased in all groups of adrenocortical tumors, including non-hyperfunctioning and aldosterone-producing tumors. The extent of this decrease and the postoperative persistence of suppressed plasma DHEAS levels may be related to the glucocorticoid production of adrenocortical tumors.

P53 mutations in adrenal tumors: Caucasian patients do not show the exon 4 "hot spot" found in Taiwan.

Mutations in the p53 tumor suppressor gene are frequently present in human cancers but have rarely been described in benign tumors. We previously reported mutations in the "hot spots" between exons 5-8 of the p53 gene in adrenocortical carcinomas but not in adenomas. Recently, a previously unknown hot spot in exon 4 of the p53 gene was described in adrenal adenomas and pheochromocytomas of Taiwanese patients. We, therefore, investigated whether these mutations are also present in Caucasian patients from the U.S. and Europe. We analyzed tumor tissue of 12 aldosterone-producing adenomas, 7 cortisol-producing adenomas, and 6 pheochromocytomas. Overexpression of the p53 protein was investigated by immunohistochemistry. Point mutations within exon 4 were identified by polymerase chain reaction (PCR) amplification and direct sequencing of the PCR product. The pYNZ22 microsatellite located on chromosome 17p, close to the p53 gene, was used to screen for allelic loss (LOH) of the p53 gene. Overexpression of p53 was not identified in any of the adenomas and pheochromocytomas. Point mutations within exon 4 were found in 0/25 tumors. LOH was present in 1/13 informative adenomas and 0/2 informative pheochromocytomas. We conclude that p53 mutations do not play a major role in the tumorigenesis of adrenal adenomas and pheochromocytomas of Caucasian patients. Thus, ethnic and environmental factors may be responsible for the mutational spectrum found in Taiwanese patients.

Somatostatin analogs in ectopic corticotropin production

Eutopic corticotroph pituitary adenomas and adrenal cortisol-producing adenomas do not usually express somatostatin receptors. However, ectopic corticotropin (ACTH)-producing tumors often express somatostatin receptors. Thus, the octreoscan can detect and localize tumors in 80% of patients with ectopic ACTH syndrome, and so it can be used to differentiate between eutopic and ectopic ACTH-dependent bilateral adrenal hyperplasia. Octreotide therapy can produce a rapid and sustained reduction of ACTH and cortisol levels in patients with ectopic ACTH-dependent Cushing's syndrome and, in some, may be the only long-term therapy possible. Although no large series have been reported, a review of the literature reveals a large number of case reports that have demonstrated the effectiveness of octreotide.

Ultrastructural dynamics of mitochondrial morphology in varying functional forms of human adrenal cortical adenoma.

Adrenal cortical mitochondria display an extensive capacity to adapt morphologically to the functional state of the adrenal cortical cell. In the present study, we have used transmission electron microscopy to analyze cortical tissues from 3 normal human adrenal glands (zona fasciculata and zona glomerulosa), and from 8 steroid-secreting adrenal cortical adenomas (3 cortisol-producing, 4 aldosterone-producing, and 1 progesterone-producing tumor), correlating both clinical and biochemical features with cellular ultrastructure. The morphology of mitochondria was related to the enzyme activity and steroid-biosynthetic capacity of each tumor. Cells from aldosterone-producing adenomas demonstrated a large number of elongated tubular mitochondria with characteristic bridging of inner membranes, producing a lamellar-type pattern. Cells from cortisol-producing adenomas showed large round mitochondria with vesicular or tubulovesicular inner membranes surrounded by a characteristic dilated smooth endoplasmic reticulum. A highly unusual progesterone-producing adenoma, in which a deficiency of 21 alpha-hydroxylase activity was demonstrated, showed a peculiar type of enlarged lamellar mitochondria with bright inner matrix and a reduced number of inner membranes. Therefore, the ultrastructural characteristics of adrenal cortical mitochondria appear to be potential markers for the differentiation of steroid-producing adenomas. These studies point to the possibility of a broader use of electron microscopy in the study of adrenal tumors.

Immunohistochemical localization of endothelin-1 in non-neoplastic and neoplastic adrenal gland tissue.

