Immunoreactive trypsin in the blood of patients with functional disorders of the adrenal cortex]

Blood serum trypsin was radioimmunoassayed in 46 patients with adrenocortical hyperfunction and in 24 ones with its hypofunction. The findings evidence that excess of endogenous adrenal steroids leads to elevation of radioimmune trypsin (RIT) concentration. The presence of chronic pancreatitis in hypercorticism did not essentially influence the value of the examined parameter, nor did the development of diabetes mellitus. Corticosteroid deficit in the body was not associated with changes in the blood serum RIT concentration. Systematic glucocorticoid therapy resulted in elevation of RIT level. The serum enzyme concentration was also increased in hypoadrenocorticism patients not administered glucocorticoids, suffering from concomitant chronic pancreatitis. Therefore the test was not informative for the diagnosis of chronic pancreatitis in the patients with the endogenous hyperadrenocorticism syndrome but may be helpful in the recognition of the condition in the patients with chronic adrenal insufficiency; interpretation of this test results in hypoadrenocorticism patients treated with glucocorticoids should be performed by efficient specialists.     

Congenital adrenal hyperplasia: molecular genetics and alternative approaches to treatment.

Several autosomal recessive disorders affecting the adrenal cortex and its development and leading to defective cortisol biosynthesis are known under the collective term "congenital adrenal hyperplasia" (CAH). Over the last two decades, the genes causing most of these disorders have been identified and molecular genetics may supplement their clinical and biochemical diagnosis. In addition, new treatments have emerged; although gene therapy has yet to be applied in humans, studies are ongoing in gene transfer in adrenocortical cell lines and animal models. In this review, after a brief introduction on the developmental biology and biochemistry of the adrenal cortex and its enzymes, we will list the new developments in the genetics and treatment of diseases causing CAH, starting with the most recent findings. This order happens to follow adrenal steroidogenesis from the mitochondrial entry of cholesterol to cortisol synthesis; it is unlike other presentations of CAH syndromes that start with the most frequently seen syndromes, because the latter were also the first to be investigated at the genetic level and have been extensively reviewed elsewhere. We will start with the latest syndrome to be molecularly investigated, congenital lipoid adrenal hyperplasia (CLAH), which is caused by mutations in the gene coding for the steroidogenic acute regulatory (StAR) protein. We will then present new developments in the genetics of 3-beta-hydroxysteroid dehydrogenase (3 beta HSD), 17 hydroxylase and 17,20-lyase (P450c17), 11 hydroxylase (P450c11 beta), and 21 hydroxylase (P450c21) deficiencies. Alternative treatment approaches and gene therapy experiments are reviewed collectively in the last section, because they are still in their infantile stages.     

Diagnosis and pathophysiology of Cushing's syndrome

Cushing's syndrome is the consequence of a sustained overproduction of cortisol (hydrocortisone) by the adrenal cortex. This may be due to excessive secretion of cortisol by functioning adrenocortical tumors or to "nontumorous" adrenocortical hyperfunction. The latter may be a result of stimulation of the adrenal cortex by increased release of corticotropin (ACTH) from a small pituitary tumor or from nonpituitary nonadrenal tumor. Carcinoids or carcinomas of the lung or pancreas, and even pheochromocytomas have caused the syndrome of ectopic ACTH production. The problems involved in the diagnosis of Cushing's syndrome are establishing its presence and determining the underlying cause. Treatment is then dependent upon the underlying pathogenetic lesion.     

Polyglandular autoimmune syndrome, type 2

We have described two patients with Addison's disease and associated endocrinopathies, a condition termed polyglandular autoimmune (PGA) syndrome, type 2. One of our patients also had autoimmune hypothyroid disease, and the other had premature gonadal failure and Hashimoto's thyroiditis. This syndrome shows that glandular disorders tend to occur together. It has been suggested that an HLA-associated genetic predisposition coupled with environmental factors triggers an autoimmune process resulting in glandular hypofunction or hyperfunction. We stress the necessity for evaluation of every individual with idiopathic Addison's disease for associated endocrinopathies.     

Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex

Transgenic (TG) female mice expressing bLHbeta-CTP (a chimeric protein derived from the beta-subunit of bovine luteinizing hormone [LH] and a fragment of the beta-subunit of human chorionic gonadotropin [hCG]) exhibit elevated serum LH, infertility, polycystic ovaries, and ovarian tumors. In humans, increased LH secretion also occurs in infertility and polycystic ovarian syndrome, often concomitant with adrenocortical dysfunction. We therefore investigated adrenal function in LH overexpressing bLHbeta-CTP female mice. The size of their adrenals was increased by 80% with histological signs of cortical stimulation. Furthermore, adrenal steroid production was increased, with up to 14-fold elevated serum corticosterone. Primary adrenal cells from TG and control females responded similarly to ACTH stimulation, but, surprisingly, the TG adrenals responded to hCG with significantly increased cAMP, progesterone, and corticosterone production. LH receptor (LHR) expression and activity were also elevated in adrenals from female TG mice, but gonadectomized TG females showed no increase in corticosterone, suggesting that the dysfunctional ovaries of the intact TG females promote adrenocortical hyperfunction. We suggest that, in intact TG females, enhanced ovarian estrogen synthesis causes increased secretion of prolactin (PRL), which elevates LHR expression. Chronically elevated serum LH, augmented by enhanced PRL production, induces functional LHR expression in mouse adrenal cortex, leading to elevated, LH-dependent, corticosterone production. Thus, besides polycystic ovaries, the bLHbeta-CTP mice provide a useful model for studying human disorders related to elevated LH secretion and adrenocortical hyperfunction.     

Therapeutics of disordered movement.

Human motor behavior is organized around two major neurotransmitter systems in the basal ganglia--dopaminergic and cholinergic. Hypokinetic disease may result from hypofunction of the dopaminergic system or cholinergic hyperfunction. The reverse seems true for many hyperkinetic movement disorders. Drugs which facilitate dopaminergic neurotransmission or which block cholinergic transmission relieve many hypokinetic disorders; the opposite approach is useful in treating many hyperkinetic disorders.     

Free urinary cortisol radioimmunoassay

Summary The availability of a specific antiserum has made it possible to develop in our laboratory a radioimmunoassay for free urinary cortisol which is quite simple and rapid to perform. No preliminary procedures of chromatographic purification are necessary, and no correction for losses is required. Precision and accuracy tests are satisfactory. Seventeen normal subjects, 10 obese subjects, 18 patients with Cushing's syndrome, 4 hypopituitaric patients and 4 with Addison's disease were studied. The values of free urinary cortisol were compared with those of urinary 17-OHCS, plasma cortisol and, in some cases, the cortisol secretion rate. In normal subjects, the mean free urinary cortisol was 77.22±7.74 μg/24 h, in obese subjects it was 112.05±13.64 μg/24 h, and in patients with Cushing's syndrome it was at significantly higher levels, with a mean value of 488.06±64.39 μg/24 h. There was no overlap between the values obtained in the first two groups and those of subjects with adrenal hyperfunction, and the tesults were similar to those shown by the cortisol secretion rate. The same was not true for urinary 17-OHCS and plasma cortisol. Thus, the assay of free urinary cortisol, that is the free biologically active circulating fraction, may provide a relatively simple alternative to measurement of the cortisol secretion rate, as a single differential test for the diagnosis of conditions with adrenal hyperfunction. Less satisfactory were the results obtained in patients with primary and secondary adrenal hypofunction. Another limitation of the method is its relative non-specificity, since the results of 16 urinary samples measured without preliminary chromatography were 29.6% higher than those after previous chromatographic purification. However, in our experience, this overestimation does not affect the value of the method as a screening test for the diagnosis of Cushing's syndrome.     

Update on the theory and management of orthostatic intolerance and related syndromes in adolescents and children

Orthostasis means standing upright. One speaks of orthostatic intolerance (OI) when signs, such as hypotension, and symptoms, such as lightheadedness, occur when upright and are relieved by recumbence. The experience of transient mild OI is part of daily life. ‘Initial orthostatic hypotension’ on rapid standing is a normal form of OI. However, other people experience OI that seriously interferes with quality of life. These include episodic acute OI, in the form of postural vasovagal syncope, and chronic OI, in the form of postural tachycardia syndrome. Less common is neurogenic orthostatic hypotension, which is an aspect of autonomic failure. Normal orthostatic physiology and potential mechanisms for OI are discussed, including forms of sympathetic hypofunction, forms of sympathetic hyperfunction and OI that results from regional blood volume redistribution. General and specific treatment options are proposed.     

