Fine structure of adrenal adenomata causing Cushing's syndrome

Summary Adenomata taken from nine patients with Cushing's syndrome were observed by electron microscopy. Agranular endoplasmic reticulum was prominently developed in all cases, occasionally fine dotty granules were observed in the tubules of agranular endoplasmic reticulum.Mitochondria showed a wide variety of changes in size, shape and internal structure, and somtimes contained electron dense droplets in their matrix. Mitochondria resembling those in the normal zona fasciculata intermingled with pathologically altered ones, suggesting that the adenomata which caused Cushing's syndrome were derived from the zona fasciculata.Fibrous structures were seen in the cytoplasm in one case. It is proposed that all of the changes in cellular organelles of the adenoma cells are correlated with increased secretory activity.     

Gastric inhibitory polypeptide-dependent cortisol hypersecretion--a new cause of Cushing's syndrome.

BACKGROUND. Corticotropin-independent nodular adrenal hyperplasia is a rare cause of Cushing's syndrome, and the factors responsible for the adrenal hyperplasia are not known. METHODS. We studied a 48-year-old woman with Cushing's syndrome, nodular adrenal hyperplasia, and undetectable plasma corticotropin concentrations in whom food stimulated cortisol secretion. RESULTS. Cortisol secretion had an inverse diurnal rhythm in this patient, with low-to-normal fasting plasma cortisol concentrations and elevated postprandial cortisol concentrations that could not be suppressed with dexamethasone. The cortisol concentrations increased in response to oral glucose (4-fold increase) and a lipid-rich meal (4.8-fold increase) or a protein-rich meal (2.6-fold increase), but not intravenous glucose. The infusion of somatostatin blunted the plasma cortisol response to oral glucose. Intravenous infusion of gastric inhibitory polypeptide (GIP) for one hour increased the plasma cortisol concentration in the patient but not in four normal subjects. Fasting plasma GIP concentrations in the patient were similar to those in the normal subjects; feeding the patient test meals induced increases in plasma GIP concentrations that paralleled those in plasma cortisol concentrations. Cell suspensions of adrenal tissue from the patient produced more cortisol when stimulated by GIP than when stimulated by corticotropin. In contrast, adrenal cells from normal adults and fetuses or patients with cortisol-producting or aldosterone-producing adenomas responded to corticotropin but not to GIP. CONCLUSIONS. Nodular adrenal hyperplasia and Cushing's syndrome may be food-dependent as a result of abnormal responsiveness of adrenal cells to physiologic secretion of GIP. "Illicit" (ectopic) expression of GIP receptors on adrenal cells presumably underlies this disorder.     

Combined adrenal myelolipoma and adenoma associated with Cushing's syndrome

A case of Cushing's syndrome in a 31-year-old woman is presented. The resected left adrenal gland revealed a tumor consisting of cortical cells intermingled with myelolipomatous tissue comparable to that of normal bone marrow. The adjacent cortex was atrophic. Postoperative plasma cortisol concentrations have remained quite low. Previously, 28 cases of surgically removed adrenocortical tumors with a main diagnosis of myelolipoma have been published. Of these, three cases (two pituitary Cushing's disease, one steroid 21-hydroxylase deficiency) were associated with endocrine dysfunction. The combination of a myelolipoma and a true adenoma has only been described once before (in a case of virilization) and never in connection with Cushing's syndrome. The etiology of myelolipoma is discussed, and a local trigger mechanism related to adrenocortical growth disturbances is suggested.     

Gene silencing of TSPYL5 mediated by aberrant promoter methylation in gastric cancers

DNA methylation is crucial for normal development, but gene expression altered by DNA hypermethylation is often associated with human diseases, especially cancers. The gene TSPYL5, encoding testis-specific Y-like protein, was previously identified in microarray screens for genes induced by the inhibition of DNA methylation and histone deacetylation in glioma cell lines. The TSPYL5 showed a high frequency of DNA methylation-mediated silencing in both glioma cell lines and primary glial tumors. We now report that TSPYL5 is also inactivated by DNA methylation and could be a putative epigenetic target gene in gastric cancers. We found that the expression of TSPYL5 mRNA was frequently downregulated and inversely correlated with DNA methylation in seven out of nine gastric cancer cell lines. TSPYL5 mRNA expression was also restored after treating with a DNA methyltransferase inhibitor. In primary gastric tumors, methylation-specific PCR results in 23 of the 36 (63.9%) cases revealed that the hypermethylation at CpG islands of the TSPYL5 was detectable at a high frequency. Furthermore, TSPYL5 suppressed the growth of gastric cancer cells as demonstrated by a colony formation assay. Thus, strong associations between TSPYL5 expression and hypermethylation were observed, and aberrant methylation at a CpG island of TSPYL5 may play an important role in development of gastric cancers.     

Schizophrenia and Cushing's syndrome cured by adrenalectomy.

A case of Cushing's syndrome in a woman aged 50 years is described, with psychosis of schizophrenic type. The psychosis and endocrine disorder were subsequently cured by adrenalectomy. Twenty-five years previously the patient had a typical schizophrenic psychosis treated in mental hospital with a deep insulin therapy and ECT. The possibility is raised that deep insulin therapy could have induced the Cushing's syndrome through its non-specific stressor effect on the pituitary-adrenal axis.     

Cushing's syndrome and autoimmunity.