Endothelin (ET)-1 is a 21-amino acid peptide with potent vasopressor and vasocontrictive properties. Biochemical studies suggest that this peptide occurs in adrenal glands, where it influences steroid hormone production. However, we have found no report of the topographical distribution of this peptide. The localization of ET-1 immunoreactivity in non-neoplastic (37 cases) and neoplastic adrenal glands (48 cases) was investigated with a sensitive immunohistochemical technique applied to routinely processed tissue specimens. ET-1 immunoreactivity was regularly seen in the cortex, especially in the zona fasciculata and to a varying extent also in the other two zones, but not in the medulla. The immunoreactive material appeared in the cytoplasm mostly in the form of vacuolar structures but also as grains. Focally, the cell membrane also showed immunoreactive staining. In the zona reticularis the immunoreactivity appeared mainly as cytoplasmic grains. Most cortical adenomas displayed numerous immunoreactive cells. The immunoreactivity in the tumour tissue appeared in the same forms as in normal cortex, but the reactive products were generally fewer in number. No obvious differences in immunostaining were seen between the aldosterone- and cortisol-producing adenomas or the non-functioning ones. Three of the ten carcinomas contained immunoreactive cells, but they were few, appearing focally and the ET-1 immunoreactive structures were seen as 'dust-like' material. The difference in immunoreactivity between the benign and the malignant cortical neoplasms may be of diagnostic value. Functionally our results support a relationship between ET-1 and steroid regulation in non-neoplastic cortical tissue.

Point mutations of ras genes in human adrenal cortical tumors: absence in adrenocortical hyperplasia.

Point mutations of ras genes (K-, H-, and N-ras) at codons 12, 13, and 61 and of the Gi2 alpha gene at codons 179 and 205, were studied in 56 primary adrenal cortical tumors and 6 adrenal cortical hyperplasias. Of 56 tumors, 24 were carcinomas and 32 were benign. The 24 carcinomas and 20 of the benign tumors were from American patients; the 12 remaining adenomas were from Japanese patients. Of the benign tumors 12 were cortisol-producing adenomas, 15 were aldosterone-producing adenomas, 3 were nonfunctioning adenomas, and 2 were adenomas that produced a virilizing syndrome. Tumor DNA obtained from archival formalin-fixed, paraffin-embedded tissue or fresh frozen tissue was amplified by polymerase chain reaction; and point mutations were detected by sequence-specific oligonucleotide hybridization. Activating ras mutations were found in 7 of 56 (12.5%) of all tumors: 3 of 24 (12.5%) carcinomas and 4 of 32 (12.5%) adenomas. Of adenomas from an American population, 4 of 20 (20%) exhibited positive ras mutations, whereas none was present in the Japanese tumors. All mutations detected were adenine to guanine transitions at the second position of N-ras codon 61, resulting in a conversion from glutamine to arginine. No mutations were found in K-ras or H-ras genes. Furthermore, no mutations of the Gi2 alpha gene were identified. These findings demonstrate that N-ras mutations at codon 61 may contribute to the genesis of both benign and malignant human adrenal cortical tumors. Finally, no mutations of the ras or Gi2 alpha genes were identified in hyperplastic adrenocortical tissues.

Significance of steroidogenic enzymes in the pathogenesis of adrenal tumour

We examined both activities and amounts of steroidogenic cytochrome P-450s at the posttranslational protein level and steroid contents in the adrenocortical adenoma from patients with primary aldosteronism and Cushing's syndrome. Aldosterone synthase cytochrome P-450 (human P-450aldo) was detected in the tumour portion of aldosterone-producing adenoma, but not in the normal control adrenals, at the protein level. Neither the activities nor the amounts of other P-450s in the tumour portion of aldosterone-producing adenoma were significantly different from those in the non-tumour portion in the adenoma and the normal control adrenals. The aldosterone content was significantly elevated, while the androstenedione content was significantly decreased in the tumour portion of the adenoma compared with that in the normal control adrenals. In Cushing's syndrome, both the activities and amounts of P-450(17 alpha) and P-450c21 were significantly elevated in the tumour portion compared with the non-tumour portion of the adenoma and the normal control adrenals, while those of P-450scc and P-450(11 beta) in the tumour portion were not significantly different from the normal control adrenals. The cortisol content was significantly elevated, while the amounts of aldosterone and 18-hydroxydeoxycorticosterone in the tumour portion of the adenoma were significantly decreased compared with those in the normal control adrenals. These results demonstrate that overexpression of P-450aldo in aldosterone-producing adenoma, and those of P-450(17 alpha) and P-450c21 in cortisol-producing adenoma may play some role in the pathogenesis of primary aldosteronism and Cushing's syndrome, respectively.

Coexisting acromegaly and a unilateral cortisol-producing adrenal adenoma: a possible variant of multiple endocrine neoplasia type I.