Arterial hypertension in patients with undifferentiated adrenal tumors

AIM: To study clinical and laboratory manifestations of hormonal activity in hypertensive patients with undifferentiated adrenal tumors. MATERIAL AND METHODS: 40 patients (19 males and 21 females aged 16-60 years) with undifferentiated adrenal tumors were examined. They were treated surgically. The results of the examination were compared with histological evidence on the resected adrenals. Clinical and laboratory signs of hormonal activity of the tumor were ascertained. RESULTS: Clinical symptoms in patients with adrenal tumors differed from those of typical symptoms of Icenko-Cushing, Cohn syndromes, pheochromocytoma. Hypertension in patients with cortical tumor may arise because of high synthesis of hydrocortisone, in patients with medullary tumor--of catecholamines. However, the level of hormones was not high enough for development of classic syndromes. That's why these tumors were named undifferentiated. CONCLUSION: Adrenal cortical tumors have signs of mixed androgeno-mineral-glucocorticoid activity. In medullary adrenal tumors hypersecretion of catecholamines is associated with cortical hyperfunction.     

Nervous system changes in adrenal failure

AIM: To study nervous systems in chronic adrenal failure (CAF). MATERIAL AND METHODS: 262 patients with CAF were studied clinically, biochemically and electrophysiologically before and after treatment. RESULTS: The patients were found to have syndromes of vegetovascular dystonia by hypotonic type, syncopal paroxysms, myastenic, minor strokes, dyscirculatory-dysmetabolic encephalopathy, polyneuropathy. A direct correlation was established between the severity and duration of adrenal failure (AF), lowering of adrenal cortex hormones, coefficient Na/K and clinical manifestations of the neurological syndromes. Adequate hormone replacing and symptomatic therapy promoted a regress of neurological disorders in most of the patients especially in mild and moderate AF. CONCLUSION: Adequate therapy corrects neurological disturbances in patients with chronic NN.     

Peripheral autonomic potentials in primary headache and drug-induced headache

Autonomic functions of different primary headache types have been investigated in several studies, most of them analyzing cardiovascular reflex mechanisms or biochemical changes. The results are contradictory; only in tension-type headache and in cluster headache has a sympathetic hypofunction been shown in a preponderance of studies. We analyzed the peripheral autonomous potentials (PAPs) in different primary headache types and in drug-induced headache and compared the results with those of healthy subjects and of patients with low back pain. Latencies of PAPs were significantly increased in all headache types but not in low back pain; amplitudes of PAPs did not show significant differences compared to healthy subjects. Patients with a long duration of drug abuse had increased PAP latencies, whereas patients with a high number of migraine attacks per year had decreased latencies. Our data suggest that sympathetic hypofunction as measured by PAP latencies is a general phenomenon in headache but not in all pain syndromes. Drug abuse leads to an increase of this hypofunction. While measuring PAPs is not an appropriate method by which to differentiate between headache disorders, it allows assessment of autonomic disturbances in primary and drug-induced headache.     

Episodic Syndromes That May Be Associated With Migraine: A.K.A. “the Childhood Periodic Syndromes”

Previously called “childhood periodic syndromes that are commonly precursors of migraine” in International Headache Classification of Headache Disorders (ICHD)‐II, these disorders were renamed “episodic syndromes that may be associated with migraine” in ICHD‐III beta. The specific disorders reviewed in this article include: benign paroxysmal torticollis, benign paroxysmal vertigo, abdominal migraine, and cyclical vomiting syndrome, as well as infantile colic, which was recently added under the appendix section in ICHD‐III beta.     

Inherited bone marrow failure syndromes in adolescents and young adults

Abstract

The inherited bone marrow failure syndromes are a diverse group of genetic diseases associated with inadequate production of one or more blood cell lineages. Examples include Fanconi anemia, dyskeratosis congenita, Diamond–Blackfan anemia, thrombocytopenia absent radii syndrome, severe congenital neutropenia, and Shwachman–Diamond syndrome. The management of these disorders was once the exclusive domain of pediatric subspecialists, but increasingly physicians who care for adults are being called upon to diagnose or treat these conditions. Through a series of patient vignettes, we highlight the clinical manifestations of inherited bone marrow failure syndromes in adolescents and young adults. The diagnostic and therapeutic challenges posed by these diseases are discussed.     

