Mechanism of ACTH action

ACTH regulates both the differentiated function (steroidogenesis) and the growth and replicative potential of the adrenal cortex. Cyclic AMP (cAMP) serves as the mediator of ACTH action within the cell. The binding of cAMP to its specific receptor activates a protein phosphokinase enzyme with resultant phosphorylation and altered function of several important substrates. The regulation of steroidogenesis requires protein synthesis and affects the conversion of cholesterol to pregnenolone, the rate-limiting step under hormonal control. In normal adrenal cortical tissue, ACTH stimulates DNA synthesis and replication, and in a functional adrenal tumor in tissue culture, ACTH inhibits DNA synthesis and replication. ACTH and cAMP thus appear to direct the adrenal cell toward the differentiated, maximally functional state.     

Gynecomastia associated with isolated ACTH deficiency

A 57-year-old man with gynecomastia associated with isolated adrenocorticotropic hormone deficiency is reported. Basal levels of estrogens, luteinizing hormone and prolactin were elevated, whereas plasma testosterone levels were normal. Luteinizing hormone and prolactin showed exaggerated responses to gonadotropin-releasing hormone and thyrotropin-releasing hormone, respectively. These hormonal abnormalities were corrected and gynecomastia resolved with steroid replacement therapy. These findings suggest that gynecomastia may result from hormonal changes which were modified by glucocorticoid deficiency.     

Inherited ACTH insensitivity illuminates the mechanisms of ACTH action

Adrenocorticotrophin (ACTH) insensitivity is a potentially lethal inherited disorder of ACTH signalling in the adrenal. Inactivating mutations of the ACTH receptor account for approximately 25% of these cases. A second genetic cause for this syndrome has recently been identified in the MRAP gene. The MRAP protein appears to function in the trafficking and cell surface expression of the ACTH receptor, and might indicate the existence of more widespread G-protein-coupled receptor trafficking mechanisms. Molecular defects underlying other causes of ACTH insensitivity syndromes will probably contribute further to our understanding of these pathways.     

Ectopic ACTH syndrome associated with anorectal carcinoma

Summary A 25-year-old black homosexual was noted to be hypertensive, hypokalemic, and to have a rectal mass. Histopathology of the biopsied lesion revealed a mixture of poorly differentiated squamous cell and undifferentiated small cell carcinoma. Abdominopelvic CT showed multiple liver metastases, minimal local tumor extension, and normal adrenal glands. Despite aggressive treatment, he remained hypertensive and hypokalemic. Endocrine work-up revealed: normal 24-hr VMA and catecholamines, normal serum aldosterone and renin levels, elevated urinary free cortisol (3360 g/24 hr), elevated serum cortisol (60 g/dl), and elevated serum ACTH (1697 pg/dl). Liver biopsy confirmed metastatic anorectal carcinoma, and immunohistochemical stains of the rectal biopsy were positive for ACTH and neuron-specific enolase. Although many types of neoplasms have been associated with ectopic ACTH production, small cell carcinoma of the lung is the most common. While there are many reports of colorectal and anorectal neuroendocrine small cell carcinomas, few of these tumors have been associated with clinical ectopic hormone production. This case represents the first report of the ectopic ACTH syndrome associated with anorectal carcinoma.Presented in abstract form at the Virginia State American College of Physicians meeting, Charlottesville, Virginia, March 1991.     

Isolated ACTH deficiency associated with Crohn's disease

We report a case of a 37-yr-old man with a 11-yr history of Crohn's disease (CD), who presented with mucous diarrheas of 1-week duration and a 3-month history of anorexia, increasing fatigue and weight loss of 7 kg. The patient was treated with sulfasalazine 3 g/day until 2 weeks prior to the present admission, when he reduced the dose to half as he considered the drug responsible for his symptoms. Despite aggressive iv rehydration and resolution of diarrheas with an increase in sulfasalazine dose, the patient remained hemodynamically unstable, while laboratory results showed anemia, hypoglycemia, hypertransaminasemia and hyponatremia with marked natriuresis. Thyroid function tests were consistent with primary hypothyroidism, without evidence of autoimmunity. Further laboratory investigation revealed a low basal cortisol and undetectable ACTH with preserved secretory responses of the other trophic pituitary hormones, establishing the diagnosis of isolated ACTH deficiency. Hydrocortisone replacement treatment induced a clinical and laboratory improvement. The autoimmune basis of isolated ACTH deficiency is discussed in association with the presumed contribution of immunologic reactions in the pathogenesis of CD. However more evidence is needed before isolated ACTH deficiency is added to the list of extraintestinal manifestations of CD.     

Mechanism of action of ACTH

The intent in writing this chapter has been to review selected areas in which several observations by one or more workers have led to the emergence of new concepts in the mechanisms of action of ACTH. Therefore, the involvement of the lipid metabolism and of the cytoskeleton on the steroidogenic action of ACTH were studied in the two initial sections. The two other sections concern ACTH control of the protein synthesis and of the replicative capacity of the adrenal gland.     

Ectopic ACTH syndrome associated with ovarian steroid-cell tumor

Several cases of ovarian neoplasms resulting in Cushing's syndrome due to ectopic secretion of ACTH or ectopic secretion of F have been reported. Tumors producing ACTH include adenocarcinoma, androblastoma, Sertoli cell carcinoma, carcinoid tumor and teratoma. Cortisol secretion has been reported in ovarian steroid cell tumor (unclassified steroid cell tumor). We present a case of a 19-year-old woman with Cushing's syndrome in course of an ovarian steroid cell tumor with ectopic ACTH production. To our knowledge, it is the first reported case of ACTH secreting ovarian steroid cell tumor causing Cushing's syndrome.     

Episodic ectopic ACTH syndrome associated with pulmonary infarctions

The etiology of the ectopic ACTH syndrome, associated with certain tumors, is unclear. The ectopic ACTH syndrome was diagnosed in our patient by the characteristic clinical and laboratory findings. Shortly after admission, pulmonary infarctions were documented by lung scans and computed tomography. After treatment with anticoagulants, his plasma ACTH level and its suppressibility became normal. There was no evidence of a tumor. The ectopic ACTH syndrome recurred one year later in conjunction with another episode of pulmonary infarctions. During anticoagulant therapy his infarctions cleared and his plasma ACTH level normalized. In the five years since the onset, no tumor has been found, and plasma ACTH level remains normal and suppressible. We propose that our patient's pulmonary infarctions stimulated pulmonary ACTH production, leading to Cushing's syndrome.     

Intracellular events and cell fate in filovirus infection

Marburg and Ebola viruses cause a severe hemorrhagic disease in humans with high fatality rates. Early target cells of filoviruses are monocytes, macrophages, and dendritic cells. The infection spreads to the liver, spleen and later other organs by blood and lymph flow. A hallmark of filovirus infection is the depletion of non-infected lymphocytes; however, the molecular mechanisms leading to the observed bystander lymphocyte apoptosis are poorly understood. Also, there is limited knowledge about the fate of infected cells in filovirus disease. In this review we will explore what is known about the intracellular events leading to virus amplification and cell damage in filovirus infection. Furthermore, we will discuss how cellular dysfunction and cell death may correlate with disease pathogenesis.