An unusual case of coexisting acromegaly and Cushing's syndrome is reported in a 34-yr-old female. There was no biochemical or morphological evidence to suggest the presence of other endocrinopathies. She did not have any family history to suggest a hereditary tendency to endocrine disorders. Her acromegaly and Cushing's syndrome were proven to be due to a pituitary somatotroph adenoma and a cortisol-producing adenoma in the right adrenocortex, respectively. Surgical removal of both tumors led to a marked biochemical improvement of the two endocrinopathies. To account for the simultaneous occurrence of the two endocrine tumors, at least two endocrine syndromes may be considered. One of them is Carney's complex. However, Cushing's syndrome in this complex is unexceptionally due to primary pigmented nodular adrenocortical disease, differing from the adrenal pathology of our patient. In addition, a lack in this case of any other characteristic suggestive of this syndrome appears to speak against this possibility. A second possibility is multiple endocrine neoplasia type 1. The absence of a parathyroid or pancreatic islet cell tumor does not strongly support this possibility, but adrenocortical lesions are not rare in this syndrome although they are only rarely functional. However, existence of similar case reports, although very few, in the literature leaves the possibility that she represents another rare variant of sporadic multiple endocrine neoplasia type I syndrome.

Adrenocorticotropic hormone-independent bilateral adrenocortical macronodular hyperplasia as a distinct subtype of Cushing's syndrome. Enzyme histochemical and ultrastructural study of four cases with a review of the literature.

Four patients with adrenocorticotropic hormone (ACTH)-independent bilateral adrenocortical macronodular hyperplasia (AIMAH) were examined. All of them were men whose ages ranged from 37 to 52 years. Plasma cortisol levels were high, with a loss of diurnal rhythmicity, and plasma ACTH was undetectable. Adrenal cortisol secretion was not suppressed by dexamethasone, but it was ACTH responsive. Test results for corticotropin-releasing hormone (CRH) also were negative. Image analyses revealed a normal sella turcica and significantly enlarged adrenal glands, which showed enhanced uptake of isotope. Both adrenal glands in all cases were between 72 and 176 g in combined weight and were composed of, and distorted by, yellow nodules. Histologically, small cortical cells with or without lipid, occasional clear cells, and rare compact cells of the usual size were increased in number in the glandular cords. Enzyme histochemically, cortical cells showed weaker activity for 3 beta hydroxysteroid dehydrogenase and other enzymes than did usual cortisol-producing adenomas. Ultrastructurally, they had moderately to poorly developed smooth endoplasmic reticulum. Nonnodular areas of the cortex consisting of nonproliferating cells were atrophic and contained no compact cell zone. This is similar to the adrenal cortices attached to cortisol-producing adenomas. These features are unique to AIMAH and suggest the presence of a distinct subtype of Cushing's syndrome.

Physiology of the Adrenal Cortex

Knowledge of the functional morphology and physiology of the adrenal cortex and of the regulation of its secretory products is essential to understanding the meaning of the results of various tests in the diagnosis of adrenocortical disease and to providing the postoperative care necessary to correct this condition. Removal of a cortisol-producing adenoma will necessitate replacement of glucocorticoids only, whereas after resection of an aldosterone-producing adenoma, no steroid replacement will be required.

Angiotensin II receptors of human and primate adrenal fasciculata and glomerulosa: Correlations of binding and steroidogenesis

Subcellular fraction and collagenase-dispersed isolated adrenal fasciculata and glomerulosa cells from human and primate adrenal glands and cortisol-producing tumors have been utilized to study angiotensin II (Ang II) receptors and steroid biosynthesis. The receptor density of glomerulosa was threefold higher than that of fasciculata. A benign cortisol-producing adenoma did not differ from normal fasciculata, but a malignant tumor had significantly lower affinity binding. Agonist and antagonist analogues of Ang II competed for binding sites commensurate with known biologic activity. The K d of binding to fasciculata (2 nmol/L) correlated well with the ED 50 of cortisol biosynthesis in normal and adenomatous tissue. Analogue binding also had corresponding changes in cortisol biosynthesis. The ED 50 for aldosterone biosynthesis by glomerulosa cells was significantly lower at 55 pmol/L. Fewer receptors in human fasciculata as compared to glomerulosa and a less sensitive response to Ang II are consistent with previous in vitro observations in other species. These studies suggest that there may be a biologically relevant Ang II receptor of human and primate adrenal fasciculata that share many characteristics with the receptor of the glomerulosa.