Aldosterone hypersecretion in “non-salt-losing” congenital adrenal hyperplasia

Patients with the "non-salt-losing" form of the adrenogenital syndrome were studied before and after suppression of adrenal cortical activity with carbohydrate-active steroids. The response of aldosterone secretion to sodium deprivation was measured; in some patients response to adrenocorticotropic hormone (ACTH) was measured as well.The aldosterone secretion was normal and responded normally to sodium deprivation in all patients studied during suppression with carbohydrate-active steroids. This finding suggests that 21-hydroxylation of progesterone is normal in this syndrome.The sole abnormality in the production of aldosterone in these patients was found to be excessive secretion of aldosterone while they were not receiving suppressive doses of carbohydrate-active steroids. This finding strongly supports the view that the biogenetic pathways through which aldosterone is produced from progesterone are intact in this syndrome.No patient showed hypertension or hypokalemic alkalosis despite very high aldosterone secretion rates. This observation suggests that the hyper-aldosteronism is secondary to a tendency to sodium loss in the patient whose ACTH production is not suppressed.These studies provide additional evidence in support of the hypothesis that the salt-losing and "non-salt-losing" forms of adrenogenital syndrome are genetically and biochemically distinct.     

ENDOTOXEMIA AND ADRENAL HEMORRHAGE : A MECHANISM FOR THE WATERHOUSE-FRIDERICHSEN SYNDROME

An experimental model that produces adrenal cortical hemorrhage with endotoxin has been described. When stimulated by thorotrast, endotoxin, or its tropic hormone (ACTH), the adrenal cortex is susceptible to the development of a hemorrhagic reaction during endotoxemia. The hemorrhagic reaction resembles that described in the Waterhouse-Friderichsen syndrome. A pathophysiologic mechanism for the occurrence of adrenal hemorrhage occurring during acute sepsis is presented. Increased metabolic activity associated with the production of corticosteroids seems to make the adrenal cortex susceptible to endotoxin-induced hemorrhage. Adrenal hemorrhage observed during sepsis, as in the Waterhouse-Friderichsen syndrome, may be attributable to endotoxemia occurring during or shortly after stimulation of the adrenal cortex by infection. Significant differences between adrenal cortical hemorrhage and the Shwartzman phenomenon are described.     

Peripheral neuropathy in HIV disease

Neurologic disorders are a devastating and common complication of HIV infection and are likely to become more prevalent as patients survive longer. Nerve disorders common to HIV include distal symmetric polyneuropathy (DSP), inflammatory demyelinating polyneuropathy (IDP), mononeuritis multiplex (MM), progressive polyradiculopathy (PP), and autonomic neuropathy (AN). The debilitating pain associated with each of these syndromes can severely impact the quality of life of a patient. Each syndrome is described, including information on the syndrome's causes and possible treatments.     

Estimation of urinary unconjugated androstenedione, dehydroepiandrosterone, testosterone, cortisol, aldosterone and 18-hydroxycorticosterone as a potential tool for assessing adrenal status

A method is described for the simultaneous assay of non-conjugated androstenedione, dehydroepiandrosterone, testosterone, cortisol, aldosterone and 18-hydroxycorticosterone in urine. The method involves solid-phase extraction, automatic high performance liquid chromatography and subsequent radioimmunological quantitation of the individual steroids. Excretion rates of these urinary free steroids were determined in normal males and females. There were no significant sex differences in excretion rates, although both urinary free testosterone and dehydroepiandrosterone were distinctly lower in females than in males. Representative measurements of the excretion rates of patients with Cushing's disease, Addison's disease, ectopic corticotropin syndrome and hirsutism were made. The present method has been shown to be well suited for routine purposes. Its final diagnostic significance for monitoring alterations in glucocorticoid, mineralocorticoid and androgenic activity of the adrenal cortex has yet to be explored.     

Clinical use in the radioimmunologic determination of plasmatic TSH]

Clinical value of plasma TSH radioimmunoassay in various thyroid diseases (primary hypothyroidism, hyperthyroidism and simple goiter) is discussed. In particular, the results obtained of plasma TSH after TRH administration either in thyroid disease either in various disorders of endocrinologic interest (massive obesity, Laurence-Moon Biedl's syndrome, true precocious puberty, congenital adrenal hyperplasia, Klinfelter's and Turner's syndromes) are discussed.     

Laboratory medicine. Series on clinical testing. 2. Fractionation of urinary ketosteroids. Procedure and clinical significance.