Is Cushing's syndrome ever caused by adrenal stimulating autoantibodies? Specific antiadrenal antibodies were found in the serum of three of seven patients with Cushing's syndrome. The immunologic techniques that showed positive results were complement fixation, tanned RBC hemagglutination, and immunofluorescence. Lymphocytic infiltration of the adrenal was present in two cases, in one of which nodular hyperplasia seemed to be of primary adrenal origin with autoimmunity as a possible cause. However, in cases with clear-cut pituitary origin, the lymphocytic adrenalitis and circulating adrenal antibodies are likely secondary to antigen leaking from damaged tissue.     

Multiple pigmented adrenal cortical nodules associated with Cushing's syndrome. Histochemical, ultrastructural and quantitative studies

Multiple pigmented adrenocortical nodules were found in a 25-year-old woman associated with Cushing's syndrome, whose laboratory data indicated that the adrenal cortex had been functioning autonomously and adrenocorticotrophic hormone (ACTH) from the pituitary gland as suppressed. The surgically removed left adrenal gland disclosed multiple black nodules measuring up to 3 mm in diameter and histologically consisting of large "compact cells" which contained numerous yellow-brown pigments, but adjacent cortical cells were not atrophied. This kind of adrenal lesion is generally regarded as nodular hyperplasia of the cortex. The present case revealed scanty lipid and markedly increased activity of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) and glucose-6-phosphate-dehydrogenase (G6PD). Ultrastructural study showed abundant cytoplasm with a large number of mitochondria, well-developed smooth-surfaced endoplasmic reticulum (SER), less rough-surfaced endoplasmic reticulum (RER), lysosomes, and numerous granules in cells of the nodules. Mitochondria varied in size and shape up to occasional giant mitochondria. SER was vesicular or tubular forming a network of anastomosing tubules. Granules varied greatly in size from 400 millimicrons to 6 microns in diameter, with diverse electron densities, mostly exhibiting the structural features of lipofuscin. The ultrastructural features resembled those in black adenoma associated with Cushing's syndrome ever reported. Concentration of cortisol was increased in the tissue where numerous black nodules were contained.     

Insulin and gastric inhibitory polypeptide secretion in young milk-fed and adult goats

Plasma concentrations of glucose, immunoreactive insulin (IRI), and immunoreactive gastric inhibitory polypeptide (IR-GIP) were studied in six adult and five young milk-fed goats after intravenous or intraduodenal infusions of glucose. Glucose concentrations after intraduodenal infusions were elevated from 3.5 to 4.7 mmol/liter on the average in adult and from 4 to 7 mmol/liter in young goats. Intravenous infusions were given at rates adjusted to mimic very closely the plasma glucose curves after intraduodenal infusions. Plasma IRI increased from 250 to 600 pmol/liter in adult and from 180 to 500-600 pmol/liter in young goats, but no significant differences were observed between intravenous and intraduodenal infusions. Duodenal infusions of glucose did not stimulate the release of IR-GIP in adult or young goats. It is concluded that the goat is lacking the incretin system for rapid disposal of oral glucose loads and that IR-GIP does not participate in regulation of glucose-stimulated insulin release in this species.     

Secretory effects of gastric inhibitory polypeptide on the isolated perfused porcine pancreas

The effect of gastric inhibitory polypeptide (GIP) in physiological concentrations (250, 500, 1000 and 2000 pg/ml) upon endocrine and exocrine secretion from the isolated perfused porcine pancreas was studied at various glucose concentrations in the perfusate. GIP increased insulin release in a dose-dependent manner. The sensitivity of the beta-cells to GIP was glucose dependent. No effect was observed on glucagon or exocrine secretion regardless of the glucose concentration in the perfusate. We conclude that GIP is powerful insulin-stimulator even in low physiological concentrations in the presence of glucose concentrations comparable to those seen during an oral glucose load, which makes GIP to one of the strongest incretin candidates known, i. e. the factor(s) contributing to the augmented insulin response after ingestion of glucose.     

Gonococcal sensitivity to fecal lipids can be mediated by an Mtr-independent mechanism.

Various factors affect the sensitivity of Neisseria gonorrhoeae to physiological levels of hydrophobic molecules. A total of 98 N. gonorrhoeae strains from rectal, cervical, and urethral cultures of homosexual men and heterosexual men and women were examined for their sensitivities to fecal lipids. Isolates were characterized according to cell envelope phenotype, auxotype, and protein I serogroup. Although cell envelope phenotype was an important factor in the resistance of this organism to fecal lipids (Mtr phenotype greater than wild type greater than Env phenotype), other factors were also of importance. AHU- strains (strains having a requirement for arginine, hypoxanthine, and uracil) uniformly exhibited a wild-type envelope phenotype but were as sensitive to fecal lipids as were Env strains. The protein I serogroup was not a factor in determining the sensitivity of wild-type envelope phenotype non-AHU- strains to fecal lipids. However, sexual preference and site of isolation were important factors. Wild-type envelope phenotype (non-AHU-) strains from homosexual men and heterosexual women were more resistant to fecal lipids than were similar isolates from heterosexual men. When these strains were compared by isolation site, it was observed that rectal isolates from homosexual men and heterosexual women were more resistant than were cervical isolates from heterosexual women or urethral isolates from heterosexual men. Urethral isolates from homosexual men were also more resistant to fecal lipids than were urethral isolates from heterosexual men. These data suggest that the host environment can select for increased resistance to hydrophobic molecules by an Mtr-independent mechanism. The basis for this Mtr-independent resistance is presently unknown, but it is likely that it involves an alteration of the target site(s) for fecal lipid inhibition.