Ketosteroids, the excretory metabolities of adrenal and gonadal steroids, can be analyzed individually in urine by a simple extraction procedure followed by separation and quantitation by the use of gas/liquid chromatography. The ketosteroids quantitatively detected by the technique are androsterone, etiocholanolone, dehydroepiandrosterone, 11-hydroxyandrosterone, 11-hydroxyetiocholanolone, 11-ketandrosterone, and 11-ketoetiocholanolone. Other steroid metabolities detected are pregnanediol, pregnanetriol, delta5-pregnenetriol, and 11-ketopregnanetriol. In comparison with concentrations of these steroids observed in urine specimens collected from healthy individuals, abnormal results occur in specimens from patients with testicular disease, Cushing's syndrome, adrenal hyperplasia, and several types of female hirsutism. Characteristic profiles for each of these diseases are presented.     

Paraneoplastic Syndromes: An Approach to Diagnosis and Treatment

Recent medical advances have improved the understanding, diagnosis, and treatment of paraneoplastic syndromes. These disorders arise from tumor secretion of hormones, peptides, or cytokines or from immune cross-reactivity between malignant and normal tissues. Paraneoplastic syndromes may affect diverse organ systems, most notably the endocrine, neurologic, dermatologic, rheumatologic, and hematologic systems. The most commonly associated malignancies include small cell lung cancer, breast cancer, gynecologic tumors, and hematologic malignancies. In some instances, the timely diagnosis of these conditions may lead to detection of an otherwise clinically occult tumor at an early and highly treatable stage. Because paraneoplastic syndromes often cause considerable morbidity, effective treatment can improve patient quality of life, enhance the delivery of cancer therapy, and prolong survival. Treatments include addressing the underlying malignancy, immunosuppression (for neurologic, dermatologic, and rheumatologic paraneoplastic syndromes), and correction of electrolyte and hormonal derangements (for endocrine paraneoplastic syndromes). This review focuses on the diagnosis and treatment of paraneoplastic syndromes, with emphasis on those most frequently encountered clinically. Initial literature searches for this review were conducted using PubMed and the keyword paraneoplastic in conjunction with keywords such as malignancy, SIADH, and limbic encephalitis, depending on the particular topic. Date limitations typically were not used, but preference was given to recent articles when possible.ADH = antidiuretic hormone; CSF = cerebrospinal fluid; CT = computed tomography; IL = interleukin; IV = intravenous; IVIG = IV immunoglobulin; LEMS = Lambert-Eaton myasthenia syndrome; NICTH = non–islet cell tumor hypoglycemia; PNS = paraneoplastic neurologic syndrome; PTH = parathyroid hormone; PTHrP = PTH-related protein; SIADH = syndrome of inappropriate antidiuretic hormone secretionMore than 100 years ago, it was recognized that certain cancers cause various symptoms not attributable to direct tumor invasion or compression.¹ Labeled paraneoplastic syndromes in the 1940s,² these conditions remained poorly understood until recently. Currently, the best described paraneoplastic syndromes are attributed to tumor secretion of functional peptides and hormones (as in the case of endocrine paraneoplastic syndromes) or immune cross-reactivity between tumor and normal host tissues (as in the case of neurologic paraneoplastic syndromes). During the past several years, medical advances have not only improved the understanding of paraneoplastic syndrome pathogenesis but have also enhanced the diagnosis and treatment of these disorders.Effective diagnosis and treatment of paraneoplastic syndromes may substantially affect overall clinical outcomes. In some instances, paraneoplastic syndromes are manifest before a cancer diagnosis. Thus, their timely recognition may lead to detection of an otherwise clinically occult tumor at an early and highly treatable stage. Such a scenario occurs most commonly with neurologic paraneoplastic disorders. Although considerable clinical overlap with nonparaneoplastic disorders has long confounded the diagnosis of these conditions, numerous serologic and radiographic studies are currently available to aid in this process.It is estimated that paraneoplastic syndromes affect up to 8% of patients with cancer.³ As patients with cancer live longer, and as diagnostic methods improve, this prevalence will likely increase. Yet, given the rarity of individual paraneoplastic syndromes, there are few prospective clinical trials to guide management. However, paraneoplastic syndromes frequently represent subtypes of conditions that also occur outside of a cancer association. This review incorporates clinical experience from case series of specific paraneoplastic disorders, as well as larger studies of clinically similar, nonparaneoplastic conditions, to provide an overview of the diagnosis and treatment of the most commonly encountered paraneoplastic syndromes.